Antiphospholipid syndrome is a systemic autoimmune disorder characterized by the presence of antiphospholipid antibodies that predispose to recurrent arterial and venous thromboses and pregnancy morbidity.

Exam domain	One-glance essentials
Definition / diagnosis	*Autoimmune thrombophilia causing arterial/venous thrombosis and/or pregnancy morbidity* ^[1] Diagnosis needs ≥1 qualifying clinical event + persistent aPL positivity on 2 tests ≥12 weeks apart ^[1]^[2]
Epidemiology / risks	Secondary APS is most commonly associated with SLE ^[1]^[2] Triple positivity (LA + aCL + anti-β2GPI), high titres, oestrogen, pregnancy, surgery, infection and immobility increase thrombotic risk ^[1]^[2]
Core mechanism	aPL against phospholipid-binding proteins → endothelial/platelet/monocyte and complement activation → tissue factor and thrombin generation ^[1] Placental complement injury + microthrombosis → miscarriage, fetal loss and placental insufficiency ^[1]
Clinical picture	DVT/PE is the common venous pattern; ischaemic stroke is the key arterial manifestation ^[1]^[2] Recurrent miscarriage, fetal death, early severe pre-eclampsia, livedo reticularis or mild thrombocytopenia are major clues ^[1]^[2]
Investigations	Test lupus anticoagulant (DRVVT), anticardiolipin IgG/IgM and anti-β2GPI IgG/IgM; repeat positives after ≥12 weeks ^[1]^[2] LA may prolong aPTT: mixing does not correct, but excess phospholipid corrects; objectively image the clinical thrombosis ^[1]^[3]
Management	Thrombotic APS → acute heparin, then usually long-term warfarin (INR 2–3); avoid DOACs in triple-positive or arterial APS ^[1]^[2] Obstetric APS → low-dose aspirin + prophylactic/therapeutic LMWH according to thrombosis history; CAPS → heparin + corticosteroids + plasma exchange/IVIG ^[1]^[2]
Complications	Recurrent stroke/PE, CTEPH, APS nephropathy, limb/visceral thrombosis and pregnancy loss ^[1]^[2] Catastrophic APS: rapidly developing small-vessel thrombosis affecting ≥3 organs within ≤1 week → multiorgan failure ^[2]
Prevention / follow-up	Control smoking, BP and lipids; avoid oestrogen-containing contraception/HRT and provide prophylaxis during surgery, immobility and puerperium ^[1]^[2] Monitor INR on warfarin and use close fetal-growth/BP surveillance in pregnancy ^[2]
Exam traps	*Lupus anticoagulant prolongs aPTT in vitro but causes thrombosis in vivo* ^[1]^[3] A single positive aPL test is not APS; transient infection/drug-related positivity must be excluded by repeat testing ^[1]^[2] Thrombocytopenia is an associated feature, not a formal revised-Sapporo clinical criterion ^[2]

References

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (Antiphospholipid syndrome section) ^[2] Senior notes: Ryan Ho Rheumatology.pdf (Revised Sapporo criteria, p. 73); Maksim Medicine Notes.pdf (Rheumatology — Antiphospholipid syndrome, p. 317); Ryan Ho Haemtology.pdf (DVT/PE management, p. 132) ^[3] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (Mixing study, DRVVT and lupus anticoagulant, pp. 22–23)

Antiphospholipid Syndrome (APS)

Antiphospholipid syndrome (APS) — let's break the name down:

"Anti" = against
"phospholipid" = a class of lipid molecules that form cell membranes and are critical cofactors in the coagulation cascade
"syndrome" = a collection of clinical features occurring together

APS is an autoimmune condition characterised by the production of antibodies against phospholipid-binding proteins, leading to a prothrombotic state (both arterial and venous thrombosis) and/or pregnancy morbidity ^[1]^[2].

It is a systemic autoimmune disorder — the antibodies do not simply "attack" phospholipids directly; rather, they target plasma proteins that bind to phospholipids (most importantly β2-glycoprotein I and prothrombin). This distinction is crucial: the antibodies are really directed against protein–phospholipid complexes on cell surfaces, not naked phospholipids.

APS can exist as:

Primary APS (~50%): occurring in isolation, without any underlying autoimmune disease
Secondary APS (~50%): occurring in the context of another autoimmune disease, most commonly systemic lupus erythematosus (SLE)

APLS occurs in ~30% of SLE. 2% of the population is antibody-positive ^[2].

This means that merely having antiphospholipid antibodies (aPL) does not equate to having the syndrome — you need the clinical events (thrombosis and/or pregnancy morbidity) plus persistent antibody positivity to make the diagnosis.

2. Epidemiology

Antiphospholipid antibodies are found in approximately 1–5% of the general healthy population, but only a minority of these individuals will ever develop clinical APS ^[3].
The estimated incidence of APS is approximately 5 per 100,000 persons per year, with a prevalence of about 40–50 per 100,000 ^[3].
~30% of SLE patients have antiphospholipid antibodies, and of these, roughly half will develop clinical thrombotic events over time ^[1]^[2].

Sex: Female predominance (F:M ≈ 3.5–5:1 for primary APS; even higher in secondary APS associated with SLE)
Age: Peak onset in the 3rd–4th decade (20s–40s), but can occur at any age including paediatric and elderly populations
Ethnicity: More prevalent in individuals of African, Hispanic, and Asian descent (relevant for Hong Kong population)

Given the relatively high prevalence of SLE in ethnic Chinese populations (estimated 50–100 per 100,000 in Hong Kong), secondary APS is a clinically important entity in local practice ^[4].
APS should be considered in any young patient presenting with unexplained thrombosis or recurrent pregnancy loss in Hong Kong, particularly if they have features suggestive of connective tissue disease.

3. Risk Factors

Understanding risk factors helps identify who is at risk of developing APS and who, among aPL-positive individuals, is most likely to develop thrombotic events:

Category	Examples	Mechanism
Autoimmune diseases	SLE (strongest association), RA, Sjögren syndrome, systemic sclerosis	Loss of self-tolerance → cross-reactive autoantibody production
Genetic predisposition	HLA-DR4, HLA-DR7, HLA-DRw53; complement deficiencies	Immune dysregulation genes → predispose to autoantibody formation
Infections	HIV, HCV, syphilis, bacterial endocarditis, COVID-19	Molecular mimicry; transient aPL production (usually non-pathogenic)
Medications	Chlorpromazine, hydralazine, procainamide, quinidine	Drug-induced aPL (usually transient, rarely thrombogenic)

The concept of a "two-hit hypothesis" is central: aPL antibodies create a prothrombotic milieu (first hit), but a second provoking factor is often needed to trigger the actual thrombotic event:

Second Hit	Examples
Immobilisation	Prolonged bed rest, long-haul flights
Surgery/Trauma	Post-operative state
Pregnancy/Postpartum	Hypercoagulable state of pregnancy
Oestrogen exposure	Combined oral contraceptive pills, HRT
Smoking	Endothelial injury
Obesity	Prothrombotic adipokines
Infection/Inflammation	Acute illness, sepsis
Malignancy	Mucin-secreting adenocarcinomas
Cardiovascular risk factors	Hypertension, diabetes, dyslipidaemia

High Yield – Triple Positivity

Patients who are triple-positive (positive for all three aPL tests: lupus anticoagulant + anti-cardiolipin + anti-β2-glycoprotein I) have the highest risk of thrombosis and pregnancy morbidity. This is the most dangerous antibody profile and dictates more aggressive management.

4. Anatomy and Function: The Coagulation System in Context

To understand APS, you must understand what the antiphospholipid antibodies are targeting and why this leads to thrombosis (paradoxically, not bleeding).

Phospholipids (PL) are essential components of cell membranes. In the coagulation cascade, negatively charged phospholipids (particularly phosphatidylserine, which is exposed on the outer leaflet of activated platelets and damaged endothelium) serve as a surface upon which coagulation factor complexes assemble:

Tenase complex: Factor IXa + Factor VIIIa on phospholipid surface → activates Factor X
Prothrombinase complex: Factor Xa + Factor Va on phospholipid surface → converts prothrombin (II) to thrombin (IIa)

These reactions are phospholipid-dependent — without the phospholipid surface, coagulation is profoundly slowed.

A plasma protein that normally binds phospholipids on cell surfaces
Has natural anticoagulant properties: it inhibits the contact activation pathway and interferes with prothrombinase complex assembly
In APS, anti-β2GPI antibodies bind to β2GPI → the antibody–β2GPI complex then binds to cell surfaces → this paradoxically activates endothelial cells, platelets, and monocytes → prothrombotic state

Some aPL antibodies target prothrombin (Factor II) itself
Anti-prothrombin antibodies can enhance thrombin generation

Pathway	Normal Function	Effect of aPL
Protein C/S system	Activated Protein C (with Protein S as cofactor) inactivates Factors Va and VIIIa → limits clot formation	aPL interfere with Protein C activation and its binding to phospholipid surfaces → impaired anticoagulation
Antithrombin III	Inhibits thrombin and Factor Xa	aPL may reduce antithrombin activity
Tissue factor pathway inhibitor (TFPI)	Inhibits the TF–FVIIa complex	aPL may reduce TFPI function
Annexin A5	Forms a "shield" over phospholipid surfaces → prevents coagulation factor binding	aPL displace Annexin A5 → exposes phospholipid → promotes coagulation

Why Does Lupus Anticoagulant Cause Thrombosis but Prolong APTT?

This is one of the most commonly tested and most confusing concepts in haematology:

In vitro (in the test tube): Lupus anticoagulant antibodies bind to phospholipid reagents used in the aPTT assay → they block coagulation factor assembly on these phospholipid surfaces → the aPTT is prolonged (because the test "sees" an anticoagulant effect).
In vivo (in the patient): The same antibodies bind to phospholipids on endothelial cells, platelets, and monocytes → they activate these cells → upregulate tissue factor expression, activate complement, displace Annexin A5, and interfere with natural anticoagulants (Protein C/S) → net result is a prothrombotic state.

So: aPTT prolonged in vitro, but thrombosis in vivo — the name "lupus anticoagulant" is a misnomer! ^[1]^[5]

5. Etiology and Pathophysiology

5.1 Etiology

APS is an autoimmune condition that causes the production of antibodies against phospholipid-binding proteins ^[1].

No identifiable underlying autoimmune disease
Accounts for ~50% of cases
May have a genetic predisposition (HLA associations, familial clustering)

Associated with an underlying autoimmune condition
SLE is by far the most common association (~30% of SLE patients have aPL antibodies)
Other associations: rheumatoid arthritis, Sjögren syndrome, systemic sclerosis, dermatomyositis

Infections (syphilis, HIV, HCV, EBV, COVID-19) can transiently induce aPL antibodies via molecular mimicry
These are usually non-thrombogenic and resolve spontaneously
This is why diagnostic criteria require two positive tests at least 12 weeks apart — to exclude transient, clinically irrelevant antibodies ^[1]^[2]

A rare (~1% of APS), life-threatening variant
Defined by thrombotic storm: ≥3 organs involved within ≤1 week
Mortality ~30–50% despite treatment
Often precipitated by infection, surgery, or withdrawal of anticoagulation

5.2 Pathophysiology — A Multi-Hit Model

The pathophysiology of APS is complex and involves multiple mechanisms working in concert. Think of it as a "perfect storm" of prothrombotic mechanisms:

aPL (especially anti-β2GPI) bind to endothelial cells → activate them via TLR4 and annexin A2 receptors
Activated endothelium upregulates tissue factor (TF) → initiates extrinsic coagulation pathway
Upregulates adhesion molecules (E-selectin, ICAM-1, VCAM-1) → promotes leukocyte recruitment and inflammation
Reduces nitric oxide and prostacyclin production → impaired vasodilation → promotes vasoconstriction and platelet adhesion

aPL bind to platelet surface β2GPI and other glycoproteins → activate platelets
Activated platelets release thromboxane A2 → vasoconstriction + further platelet aggregation
Express P-selectin → recruit monocytes
Expose phosphatidylserine → provides more surface for coagulation factor assembly

aPL activate monocytes → upregulate tissue factor expression on monocytes
This creates an additional procoagulant surface in the circulation

aPL–β2GPI complexes activate the classical complement pathway
Generation of C5a (anaphylatoxin) → recruits and activates neutrophils → release NETs (neutrophil extracellular traps) → further promote thrombosis
C5b-9 (membrane attack complex) → direct endothelial injury
Complement activation is particularly important in obstetric APS (placental injury)

aPL interfere with Protein C activation on endothelial surfaces
aPL reduce Protein S availability
aPL may inhibit antithrombin III activity
Net effect: loss of "braking mechanisms" on coagulation

Annexin A5 normally forms a protective anticoagulant shield over phospholipid surfaces (especially on trophoblasts in the placenta)
aPL displace Annexin A5 → expose phosphatidylserine → promote coagulation on trophoblast surfaces → placental thrombosis and infarction → pregnancy loss

The obstetric manifestations of APS deserve special attention because the mechanisms go beyond simple thrombosis:

Mechanism	Consequence
Placental thrombosis	Placental infarction → fetal growth restriction, late fetal death
Complement-mediated placental inflammation	Direct trophoblast injury, decidual inflammation → early miscarriage
Impaired trophoblast invasion	aPL reduce trophoblast migration and differentiation → defective placentation → pre-eclampsia
Annexin A5 displacement	Loss of protective shield on syncytiotrophoblast → thrombosis on placental surface
Direct trophoblast apoptosis	aPL–β2GPI complexes directly induce apoptosis in trophoblasts

Key Concept – Not Just Thrombosis in Obstetric APS

Early pregnancy losses in APS are primarily due to complement-mediated inflammation and direct trophoblast injury, not just thrombotic placental infarction. This explains why heparin (which has anti-complement properties in addition to anticoagulant effects) is effective in obstetric APS, whereas warfarin (purely anticoagulant) is not appropriate in pregnancy.

6. Classification

Type	Description
Primary APS	APS without any underlying autoimmune disease
Secondary APS	APS in the context of an underlying autoimmune disease (most commonly SLE)
Catastrophic APS (CAPS)	Rare, fulminant form with multiorgan thrombotic microangiopathy (≥3 organs involved within ≤1 week)
Seronegative APS	Clinical features consistent with APS but persistently negative for conventional aPL tests; may have non-criteria antibodies (e.g., anti-phosphatidylserine/prothrombin)

The name of these antibodies depends on the test you use to measure them ^[1]:

Antibody	Test Method	Clinical Significance
Lupus anticoagulant (LA)	Clotting-based assay (e.g., dRVVT, silica clotting time)	Most thrombogenic of the three; strongest predictor of thrombosis ^[1]^[2]
Anti-cardiolipin antibodies (aCL) (IgG or IgM)	Immunoassay (ELISA)	Medium thrombogenic risk; IgG > IgM in clinical significance
Anti-β2-glycoprotein I (anti-β2GPI) (IgG or IgM)	Immunoassay (ELISA)	Most specific for APS but limited sensitivity → only check if the other two are negative ^[2]

Require TWO measurements 12 weeks apart for diagnosis ^[1]^[2].

High Yield – Antibody Hierarchy

Lupus anticoagulant > anti-cardiolipin > anti-β2-glycoprotein I in terms of thrombogenicity ^[2].

Anti-β2-glycoprotein I is the most specific but has limited sensitivity — check it when the other two are negative ^[2].

Triple positivity (all three positive) = highest risk profile for thrombosis and recurrence.

6.3 Updated Classification: ACR/EULAR 2023 APS Classification Criteria

The 2023 ACR/EULAR APS classification criteria replaced the older 2006 revised Sapporo criteria. Key changes include:

Entry criterion: At least one positive aPL test (LA, aCL, or anti-β2GPI) within 3 years of a clinical criterion

Scoring system: Weighted scoring across clinical domains and laboratory domains:

Domain	Items	Points
Macrovascular – Venous	DVT, PE, cerebral venous sinus thrombosis, other venous	1–5 (based on risk profile)
Macrovascular – Arterial	Stroke, MI, peripheral arterial	2–5
Microvascular	Livedo racemosa, livedoid vasculopathy, acute skin ulcers, kidney TMA, pulmonary haemorrhage	2–5
Obstetric	Early pregnancy loss (< 10 wk), late pregnancy loss (≥10 wk), pre-eclampsia with severe features, placental insufficiency	1–4
Cardiac valve	Valve thickening, vegetation (Libman-Sacks endocarditis)	2
Haematological	Thrombocytopenia (platelet 20–130 × 10⁹/L)	2

Test	Criteria	Points
aPL persistence	Persistent positivity ≥12 weeks apart	Required
LA positive	Positive lupus anticoagulant	4
aCL or anti-β2GPI	Moderate-high titre IgG or IgM	4–7

Classification as APS requires: Entry criterion met + Clinical domain score ≥3 + Laboratory domain score ≥3.

Exam Note – Sapporo vs ACR/EULAR 2023

The Sapporo (Sydney) criteria ^[1] are still commonly referenced in clinical practice and older exam questions. Know both, but be aware the 2023 criteria add a weighted scoring system and incorporate microvascular disease and cardiac valve disease as clinical domains. For HKUMed exams, the GC lecture slides reference the Sapporo criteria — use this framework unless told otherwise.

7. Clinical Features

The clinical manifestations of APS are protean — virtually any organ can be affected because the fundamental problem is vascular (thrombosis of arteries, veins, and microvasculature). I'll organize them systematically by organ system, always linking back to the underlying pathophysiology.

7.1 Symptoms

Recurrent arterial (stroke, MI) and venous (DVT, PE) thrombosis ^[1]^[2]

Symptom	Vessel Involved	Pathophysiological Basis
Unilateral leg swelling, pain, warmth	Deep vein thrombosis (DVT) — most commonly iliofemoral	aPL → endothelial activation + platelet activation + impaired natural anticoagulants → venous thrombosis; venous stasis + hypercoagulability (Virchow's triad) ^[6]
Acute dyspnoea, pleuritic chest pain, haemoptysis	Pulmonary embolism (PE)	DVT propagation → embolisation to pulmonary arteries → V/Q mismatch → hypoxaemia; large PE → obstructive shock ^[6]
Sudden focal neurological deficit (hemiplegia, aphasia, visual field defect)	Arterial stroke (most common arterial manifestation)	aPL → large vessel thrombosis or cardioembolism (from Libman-Sacks vegetations) → cerebral artery occlusion → ischaemic infarction ^[7]
Acute chest pain radiating to arm/jaw	Myocardial infarction	Coronary artery thrombosis (in young patients without traditional cardiovascular risk factors — should raise suspicion for APS)
Transient visual loss (amaurosis fugax) or persistent visual loss	Retinal artery/vein occlusion	Retinal vessel thrombosis → ischaemic retinopathy; can present as central retinal artery occlusion (CRAO) or branch retinal vein occlusion (BRVO)
Headache, seizures, cognitive dysfunction	Cerebral venous sinus thrombosis	Venous thrombosis of dural sinuses → impaired venous drainage → raised ICP → headache, papilloedema, seizures
Abdominal pain	Mesenteric/hepatic/renal vein thrombosis	Visceral venous or arterial thrombosis → organ ischaemia (e.g., Budd-Chiari syndrome from hepatic vein thrombosis)
Claudication, rest pain, gangrene	Peripheral arterial thrombosis	Arterial occlusion of limb vessels → limb ischaemia

DVT is the most common thrombotic manifestation of APS (most common overall presentation) Ischaemic stroke is the most common arterial manifestation of APS

Recurrent fetal loss / miscarriage ^[1]

Symptom	Pathophysiological Basis
Early recurrent miscarriage (< 10 weeks, ≥3 consecutive)	Complement-mediated trophoblast injury + impaired trophoblast invasion → defective embryo implantation
Late fetal death (≥10 weeks, ≥1 unexplained)	Placental thrombosis and infarction → fetal hypoxia → intrauterine death
Pre-eclampsia/eclampsia (especially severe, early-onset < 34 weeks)	Defective placentation → abnormal spiral artery remodelling → placental ischaemia → release of anti-angiogenic factors → maternal endothelial dysfunction → hypertension + proteinuria ^[8]
HELLP syndrome	Microangiopathic process in hepatic vasculature
Intrauterine growth restriction (IUGR)	Chronic placental insufficiency from ongoing microthrombi
Premature delivery (< 34 weeks due to severe pre-eclampsia/placental insufficiency)	Consequence of the above mechanisms

Symptom	Mechanism
Migraine (especially with aura)	Unclear — may relate to microvascular ischaemia or endothelial activation
Chorea	Basal ganglia microinfarction or anti-neuronal antibody cross-reactivity
Cognitive dysfunction / "brain fog"	Chronic cerebral microangiopathy
Seizures	Cortical microinfarcts or cerebral venous thrombosis
Transverse myelitis	Spinal cord vasculitis/thrombosis (important differential with NMO and MS)

Symptom	Mechanism
Fatigue, malaise	Chronic inflammation, co-existing SLE, chronic disease
Dyspnoea (progressive)	Pulmonary hypertension from chronic thromboembolic disease (CTEPH)
Easy bruising	Thrombocytopenia (paradoxically, despite the prothrombotic state)
Non-healing skin ulcers	Livedoid vasculopathy — microvascular thrombosis in dermal vessels

7.2 Signs

Sign	Description	Pathophysiological Basis
Livedo reticularis ^[1]	Mottled, net-like purplish discolouration of the skin, particularly on the legs and trunk	Microvascular thrombosis in dermal arterioles → slow/stagnant blood flow in surrounding venules → deoxyhaemoglobin accumulation → bluish-purple pattern. The net pattern follows the vascular watersheds between arterioles.
Livedo racemosa	Irregular, broken, non-reversible livedo pattern (more pathological than livedo reticularis)	Same mechanism but more severe and permanent → suggests fixed vascular damage
Skin ulcers	Non-healing ulcers, especially on lower extremities	Dermal vessel thrombosis → ischaemic necrosis
Splinter haemorrhages	Linear red-brown lines under nails	Microemboli to nail bed capillaries from cardiac valve vegetations (Libman-Sacks)
Digital gangrene/necrosis	Painful, blackened fingertips or toes	Thrombosis of digital arteries → complete ischaemia
Pseudovasculitic lesions	Purpura, nodules, ecchymoses	Thrombotic microangiopathy mimicking vasculitis
Superficial thrombophlebitis	Tender, erythematous cord along superficial vein	Superficial venous thrombosis

Sign	Pathophysiological Basis
Libman-Sacks endocarditis (sterile vegetations, typically on mitral > aortic valve)	aPL → thrombotic vegetations on valve leaflets → valve thickening, regurgitation. Vegetations are composed of fibrin, immune complexes, and platelets — NOT bacteria. Usually on the atrial side of the mitral valve (cf. infective endocarditis on the ventricular/atrial side depending on pressure).
Cardiac murmur (mitral regurgitation most common)	Valve thickening and distortion from Libman-Sacks vegetations
Accelerated atherosclerosis	Chronic endothelial activation → premature coronary artery disease

Sign	Pathophysiological Basis
Hypertension	Renal artery thrombosis, renal microangiopathy, or renovascular disease → activation of RAAS
Proteinuria / Haematuria	APS nephropathy — thrombotic microangiopathy (TMA) of glomerular capillaries → endothelial swelling, fibrin thrombi → GBM damage
Renal impairment	Acute: renal artery/vein thrombosis, cortical necrosis. Chronic: fibrous intimal hyperplasia, arteriosclerosis, tubular atrophy

APS Nephropathy vs Lupus Nephritis

In a patient with SLE + APS, it is critical to distinguish APS nephropathy (thrombotic microangiopathy) from lupus nephritis (immune complex-mediated glomerulonephritis) because the treatment is different:

APS nephropathy → anticoagulation
Lupus nephritis → immunosuppression

Renal biopsy is essential to differentiate. APS nephropathy shows TMA with fibrin thrombi and arteriosclerosis, NOT immune complex deposits.

Sign	Pathophysiological Basis
Thrombocytopenia ^[1]^[2]	Multiple mechanisms: (1) aPL directly bind platelet surface β2GPI → immune-mediated platelet destruction (similar to ITP mechanism); (2) consumption of platelets in microthrombi; (3) bone marrow suppression (rare). Usually mild-moderate (50–130 × 10⁹/L) — rarely severe enough to cause bleeding.
Autoimmune haemolytic anaemia (AIHA)	Co-existing warm autoantibodies (particularly in secondary APS with SLE). When AIHA + ITP coexist = Evans syndrome.
Prolonged aPTT (paradoxical)	Lupus anticoagulant binds phospholipid reagent in the aPTT assay → artifactually prolongs the test ^[5]

For an isolated prolonged aPTT, how do you differentiate between von Willebrand disease and lupus anticoagulant? Use a mixing study ^[5]:

VWD: Factor VIII deficiency → mixing patient plasma (0% FVIII) with normal plasma (100% FVIII) → 50% FVIII → corrects the aPTT

Lupus anticoagulant: Antibodies in patient plasma immediately destroy phospholipids in normal plasma → does NOT correct the aPTT (immediate non-correction — this "immediacy" is characteristic of lupus anticoagulant, cf. other inhibitors which show delayed non-correction after incubation) ^[5]

Sign	Pathophysiological Basis
Focal neurological deficits (hemiplegia, hemisensory loss, visual field defects)	Corresponding to territory of arterial stroke
Papilloedema	Raised ICP from cerebral venous sinus thrombosis
Chorea	Basal ganglia involvement
Multi-infarct dementia (chronic)	Cumulative cerebral microinfarction

Sign	Pathophysiological Basis
Signs of pulmonary hypertension (loud P2, parasternal heave, JVP elevation, TR murmur)	Chronic thromboembolic pulmonary hypertension (CTEPH) — recurrent subclinical PE → organised thrombi in pulmonary vasculature → progressive right heart failure
Diffuse alveolar haemorrhage (rare, in CAPS)	Pulmonary capillaritis from complement activation

Sign	Pathophysiological Basis
Acute adrenal insufficiency (Addisonian crisis — hypotension, hyponatraemia, hyperkalaemia)	Bilateral adrenal vein thrombosis → adrenal haemorrhagic infarction (particularly in CAPS). The adrenal glands have a single draining vein — making them vulnerable to venous infarction.

Catastrophic APS deserves emphasis as it is the most severe and life-threatening form:

Feature	Detail
Definition	Thrombotic microangiopathy involving ≥3 organ systems within ≤1 week
Triggers	Infection (~40%), surgery, anticoagulation withdrawal, SLE flare
Mortality	~30–50% despite aggressive treatment
Organs affected	Kidneys (most common), lungs, brain, heart, skin, adrenals
Key differentials	TTP/HUS, DIC, HELLP syndrome — may coexist
Lab findings	aPL positive + schistocytes on blood film (MAHA) + thrombocytopenia + evidence of multi-organ failure

System	Manifestation
Vascular	DVT, PE, arterial thrombosis (stroke, MI, peripheral)
Obstetric	Recurrent miscarriage, late fetal death, pre-eclampsia, IUGR, premature delivery
Cutaneous	Livedo reticularis/racemosa, skin ulcers, digital gangrene, splinter haemorrhages
Cardiac	Libman-Sacks endocarditis, valvular regurgitation, accelerated atherosclerosis
Neurological	Stroke, TIA, seizures, chorea, cognitive dysfunction, cerebral venous sinus thrombosis, transverse myelitis
Renal	APS nephropathy (TMA), renal artery stenosis, hypertension
Haematological	Thrombocytopenia, AIHA, prolonged aPTT
Pulmonary	PE, CTEPH, diffuse alveolar haemorrhage
Adrenal	Adrenal insufficiency (bilateral adrenal infarction)
Ocular	Retinal artery/vein occlusion
Bone	Avascular necrosis (especially femoral head)

High Yield Summary

APS = autoimmune condition with antibodies against phospholipid-binding proteins → prothrombotic state (arterial + venous) + pregnancy morbidity.
Primary (isolated) vs Secondary (most commonly with SLE — ~30% of SLE patients have aPL antibodies).
Three antibodies — tested by different methods:
- Lupus anticoagulant (clotting-based assay) — most thrombogenic
- Anti-cardiolipin (ELISA) — moderate thrombogenicity
- Anti-β2GPI (ELISA) — most specific but limited sensitivity
Diagnosis requires: Clinical criterion (thrombosis or pregnancy morbidity) + Positive aPL on two occasions ≥12 weeks apart.
Paradox: Lupus anticoagulant prolongs aPTT in vitro but causes thrombosis in vivo. Mixing study does NOT correct the aPTT (immediate inhibitor), unlike factor deficiencies which correct.
Key clinical features: DVT/PE (most common), stroke (most common arterial), recurrent miscarriage, livedo reticularis, thrombocytopenia, Libman-Sacks endocarditis.
Triple positivity (LA + aCL + anti-β2GPI) = highest risk of thrombosis.
Catastrophic APS = ≥3 organ thrombotic microangiopathy within ≤1 week → medical emergency with ~30–50% mortality.
Pathophysiology: Endothelial activation + platelet activation + complement activation + impaired natural anticoagulants + Annexin A5 displacement → multi-mechanism prothrombotic state.
Two-hit hypothesis: aPL creates the prothrombotic milieu (first hit), but a second provoking factor (surgery, pregnancy, immobilisation, infection) often triggers the actual thrombotic event.

Active Recall - Antiphospholipid Syndrome (Definition, Epidemiology, Pathophysiology & Clinical Features)

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia (Antiphospholipid syndrome section) ^[2] Senior notes: Maksim Medicine Notes (Rheumatology - Antiphospholipid syndrome, p. 317) ^[3] Current literature: ACR/EULAR 2023 APS Classification Criteria; Prevalence data from epidemiological studies ^[4] Senior notes: Block A - Facial rash and painful fingers: SLE (SLE epidemiology and APS association) ^[5] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting) (Mixing study, lupus anticoagulant vs VWD differentiation, p. 22) ^[6] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai) (DVT/PE risk factors, Virchow's triad, clinical features, p. 964-965) ^[7] Senior notes: Ryan Ho Neurology (Stroke secondary prevention - anticoagulants for APS, p. 83) ^[8] Lecture slides: GC 224. Hypertension and Pregnancy (Pre-eclampsia pathophysiology)

Differential Diagnosis of Antiphospholipid Syndrome

The differential diagnosis (DDx) of APS is best approached by thinking about which clinical presentation brought the patient to you, because APS is a syndrome — it doesn't present with a single pathognomonic complaint. A patient might arrive with unexplained DVT, recurrent miscarriage, a young stroke, thrombocytopenia, or livedo reticularis. For each of these "entry presentations," you need to consider what else could be causing it, and why APS should (or should not) be at the top of your list.

I'll structure this section in two parts:

Differential diagnosis organised by clinical presentation (the way you'd think at the bedside)
Conditions that mimic APS as a whole (systemic prothrombotic/autoimmune disorders)

A. Differential Diagnosis by Clinical Presentation

When you see a young patient with recurrent DVT or PE, your differential must consider all causes of hypercoagulability — the "H" in Virchow's triad. The key question is: is this APS, inherited thrombophilia, malignancy, or something else?

Differential	Key Distinguishing Features	Why It's Different from APS
Inherited thrombophilia ^[1]^[9]
— Protein C deficiency	AD inheritance; VTE, warfarin-induced skin necrosis in first few days of warfarin use (due to initial Protein C depletion before factors II/X are depleted); 7× VTE risk ^[9]	No pregnancy morbidity pattern, no livedo, no aPL antibodies, no arterial events; purely venous thrombosis; quantitative Protein C assay diagnostic
— Protein S deficiency	AD inheritance; similar to Protein C deficiency (acts as cofactor of Protein C); VTE risk similar ^[9]	Same as above; quantitative Protein S assay
— Antithrombin III deficiency	AD with variable penetrance; 16.3× VTE risk; ~70% have VTE before 60 years; VTE often resistant to normal doses of heparin ^[9]	No aPL; purely venous; requires higher-dose LMWH; antithrombin level assay diagnostic
— Factor V Leiden	Activated Factor Va becomes resistant to activated Protein C inactivation → cannot be inactivated, coagulation cascade continues ^[1]; most common inherited thrombophilia in Caucasians; NOT found in Chinese ^[9]	Irrelevant in Hong Kong/Chinese patients! Pure venous risk; no pregnancy morbidity pattern; activated Protein C resistance assay or genetic testing diagnostic
Malignancy (occult)	Most important cause of unprovoked VTE ^[9]; especially mucin-secreting adenocarcinomas, myeloproliferative neoplasms, gynecological malignancy ^[6]; Trousseau syndrome (migratory superficial thrombophlebitis)	Age-appropriate cancer screening; aPL negative; weight loss, night sweats; elevated tumour markers; CT TAP for occult malignancy
Nephrotic syndrome	Loss of natural anticoagulants (antithrombin III, Protein C/S) in urine → hypercoagulable state ^[10]; heavy proteinuria (> 3.5 g/day), hypoalbuminaemia, oedema	Heavy proteinuria and hypoalbuminaemia dominate the picture; no aPL; renal biopsy for underlying glomerular disease
Paroxysmal nocturnal haemoglobinuria (PNH)	Complement-mediated intravascular haemolysis + thrombosis (especially hepatic/cerebral veins — Budd-Chiari); morning haemoglobinuria (coca-cola urine); pancytopenia ^[11]	Flow cytometry for GPI-anchored proteins (CD55/CD59); no aPL; Coombs-negative haemolysis
Myeloproliferative neoplasms (MPN)	Polycythaemia vera, essential thrombocythaemia — thrombosis from hyperviscosity and abnormal platelet function; splenomegaly; JAK2 V617F mutation	High Hb/Hct (PV) or high platelet count (ET); JAK2/CALR mutations; no aPL
Hyperhomocysteinaemia	Controversial — observational data suggest higher levels cause more thrombosis, but lowering levels does not confer protective effect ^[1]	Homocysteine level measurement; usually no other APS features
Immobilisation / Surgery / OCP use	Provoked VTE — clear temporal relationship with risk factor ^[6]^[10]	Single episode with clear provoking factor; no aPL; usually no recurrence after risk factor removed

Hong Kong Exam Pearl – Factor V Leiden

Factor V Leiden is NOT found in Chinese ^[9]. Do not include this as a differential diagnosis for thrombophilia in a Chinese patient in Hong Kong. The most important inherited thrombophilias in Chinese are Protein C deficiency, Protein S deficiency, and Antithrombin III deficiency. The most important acquired thrombophilia in Chinese is antiphospholipid syndrome ^[1]^[9].

When a young patient (< 50 years) presents with ischaemic stroke or MI without traditional cardiovascular risk factors, APS must be considered. The DDx is different from venous thrombosis:

Differential	Key Distinguishing Features	Why It's Different from APS
Atherosclerotic disease (premature)	Traditional RF: smoking, DM, HTN, dyslipidaemia, family history; carotid IMT/plaque; coronary calcification	Older age group typically; established RF present; no aPL
Cardioembolism (AF, valvular disease)	AF on ECG; rheumatic mitral stenosis; prosthetic valve; LA thrombus on echo	ECG, echo diagnostic; no aPL (though APS can cause Libman-Sacks → cardioembolism, creating overlap)
Arterial dissection (carotid/vertebral)	Neck pain, Horner syndrome, bruit; history of trauma/chiropractic manipulation; young patient	CTA/MRA showing intimal flap/pseudoaneurysm; no aPL
Vasculitis (Takayasu, GPA, PAN, CNS vasculitis)	Systemic inflammation (fever, ↑ESR/CRP); claudication of extremities (Takayasu); sinusitis + nephritis (GPA); skin nodules along arteries (PAN)	ANCA positivity (GPA, MPA); angiographic findings; biopsy; no aPL
Paradoxical embolism (PFO)	DVT + PFO → venous clot crosses to arterial circulation; often young patient with cryptogenic stroke	Bubble contrast echo diagnostic; no aPL
SLE itself (without formal APS)	Accelerated atherosclerosis from chronic inflammation and steroid use; cerebral vasculitis	ANA, anti-dsDNA positive; complement low; aPL may be negative
Sickle cell disease	Vaso-occlusive crises, chronic haemolysis; more common in African populations	Hb electrophoresis; blood film showing sickle cells; not relevant in Chinese population
Fibromuscular dysplasia	Young women; renal artery stenosis → hypertension; carotid/vertebral dissection; "string of beads" on angiography	CTA/MRA diagnostic; no aPL

Anticoagulants are indicated for cardioembolic ischaemic stroke and antiphospholipid syndrome — not antiplatelets alone ^[7].

This is a critical DDx for obstetric APS. Most recurrent miscarriages are NOT due to APS — the differential is broad:

Differential	Trimester Typically Affected	Key Distinguishing Features
Chromosomal abnormalities (most common cause)	1st trimester (< 10 weeks)	Sporadic; karyotyping of products of conception; parental karyotyping for balanced translocations
Uterine anatomical abnormalities (septate uterus, fibroids, Asherman syndrome)	2nd trimester / recurrent 1st trimester	Hysteroscopy / MRI pelvis diagnostic
Cervical incompetence	2nd trimester (painless cervical dilatation)	History of painless cervical dilatation; cervical length on USS; treated with cervical cerclage
Endocrine disorders (hypothyroidism, uncontrolled DM, PCOS, luteal phase defect)	1st trimester	TFTs, HbA1c, progesterone levels; treat underlying endocrine disorder
Antiphospholipid syndrome	Both 1st and 2nd/3rd trimester — ≥3 consecutive losses < 10 wk OR ≥1 unexplained fetal death ≥10 wk ^[1]^[12]	Persistent aPL antibodies × 2 tests ≥12 weeks apart; late losses and severe pre-eclampsia < 34 weeks are particularly suggestive
Thrombophilia (inherited — Protein C/S, AT III deficiency)	2nd/3rd trimester (placental thrombosis)	Thrombophilia screen; no aPL
Infection (TORCH, Listeria, syphilis)	Variable	Serology; culture; clinical features of infection
Alloimmune factors	Variable	Diagnosis of exclusion

Key Pattern Recognition – When to Suspect APS in Pregnancy Loss

APS should be high on your differential when:

There are ≥3 consecutive early losses (< 10 weeks) — but only after chromosomal and anatomical causes are excluded
There is any unexplained fetal death ≥10 weeks of a morphologically normal fetus
There is premature delivery < 34 weeks due to severe pre-eclampsia or placental insufficiency
There is concurrent thrombotic history or livedo reticularis in the mother

APS causes thrombocytopenia ^[1]^[2] — but it is usually mild (50–130 × 10⁹/L). The DDx of thrombocytopenia is broad, and the question is: is this APS-related, or something else?

Differential	Key Distinguishing Features	Pathophysiological Basis
Immune thrombocytopenia (ITP)	Most common cause of symptomatic thrombocytopenia ^[13]; primary ITP = isolated thrombocytopenia without apparent cause; secondary ITP may be a/w SLE, APS, Evans syndrome ^[13]	Anti-platelet antibodies (anti-GPIIb/IIIa, anti-GPIb/IX) → premature platelet destruction by RES
Drug-induced thrombocytopenia	Temporal relationship with drug initiation; common culprits: heparin (HIT), ibuprofen, ampicillin, quinine ^[14]	Drug-dependent platelet antibodies or direct BM suppression
Thrombotic thrombocytopenic purpura (TTP)	Pentad: MAHA + thrombocytopenia + fever + neurological symptoms + renal impairment; schistocytes on blood film; ADAMTS13 activity < 10% ^[15]	Deficiency of ADAMTS13 → ultra-large vWF multimers accumulate → platelet-rich microthrombi
Haemolytic uraemic syndrome (HUS)	Triad: MAHA + thrombocytopenia + AKI; often post-diarrhoeal (Shiga toxin-producing E. coli); more common in children	Shiga toxin → endothelial injury → TMA predominantly in renal microvasculature
Disseminated intravascular coagulation (DIC)	Consumption of clotting factors AND platelets; prolonged PT + aPTT + ↓fibrinogen + ↑D-dimer; schistocytes; catastrophic APS can cause DIC ^[16]	Systemic activation of coagulation → consumption of factors and platelets
SLE itself	Thrombocytopenia occurs in SLE without APS (Type II HSR — anti-platelet autoantibodies); ↓C3/C4, ↑anti-dsDNA ^[17]	Autoantibodies against platelets as part of multi-system autoimmunity
Hypersplenism	Splenomegaly on examination; pancytopenia with proportional decreases	Splenic sequestration/pooling of platelets
Bone marrow failure (aplastic anaemia, MDS, infiltration by leukaemia/lymphoma)	Pancytopenia; abnormal BM biopsy	Decreased platelet production
Evans syndrome	AIHA + ITP occurring simultaneously; DAT positive; associated with SLE and APS ^[13]	Autoantibodies against both RBCs and platelets

APS-related thrombocytopenia is usually mild (50–130 × 10⁹/L) and rarely causes significant bleeding — this is a key distinguishing feature from TTP/HUS where thrombocytopenia is often severe.

TTP vs APS — A Critical Distinction

Both TTP and catastrophic APS can present with MAHA + thrombocytopenia + multi-organ dysfunction. The critical distinguishing test is ADAMTS13 activity: severely reduced (< 10%) in TTP, normal or mildly reduced in APS. Clotting profile is normal in TTP (because it's a platelet-mediated TMA, not a coagulation cascade problem), but may be deranged in DIC or catastrophic APS ^[15]^[16]. Always check ADAMTS13, aPL antibodies, and a clotting profile when the diagnosis is unclear.

Differential	Key Features	How to Distinguish from APS
Physiological livedo reticularis	Symmetric, fine, reversible with warming; common in young women	Disappears with warming; no thrombotic events; no aPL
Polyarteritis nodosa (PAN)	Skin nodules along arteries; livedo reticularis; renal artery microaneurysms; nerve involvement (mononeuritis multiplex); HBV-associated in some	Biopsy showing necrotising vasculitis of medium vessels; angiography showing microaneurysms; aPL negative
SLE	Livedo reticularis can occur in SLE without APS; malar rash, photosensitivity, alopecia, oral ulcers ^[4]	Check aPL — if positive + thrombosis/pregnancy morbidity → co-existing APS
Cholesterol crystal embolisation	Post-vascular procedure (catheterisation); blue toe syndrome; livedo reticularis; renal failure; eosinophilia; "trash foot"	Temporal relationship with procedure; skin biopsy showing biconvex cholesterol clefts
Cryoglobulinaemia	Livedo, purpura, Raynaud's; HCV-associated; GN, neuropathy	Cryocrit positive; HCV serology; complement ↓C4; aPL negative
Sneddon syndrome	Livedo racemosa + cerebrovascular disease; may overlap with APS (some are aPL-positive)	If aPL-positive → classified as APS-associated Sneddon syndrome; if aPL-negative → primary Sneddon syndrome

Differential	Key Features	How to Distinguish from APS
Libman-Sacks endocarditis (APS/SLE)	Sterile vegetations; mitral > aortic; typically atrial surface; usually mild regurgitation; source of cardioembolism	aPL positive; no fever or positive blood cultures; vegetations are small, irregular, may calcify
Infective endocarditis (IE)	Fever; positive blood cultures (Staph aureus, Streptococcus); new murmur; Osler nodes, Janeway lesions, Roth spots; septic emboli	Duke criteria; blood cultures positive; vegetations are larger, more mobile, typically on ventricular surface of AV valves
Rheumatic heart disease	History of rheumatic fever (developing countries); mitral stenosis (diastolic murmur); valve thickening/calcification	ASO titre; echocardiographic findings of commissural fusion; geographic/demographic risk
Non-bacterial thrombotic endocarditis (marantic)	Associated with advanced malignancy (especially mucin-secreting cancers), DIC; sterile vegetations	Cancer history; DIC screen; aPL negative

These are conditions that share multiple features with APS and must be considered as an overall diagnostic alternative:

Condition	Shared Features with APS	Key Distinguishing Features
Systemic lupus erythematosus (SLE) ^[4]^[17]	Thrombosis, thrombocytopenia, pregnancy loss, livedo, Libman-Sacks endocarditis, positive ANA	SLE has additional features: malar rash, photosensitivity, alopecia, oral ulcers, arthritis, nephritis, serositis, CNS involvement; anti-dsDNA, ↓C3/C4; ~30% of SLE patients also have APS (secondary APS) — they can coexist
Thrombotic thrombocytopenic purpura (TTP) ^[15]	MAHA, thrombocytopenia, neurological Sx, renal impairment	ADAMTS13 < 10%; clotting normal; schistocytes prominent; no aPL
Disseminated intravascular coagulation (DIC) ^[16]	Thrombosis + bleeding, thrombocytopenia, multi-organ failure; catastrophic APS can cause DIC	Prolonged PT + aPTT, ↓fibrinogen, ↑D-dimer; schistocytes; identify underlying cause (sepsis, malignancy, APML)
Heparin-induced thrombocytopenia (HIT)	Thrombocytopenia + paradoxical thrombosis (both arterial and venous)	Temporal relationship with heparin exposure (5–10 days); anti-PF4 antibodies; 4T score
Inherited thrombophilia (Protein C/S deficiency, AT III deficiency) ^[1]^[9]	Recurrent VTE	Purely venous; no pregnancy morbidity pattern; no livedo; quantitative assays diagnostic; Factor V Leiden NOT found in Chinese
Paroxysmal nocturnal haemoglobinuria (PNH) ^[11]	Thrombosis (especially unusual sites — Budd-Chiari, cerebral veins), haemolysis, cytopenia	Flow cytometry (↓CD55/CD59); Coombs-negative intravascular haemolysis; no aPL
Malignancy ^[6]^[9]	Hypercoagulability, migratory thrombophlebitis (Trousseau), DIC, sterile endocarditis (marantic)	Age-appropriate cancer screening; tumour markers; CT TAP; no aPL
Vasculitis (Behçet, PAN, ANCA-associated)	Thrombosis, skin lesions, multi-organ involvement	ANCA, biopsy, specific clinical features (oral/genital ulcers for Behçet; medium-vessel necrotising vasculitis for PAN)
Catastrophic APS vs TTP/HUS/DIC/HELLP	Multi-organ failure, MAHA, thrombocytopenia — these conditions can be almost indistinguishable	Check ADAMTS13, aPL antibodies, clotting profile, and fibrinogen to differentiate; catastrophic APS requires aPL positivity + ≥3 organ involvement within ≤1 week

The following mermaid diagram shows how to approach the differential when you encounter a young patient with unexplained thrombosis (the most common entry point for APS):

Investigation	APS	TTP	DIC	HIT	Inherited Thrombophilia
aPL antibodies	Positive × 2, ≥12 wk apart	Negative	Negative	Negative	Negative
ADAMTS13	Normal	< 10%	Normal/mild ↓	Normal	Normal
aPTT	Prolonged (LA effect)	Normal	Prolonged	Normal	Normal
PT	Normal	Normal	Prolonged	Normal	Normal
Fibrinogen	Normal	Normal	Low	Normal	Normal
D-dimer	↑ (if active VTE)	Mildly ↑	Markedly ↑	↑	↑ (if active VTE)
Blood film	Usually normal	Schistocytes	Schistocytes	Normal	Normal
Platelet count	Mild ↓ (50–130)	Severe ↓	Variable ↓	↓ by ≥50%	Normal
DAT (Coombs)	May be + (if AIHA)	Negative	Negative	Negative	Negative
Anti-PF4	Negative	Negative	Negative	Positive	Negative
Mixing study	Does NOT correct (immediate) ^[5]	Corrects	Corrects	N/A	Corrects

Exam Pearl – The Mixing Study

Lupus anticoagulant causes autoantibodies against phospholipids, which aPTT is dependent on → but actually results in thrombotic tendency rather than bleeding tendency ^[5]. In a mixing study, the patient's antibodies immediately destroy the phospholipids in normal plasma → aPTT does NOT correct. This "immediacy" distinguishes lupus anticoagulant from other acquired factor inhibitors (e.g., acquired Factor VIII inhibitor) where the non-correction is delayed after incubation ^[5].

Not every positive aPL test means APS. Several conditions can cause transient aPL positivity that is clinically irrelevant:

Cause of Transient aPL	Mechanism	Clinical Significance
Infections (syphilis, HIV, HCV, EBV, CMV, COVID-19)	Molecular mimicry — microbial antigens structurally resemble phospholipid-binding proteins → cross-reactive antibodies	Usually low titre; rarely thrombogenic; resolves after infection clears
Medications (chlorpromazine, hydralazine, procainamide, quinidine)	Drug-induced autoantibody formation	Transient; resolves after drug discontinuation
Elderly population	Age-related immune dysregulation	Low titre; usually not associated with thrombosis

This is exactly why diagnostic criteria require TWO positive measurements at least 12 weeks apart ^[1]^[2] — to exclude transient, non-pathogenic aPL that would not warrant lifelong anticoagulation.

Some viral infections or drugs can transiently induce the presence of antibodies → lupus anticoagulant / anticardiolipin antibodies can present as a sole laboratory abnormality. Therefore, if patient is positive for these antibodies 12 or more weeks apart, can demonstrate persistence, allowing for diagnosis ^[1].

Catastrophic APS can be almost indistinguishable from several other thrombotic microangiopathies. The differential for a patient presenting with multi-organ failure + MAHA + thrombocytopenia includes:

Condition	Key Distinguishing Feature
Catastrophic APS	aPL positive; ≥3 organs in ≤1 week; may have DIC overlap; biopsy shows small vessel thrombosis
TTP	ADAMTS13 < 10%; neurological predominance; clotting profile NORMAL ^[15]
HUS	Renal predominance; post-diarrhoeal (STEC) or complement-mediated (aHUS); ADAMTS13 normal
DIC	Identifiable trigger (sepsis, malignancy, APML); prolonged PT + aPTT; ↓fibrinogen; ↑D-dimer ^[16]
HELLP syndrome	Pregnancy context; haemolysis + elevated liver enzymes + low platelets; resolves after delivery
Malignant hypertension	Severe HTN (> 180/120); target organ damage; MAHA from mechanical shearing of RBCs through damaged arterioles
Scleroderma renal crisis	Scleroderma history; anti-RNA polymerase III; acute HTN + AKI + MAHA; treated with ACEi

Secondary TMA causes include: HELLP syndrome, malignant HTN, SLE, scleroderma, antiphospholipid syndrome ^[16].

High Yield Summary – Differential Diagnosis of APS

Recurrent VTE in a young patient: DDx includes inherited thrombophilia (Protein C/S/AT III deficiency — NOT Factor V Leiden in Chinese), malignancy, nephrotic syndrome, PNH, MPN, and APS.
Young stroke/MI: DDx includes premature atherosclerosis, cardioembolism (AF, valvular), dissection, vasculitis, PFO, and APS.
Recurrent pregnancy loss: DDx includes chromosomal abnormalities (most common), uterine anomalies, cervical incompetence, endocrine disorders, infections, and APS. Late fetal death and severe early-onset pre-eclampsia are particularly suggestive of APS.
Thrombocytopenia with thrombosis (paradox): DDx includes APS, TTP, HIT, DIC, and catastrophic APS. Key tests: ADAMTS13 (TTP < 10%), aPL (APS), anti-PF4 (HIT), clotting profile + fibrinogen (DIC).
Livedo reticularis: DDx includes physiological, PAN, cholesterol emboli, cryoglobulinaemia, Sneddon syndrome, and APS.
Mixing study: Lupus anticoagulant → immediate non-correction of aPTT (vs VWD which corrects; vs other inhibitors which show delayed non-correction).
Transient aPL positivity (infections, drugs) is clinically irrelevant → this is why TWO tests ≥12 weeks apart are required.
CAPS mimics: TTP, HUS, DIC, HELLP, malignant HTN, scleroderma renal crisis — differentiate with ADAMTS13, aPL, clotting profile, and clinical context.

Active Recall - Differential Diagnosis of APS

References

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia (Antiphospholipid syndrome section) ^[2] Senior notes: Maksim Medicine Notes (Rheumatology - Antiphospholipid syndrome, p. 317) ^[4] Senior notes: Block A - Facial rash and painful fingers: SLE ^[5] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting) (Mixing study, lupus anticoagulant vs VWD, p. 22) ^[6] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai) (DVT/PE risk factors, p. 964) ^[7] Senior notes: Ryan Ho Neurology (Stroke secondary prevention, p. 83) ^[9] Senior notes: Adrian Lui Pediatrics Notes (Thrombophilia screening, inherited thrombophilia in Chinese, p. 397) ^[10] Senior notes: Ryan Ho Respiratory (PE risk factors, p. 133) ^[11] Senior notes: Block A - Family history of anaemia (Haemolytic anaemia differential, p. 3) ^[12] Senior notes: Ryan Ho Rheumatology (Revised Sapporo criteria, p. 73) ^[13] Senior notes: Ryan Ho Haemtology (ITP, p. 117) ^[14] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai) (Differential diagnosis of purpura, acquired platelet disorders, p. 607, 699) ^[15] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai) (TTP, p. 615, 618) ^[16] Senior notes: Ryan Ho Haemtology (DIC causes and TMA terminology, p. 137) ^[17] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai) (SLE investigations and antibodies, p. 719-720)

Diagnostic Criteria, Diagnostic Algorithm & Investigations for Antiphospholipid Syndrome

A. Diagnostic Criteria

The diagnosis of APS requires the convergence of clinical events and persistent laboratory positivity. You cannot diagnose APS on antibodies alone (many healthy people and patients with infections transiently carry aPL), nor can you diagnose it on clinical events alone (thrombosis and miscarriage are common and have many causes). You need both.

A1. Revised Sapporo (Sydney) Criteria — The Standard for HKUMed Exams

This is the classification framework most commonly referenced in GC lecture slides and senior notes ^[1]^[2]^[12]^[18].

Primary antiphospholipid syndrome (APS) — Diagnostic criteria — Sapporo: One clinical and one laboratory criteria ^[18]

Criterion	Definition	Key Details
1. Vascular thrombosis	≥1 episode of non-superficial thrombosis in any tissue or organ, with imaging or histologic evidence ^[12]	Venous (DVT, PE, cerebral venous sinus thrombosis, renal vein thrombosis, etc.) OR arterial (stroke, MI, peripheral arterial) OR small vessel thrombosis. Must be non-superficial — superficial thrombophlebitis alone does not count. Imaging (Doppler USS, CT angiography, MRA) or histopathology must confirm. Histology should show thrombosis without significant vessel wall inflammation (to differentiate from vasculitis).
2. Pregnancy morbidity	Any of the following ^[12]:	See sub-criteria below

Pregnancy morbidity sub-criteria (any one of):

Sub-criterion	Detail	Rationale
≥3 consecutive spontaneous pregnancy losses < 10 weeks	Without chromosomal disorders, maternal anatomical or hormonal causes ^[12]	Must exclude the most common causes first (chromosomal abnormalities, uterine malformations, endocrine causes). Three consecutive losses is statistically unlikely to be random chance.
≥1 unexplained death of a morphologically normal fetus ≥10 weeks	Confirmed by ultrasound or direct examination	Late fetal death is strongly suggestive of placental thrombosis/insufficiency — the hallmark obstetric manifestation of APS.
≥1 premature birth < 34 weeks	Of a morphologically normal fetus due to eclampsia, severe pre-eclampsia, or recognised features of placental insufficiency ^[12]	Early-onset severe pre-eclampsia or IUGR requiring premature delivery → suspect defective placentation from aPL-mediated trophoblast and spiral artery damage.

The lecture slide also lists "3. Thrombocytopenia" as a clinical criterion ^[18]. This reflects the practical importance of thrombocytopenia in APS, though the formal revised Sapporo criteria group it under "associated features" rather than a standalone diagnostic criterion. For exam purposes, follow the GC lecture-slide framing.

GC Lecture-Slide Framing – Clinical Criteria

The GC Haematology lecture slide lists three clinical criteria for Sapporo: (1) Thrombosis, (2) Recurrent miscarriage, (3) Thrombocytopenia ^[18]. The formal revised Sapporo criteria only include vascular thrombosis and pregnancy morbidity as clinical criteria, with thrombocytopenia as an associated feature. For HKUMed in-house exams, use the lecture-slide list unless specifically asked about formal classification criteria.

Test	Method	Detail	Clinical Significance
Lupus anticoagulant (LA)	Clotting-based assay ^[1] (e.g., DRVVT — Dilute Russell's Viper Venom Time ^[5])	Detectable lupus anticoagulant on two occasions ≥12 weeks apart	Most thrombogenic of the three ^[2]; strongest predictor of clinical events
Anti-cardiolipin antibodies (aCL)	Immunoassay (ELISA) ^[1]	Moderate to high titre ( > 40 units) IgG or IgM on two occasions ≥12 weeks apart ^[12]	Medium thrombogenic risk; IgG more clinically significant than IgM
Anti-β2-glycoprotein I antibodies (anti-β2GPI)	Immunoassay (ELISA) ^[1]	Moderate to high titre ( > 40 units) IgG or IgM on two occasions ≥12 weeks apart ^[12]	Most specific for APS but limited sensitivity → only check if the other two are negative ^[2]

Require TWO measurements 12 weeks apart ^[1]^[2]^[18] — this is to exclude transient, non-pathogenic aPL from infections or drugs.

The name of these antibodies depends on the test you use to measure them ^[1]:

Measuring with immunoassays → anti-cardiolipin (IgG/IgM) and anti-β2-glycoprotein I

Measuring with clotting-based assay → lupus anticoagulant

Why 12 Weeks Apart?

Some viral infections or drugs can transiently induce the presence of antibodies → lupus anticoagulant / anticardiolipin antibodies can present as a sole laboratory abnormality. Therefore, if patient is positive for these antibodies 12 or more weeks apart, can demonstrate persistence, allowing for diagnosis ^[1]. If you tested just once and acted on it, you could misdiagnose transient infection-related aPL positivity as APS and commit a patient to lifelong anticoagulation unnecessarily.

APS is diagnosed when the patient meets:

≥1 clinical criterion (vascular thrombosis OR pregnancy morbidity)
AND ≥1 laboratory criterion (any aPL test positive on ≥2 occasions, ≥12 weeks apart)

A2. ACR/EULAR 2023 Classification Criteria — Updated Framework

The 2023 criteria are a weighted scoring system that provides more granularity and incorporates features not in Sapporo (e.g., microvascular disease, cardiac valve disease). While the Sapporo criteria are still used clinically and are the primary exam framework at HKUMed, awareness of the 2023 update is important for clinical practice.

At least one positive aPL test (LA, aCL IgG/IgM, or anti-β2GPI IgG/IgM) within 3 years of a qualifying clinical criterion

Classified as APS if: Clinical domain score ≥3 AND Laboratory domain score ≥3

Domain	Items	Weight
Clinical Domains
Macrovascular — Venous	DVT (with/without high-risk profile), PE, unusual site venous thrombosis	1–5
Macrovascular — Arterial	Stroke, MI, peripheral arterial thrombosis	2–5
Microvascular	Livedo racemosa, livedoid vasculopathy, APS nephropathy (TMA), pulmonary haemorrhage	2–5
Obstetric	≥3 pre-embryonic/early embryonic losses, fetal death ≥10 wk, pre-eclampsia < 34 wk	1–4
Cardiac valve	Valve thickening, Libman-Sacks vegetation	2
Haematological	Thrombocytopenia (20–130 × 10⁹/L)	2
Laboratory Domains
aPL persistence	Positive on ≥2 occasions ≥12 weeks apart	Required
LA positive	Detectable lupus anticoagulant	4
aCL or anti-β2GPI	Moderate–high titre IgG or IgM	4–7

Key improvements over Sapporo:

Microvascular disease (APS nephropathy, livedoid vasculopathy) is now a formal clinical domain
Cardiac valve disease (Libman-Sacks) is explicitly included
Weighted scoring allows more nuanced risk stratification
Risk-stratification within thrombotic events (e.g., provoked vs unprovoked VTE scored differently)

Exam Strategy – Which Criteria to Use?

For HKUMed in-house written papers, default to the Sapporo (Sydney) criteria as presented in the GC lecture slides ^[18] unless the question specifically asks about 2023 criteria. The Sapporo framework is simpler and more commonly examined: one clinical + one laboratory criterion, with lab tests positive ≥2 times ≥12 weeks apart.

The diagnostic approach to APS depends on the clinical entry point — the presentation that first makes you suspect APS. Here is a systematic algorithm:

Step-by-Step Explanation

Step 1: Confirm the clinical event

You must objectively document the thrombotic event (imaging or histology) or the pregnancy morbidity pattern (obstetric records, pathology of products of conception)
Superficial thrombophlebitis alone is insufficient
For pregnancy loss, you must actively exclude chromosomal, anatomical, and hormonal causes first

Step 2: Order the aPL panel — all three tests simultaneously

Lupus anticoagulant (clotting-based assay — DRVVT in QMH) ^[5]
Anti-cardiolipin IgG and IgM (ELISA)
Anti-β2-glycoprotein I IgG and IgM (ELISA)

Step 3: Repeat at ≥12 weeks if first test positive

This is non-negotiable — a single positive test cannot establish the diagnosis

Step 4: Apply Sapporo criteria

≥1 clinical criterion + ≥1 laboratory criterion (persistent) = APS

Step 5: Risk stratify and classify

Single, double, or triple positivity → triple positivity (all three aPL positive) carries the highest thrombotic risk
Primary vs secondary → screen for SLE with ANA, anti-dsDNA, complement levels (C3/C4)
Assess for additional organ involvement (renal, cardiac, neurological, haematological)

C. Investigation Modalities — Comprehensive Guide

I'll organize investigations into: (i) aPL-specific laboratory tests, (ii) baseline blood investigations, (iii) coagulation studies, (iv) investigations to assess end-organ damage, (v) investigations to exclude alternative diagnoses.

C1. Antiphospholipid Antibody Panel — The Core Diagnostic Tests

Aspect	Detail
Test principle	LA antibodies interfere with phospholipid-dependent coagulation in vitro → they prolong phospholipid-dependent clotting times
Assay used	DRVVT — Dilute Russell's Viper Venom Time (the test used at QMH/HKU lab) ^[5]; or silica clotting time (SCT)
How DRVVT works	Russell's Viper Venom directly activates Factor X → bypasses the intrinsic and extrinsic pathways → the assay is phospholipid-dependent. By using dilute phospholipid reagent, you amplify the effect of any anti-phospholipid antibody present.
Steps	Screen: run DRVVT with dilute phospholipid → if prolonged, proceed. Mix: add normal plasma → if doesn't correct, suggests an inhibitor (not factor deficiency). Confirm: add excess phospholipid → if clotting time normalises, confirms the inhibitor is phospholipid-dependent = LA positive.
Interpretation	LA positive = prolonged screen time that does NOT correct with mixing but DOES correct with excess phospholipid
Pitfalls	Anticoagulant therapy (warfarin, heparin, DOACs) can interfere with results → timing: ≥2 weeks after stopping anticoagulation ^[9]^[19]; acute thrombosis can transiently affect results
Clinical significance	Most thrombogenic of the three aPL tests ^[2]; strongest predictor of thrombosis and pregnancy morbidity

In QMH lab, we have special coagulation tests to be used — DRVVT → Dilute Russell's Viper Venom Time ^[5]

Lupus anticoagulant classically causes a prolonged aPTT and a normal PT ^[5] — but if prolonged aPTT suggests bleeding, why does LA cause thrombosis? Because the aPTT prolongation is an in vitro artefact (the antibody interferes with the phospholipid reagent in the test), whereas in vivo the antibody activates endothelial cells, platelets, and complement → thrombosis.

Aspect	Detail
Test principle	ELISA detects antibodies (IgG and/or IgM) that bind to cardiolipin (a phospholipid found in mitochondrial membranes and used as a coating antigen) in the presence of β2GPI as a cofactor
Threshold	Moderate to high titre ( > 40 GPL or MPL units) ^[12] — low titre positivity is less clinically meaningful and more likely to be transient/non-specific
Report	Reported as IgG and IgM separately; IgG is more clinically significant than IgM
False positives	Syphilis (VDRL/RPR cross-reactivity — false positive RPR is actually listed as a feature in SLE classification criteria ^[17]), infections (EBV, HIV, HCV), medications
Clinical significance	Medium thrombogenic risk; IgG > IgM; useful as screening test together with LA

Syphilis and aPL — The VDRL Connection

The VDRL (Venereal Disease Research Laboratory) test for syphilis uses cardiolipin as the antigen. Patients with APS often have a false positive VDRL/RPR because their anti-cardiolipin antibodies cross-react with the cardiolipin antigen used in the syphilis test. This is why a false positive test result for rapid plasma reagin (RPR) is included in the SLICC classification criteria for SLE ^[17]. If you see a "positive VDRL" in a young woman with thrombosis but no STI history — think APS!

Aspect	Detail
Test principle	ELISA detects antibodies (IgG and/or IgM) directed specifically against β2-glycoprotein I protein
Threshold	Moderate to high titre ( > 40 units or > 99th percentile) ^[12]
Clinical significance	Most specific for APS but limited sensitivity → only check if the other two are negative ^[2]. In practice, most centres now test all three simultaneously.
Why most specific?	β2GPI is the actual pathogenic target of most aPL antibodies. Anti-β2GPI antibodies are directly pathogenic (they bind β2GPI on cell surfaces and activate endothelium/platelets), unlike some aCL antibodies which may be non-pathogenic bystanders.

Test	Method	Sensitivity	Specificity	Thrombogenicity	When to Test
Lupus anticoagulant	Clotting-based (DRVVT)	Moderate	Moderate-High	Highest	First-line
Anti-cardiolipin IgG/IgM	ELISA	High	Moderate	Moderate	First-line
Anti-β2GPI IgG/IgM	ELISA	Low-Moderate	Highest	Moderate	Check if other two negative ^[2], or test all three simultaneously

Lupus anticoagulant (↑aPTT, most thrombogenic) > anti-cardiolipin > anti-β2 glycoprotein (most specific for APS, but limited sensitivity → only check if another two negative) ^[2]

Investigation	Expected Finding in APS	Rationale / Interpretation
CBC with differential	Thrombocytopenia (typically mild, 50–130 × 10⁹/L) ^[1]; possible anaemia (if AIHA coexists or chronic disease); leukopenia if secondary to SLE	aPL bind platelet surface β2GPI → immune-mediated platelet destruction; also consumption in microthrombi
Peripheral blood film	Usually normal in uncomplicated APS; schistocytes if catastrophic APS/TMA present ^[16]	Schistocytes = RBC fragmentation from passing through platelet-fibrin thrombi in microvasculature → indicates microangiopathic haemolytic anaemia (MAHA)
Reticulocyte count	Elevated if AIHA present	Compensatory marrow response to haemolysis
Direct antiglobulin test (DAT / Coombs)	May be positive (especially if Evans syndrome — AIHA + ITP) ^[17]	Detects antibodies coating RBCs; positive DAT = immune-mediated haemolysis. In SLE context: positive DAT in the absence of haemolytic anaemia is a SLICC criterion ^[17]
LDH	Elevated if haemolysis or tissue ischaemia	Released from damaged RBCs (haemolysis) and ischaemic tissues
Haptoglobin	Low if haemolysis present	Free Hb from haemolysis binds haptoglobin → complex cleared by liver → serum haptoglobin drops
Unconjugated bilirubin	Mildly elevated if haemolysis	Product of haem breakdown from destroyed RBCs

Investigation	Expected Finding	Interpretation
aPTT	Prolonged ^[1]^[5]	Lupus anticoagulant causes autoantibodies against phospholipids, which aPTT is dependent on ^[5] → LA interferes with phospholipid reagent → aPTT prolonged in vitro. Does NOT indicate bleeding risk — this is a prothrombotic condition!
PT / INR	Usually normal ^[5]	PT uses thromboplastin (which contains abundant phospholipid) → less sensitive to LA interference. If both PT and aPTT are prolonged → consider DIC, liver disease, or common pathway factor deficiency rather than LA alone
Mixing study	Does NOT correct (immediate non-correction) ^[5]	Mix 50% patient plasma + 50% normal plasma. If aPTT remains prolonged → inhibitor present (not factor deficiency). Lupus anticoagulant results in immediate non-correction — the antibodies start inhibiting the normal plasma phospholipids right away ^[5]. Other inhibitors (e.g., acquired FVIII inhibitor) show delayed non-correction after incubation.
Fibrinogen	Normal (unless DIC/CAPS)	In uncomplicated APS, the coagulation cascade factors themselves are not consumed. If fibrinogen is low → think DIC overlap
D-dimer	Elevated if active VTE	D-dimer is a fibrin/blood clot degradation product ^[5] → elevated whenever there is ongoing thrombosis and fibrinolysis. Sensitive but not specific ^[5] — elevated in many conditions (infection, malignancy, pregnancy, surgery)

The Mixing Study — A Key Concept

Von Willebrand disease is just a deficiency of Factor 8 → after mixing, you get 50% Factor 8, which is sufficient to correct the aPTT.

Lupus anticoagulant: you have antibodies actively trying to mess up your phospholipids → after mixing, the antibodies begin immediately destroying the healthy plasma phospholipids → resulting in the inability to correct the aPTT.

"Immediately" is one of the characteristics of lupus anticoagulant → other autoimmune conditions that also cause destruction will not be immediate, but delayed following incubation. ^[5]

Organ System	Investigation	Finding & Interpretation
Renal	RFT (urea, creatinine, eGFR), urinalysis (proteinuria, haematuria), spot urine protein-to-creatinine ratio, renal biopsy if indicated	APS nephropathy: TMA on biopsy (fibrin thrombi in glomerular capillaries, arteriolar thrombosis, fibrous intimal hyperplasia) — distinct from lupus nephritis (immune complex GN). Renal biopsy is essential to distinguish APS nephropathy from lupus nephritis because treatment differs (anticoagulation vs immunosuppression) ^[2]
Cardiac	ECG, transthoracic echocardiography (TTE), consider transoesophageal echo (TOE)	Libman-Sacks endocarditis: sterile vegetations on mitral > aortic valve, typically atrial surface; valve thickening and regurgitation. TOE is more sensitive than TTE for detecting small vegetations.
Neurological	MRI brain (with DWI/FLAIR), MRA/CTA, cerebral angiography if vasculitis suspected	Acute ischaemic stroke: restricted diffusion on DWI-MRI; chronic: multiple white matter lesions (multi-infarct pattern). Cerebral venous sinus thrombosis: MRV shows absent flow in affected sinus.
Pulmonary	CTPA (CT pulmonary angiography), V/Q scan, echocardiography (RV function/PAP)	PE: filling defects in pulmonary arteries on CTPA. Chronic: CTEPH — elevated PA pressures on echo, webs/bands in pulmonary arteries.
Vascular	Doppler USS of lower limbs, CT angiography of relevant vascular territory	DVT: non-compressible vein on compression USS, absent flow on colour Doppler. Arterial: occlusion or stenosis on CTA.
Adrenal	CT abdomen, morning cortisol, short Synacthen test	Bilateral adrenal haemorrhagic infarction → adrenal insufficiency (low cortisol, inadequate Synacthen response). CT shows enlarged, haemorrhagic adrenals.
Skin	Clinical assessment, skin biopsy if diagnostic uncertainty	Livedo reticularis/racemosa: non-inflammatory thrombosis of dermal arterioles on biopsy; livedoid vasculopathy: hyaline thrombosis of dermal vessels with segmental hyalinisation.
Ophthalmological	Fundoscopy, fluorescein angiography, OCT	Retinal artery/vein occlusion: pale retina with cherry-red spot (CRAO), dilated tortuous veins with haemorrhages (CRVO)

Investigation	Purpose	Expected Finding if Relevant
ANA	Screen for underlying SLE (secondary APS) ^[12]	Positive in > 95% of SLE; if positive → proceed with anti-dsDNA, ENA panel, complement
Anti-dsDNA	Confirm SLE if ANA positive ^[12]	High specificity for SLE; correlates with disease activity
Complement (C3, C4)	Assess SLE disease activity; complement consumption	Low C3/C4 in active SLE (complement consumed by immune complexes); may also be consumed in catastrophic APS
Anti-ENA panel (Anti-Sm, anti-RNP, anti-Ro/La)	Differentiate SLE from other connective tissue diseases	Anti-Sm: highly specific for SLE; Anti-RNP: MCTD
ADAMTS13 activity	Exclude TTP (critical differential for CAPS)	< 10% = TTP ^[15]; normal in APS
Thrombophilia screen	Inherited thrombophilia	Protein C, Protein S, Antithrombin III levels; activated protein C resistance (APCR); Factor V Leiden — NOT relevant in Chinese ^[9]
Serology	Exclude infections causing transient aPL	HBV, HCV, HIV, syphilis (RPR/VDRL — may be false positive in APS!), EBV
Occult malignancy screen	Malignancy as cause of hypercoagulability ^[9]^[19]	CXR, CT A+P, age-appropriate screening (mammogram if female > 40), tumour markers, PSA
Homocysteine	Hyperhomocysteinaemia (controversial) ^[1]	May be elevated; lowering levels does not confer protective effect ^[1]

Timing of Thrombophilia Screen

Timing: ≥2 weeks after stopping anticoagulation, after initial thrombotic event ^[9]^[19].

Why? Two reasons:

Acute thrombosis can reduce plasma anticoagulant levels (due to consumption) — measuring Protein C/S during acute thrombosis may give falsely low results.
Anticoagulants interfere with testing — warfarin reduces Protein C/S (vitamin K-dependent); heparin reduces antithrombin; DOACs can interfere with LA testing via DRVVT.

So: treat the acute thrombosis first, then test for the underlying cause once the dust has settled.

This table synthesises the recommended investigations when a patient presents with unexplained or recurrent thrombosis ^[9]^[19]:

Indication	Investigations
Young patient with unprovoked VTE, recurrent VTE, unusual site thrombosis, warfarin-induced skin necrosis, arterial thrombosis < 40 years, recurrent miscarriage ^[9]^[19]	Antiphospholipid syndrome panel: LA, aCL IgG/IgM, anti-β2GPI IgG/IgM
	Inherited thrombophilia: Protein C, Protein S, Antithrombin III, APCR, Factor V Leiden (not in Chinese ^[9])
Occult malignancy screen (NICE 2015: screen ALL unprovoked VTE not already known to have cancer) ^[19]	P/E guided by full history; CXR; blood tests (CBC, Ca, LFT); urinalysis; ± CT A+P, mammogram if > 40y and initial investigations negative ^[19]

When CAPS is suspected (multi-organ failure + MAHA + thrombocytopenia developing over ≤1 week):

Investigation	Purpose	Expected Finding
aPL panel (urgently)	Confirm aPL positivity	Positive LA, aCL, or anti-β2GPI
ADAMTS13	Exclude TTP	Normal or mildly reduced (vs < 10% in TTP)
Clotting profile + fibrinogen	Assess for DIC overlap	May show DIC features (↑PT, ↑aPTT, ↓fibrinogen, ↑D-dimer) if CAPS triggers DIC
Blood film	Confirm MAHA	Schistocytes
Tissue biopsy (skin, kidney, or other affected organ)	Histological confirmation	Small vessel thrombosis without significant vessel wall inflammation
Multi-organ assessment	Document ≥3 organ involvement	Renal (RFT, urinalysis), hepatic (LFT), pulmonary (CTPA, CXR), cardiac (echo, troponin), neurological (MRI), adrenal (cortisol)

Investigation	Role in APS	Key Interpretation Points
Lupus anticoagulant (DRVVT)	Diagnostic (most thrombogenic)	Prolonged screen → not corrected by mixing → corrected by excess PL = LA positive
Anti-cardiolipin IgG/IgM	Diagnostic (most sensitive)	Moderate-high titre ( > 40 units) × 2 occasions ≥12 wk apart
Anti-β2GPI IgG/IgM	Diagnostic (most specific)	Moderate-high titre × 2 occasions ≥12 wk apart
aPTT	Screening clue	Prolonged (LA effect); does NOT mean bleeding risk
Mixing study	Differentiate LA from factor deficiency	LA = immediate non-correction; factor deficiency = corrects
PT / INR	Exclude common pathway / DIC	Usually normal in APS; monitor warfarin therapy
D-dimer	Assess active thrombosis	Sensitive, not specific; rule-out utility
CBC + film	Assess cytopenia, MAHA	Mild thrombocytopenia; schistocytes if CAPS/TMA
ANA, anti-dsDNA, C3/C4	Screen for SLE (secondary APS)	Positive → secondary APS likely
ADAMTS13	Exclude TTP	< 10% = TTP, not APS
Thrombophilia screen	Exclude inherited causes	Protein C/S/AT III; timing important (≥2 wk off anticoagulation)
Imaging (USS, CTPA, MRI)	Document thrombotic events	Site-specific confirmation of thrombosis
Echocardiography	Assess valvular involvement	Libman-Sacks vegetations; RV function (CTEPH)
Renal biopsy	Distinguish APS nephropathy from lupus nephritis	TMA pattern (fibrin thrombi) vs immune complex GN
Tissue biopsy	CAPS confirmation	Small vessel thrombosis without significant inflammation

High Yield Summary – Diagnosis of APS

Sapporo criteria (GC exam framework): ≥1 clinical criterion (vascular thrombosis OR pregnancy morbidity) + ≥1 laboratory criterion (any aPL positive on ≥2 occasions ≥12 weeks apart).
Three antibodies, three tests: LA (DRVVT, clotting-based — most thrombogenic), aCL (ELISA — most sensitive), anti-β2GPI (ELISA — most specific, check if others negative).
aPTT prolonged by LA in vitro → mixing study does NOT correct (immediate) → but adding excess phospholipid DOES correct → confirms phospholipid-dependent inhibitor = LA.
12-week interval between positive tests is mandatory to exclude transient aPL (infection, drugs).
Timing of thrombophilia screen: ≥2 weeks after stopping anticoagulation; acute thrombosis consumes anticoagulant proteins → falsely low Protein C/S.
False positive RPR/VDRL in APS — cross-reactivity with cardiolipin antigen.
Secondary APS: always screen with ANA, anti-dsDNA, C3/C4 to identify underlying SLE.
CAPS workup: aPL panel + ADAMTS13 (exclude TTP) + clotting profile/fibrinogen (assess DIC overlap) + blood film (schistocytes) + multi-organ assessment + tissue biopsy.
Triple positivity (LA + aCL + anti-β2GPI) = highest risk → most aggressive management.
Factor V Leiden is NOT relevant in Chinese patients — do not include in thrombophilia screen for Hong Kong patients.

Active Recall - Diagnostic Criteria, Algorithm & Investigations for APS

References

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia (Antiphospholipid syndrome section) ^[2] Senior notes: Maksim Medicine Notes (Rheumatology - Antiphospholipid syndrome, p. 317) ^[5] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting) (Mixing study, DRVVT, lupus anticoagulant, p. 22-23) ^[9] Senior notes: Adrian Lui Pediatrics Notes (Thrombophilia screening workup, p. 398) ^[12] Senior notes: Ryan Ho Rheumatology (Revised Sapporo criteria, p. 73) ^[15] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai) (TTP diagnosis — ADAMTS13, p. 618) ^[16] Senior notes: Ryan Ho Haemtology (TMA terminology, MAHA, DIC, p. 137) ^[17] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai) (SLE classification criteria — antiphospholipid item, DAT, false positive RPR, p. 718-720) ^[18] Lecture slides: Haematology Introduction to Haematological investigations (CBP, Clotting) (Primary APS — Sapporo criteria slide, p. 25) ^[19] Senior notes: Ryan Ho Haemtology (Workup for unexplained thrombosis, p. 136)

Management of Antiphospholipid Syndrome

The management of APS is conceptually straightforward but nuanced in execution. The core principle is: APS is fundamentally a prothrombotic disorder, so the backbone of treatment is anticoagulation. However, the specific regimen varies depending on the clinical scenario — venous thrombosis alone, arterial thrombosis, obstetric APS, catastrophic APS, or asymptomatic aPL carriers.

Let me walk you through each scenario systematically.

Before diving into specific regimens, understand the overarching principles:

Anticoagulation is the mainstay — you are treating a hypercoagulable state, not an inflammatory or infectious process. Immunosuppression is generally NOT the primary treatment (exception: catastrophic APS and co-existing SLE).
Cannot be managed by the new, direct oral anticoagulants (DOAC) → since it is the most thrombotic, needs something stronger ^[1]. This is a critical exam point — the TRAPS trial (2016) was stopped early because rivaroxaban was associated with significantly more thrombotic events than warfarin in triple-positive APS patients. While some evidence supports DOACs in low-risk (single-positive, venous-only) APS, the current standard remains warfarin for confirmed APS.
Lifelong/indefinite anticoagulation is required after a thrombotic event ^[1] — unlike provoked DVT in a non-APS patient where you might anticoagulate for 3–6 months. In APS, the underlying prothrombotic state is permanent (the antibodies persist), so stopping anticoagulation means the patient will likely re-thrombose.
Obstetric APS is managed with heparin (+ low-dose aspirin), NOT warfarin — warfarin crosses the placenta and is teratogenic ^[20]^[21].
Cardiovascular risk factor modification is essential as an adjunct — APS patients have accelerated atherosclerosis, and controlling modifiable risk factors reduces the "second hit" that triggers thrombosis.

C. Treatment Modalities by Clinical Scenario

C1. APS with Venous Thromboembolism (DVT / PE)

This is the most common presentation and the most straightforward to manage.

Treatment	Detail	Mechanism
IV Unfractionated Heparin (UFH) or Subcutaneous LMWH	Treatment dose LMWH (1 mg/kg BD for enoxaparin) or UFH infusion titrated to aPTT 1.5–2.5 × control	Heparin potentiates antithrombin III → antithrombin III then inactivates thrombin (IIa) and Factor Xa → prevents clot propagation. Heparin does not lyse existing clots ^[20] — it stops them from growing while the body's own fibrinolytic system (plasmin) dissolves the clot over time.
Bridge to warfarin	Start warfarin concurrently; LMWH should be continued in parallel with warfarin until INR 2–3 is reached ^[22] (usually takes ~5 days)	Warfarin inhibits vitamin K-dependent clotting factor synthesis (Factors II, VII, IX, X, and also Protein C and S). Initially, Protein C (short half-life ~6 hours) drops before Factor II (long half-life ~60 hours) → transient hypercoagulable state in the first few days → this is why heparin must overlap.

Why Not DOACs in APS?

Cannot be managed by the new, direct oral anticoagulants (DOAC) → since it is the most thrombotic, needs something stronger ^[1].

The TRAPS trial (2016) was a landmark RCT that randomised triple-positive APS patients to rivaroxaban vs warfarin. The trial was stopped early due to an excess of arterial thrombotic events (including stroke and MI) in the rivaroxaban arm. Since then, multiple guidelines (EULAR 2019, ISTH 2020, BSH 2024) recommend against DOACs in APS, particularly in:

Triple-positive patients
Patients with arterial thrombosis
Patients with prior thrombosis while on DOACs

Exception: In carefully selected low-risk patients (single aPL-positive, venous-only, well-controlled), some guidelines allow consideration of DOACs — but this is not the standard and should not be the exam answer.

Treatment	Detail	Monitoring
Warfarin	Lifelong/indefinite administration ^[1]	INR target 2–3 ^[1]; monitor with regular INR checks (initially weekly, then monthly once stable)

How can we monitor whether the warfarin is in therapeutic levels for a patient with antiphospholipid syndrome? Using the International Normalised Ratio (INR) — should be between 2 and 3 ^[1]

Why lifelong? Unlike a provoked DVT (e.g., post-surgical, immobilisation-related) where the provoking factor is removed and anticoagulation can be stopped after 3–6 months, in APS the provoking factor is the persistent aPL antibodies — they never go away. Stopping warfarin means the prothrombotic milieu persists → very high recurrence rate (estimated 50–70% within 5 years if anticoagulation stopped).

Why INR 2–3 and not higher? The WARPS (Warfarin in Antiphospholipid Syndrome) and ALIWAPAS trials showed that high-intensity warfarin (INR 3–4) did NOT reduce recurrence compared with standard-intensity (INR 2–3), but DID increase bleeding risk. So standard-intensity is the sweet spot.

LMWH can be used as an alternative to warfarin for long-term treatment if:

Warfarin is contraindicated or difficult to monitor
Patient preference (no INR monitoring needed)
Pregnancy (see obstetric section)
Co-existing active cancer (LMWH preferred over warfarin in cancer-associated thrombosis as per CLOT trial)

C2. APS with Arterial Thrombosis (Stroke / MI)

Same as venous — heparin acutely
For acute ischaemic stroke: standard stroke management applies (thrombolysis if within window, thrombectomy if LVO); anticoagulants are indicated for cardioembolic ischaemic stroke and antiphospholipid syndrome ^[7]
For acute MI: PCI + standard ACS management, but be aware of the need for long-term anticoagulation

What if your patient with antiphospholipid syndrome presents with additional arterial thrombosis? ^[1]

Lifelong administration of either LMWH OR Warfarin (INR 2–3) AND Aspirin ^[1]

Component	Detail	Mechanism
Warfarin (INR 2–3)	Lifelong	Inhibits clotting factor synthesis → reduces fibrin-rich clots
Aspirin (75–100 mg daily)	Added for arterial events	Aspirin irreversibly acetylates cyclooxygenase-1 (COX-1) on platelets → blocks thromboxane A2 synthesis → reduces platelet aggregation. Arterial thrombi are platelet-rich (white thrombi), so antiplatelet therapy is important in addition to anticoagulation.

When to add aspirin in patients with antiphospholipid syndrome? If they develop arterial thrombosis ^[1]

Why the distinction between venous and arterial?

Venous thrombi are "red thrombi" — predominantly fibrin and trapped RBCs → best addressed by anticoagulation alone
Arterial thrombi are "white thrombi" — predominantly platelets held together by fibrin at high-shear sites → need both anticoagulation (to address the fibrin component) and antiplatelet (to address the platelet component)

High Yield – Treatment Differences by Thrombosis Type

Scenario	Treatment	Duration
APS + venous thrombosis	Warfarin (INR 2–3) OR LMWH	Lifelong
APS + arterial thrombosis	Warfarin (INR 2–3) + Aspirin	Lifelong
APS + obstetric only	LMWH + low-dose aspirin (during pregnancy)	Throughout pregnancy + 6 weeks postpartum

^[1]

C3. Obstetric APS — Management During Pregnancy

This is a distinct clinical scenario because:

Warfarin crosses the placenta → teratogenic (warfarin embryopathy: nasal hypoplasia, stippled epiphyses in 1st trimester; CNS abnormalities in 2nd/3rd trimester) and risk of fetal ICH ^[20]
DOACs cross the placenta → contraindicated in pregnancy
Heparin does NOT cross the placenta → safe for the fetus

Medications that are CONTRAINDICATED in pregnancy include cyclophosphamide, mycophenolate mofetil (MMF), methotrexate ^[21] — relevant if managing concurrent SLE.

Category	Definition	Treatment	Rationale
Obstetric APS without prior thrombosis	Pregnancy morbidity meeting Sapporo criteria, no history of thrombosis	Low-dose aspirin (75–100 mg/day) started pre-conception + prophylactic-dose LMWH (e.g., enoxaparin 40 mg SC OD) from positive pregnancy test	Aspirin improves placental blood flow (inhibits TxA2-mediated vasoconstriction); prophylactic LMWH has anti-complement effects (inhibits complement-mediated trophoblast injury) + prevents placental microthrombi
Obstetric APS WITH prior thrombosis	Prior venous or arterial thrombosis + pregnancy	Low-dose aspirin + therapeutic-dose LMWH (e.g., enoxaparin 1 mg/kg BD) throughout pregnancy	Higher dose of LMWH needed because this patient has both thrombotic and obstetric APS → higher risk
aPL-positive without APS criteria (incidental finding)	Positive aPL but no prior thrombosis or pregnancy morbidity	Low-dose aspirin alone during pregnancy	Minimal but not zero risk → aspirin provides some protection

Continue LMWH + aspirin throughout pregnancy until delivery
Cover up to 6 weeks postpartum ^[20] — the postpartum period is the highest-risk period for thrombosis (blood returning from the contracted uterus creates a hypercoagulable state; coagulation factor levels remain elevated for weeks after delivery)
If the patient was previously on warfarin, restart warfarin postpartum (safe in breastfeeding — warfarin does not pass into breast milk in clinically significant amounts)

Switch to LMWH when 1st trimester (↓ teratogenicity) and > 36 weeks (avoid PPH) ^[20]

In practice, the switch should happen before conception or as early as possible (ideally pre-conception in planned pregnancies), because warfarin embryopathy risk is highest at 6–12 weeks' gestation.

Timing	Anticoagulation
Pre-conception	Switch warfarin → LMWH (ideally before conception if planned)
Pregnancy (1st → 3rd trimester)	LMWH throughout
> 36 weeks	Continue LMWH (may switch to UFH near delivery for better reversibility — protamine reversal if emergency delivery)
Labour/delivery	Hold LMWH ~24 hours before planned delivery; UFH if needed
Postpartum	Restart LMWH → bridge to warfarin; continue for ≥6 weeks postpartum

Why Heparin Works in Obstetric APS — Beyond Anticoagulation

Heparin is not just an anticoagulant in obstetric APS. It has anti-complement properties — it inhibits the classical and alternative complement pathways. Since early pregnancy loss in APS is driven heavily by complement-mediated trophoblast injury (not just thrombosis), heparin's anti-complement effect is a key part of its efficacy. This is why heparin + aspirin is superior to aspirin alone in obstetric APS, and why warfarin (which lacks anti-complement effects) is not suitable even ignoring teratogenicity.

Measure	Detail
Hydroxychloroquine (HCQ)	Recommended for all SLE patients, including during pregnancy; evidence suggests HCQ may reduce aPL-related pregnancy complications; safe in pregnancy ^[21]^[23]
Close obstetric monitoring	Regular growth scans (IUGR detection), uterine artery Doppler, blood pressure monitoring (pre-eclampsia screening)
Avoid OCP	OCP are not advisable due to thromboembolic risk ^[21]; use barrier methods or progesterone-only methods for contraception

CAPS is a medical emergency with ~30–50% mortality. It requires aggressive multi-modal therapy — the mnemonic is "Triple therapy":

Component	Treatment	Mechanism
1. Anticoagulation	IV UFH (therapeutic dose, aPTT-guided)	Prevents ongoing thrombosis; UFH preferred over LMWH for its shorter half-life and reversibility (protamine) in a critically ill patient
2. High-dose corticosteroids	IV methylprednisolone 1 g/day × 3 days (pulse), then oral prednisolone taper	Suppresses the inflammatory and complement-mediated component of the thrombotic storm; reduces cytokine release and immune activation
3. Plasma exchange (PLEX) and/or IV immunoglobulin (IVIG)	Plasmapheresis removes aPL antibodies, complement components, and cytokines from circulation; IVIG provides immunomodulation and Fc receptor blockade	PLEX physically removes the pathogenic antibodies; IVIG blocks Fc receptors on macrophages → reduces clearance of antibody-coated cells; also provides anti-idiotypic antibodies that neutralise aPL

Refractory CAPS — Rescue Therapies

Treatment	Indication	Mechanism
Rituximab (anti-CD20)	Refractory CAPS not responding to triple therapy	Depletes B cells → reduces autoantibody production; takes weeks to work, so used as an adjunct
Eculizumab (anti-C5)	Refractory CAPS with prominent complement activation	Monoclonal antibody against complement component C5 → blocks C5 cleavage → prevents C5a generation (pro-inflammatory) and membrane attack complex (C5b-9) formation. "eculizumab" → "ec-" = away, "-lizumab" = humanised monoclonal antibody
Treat the trigger	Infection (~40% of CAPS), post-surgery, post-anticoagulation withdrawal	Antibiotics for infection, wound care, etc. — removing the trigger is essential

These are patients found to have positive aPL antibodies (on ≥2 occasions ≥12 weeks apart) but who have never had a thrombotic event or pregnancy morbidity. They do NOT meet criteria for APS. How should you manage them?

Risk Profile	Management	Rationale
High-risk aPL carrier (triple-positive, high-titre, concurrent SLE, additional cardiovascular risk factors)	Low-dose aspirin (75–100 mg/day) + Hydroxychloroquine (if SLE present) + aggressive CV risk factor modification	Triple-positive carriers have ~5–10% annual thrombosis risk; aspirin provides a modest protective effect; HCQ has antithrombotic properties independent of its immunomodulatory effects
Low-risk aPL carrier (single-positive, low-titre, no SLE, no additional risk factors)	Risk factor modification only — smoking cessation, BP control, lipid management, avoid OCP/HRT, thromboprophylaxis for high-risk situations (surgery, immobilisation, long-haul flights)	Low annual thrombosis risk (< 1%); routine anticoagulation or aspirin not justified by the evidence

APS-related thrombocytopenia is usually mild (50–130 × 10⁹/L) and rarely requires specific treatment. However, if severe (< 50 × 10⁹/L) or causing bleeding, management follows ITP-like principles:

Treatment	Detail	Mechanism
Corticosteroids	Prednisolone 1 mg/kg/day, taper over weeks	Reduces autoantibody-mediated platelet destruction; decreases macrophage Fc receptor expression → less phagocytosis of antibody-coated platelets
IVIG	For rapid platelet elevation (e.g., before surgery)	Fc receptor blockade on splenic macrophages → temporarily blocks platelet destruction
Rituximab	For refractory cases	B-cell depletion → reduces autoantibody production
HCQ	In SLE-associated APS	Immunomodulatory; may improve platelet counts

Anticoagulation with Thrombocytopenia — A Balancing Act

APS patients who need anticoagulation but have thrombocytopenia present a management dilemma. The general approach:

If platelets > 50 × 10⁹/L → anticoagulate at standard dose
If platelets 30–50 × 10⁹/L → anticoagulate with caution, consider reduced dose
If platelets < 30 × 10⁹/L → withhold anticoagulation until platelets are raised (steroids, IVIG); do NOT platelet-transfuse routinely (in a thrombotic microangiopathy, transfused platelets may fuel the thrombosis)

D. Drug Detail Cards

Aspect	Detail
Mechanism	Inhibits vitamin K epoxide reductase (VKORC1) → blocks recycling of vitamin K → impairs γ-carboxylation of vitamin K-dependent clotting factors (II, VII, IX, X) AND natural anticoagulants (Protein C, S)
Onset	Slow (2–7 days for full anticoagulant effect) — because existing clotting factors must be cleared before the effect is seen. Factor VII (shortest half-life, ~6 hours) drops first → PT/INR rises first; Factor II (longest half-life, ~60 hours) drops last → full antithrombotic effect delayed
Monitoring	INR — target 2–3 for APS ^[1]; measured from PT (extrinsic pathway reflects Factor VII, which warfarin affects most)
Antidote	Vitamin K (phytomenadione — 5–10 mg IV for life-threatening bleeding, 1–5 mg oral for non-urgent reversal); prothrombin complex concentrate (PCC) for immediate reversal in major bleeding; FFP as an alternative
Drug interactions	Numerous (CYP2C9 and CYP3A4 metabolism): antibiotics (metronidazole, macrolides → ↑INR), antifungals (fluconazole → ↑INR), NSAIDs (↑bleeding risk), amiodarone (↑INR), rifampicin (↓INR — enzyme inducer)
Contraindications	Pregnancy (teratogenic — warfarin embryopathy in 1st trimester; fetal ICH in 2nd/3rd) ^[20]; active bleeding; severe hepatic impairment; non-compliance (variable INR → dangerous)
APS-specific note	DOACs should NOT replace warfarin in APS ^[1]; LA can interfere with INR measurement in some assays → use chromogenic Factor X assay if INR is unreliable

Aspect	Detail
Mechanism	Binds to and potentiates antithrombin III → AT III then inactivates Factor Xa (predominantly) and thrombin (IIa, to a lesser degree than UFH). "Low-molecular-weight" means shorter heparin chains → preferentially inhibit Xa over IIa
Dosing	Prophylactic: enoxaparin 40 mg SC OD (or 0.5 mg/kg OD). Therapeutic: enoxaparin 1 mg/kg BD (or 1.5 mg/kg OD)
Monitoring	Usually no monitoring needed (predictable pharmacokinetics); if needed (renal impairment, obesity, pregnancy), check anti-Xa levels (target 0.5–1.0 IU/mL for therapeutic dose)
Advantages over UFH	Predictable pharmacokinetics, SC administration (outpatient use), lower risk of HIT, no routine monitoring
Antidote	Protamine sulphate — but only partially reverses LMWH (~60% neutralisation, because protamine cannot neutralise the very short anti-Xa-active fragments)
Contraindications	Active bleeding; severe renal impairment (eGFR < 15 — accumulates); HIT (history of heparin-induced thrombocytopenia)
APS-specific note	Preferred in pregnancy (does not cross placenta); alternative to warfarin for long-term therapy; in patients with AT III deficiency, VTE often resistant to normal doses of heparin → need higher dose LMWH (≥100 U/kg/day) ^[9]

Aspect	Detail
Mechanism	Irreversibly acetylates COX-1 on platelets → blocks synthesis of thromboxane A2 (TxA2) → reduces platelet aggregation and vasoconstriction. Effect lasts for the lifetime of the platelet (~7–10 days) because platelets are anucleate and cannot synthesise new COX-1
Dosing	Low-dose: 75–100 mg daily for thromboprophylaxis ^[1]
Indications in APS	Add aspirin if arterial thrombosis ^[1]; used in obstetric APS (low-dose + LMWH); considered for high-risk asymptomatic aPL carriers
Side effects	GI bleeding (mucosal injury from reduced prostaglandin-mediated gastroprotection), aspirin-exacerbated respiratory disease (AERD), Reye syndrome (children), tinnitus (overdose)
Contraindications	Active GI bleeding; aspirin hypersensitivity; children < 16 years (Reye syndrome); severe bleeding disorder

Aspect	Detail
Mechanism	Multiple: (1) Raises lysosomal pH → impairs antigen processing and MHC-II loading → reduces T-cell activation; (2) Inhibits TLR7/9 signalling → reduces type I interferon production; (3) Antithrombotic effect independent of immunomodulation → inhibits platelet aggregation, reduces aPL binding to phospholipid surfaces, reduces aPL titres
Indications in APS	All SLE patients should be on HCQ unless contraindicated ^[23]; increasingly recommended for primary APS as well; safe in pregnancy ^[21]
Side effects	Bull's eye maculopathy (irreversible retinal toxicity — dose and duration dependent); corneal deposits (reversible); bluish skin discolouration (especially with UV exposure) ^[23]; QT prolongation (rare)
Monitoring	Eye check before treatment and yearly after 5 years of use ^[23]; dose should be < 5 mg/kg/day (updated from < 7 mg/kg in 2025 AAO guidelines) to minimise retinal toxicity
Pregnancy	Safe in pregnancy — should NOT be discontinued during pregnancy ^[21]

Clinical Scenario	Acute Treatment	Long-term Treatment	Duration	Key Points
APS + VTE	UFH or LMWH (therapeutic)	Warfarin INR 2–3 (or LMWH)	Lifelong	No DOACs; bridge heparin → warfarin
APS + arterial thrombosis	UFH or LMWH ± thrombolysis (if stroke/MI)	Warfarin INR 2–3 + Aspirin	Lifelong	Add aspirin for arterial events
Obstetric APS (no prior thrombosis)	—	Low-dose aspirin + prophylactic LMWH	Pregnancy + 6 weeks postpartum	HCQ if SLE; close obstetric monitoring
Obstetric APS (prior thrombosis)	—	Low-dose aspirin + therapeutic LMWH	Pregnancy + 6 weeks postpartum	Switch warfarin → LMWH pre-conception
CAPS	UFH + IV methylprednisolone + PLEX/IVIG	Warfarin INR 2–3 (after acute phase)	Lifelong	Treat trigger; rituximab/eculizumab if refractory
Asymptomatic aPL carrier (high-risk)	—	Low-dose aspirin ± HCQ	Indefinite	Risk factor modification
Asymptomatic aPL carrier (low-risk)	—	Risk factor modification only	—	Thromboprophylaxis for high-risk situations

Measure	Rationale
Smoking cessation	Smoking → endothelial injury → provides "second hit" for thrombosis; smoking is associated with more active disease ^[21]
Blood pressure control	Hypertension → endothelial dysfunction, accelerated atherosclerosis, increased stroke risk
Lipid management (statins)	Statins for all ischaemic stroke due to thrombosis (regardless of LDL level) — role: plaque stabilisation, corrects endothelial dysfunction (not limited to ↓LDL) ^[7]
Avoid OCP and HRT	OC pills are not advisable due to thromboembolic risk ^[21]; oestrogen-containing preparations increase VTE risk 2–4×
Thromboprophylaxis in high-risk situations	Prophylactic LMWH perioperatively, during hospitalisation, long-haul flights (> 6 hours)
Vaccination	Immunization prior to institution of immunosuppressive therapies; do NOT give live attenuated vaccines ^[21] (relevant if secondary APS with SLE on immunosuppression)
HCQ for all SLE patients	Indication: all SLE patients unless contraindicated ^[23]; antithrombotic, immunomodulatory

Parameter	Frequency	Purpose
INR (if on warfarin)	Weekly until stable → monthly	Ensure therapeutic range (2–3)
CBC	Every 3–6 months	Monitor thrombocytopenia; detect AIHA
RFT	Every 3–6 months	Monitor for APS nephropathy
aPL titres	Not routinely repeated for treatment decisions (they don't change management once diagnosis is established)	May be useful for prognostication; some patients seroconvert to negative (very rare — reassess need for anticoagulation)
ANA, anti-dsDNA, C3/C4 (if secondary APS)	Every 3–6 months	Monitor SLE disease activity
Eye examination (if on HCQ)	Before treatment and yearly after 5 years ^[23]	Bull's eye maculopathy screening
Obstetric monitoring (if pregnant)	Regular growth scans, uterine artery Doppler, BP monitoring	Detect IUGR, pre-eclampsia early

High Yield Summary – Management of APS

Backbone of treatment = anticoagulation — warfarin (INR 2–3) is the standard; DOACs are NOT recommended in APS (TRAPS trial).
VTE only → warfarin alone (lifelong). Arterial thrombosis → warfarin + aspirin (lifelong). Add aspirin only for arterial events ^[1].
Obstetric APS → LMWH + low-dose aspirin throughout pregnancy and 6 weeks postpartum. Warfarin is contraindicated in pregnancy (teratogenic). Heparin has anti-complement effects that are specifically beneficial in obstetric APS.
Catastrophic APS → triple therapy: anticoagulation (UFH) + high-dose steroids + PLEX/IVIG. Rituximab and eculizumab for refractory cases.
Asymptomatic aPL carriers: high-risk → low-dose aspirin ± HCQ; low-risk → risk factor modification only.
All patients: smoking cessation, BP control, lipid management, avoid OCP/HRT, HCQ if SLE, thromboprophylaxis in high-risk situations.
Warfarin monitoring: INR 2–3. HCQ monitoring: eye check before and yearly after 5 years.
In pregnancy: switch warfarin to LMWH pre-conception; continue 6 weeks postpartum; safe medications include HCQ, azathioprine, prednisolone. Contraindicated: cyclophosphamide, MMF, methotrexate ^[21].

Active Recall - Management of APS

References

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia (APS management — warfarin, aspirin, DOACs, INR 2–3) ^[2] Senior notes: Maksim Medicine Notes (Rheumatology — APS diagnostic criteria and antibody hierarchy, p. 317) ^[7] Senior notes: Ryan Ho Neurology (Stroke secondary prevention — anticoagulants for APS, statins, p. 83) ^[9] Senior notes: Adrian Lui Pediatrics Notes (Thrombophilia workup, AT III deficiency requiring higher LMWH dose, p. 397–398) ^[20] Senior notes: Ryan Ho Haemtology (DVT/PE management — pregnancy anticoagulation, APS regimen, p. 132) ^[21] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai) (SLE pregnancy management — contraindicated drugs, OCP avoidance, p. 724); also MBBS Final MB (Medicine) (Felix PY Lai) (p. 1730) ^[22] Lecture slides: Handbook of Internal Medicine 2024 (VTE anticoagulation — LMWH bridge to warfarin, DOAC dosing, p. 42) ^[23] Senior notes: Ryan Ho Rheumatology (SLE management — HCQ dosing, eye screening, severity-based regimen, p. 76–77)

Complications of Antiphospholipid Syndrome

APS is a chronic systemic disorder whose complications arise from two fundamental processes: (1) ongoing thrombosis affecting virtually any vascular bed, and (2) adverse effects of lifelong anticoagulation therapy itself. Additionally, there are disease-specific complications related to pregnancy, haematological derangements, and the rare but devastating catastrophic APS. I'll organise these systematically by organ system, always explaining the "why" from the underlying pathophysiology.

A. Complications from Recurrent Thrombosis — Organ-by-Organ

Despite anticoagulation, APS patients remain at risk for recurrent thrombotic events. The recurrence rate is approximately 5–12% per year even on warfarin (INR 2–3), and much higher if anticoagulation is subtherapeutic or discontinued. Each episode of thrombosis causes cumulative organ damage.

Complication	Pathophysiology	Clinical Impact
Recurrent ischaemic stroke	Recurrent arterial thrombosis ^[1] → cumulative cerebral infarction	The most feared arterial complication. Each stroke causes further neurological deficit. Young patients with APS may develop multi-infarct dementia from repeated small cortical infarcts.
Multi-infarct cognitive decline / Vascular dementia	Cumulative microinfarctions in cerebral white matter and cortex over years	Progressive cognitive dysfunction, personality change, executive dysfunction — often insidious and underdiagnosed. MRI shows multiple T2/FLAIR hyperintensities.
Epilepsy	Cortical infarction → gliotic scarring → epileptogenic focus	Secondary epilepsy develops in ~10% of APS patients with CNS involvement. Seizures may be focal or generalised depending on infarct location.
Cerebral venous sinus thrombosis (CVST)	Venous thrombosis of dural sinuses → impaired CSF/venous drainage → raised ICP	Headache, papilloedema, seizures, focal deficits. Can progress to venous infarction with haemorrhagic transformation.
Transverse myelitis	Thrombosis of spinal cord vasculature → spinal cord ischaemia	Acute bilateral leg weakness, sensory level, sphincter dysfunction. Important differential with NMO and MS.
Chorea	Basal ganglia microinfarction or autoantibody-mediated neuronal dysfunction	Involuntary, irregular movements. Can be the presenting feature of APS ("antiphospholipid chorea").

Anticoagulants are indicated for cardioembolic ischaemic stroke and antiphospholipid syndrome ^[7] — this is the cornerstone of secondary stroke prevention in APS.

Complication	Pathophysiology	Clinical Impact
Premature myocardial infarction	Coronary artery thrombosis (often in young patients without traditional RF) ± accelerated atherosclerosis from chronic endothelial activation	Young MI should always prompt consideration of APS. Recurrent MIs cause progressive myocardial damage → ischaemic cardiomyopathy → heart failure.
Libman-Sacks endocarditis → Valvular regurgitation	Valvular heart lesions ^[1]^[12] — sterile fibrin-platelet vegetations on valve leaflets (mitral > aortic) → progressive valve thickening, fibrosis, calcification	Begins as small vegetations → over years, causes progressive mitral regurgitation (most common) or aortic regurgitation. May require valve replacement in severe cases. The vegetations can also fragment → cardioembolism (stroke, peripheral arterial occlusion).
Accelerated atherosclerosis	Chronic endothelial activation by aPL → ↑adhesion molecule expression, ↓NO production, oxidative stress → premature atherosclerotic plaque formation	APS patients develop coronary and cerebrovascular atherosclerosis decades earlier than age-matched controls. This is compounded in secondary APS by chronic inflammation from SLE and steroid use.
Intracardiac thrombus	Endocardial surface thrombosis (especially in dilated or dysfunctional chambers)	Can occur even without AF; acts as source of systemic embolism.

Complication	Pathophysiology	Clinical Impact
Recurrent pulmonary embolism	Recurrent venous thrombosis → DVT → PE ^[1]	Each PE episode damages the pulmonary vascular bed. Recurrent PE despite anticoagulation is a hallmark of APS.
Chronic thromboembolic pulmonary hypertension (CTEPH)	Organised, non-resolving thromboemboli in pulmonary arteries → fixed obstruction → ↑pulmonary vascular resistance → RV pressure overload	Pulmonary embolism: especially in antiphospholipid syndrome ^[24]. CTEPH develops in ~2–5% of APS patients with recurrent PE. Presents with progressive exertional dyspnoea, loud P2, parasternal heave, raised JVP, peripheral oedema (signs of right heart failure). Diagnosed by V/Q scan (mismatched perfusion defects), right heart catheterisation, CTPA. May be amenable to pulmonary endarterectomy (potentially curative surgical option).
Diffuse alveolar haemorrhage (DAH)	Pulmonary capillaritis → complement-mediated microvascular injury → haemorrhage into alveolar spaces	Rare but life-threatening; presents with haemoptysis, acute dyspnoea, rapidly falling Hb, bilateral infiltrates on CXR. More common in catastrophic APS.

CTEPH — A Potentially Curable Complication

CTEPH is one of the few causes of pulmonary hypertension that can be surgically cured with pulmonary endarterectomy (PEA). APS patients with progressive dyspnoea and a history of PE should be screened with echocardiography (estimated PA pressures) and V/Q scan. If CTEPH is confirmed, refer to a specialist PEA centre. Balloon pulmonary angioplasty (BPA) is an alternative for inoperable cases.

Complication	Pathophysiology	Clinical Impact
APS nephropathy	Thrombotic microangiopathy (TMA) of renal microvasculature → fibrin thrombi in glomerular capillaries, arteriolar thrombosis, fibrous intimal hyperplasia	Presents with hypertension, proteinuria, haematuria, progressive renal impairment. Distinguished from lupus nephritis by renal biopsy showing TMA (not immune complex GN). If untreated → chronic kidney disease → ESRD.
Renal artery thrombosis / stenosis	Large vessel thrombosis or intimal fibroplasia of renal arteries	Acute: renal infarction (flank pain, haematuria, LDH elevation, AKI). Chronic: renovascular hypertension from RAAS activation due to reduced renal perfusion ("Goldblatt kidney").
Renal vein thrombosis	Hypercoagulable state + potential co-existing nephrotic syndrome (nephrotic syndrome itself causes renal vein thrombosis from AT III loss)	Acute flank pain, proteinuria worsening, haematuria, renal impairment.

Complication	Pathophysiology	Clinical Impact
Budd-Chiari syndrome	Hepatic vein thrombosis → impaired hepatic venous outflow → hepatic congestion → ↑sinusoidal pressure	Acute: abdominal pain, ascites, hepatomegaly, jaundice, liver failure. Chronic: portal hypertension, variceal bleeding, cirrhosis. APS is one of the leading causes of Budd-Chiari in young patients.
Mesenteric ischaemia	Mesenteric artery or vein thrombosis → bowel ischaemia	Acute: severe abdominal pain out of proportion to examination, bloody diarrhoea, metabolic acidosis → bowel gangrene if not treated emergently. Chronic: postprandial pain, weight loss ("intestinal angina").
Hepatic infarction	Hepatic artery thrombosis → ischaemic necrosis of liver parenchyma	Rare; presents with RUQ pain, ↑↑LFT, possible liver failure in extensive infarction.

Complication	Pathophysiology	Clinical Impact
Post-thrombotic syndrome (PTS)	After DVT → venous valve damage → chronic venous insufficiency → venous hypertension in the affected limb	Chronic leg swelling, pain, skin changes (stasis dermatitis, lipodermatosclerosis), venous ulcers. Develops in 20–50% of patients after DVT. Severity correlates with extent and recurrence of DVT.
Acute limb ischaemia	Arterial thrombosis of limb vessels → acute ischaemia (the 6 Ps: pain, pallor, pulselessness, paraesthesia, paralysis, perishingly cold) ^[25]	Surgical emergency. May require embolectomy, bypass, or thrombolysis. In APS, causes include hypercoagulability as a cause of acute thrombosis-in-situ ^[25].
Digital gangrene	Thrombosis of digital arteries → complete ischaemia → tissue necrosis	Painful, blackened fingertips or toes; may require amputation.

Complication	Pathophysiology	Clinical Impact
Adrenal haemorrhagic infarction → Adrenal insufficiency	Adrenal glands have a rich arterial supply but drain via a single central vein → makes them uniquely vulnerable to venous infarction. Bilateral adrenal vein thrombosis → haemorrhagic necrosis of adrenal glands	Acute Addisonian crisis: hypotension, shock, hyponatraemia, hyperkalaemia, hypoglycaemia. Can be the presenting feature of catastrophic APS. Requires emergency hydrocortisone.

Complication	Pathophysiology	Clinical Impact
Central / Branch retinal artery occlusion (CRAO / BRAO)	Thrombosis or embolism of retinal artery → retinal ischaemia	CRAO: painless, sudden, profound monoocular visual loss; cherry-red spot on fundoscopy; hypercoagulable workup (APS, ESR/CRP, ANA) if < 50 years ^[26]. BRAO: segmental visual field loss.
Retinal vein occlusion (CRVO / BRVO)	Thrombosis of retinal veins → impaired venous drainage → retinal haemorrhage, oedema	Hypercoagulable state is a risk factor for retinal vein occlusion ^[26]. Presents with sudden painless blurred vision; fundoscopy shows dilated, tortuous veins with flame-shaped haemorrhages ("blood and thunder" appearance in CRVO).
Ischaemic optic neuropathy	Thrombosis of posterior ciliary arteries → optic nerve head ischaemia	Acute painless monoocular visual loss with disc oedema (anterior IOPN) or normal disc initially (posterior IOPN).

Complication	Pathophysiology	Outcome
Recurrent early miscarriage (< 10 weeks)	Complement-mediated trophoblast injury, impaired trophoblast invasion, Annexin A5 displacement	Even with treatment (LMWH + aspirin), ~20–30% of pregnancies in APS may still result in loss
Late fetal death (≥ 10 weeks)	Placental thrombosis and infarction → fetal hypoxia	Devastating outcome; requires intensive obstetric monitoring
Pre-eclampsia / Eclampsia	Defective placentation → abnormal spiral artery remodelling → placental ischaemia → anti-angiogenic factors → maternal endothelial dysfunction	Maternal complications: preeclampsia, preterm delivery, fetal loss (recurrent miscarriage, stillbirth) ^[21]. APS-associated pre-eclampsia tends to be early-onset ( < 34 weeks) and severe.
IUGR (intrauterine growth restriction)	Chronic placental insufficiency from ongoing microthrombi and poor uteroplacental blood flow	Small-for-gestational-age baby; may require premature delivery
HELLP syndrome	Microangiopathic process in hepatic vasculature — overlap with catastrophic APS; haemolysis + elevated liver enzymes + low platelets	Medical emergency; may coexist with catastrophic APS, making diagnosis challenging
Neonatal lupus (if secondary APS with SLE)	Anti-Ro / anti-La antibodies cross the placenta → fetal cardiac conduction system damage	Congenital complete heart block (irreversible, may require fetal/neonatal pacemaker), erythematous rash, hepatic abnormalities, cytopenias ^[21]
Premature delivery	Consequence of severe pre-eclampsia, IUGR, or placental insufficiency requiring early delivery	Neonatal ICU admission, prematurity-related morbidity

Complication	Pathophysiology	Clinical Impact
Thrombocytopenia ^[1]	aPL bind platelet surface β2GPI → immune-mediated platelet destruction (similar to ITP); also consumption in microthrombi	Usually mild (50–130 × 10⁹/L) and rarely causes clinically significant bleeding. However, creates a management dilemma — the patient is prothrombotic but has low platelets. Very rarely severe enough ( < 20 × 10⁹/L) to cause spontaneous bleeding.
Autoimmune haemolytic anaemia (AIHA)	Co-existing warm autoantibodies against RBCs (especially in secondary APS with SLE)	Anaemia, jaundice (unconjugated), reticulocytosis, positive DAT (Coombs). When AIHA + ITP coexist → Evans syndrome.
Microangiopathic haemolytic anaemia (MAHA)	In catastrophic APS → fibrin thrombi in microvasculature → mechanical shearing of RBCs as they pass through → schistocytes on blood film ^[16]	Signifies severe disease (CAPS or APS-associated TMA). Schistocytes + thrombocytopenia + multi-organ dysfunction = red flag for CAPS.

These complications are iatrogenic — direct consequences of the lifelong anticoagulation that APS patients require.

Complication	Mechanism	Prevention / Management
Major haemorrhage (GI bleeding, intracranial haemorrhage, retroperitoneal bleeding)	Warfarin over-anticoagulation (INR > 3) → impaired clot formation → excessive bleeding at sites of vascular fragility	Regular INR monitoring (target 2–3) ^[1]; avoid interacting drugs (metronidazole, macrolides, NSAIDs, amiodarone → all ↑INR); PPI for GI protection if concurrent aspirin; reversal: vitamin K, PCC, FFP
Warfarin-induced skin necrosis	In the first few days of warfarin therapy, Protein C (short half-life) drops before procoagulant factors → transient hypercoagulable state → microvascular thrombosis in skin and subcutaneous tissue → necrosis, typically of fatty areas (breasts, buttocks, thighs)	More common if co-existing Protein C deficiency. Prevented by always bridging with heparin when starting warfarin; never start warfarin without concurrent heparin cover.
Heparin-induced thrombocytopenia (HIT)	Anti-PF4/heparin antibodies → platelet activation → paradoxical thrombosis + thrombocytopenia	Monitor platelet count during heparin therapy; if HIT suspected → stop all heparin, switch to non-heparin anticoagulant (argatroban, fondaparinux), then bridge to warfarin only after platelet recovery
Heparin-induced osteoporosis	Long-term heparin (especially UFH > LMWH) → inhibits osteoblast function, activates osteoclasts → reduced bone mineral density	Relevant in obstetric APS patients on LMWH for entire pregnancy; ensure adequate calcium + vitamin D supplementation; prefer LMWH over UFH (lower osteoporosis risk)
Teratogenicity of warfarin (if inadvertently used in pregnancy)	Warfarin crosses the placenta ^[20] → inhibits vitamin K-dependent carboxylation of fetal bone and cartilage proteins → warfarin embryopathy (nasal hypoplasia, stippled epiphyses, limb abnormalities) in 1st trimester; CNS abnormalities and fetal ICH in 2nd/3rd trimester	Prevention: switch to LMWH pre-conception or as soon as pregnancy confirmed; educate all APS women of childbearing age
HCQ retinal toxicity	Bull's eye maculopathy — cumulative HCQ deposition in retinal pigment epithelium → photoreceptor damage → irreversible central visual field loss	Eye check before treatment and yearly after 5 years of HCQ use ^[23]; use < 5 mg/kg/day dosing

CAPS can be viewed as the most severe complication of APS itself — a "thrombotic storm" that occurs in approximately 1% of APS patients.

Aspect	Detail
Definition	Multi-organ thrombotic microangiopathy (≥3 organs affected within ≤1 week)
Triggers	Infection (~40%), surgery, anticoagulation withdrawal, SLE flare, pregnancy complications
Organs most commonly affected	Kidneys (renal TMA → AKI), lungs (ARDS, PE, DAH), brain (stroke, encephalopathy), heart (MI, Libman-Sacks), skin (livedo, digital gangrene), adrenals (acute insufficiency)
Mortality	~30–50% despite aggressive triple therapy (anticoagulation + steroids + PLEX/IVIG)
Key lab findings	aPL positive + schistocytes (MAHA) + thrombocytopenia + multi-organ failure + ± DIC overlap

In secondary APS, complications are compounded by the underlying SLE:

Complication	Mechanism
Lupus nephritis + APS nephropathy coexisting	Dual pathology on renal biopsy: immune complex GN (SLE) + TMA (APS). Requires both immunosuppression AND anticoagulation.
Increased infection risk	Immunosuppressive therapy for SLE (steroids, cyclophosphamide, MMF, rituximab) + inherent immune dysregulation → opportunistic infections. Common causes of death in early SLE: infection ^[27].
Premature cardiovascular disease	Chronic inflammation (SLE) + prothrombotic state (APS) + steroid-induced metabolic syndrome (diabetes, hypertension, dyslipidaemia) + renal impairment → dramatically accelerated atherosclerosis. Common causes of death in late SLE: cardiovascular deaths ^[27].
Avascular necrosis of bone (AVN)	Microvascular thrombosis of subchondral bone vasculature (APS) + steroid-induced osteonecrosis (SLE treatment) → femoral head AVN (hip pain, limp, MRI changes)
Osteoporosis	Multiple contributors: steroids (SLE treatment), heparin (APS treatment during pregnancy), cyclophosphamide-induced premature menopause, chronic inflammation, lack of sun exposure (SLE photosensitivity) ^[21]

Understanding what makes certain APS patients do worse helps guide intensity of management:

Poor prognostic factors include: presence of antiphospholipid antibodies, antiphospholipid antibody syndrome, renal disease, hypertension, high overall disease activity ^[27]

Factor	Why It Worsens Prognosis
Triple aPL positivity (LA + aCL + anti-β2GPI)	Highest thrombotic risk; highest recurrence rate despite adequate anticoagulation
Arterial thrombosis (especially stroke)	Each arterial event causes irreversible organ damage; recurrence prevention is more difficult than venous events
Renal involvement (APS nephropathy)	Progressive CKD → ESRD; renal impairment worsens cardiovascular prognosis
Co-existing SLE	Compounds immune dysregulation; adds immunosuppression-related complications (infections, malignancy)
History of CAPS	High recurrence risk; each episode carries ~30–50% mortality
Non-compliance with anticoagulation	APS recurrence is almost inevitable if anticoagulation is discontinued or subtherapeutic
Presence of additional cardiovascular RF	Smoking, hypertension, diabetes, dyslipidaemia — each provides a "second hit" for thrombosis

Aspect	Detail
Survival	With modern anticoagulation, 10-year survival is approximately 90–95% for primary APS. Lower (~75–85%) for secondary APS with SLE, reflecting the additional morbidity of the underlying disease.
Major causes of morbidity	Recurrent thrombosis (especially stroke → disability), CKD, heart failure, post-thrombotic syndrome, anticoagulation-related bleeding
Major causes of mortality	Catastrophic APS (~30–50% per episode), recurrent stroke, MI, infection (in secondary APS on immunosuppression), cardiovascular disease (late)
Quality of life impact	Lifelong anticoagulation with dietary restrictions (vitamin K-rich foods), INR monitoring, bleeding risk; pregnancy planning complexity; psychological burden of chronic disease

High Yield Summary – Complications of APS

Neurological: Recurrent stroke → multi-infarct dementia, epilepsy, CVST, transverse myelitis, chorea.
Cardiovascular: Premature MI, Libman-Sacks → progressive valvular disease → cardioembolism, accelerated atherosclerosis.
Pulmonary: Recurrent PE → CTEPH (potentially curable with pulmonary endarterectomy); diffuse alveolar haemorrhage in CAPS.
Renal: APS nephropathy (TMA → CKD → ESRD); renal artery/vein thrombosis; renovascular hypertension.
Hepatic/GI: Budd-Chiari syndrome, mesenteric ischaemia.
Obstetric: Recurrent miscarriage, late fetal death, pre-eclampsia (early-onset, severe), IUGR, HELLP. Neonatal lupus (congenital heart block) if secondary APS with anti-Ro/La.
Haematological: Thrombocytopenia (mild), AIHA/Evans syndrome, MAHA (in CAPS).
Treatment complications: Major haemorrhage (warfarin), warfarin-induced skin necrosis, HIT, heparin-induced osteoporosis, warfarin teratogenicity, HCQ retinal toxicity.
Catastrophic APS: 1% of APS patients; ≥3 organ TMA within ≤1 week; 30–50% mortality; triggered by infection, surgery, anticoagulation withdrawal.
Prognosis: 10-year survival ~90–95% (primary APS); major causes of death = CAPS, stroke, MI, infection, CVD.

Active Recall - Complications of APS

References

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia (APS clinical features and management) ^[7] Senior notes: Ryan Ho Neurology (Stroke secondary prevention — anticoagulants for APS, p. 83) ^[12] Senior notes: Ryan Ho Rheumatology (APS characterisation — valvular heart lesions, livedo reticularis, CVA, p. 73) ^[16] Senior notes: Ryan Ho Haemtology (TMA terminology, MAHA, schistocytes, p. 137) ^[20] Senior notes: Ryan Ho Haemtology (DVT/PE management — pregnancy anticoagulation, warfarin teratogenicity, p. 132) ^[21] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai) (SLE pregnancy complications — pre-eclampsia, neonatal lupus, contraindicated drugs, osteoporosis, p. 724); also MBBS Final MB (Medicine) (Felix PY Lai) (p. 1730) ^[23] Senior notes: Ryan Ho Rheumatology (HCQ eye screening, SLE management, p. 76) ^[24] Senior notes: Ryan Ho Respiratory (PE risk factors — antiphospholipid syndrome, p. 133) ^[25] Senior notes: Maksim Surgery Notes (Acute limb ischaemia — hypercoagulability as cause, p. 168) ^[26] Senior notes: Ryan Ho Opthalmology (CRAO — hypercoagulable workup in young patients, retinal vein occlusion risk factors, p. 66) ^[27] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai) (SLE prognosis — poor prognostic factors, causes of death, p. 727); also MBBS Final MB (Medicine) (Felix PY Lai) (p. 1735)

High Yield Summary

APS = autoimmune condition with antibodies against phospholipid-binding proteins → prothrombotic state (arterial + venous) + pregnancy morbidity.
Primary (isolated) vs Secondary (most commonly with SLE — ~30% of SLE patients have aPL antibodies).
Three antibodies — tested by different methods:
- Lupus anticoagulant (clotting-based assay) — most thrombogenic
- Anti-cardiolipin (ELISA) — moderate thrombogenicity
- Anti-β2GPI (ELISA) — most specific but limited sensitivity
Diagnosis requires: Clinical criterion (thrombosis or pregnancy morbidity) + Positive aPL on two occasions ≥12 weeks apart.
Paradox: Lupus anticoagulant prolongs aPTT in vitro but causes thrombosis in vivo. Mixing study does NOT correct the aPTT (immediate inhibitor), unlike factor deficiencies which correct.
Key clinical features: DVT/PE (most common), stroke (most common arterial), recurrent miscarriage, livedo reticularis, thrombocytopenia, Libman-Sacks endocarditis.
Triple positivity (LA + aCL + anti-β2GPI) = highest risk of thrombosis.
Catastrophic APS = ≥3 organ thrombotic microangiopathy within ≤1 week → medical emergency with ~30–50% mortality.
Pathophysiology: Endothelial activation + platelet activation + complement activation + impaired natural anticoagulants + Annexin A5 displacement → multi-mechanism prothrombotic state.
Two-hit hypothesis: aPL creates the prothrombotic milieu (first hit), but a second provoking factor (surgery, pregnancy, immobilisation, infection) often triggers the actual thrombotic event.

High Yield Summary – Differential Diagnosis of APS

Recurrent VTE in a young patient: DDx includes inherited thrombophilia (Protein C/S/AT III deficiency — NOT Factor V Leiden in Chinese), malignancy, nephrotic syndrome, PNH, MPN, and APS.
Young stroke/MI: DDx includes premature atherosclerosis, cardioembolism (AF, valvular), dissection, vasculitis, PFO, and APS.
Recurrent pregnancy loss: DDx includes chromosomal abnormalities (most common), uterine anomalies, cervical incompetence, endocrine disorders, infections, and APS. Late fetal death and severe early-onset pre-eclampsia are particularly suggestive of APS.
Thrombocytopenia with thrombosis (paradox): DDx includes APS, TTP, HIT, DIC, and catastrophic APS. Key tests: ADAMTS13 (TTP < 10%), aPL (APS), anti-PF4 (HIT), clotting profile + fibrinogen (DIC).
Livedo reticularis: DDx includes physiological, PAN, cholesterol emboli, cryoglobulinaemia, Sneddon syndrome, and APS.
Mixing study: Lupus anticoagulant → immediate non-correction of aPTT (vs VWD which corrects; vs other inhibitors which show delayed non-correction).
Transient aPL positivity (infections, drugs) is clinically irrelevant → this is why TWO tests ≥12 weeks apart are required.
CAPS mimics: TTP, HUS, DIC, HELLP, malignant HTN, scleroderma renal crisis — differentiate with ADAMTS13, aPL, clotting profile, and clinical context.

High Yield Summary – Diagnosis of APS

Sapporo criteria (GC exam framework): ≥1 clinical criterion (vascular thrombosis OR pregnancy morbidity) + ≥1 laboratory criterion (any aPL positive on ≥2 occasions ≥12 weeks apart).
Three antibodies, three tests: LA (DRVVT, clotting-based — most thrombogenic), aCL (ELISA — most sensitive), anti-β2GPI (ELISA — most specific, check if others negative).
aPTT prolonged by LA in vitro → mixing study does NOT correct (immediate) → but adding excess phospholipid DOES correct → confirms phospholipid-dependent inhibitor = LA.
12-week interval between positive tests is mandatory to exclude transient aPL (infection, drugs).
Timing of thrombophilia screen: ≥2 weeks after stopping anticoagulation; acute thrombosis consumes anticoagulant proteins → falsely low Protein C/S.
False positive RPR/VDRL in APS — cross-reactivity with cardiolipin antigen.
Secondary APS: always screen with ANA, anti-dsDNA, C3/C4 to identify underlying SLE.
CAPS workup: aPL panel + ADAMTS13 (exclude TTP) + clotting profile/fibrinogen (assess DIC overlap) + blood film (schistocytes) + multi-organ assessment + tissue biopsy.
Triple positivity (LA + aCL + anti-β2GPI) = highest risk → most aggressive management.
Factor V Leiden is NOT relevant in Chinese patients — do not include in thrombophilia screen for Hong Kong patients.

High Yield Summary – Management of APS

Backbone of treatment = anticoagulation — warfarin (INR 2–3) is the standard; DOACs are NOT recommended in APS (TRAPS trial).
VTE only → warfarin alone (lifelong). Arterial thrombosis → warfarin + aspirin (lifelong). Add aspirin only for arterial events ^[1].
Obstetric APS → LMWH + low-dose aspirin throughout pregnancy and 6 weeks postpartum. Warfarin is contraindicated in pregnancy (teratogenic). Heparin has anti-complement effects that are specifically beneficial in obstetric APS.
Catastrophic APS → triple therapy: anticoagulation (UFH) + high-dose steroids + PLEX/IVIG. Rituximab and eculizumab for refractory cases.
Asymptomatic aPL carriers: high-risk → low-dose aspirin ± HCQ; low-risk → risk factor modification only.
All patients: smoking cessation, BP control, lipid management, avoid OCP/HRT, HCQ if SLE, thromboprophylaxis in high-risk situations.
Warfarin monitoring: INR 2–3. HCQ monitoring: eye check before and yearly after 5 years.
In pregnancy: switch warfarin to LMWH pre-conception; continue 6 weeks postpartum; safe medications include HCQ, azathioprine, prednisolone. Contraindicated: cyclophosphamide, MMF, methotrexate ^[21].

High Yield Summary – Complications of APS

Neurological: Recurrent stroke → multi-infarct dementia, epilepsy, CVST, transverse myelitis, chorea.
Cardiovascular: Premature MI, Libman-Sacks → progressive valvular disease → cardioembolism, accelerated atherosclerosis.
Pulmonary: Recurrent PE → CTEPH (potentially curable with pulmonary endarterectomy); diffuse alveolar haemorrhage in CAPS.
Renal: APS nephropathy (TMA → CKD → ESRD); renal artery/vein thrombosis; renovascular hypertension.
Hepatic/GI: Budd-Chiari syndrome, mesenteric ischaemia.
Obstetric: Recurrent miscarriage, late fetal death, pre-eclampsia (early-onset, severe), IUGR, HELLP. Neonatal lupus (congenital heart block) if secondary APS with anti-Ro/La.
Haematological: Thrombocytopenia (mild), AIHA/Evans syndrome, MAHA (in CAPS).
Treatment complications: Major haemorrhage (warfarin), warfarin-induced skin necrosis, HIT, heparin-induced osteoporosis, warfarin teratogenicity, HCQ retinal toxicity.
Catastrophic APS: 1% of APS patients; ≥3 organ TMA within ≤1 week; 30–50% mortality; triggered by infection, surgery, anticoagulation withdrawal.
Prognosis: 10-year survival ~90–95% (primary APS); major causes of death = CAPS, stroke, MI, infection, CVD.

Antiphospholipid Syndrome

1. Definition

2. Epidemiology

Prevalence and Incidence

Demographics

Hong Kong Context

3. Risk Factors

Risk Factors for Developing APS

Risk Factors for Thrombotic Events in aPL-Positive Patients (the "Second Hit")

4. Anatomy and Function: The Coagulation System in Context

4.1 Phospholipids in Coagulation

4.2 β2-Glycoprotein I (β2GPI)

4.3 Prothrombin

4.4 Natural Anticoagulant Pathways Affected

5. Etiology and Pathophysiology

5.1 Etiology

5.1.1 Primary APS

5.1.2 Secondary APS

5.1.3 Transient/Non-Pathogenic aPL

5.1.4 Catastrophic APS (CAPS)

5.2 Pathophysiology — A Multi-Hit Model

Mechanism 1: Endothelial Cell Activation

Mechanism 2: Platelet Activation

Mechanism 3: Monocyte/Macrophage Activation

Mechanism 4: Complement Activation

Mechanism 5: Interference with Natural Anticoagulant Pathways

Mechanism 6: Displacement of Annexin A5

5.3 Pathophysiology of Pregnancy Morbidity

6. Classification

6.1 Clinical Classification

6.2 Antibody Classification

6.3 Updated Classification: ACR/EULAR 2023 APS Classification Criteria

Clinical Domains (must score ≥3 in at least one domain):

Laboratory Domains (must score ≥3):

7. Clinical Features

7.1 Symptoms

7.1.1 Vascular Thrombosis

7.1.2 Obstetric Manifestations

7.1.3 Neurological Symptoms (Beyond Stroke)

7.1.4 Other Symptoms

7.2 Signs

7.2.1 Cutaneous Signs

7.2.2 Cardiac Signs

7.2.3 Renal Signs

7.2.4 Haematological Signs

7.2.5 Neurological Signs

7.2.6 Pulmonary Signs

7.2.7 Adrenal Signs

7.3 Catastrophic APS (CAPS) — Special Mention

7.4 Summary of Clinical Manifestations by System

Active Recall - Antiphospholipid Syndrome (Definition, Epidemiology, Pathophysiology & Clinical Features)

References

A. Differential Diagnosis by Clinical Presentation

A1. Recurrent Venous Thromboembolism (DVT / PE)

A2. Arterial Thrombosis (Young Stroke / MI)

A3. Recurrent Pregnancy Loss

A4. Thrombocytopenia

A5. Livedo Reticularis / Skin Manifestations

A6. Cardiac Valve Vegetations / Murmur in a Young Patient

B. Conditions That Mimic APS as a Whole (Systemic Mimics)

C. Diagnostic Differentiation Algorithm

D. Key Differentiating Investigations at a Glance

E. Transient / Non-Pathogenic aPL — An Important Diagnostic Pitfall

F. Special DDx Considerations for CAPS (Catastrophic APS)

Active Recall - Differential Diagnosis of APS

A. Diagnostic Criteria

A1. Revised Sapporo (Sydney) Criteria — The Standard for HKUMed Exams

Clinical Criteria (at least ONE required)

Laboratory Criteria (at least ONE required, on ≥2 occasions at least 12 weeks apart)

Summary — Revised Sapporo Criteria

A2. ACR/EULAR 2023 Classification Criteria — Updated Framework

Entry Criterion

Scoring

B. Diagnostic Algorithm

C. Investigation Modalities — Comprehensive Guide

C1. Antiphospholipid Antibody Panel — The Core Diagnostic Tests

i. Lupus Anticoagulant (LA) — Clotting-Based Assay

ii. Anti-Cardiolipin Antibodies (aCL) — ELISA

iii. Anti-β2-Glycoprotein I Antibodies (Anti-β2GPI) — ELISA

Summary Table — The aPL Panel