Factor V Leiden

Factor V Leiden is a genetic mutation (Arg506Gln) in coagulation factor V that renders it resistant to inactivation by activated protein C, resulting in a hereditary hypercoagulable state with increased risk of venous thromboembolism.

Exam domain	One-glance essentials
Definition / diagnosis	Factor V G1691A (Arg506Gln) mutation → activated factor V becomes resistant to activated protein C (APC) → inherited venous thrombophilia ^[1]^[2] Usually autosomal dominant with incomplete penetrance; homozygotes carry substantially higher risk than heterozygotes ^[2]
Epidemiology / risks	Common in people of European ancestry but *not found in Chinese in the local teaching framework* ^[1]^[2] Oestrogen-containing contraception, pregnancy, surgery, immobility and another thrombophilia provide major additional thrombotic hits ^[2]
Core mechanism	Factor Va Leiden resists APC cleavage → persistent prothrombinase activity → continued thrombin generation and fibrin formation ^[1]^[2]
Clinical picture	Predominantly venous disease: young/recurrent DVT or PE; consider CVST or splanchnic thrombosis at unusual sites ^[2] Often asymptomatic until an acquired trigger such as OCP exposure, pregnancy or surgery ^[2]
Investigations	APC-resistance assay is the functional screen; confirm with Factor V Leiden PCR/genotyping ^[2]^[3] PT and aPTT are normal; investigate the acute event with DVT duplex ultrasound or CTPA as clinically indicated ^[2]^[3]
Management	Acute VTE treatment is the same as other VTE: therapeutic anticoagulation, usually with a DOAC when appropriate ^[3] Mutation status alone does not mandate lifelong therapy; duration follows whether VTE is provoked, unprovoked/recurrent, life-threatening or accompanied by other risk factors ^[3]
Complications	PE with acute RV failure, recurrent VTE, post-thrombotic syndrome and CTEPH ^[3] Unusual-site venous thrombosis may cause CVST, Budd–Chiari syndrome or mesenteric ischaemia ^[3]
Prevention / follow-up	Asymptomatic carriers: no routine long-term anticoagulation; avoid oestrogen, stop smoking and use prophylaxis in high-risk surgery/immobility ^[2]^[3] Pregnancy requiring anticoagulation → LMWH, with postpartum risk assessment; avoid warfarin and DOACs during pregnancy ^[3]
Exam traps	*Factor V Leiden is not a relevant routine thrombophilia test in an ethnic-Chinese Hong Kong patient* ^[1]^[2] It causes venous, not characteristically arterial, thrombosis ^[2] Warfarin-induced skin necrosis suggests protein C/S deficiency, not Factor V Leiden ^[2]

References

^[1] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (Factor V Leiden mechanism and local ethnic framing, pp. 14–16) ^[2] Senior notes: Ryan Ho Haemtology.pdf (Section 4.5.1 — Thrombophilia Screening, pp. 135–136); Adrian Lui Pediatrics Notes.pdf (Inherited thrombophilia table, pp. 397–398) ^[3] Senior notes: Maksim Medicine Notes.pdf (Thrombophilia screening and VTE management, pp. 165, 288–289); Handbook of Internal Medicine 2024.pdf (VTE anticoagulation, p. 42)

Factor V Leiden (FVL) is the single most common inherited thrombophilia in people of European descent. The name tells you what it is:

Factor V = coagulation Factor V (a key pro-coagulant cofactor in the common pathway)
Leiden = the Dutch city (Leiden University) where the mutation was first identified in 1994

It is a point mutation in the F5 gene (chromosome 1q24.2): a single nucleotide substitution G1691A (guanine → adenine) leading to an amino acid change at position 506 (Arg506Gln, i.e. arginine replaced by glutamine). This specific arginine residue is the cleavage site where activated protein C (APC) normally cuts and inactivates Factor Va. Because the mutant Factor Va cannot be cleaved efficiently, it resists inactivation → the coagulation cascade keeps running → hypercoagulable state → increased risk of venous thromboembolism (VTE).

The functional consequence is called APC resistance (activated protein C resistance, APCR).

In plain terms: Factor V Leiden is a genetic mutation that makes Factor V "stubborn" — it refuses to be switched off by the body's natural anticoagulant (protein C), so clots form more easily than they should.

Epidemiology

Population	Heterozygous Carrier Frequency	Homozygous Frequency
European Caucasians	3–8% (up to 15% in some Scandinavian/Greek populations)	~0.02–0.25%
Middle Eastern	2–5%	Rare
South Asian	~1–3%	Very rare
East Asian / Chinese	Essentially absent (< 0.01%)	Virtually nil
African	~1% (sub-Saharan), higher in North Africa	Very rare
Indigenous American / Australian	Essentially absent	Virtually nil

Hong Kong / Chinese Context – Extremely High Yield

Factor V Leiden is NOT found in the Chinese population. ^[1]^[2] This is repeatedly emphasized in HKU lectures. When a question asks about inherited thrombophilia in a Chinese patient presenting with unprovoked VTE, Factor V Leiden is essentially ruled out by ethnicity. The more relevant inherited thrombophilias in Chinese patients are Protein C deficiency, Protein S deficiency, and Antithrombin III deficiency. In HK clinical practice, the most common cause of "unprovoked" VTE is underlying malignancy — "more than 50% of our clinic patients with a blood clot have an underlying tumour." ^[3]

Genotype	VTE Risk (relative to normal)	Absolute Annual VTE Risk
Heterozygous FVL (one copy)	3–8× increased	~0.5–1% per year
Homozygous FVL (two copies)	~50–80× increased	~1–3% per year
FVL + another thrombophilia (e.g. prothrombin G20210A)	Synergistic (multiplicative risk)	Higher still
FVL + OCP use	~35× increased (heterozygous)	Clinically very significant

Among all patients presenting with a first VTE in Caucasian populations, ~20–25% carry Factor V Leiden
Among patients with recurrent VTE, the prevalence is even higher
FVL primarily increases the risk of venous thrombosis, not arterial thrombosis — this is a common exam distinction

Anatomy and Function: The Protein C Anticoagulant Pathway

To understand why Factor V Leiden causes thrombosis, you must understand the normal Protein C pathway — the body's built-in "braking system" for coagulation.

Factor X is activated (→ Factor Xa) by either the intrinsic or extrinsic pathway
Factor Xa combines with Factor Va (its cofactor) on a phospholipid surface in the presence of calcium → this forms the prothrombinase complex
The prothrombinase complex converts prothrombin (Factor II) → thrombin (Factor IIa)
Thrombin then converts fibrinogen → fibrin → clot formation

Factor Va is therefore a critical amplifier of coagulation. Without Factor Va, the conversion of prothrombin to thrombin is ~10,000× slower.

Key points:

Thrombin, once generated, has a negative feedback role — it binds to thrombomodulin on endothelial cells and activates Protein C
Protein S acts as a cofactor for APC (this is why Protein S deficiency also causes thrombophilia)
APC cleaves Factor Va at three sites: Arg506 (the first and most important cut), Arg306, and Arg679
Arg506 is the initial cleavage site — it must be cleaved first for efficient subsequent cleavage at Arg306

The Arg506Gln mutation means the glutamine residue at position 506 cannot be recognized and cleaved by APC
Factor Va Leiden is therefore ~10× more resistant to APC inactivation compared to normal Factor Va
The subsequent cleavage at Arg306 can still occur but is ~20× slower without prior Arg506 cleavage
Net effect: Factor Va Leiden persists longer in the circulation → continued thrombin generation → hypercoagulable state

Additionally, normal Factor V (when cleaved at Arg506) actually acts as a cofactor for APC in degrading Factor VIIIa. Factor V Leiden loses this anticoagulant cofactor function as well — so it's a double hit: the mutant Factor V is both (1) resistant to inactivation AND (2) unable to help APC inactivate Factor VIIIa.

Why Venous and Not Arterial?

The Protein C pathway is most relevant in the venous system where blood flow is slow and thrombin has time to bind thrombomodulin. In arteries, high-flow conditions and platelet-driven mechanisms dominate thrombosis. This is why FVL predominantly causes venous thrombosis (DVT, PE) rather than arterial events (MI, stroke). Arterial thrombosis in FVL patients, if it occurs, is usually in the presence of additional risk factors.

Etiology

Factor V Leiden is the result of a single, specific genetic mutation. There are no "acquired" forms of Factor V Leiden per se, but the concept of APC resistance (the functional consequence) can be acquired in certain situations.

Feature	Detail
Gene	F5 (chromosome 1q24.2)
Mutation	G1691A (nucleotide 1691, G→A)
Protein change	Arg506Gln (R506Q)
Inheritance	Autosomal dominant with incomplete penetrance
Founder effect	Arose ~21,000–34,000 years ago in a single European ancestor (post-divergence from Asian and African populations — which explains its absence in East Asians)

Certain conditions can produce functional APC resistance without the FVL mutation:

Pregnancy (Factor VIII levels rise, overwhelming APC capacity)
Oral contraceptive pills (estrogen-driven increase in coagulation factors)
Antiphospholipid syndrome (antibodies interfere with APC function)
Elevated Factor VIII levels (any cause)
Lupus anticoagulant (interferes with phospholipid-dependent reactions including APC activity)

This is clinically important: if you perform a functional APCR assay (see diagnostics later), these conditions can give a false positive result. That's why genetic testing (FVL PCR) is the confirmatory test.

The pathophysiology flows logically from what we've discussed:

Why Not Everyone with FVL Gets a Clot

FVL has incomplete penetrance — most heterozygous carriers never develop VTE in their lifetime. The mutation shifts the haemostatic balance toward thrombosis, but a "second hit" is usually needed to tip the balance:

Provoked VTE in FVL carriers typically occurs when an environmental trigger is added:
- Surgery / immobilization
- Pregnancy / postpartum
- OCP / HRT use (estrogen + FVL is a particularly dangerous combination → ~35× VTE risk)
- Long-haul travel
- Malignancy
Homozygous FVL or compound heterozygosity (FVL + another thrombophilia, e.g. prothrombin G20210A) has a much higher penetrance

Classification

Type	Description	Clinical Significance
Heterozygous	One mutant allele + one normal allele	Most common; 3–8× VTE risk
Homozygous	Two mutant alleles	Rare; ~50–80× VTE risk
Compound heterozygous	FVL + another thrombophilia mutation (e.g. Prothrombin G20210A)	Synergistically increased risk

Thrombophilias can be classified as ^[1]^[2]^[3]:

A. Inherited (Autosomal Dominant)

Antithrombin III deficiency (most thrombogenic inherited thrombophilia, but rarest)
Protein C deficiency (associated with warfarin-induced skin necrosis ^[2])
Protein S deficiency (acts as cofactor of Protein C)
Factor V Leiden (most common in Caucasians; NOT found in Chinese ^[1])
Prothrombin G20210A mutation (second most common in Caucasians; also absent in Chinese)

B. Acquired

Antiphospholipid syndrome (lupus anticoagulant, anti-cardiolipin Ab, anti-β2-GPI Ab) ^[2]
Malignancy-associated hypercoagulability
OCP / HRT / Pregnancy
Nephrotic syndrome (loss of antithrombin III in urine)
Paroxysmal nocturnal haemoglobinuria (PNH)
Hyperhomocysteinaemia
Myeloproliferative neoplasms

High Yield – Inherited Thrombophilia Risk Ranking

In terms of thrombogenicity: Antithrombin III deficiency > Protein C deficiency ≈ Protein S deficiency > Factor V Leiden (heterozygous) > Prothrombin G20210A. But in terms of prevalence (in Caucasians): Factor V Leiden >> Prothrombin G20210A >> Protein C > Protein S > Antithrombin III.

Clinical Features

Typically a young Caucasian adult (< 50 years) with a first VTE, especially if:
- Unprovoked (no obvious trigger)
- Recurrent VTE
- VTE at an unusual site
- Strong family history of VTE
- VTE provoked by a "weak" trigger (e.g. minor travel, OCP)

In Hong Kong, because FVL is essentially absent in Chinese, this is primarily relevant for non-Chinese patients or in the context of exam questions testing knowledge of inherited thrombophilia. ^[1]

Symptoms (with Pathophysiological Basis)

Symptom	Pathophysiological Basis
Unilateral leg pain	Thrombus in deep veins → venous outflow obstruction → venous distension → activates nociceptors in the vein wall and surrounding tissues
Unilateral leg swelling	Venous outflow obstruction → increased hydrostatic pressure → fluid transudation into interstitial space → oedema; typically > 3 cm difference in calf circumference compared to the unaffected side
Warmth and erythema	Inflammatory response to the thrombus (thrombin activates inflammatory mediators) + venous congestion causes redness
Heaviness / tightness of the limb	Increased venous pressure and tissue oedema

Symptom	Pathophysiological Basis
Acute dyspnoea	Embolus obstructs pulmonary artery → V/Q mismatch (perfusion defect with preserved ventilation) + increased dead space → hypoxaemia; also right heart strain reduces cardiac output
Pleuritic chest pain	Peripheral emboli cause pulmonary infarction → inflammation of visceral and parietal pleura → sharp, breathing-related pain
Haemoptysis	Pulmonary infarction → ischaemic necrosis of lung parenchyma → bleeding from necrotic tissue into airways (uncommon, occurs late)
Cough (dry)	Pleural irritation / bronchospasm from inflammatory mediators released by the embolus
Syncope / collapse	Massive PE → acute right ventricular failure → decreased left ventricular preload → reduced cardiac output → cerebral hypoperfusion
Sudden death	Saddle embolus occluding main pulmonary artery → complete obstruction of right ventricular outflow → acute cardiogenic shock

Site	Symptoms	Pathophysiological Basis
Cerebral venous sinus thrombosis	Headache, seizures, focal neurological deficits, papilloedema	Venous outflow obstruction → increased ICP → venous infarction (which may become haemorrhagic)
Mesenteric venous thrombosis	Severe abdominal pain (often out of proportion to findings), nausea, diarrhoea	Venous congestion of bowel → bowel wall oedema → ischaemia if severe
Portal vein thrombosis	Abdominal pain, ascites, splenomegaly	Obstruction of portal venous flow → portal hypertension
Hepatic vein thrombosis (Budd-Chiari)	Hepatomegaly, ascites, abdominal pain	Outflow obstruction of hepatic veins → sinusoidal congestion → hepatocyte necrosis

FVL is associated with:

Recurrent early pregnancy loss (though the association is debated — stronger for late pregnancy loss)
Placental abruption — thrombosis in placental vessels
Pre-eclampsia — impaired placental perfusion from micro-thrombosis
Intrauterine growth restriction — same mechanism
Stillbirth

The pathophysiology: placental vasculature is a low-flow, high-resistance system vulnerable to micro-thrombosis. Hypercoagulability from FVL → thrombosis in uteroplacental vessels → placental insufficiency.

Signs (with Pathophysiological Basis)

Sign	Description	Pathophysiological Basis
Unilateral pitting oedema	Asymmetric swelling of the affected limb	Venous outflow obstruction → raised hydrostatic pressure → transudation
Calf tenderness along deep veins	Pain on palpation over the course of deep veins (posterior tibial, popliteal, femoral)	Direct compression of the thrombosed, inflamed vein
Warmth	Increased skin temperature over the affected area	Inflammatory response + venous congestion
Erythema / cyanosis	Red or bluish discolouration	Venous congestion → deoxygenated blood pools → cyanotic tinge; inflammatory hyperaemia → redness
Dilated superficial veins	Visible superficial veins more prominent than usual	Deep venous obstruction → blood diverted through superficial collateral veins
Homan's sign	Calf pain on passive dorsiflexion of the foot	Stretching of the thrombosed posterior calf veins; unreliable — sensitivity ~5%, not recommended for clinical use but may be asked in exams
Phlegmasia cerulea dolens	Massively swollen, blue, painful limb	Extensive ilio-femoral DVT → complete venous outflow obstruction → venous gangrene (surgical emergency)

Sign	Pathophysiological Basis
Tachycardia	Sympathetic activation from hypoxaemia and reduced cardiac output
Tachypnoea	Compensatory response to hypoxaemia and increased dead space
Hypotension (if massive)	Right ventricular failure → reduced left ventricular preload → shock
Raised JVP	Right heart strain → back-pressure into systemic venous system
Loud P2 (accentuated pulmonary component of S2)	Acute pulmonary hypertension → forceful closure of the pulmonary valve
Right ventricular heave	Acute right ventricular pressure overload
Pleural rub	Pulmonary infarction → pleuritis → friction between inflamed visceral and parietal pleura
Low-grade fever	Inflammatory response to pulmonary infarction
Signs of DVT in the lower limb	Source of the embolus

Key Clinical Pearls for Exams

FVL causes venous, not arterial thrombosis — if the question describes arterial events (MI, ischaemic stroke), think of other causes (antiphospholipid syndrome can cause both)
In a Chinese patient with unprovoked VTE, don't think FVL — think malignancy first ^[3]
OCP + FVL = extremely high VTE risk (~35×) — this is a classic exam scenario: young European woman on OCP develops DVT
FVL heterozygotes have incomplete penetrance — most never clot; they need a "second hit"
Warfarin-induced skin necrosis is associated with Protein C deficiency, NOT Factor V Leiden ^[2]

Feature	Factor V Leiden	Protein C Deficiency	Protein S Deficiency	Antithrombin III Deficiency
Inheritance	AD	AD	AD	AD (variable penetrance)
Prevalence in Caucasians	3–8%	0.2–0.5%	Low	0.02–0.2%
Found in Chinese?	No	Yes	Yes	Yes
VTE risk (heterozygous)	3–8×	7×	Similar to Protein C	16×
Mechanism	APC resistance	Cannot inactivate Va/VIIIa	Loss of APC cofactor	Cannot inactivate thrombin/Xa
Special association	OCP synergy	Warfarin-induced skin necrosis	—	Heparin resistance
Functional test	APCR ratio	Protein C activity	Protein S activity (free/total)	AT activity
Confirmatory test	FVL PCR	Gene sequencing	Gene sequencing	Gene sequencing

Not every patient with VTE needs thrombophilia screening. The key indications are ^[2]:

Young patients with idiopathic (unprovoked) venous thrombosis

Suspected antiphospholipid syndrome (e.g. recurrent miscarriage)

Unusual sites of thrombosis (mesenteric, renal, portal vein, cerebral venous sinus)

Warfarin-induced skin necrosis (suspect Protein C/S deficiency)

Strong family history of VTE

Recurrent VTE

Timing of testing ^[2]:

Do NOT test at time of acute VTE event (acute phase changes distort results)

Withhold warfarin × 2 weeks before testing; DOAC × at least 2 days

Protein C, S, and AT levels are consumed during acute thrombosis → falsely low

Heparin lowers AT levels; warfarin lowers Protein C and S levels

Tests in a thrombophilia screen ^[2]:

Protein C, Protein S, Activated Protein C resistance (APCR), Antithrombin (AT)

Factor V Leiden PCR, Prothrombin G20210A mutation

APLS: Anti-cardiolipin, Lupus anticoagulant, Anti-β2-glycoprotein I antibody

High Yield Summary

Factor V Leiden = most common inherited thrombophilia in Caucasians; point mutation G1691A → Arg506Gln → Factor Va resistant to APC cleavage → hypercoagulable state → VTE risk
Inheritance: Autosomal dominant, incomplete penetrance. Heterozygotes 3–8× VTE risk; homozygotes ~50–80× risk
NOT found in Chinese — in Hong Kong, the relevant inherited thrombophilias are Protein C, Protein S, and Antithrombin III deficiency; the most common cause of unprovoked VTE in HK is malignancy
Mechanism: Dual defect — (a) Factor Va Leiden resists APC inactivation, (b) loses its cofactor role in APC-mediated Factor VIIIa degradation
Clinical presentation: Predominantly venous thrombosis (DVT > PE > unusual sites). NOT arterial. Associated with pregnancy complications
OCP + FVL ≈ 35× VTE risk — classic exam scenario
Thrombophilia screening indications: young unprovoked VTE, recurrent VTE, unusual site, family history, warfarin-induced skin necrosis, recurrent miscarriage. Do NOT test during acute VTE or on anticoagulants
Tests: Functional APCR assay (screening) → FVL PCR (confirmatory/genetic test)
Warfarin-induced skin necrosis = Protein C deficiency, not FVL

Active Recall - Factor V Leiden

^[1] Senior notes: Ryan Ho Haemtology.pdf (Section 4.5.1 Thrombophilia Screening) — "Factor V Leiden: NOT found in Chinese" ^[2] Senior notes: Maksim Medicine Notes.pdf (p.165, Thrombophilia screening section) — indications, tests, timing, Protein C/warfarin skin necrosis ^[3] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.16) — "In our clinic, more than 50% of our patients with a blood clot have an underlying tumour"; "We Chinese clot less" ^[4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.611–612) — inherited conditions including Factor V Leiden, Virchow's triad ^[5] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p.964–965) — same DVT/PE content ^[6] Senior notes: Ryan Ho Respiratory.pdf (p.134) — congenital risk factors including Factor V Leiden ^[7] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p.22) — mixing studies, Factor deficiencies ^[8] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf ^[9] Lecture slides: GC CP02 Clinical pharmacology of anti-platelets and anticoagulation.pdf ^[10] Lecture slides: Haematology Introduction to Haematological investigations (CBP, Clotting).pdf

Differential Diagnosis of Factor V Leiden

Factor V Leiden itself is a diagnosis (a specific genetic mutation). In clinical practice, the real differential diagnosis question arises in two contexts:

A patient presents with VTE → "What is the underlying cause of this thrombosis?" → FVL is one item on a differential list of causes of hypercoagulability / thrombophilia
A patient has a positive APCR assay → "Is this truly FVL, or is there another reason for APC resistance?" → differential of APC resistance

We will systematically cover both frameworks below.

Framework 1: Differential Diagnosis of the Underlying Cause of VTE (Thrombophilia DDx)

When a patient presents with VTE — especially if young, unprovoked, recurrent, unusual site, or with strong family history — the clinician must consider the full differential of why this person is clotting. Think through Virchow's triad ^[3]^[8]:

These are the primary differential diagnoses when considering FVL as a cause of hypercoagulability. Each disrupts a different part of the natural anticoagulant system:

Condition	Mechanism (First Principles)	Prevalence (Caucasian)	VTE Risk	Key Distinguishing Feature	Found in Chinese?
Factor V Leiden	Arg506Gln → Factor Va resistant to APC cleavage → sustained prothrombinase activity	3–8%	Het: 3–8×; Hom: 50–80×	Abnormal APCR ratio, confirmed by FVL PCR	No ^[1]^[2]^[11]
Prothrombin G20210A mutation	G→A at nucleotide 20210 in 3' UTR of prothrombin gene → increased prothrombin mRNA stability → ~30% higher plasma prothrombin levels → more substrate for thrombin generation	2–3%	2–5×	Elevated plasma prothrombin level; confirmed by PCR	No (absent in East Asians)
Protein C deficiency	Protein C normally inactivates Factor Va and VIIIa; deficiency → failure of this "brake" → hypercoagulability	0.2–0.5%	7×	Associated with warfarin-induced skin necrosis ^[1]^[2]; low Protein C activity level	Yes ^[1]^[11]
Protein S deficiency	Protein S is the cofactor of APC → deficiency → APC cannot function properly even if present	Low (unclear exact)	Similar to Protein C	Low free Protein S level	Yes ^[1]^[11]
Antithrombin III deficiency	AT-III normally inactivates thrombin and Factor Xa (enhanced by heparin) → deficiency → uncontrolled thrombin/Xa activity	0.02–0.2%	16.3× (highest among inherited thrombophilias)	VTE often resistant to normal doses of heparin (because heparin works through AT-III); ~70% develop VTE before age 60	Yes ^[1]^[11]

High Yield – Inherited Thrombophilia in Chinese vs Caucasian Patients

Factor V Leiden and Prothrombin G20210A are NOT found in Chinese populations. ^[1]^[2]^[11] In a Chinese patient in Hong Kong presenting with unprovoked VTE, the relevant inherited thrombophilia differential is limited to Protein C deficiency, Protein S deficiency, and Antithrombin III deficiency. In HKU teaching: "We Chinese clot less" ^[3] — and when we do clot without provocation, malignancy is the most important cause to exclude.

Why is Antithrombin III deficiency the most thrombogenic? Because AT-III sits at the apex of the coagulation cascade — it inhibits both thrombin AND Factor Xa directly. Losing this "master inhibitor" has more widespread downstream effects than losing Protein C (which only targets Va/VIIIa) or having APC resistance (FVL, which only affects Factor Va inactivation). Think of it as removing the main brake pedal vs removing a minor speed limiter.

Condition	Mechanism	How to Differentiate from FVL
Antiphospholipid syndrome (APLS)	Autoantibodies against phospholipid-binding proteins (cardiolipin, β2-GPI) → activate endothelium, platelets, and complement → thrombosis in both arterial AND venous systems	APLS causes both arterial and venous thrombosis (FVL is venous only); associated with recurrent miscarriage, livedo reticularis, thrombocytopenia; diagnosed by anti-cardiolipin Ab, lupus anticoagulant, anti-β2-GPI Ab on ≥2 occasions ≥12 weeks apart (Sapporo criteria) ^[3]^[12]
Malignancy-associated hypercoagulability	Tumour cells release tissue factor, cancer procoagulant, and mucin (especially adenocarcinomas) → activate extrinsic pathway; tumour compression of veins → stasis; chemotherapy → endothelial damage	"In our clinic, more than 50% of our patients with a blood clot have an underlying tumour" ^[3]; constitutional symptoms (weight loss, night sweats, fatigue); appropriate age-directed cancer screening
OCP / HRT / Pregnancy	Oestrogen → hepatic upregulation of coagulation factors (II, VII, VIII, X, fibrinogen) and downregulation of antithrombin and Protein S → net hypercoagulable state	History of exogenous hormone use or pregnancy; OCP + FVL heterozygote ≈ 35× VTE risk — synergistic, not just additive
Nephrotic syndrome	Massive proteinuria → urinary loss of Antithrombin III (MW ~58 kDa, small enough to be lost) + loss of Protein C and S + hepatic compensatory overproduction of larger pro-coagulant factors (fibrinogen, Factor V, VIII)	Peripheral oedema, heavy proteinuria (> 3.5 g/day), hypoalbuminaemia; check AT-III levels
Myeloproliferative neoplasms (MPN)	Elevated cell counts → blood hyperviscosity → stasis; JAK2 V617F mutation specifically promotes thrombosis via platelet and endothelial activation; MPN-associated thrombosis often at unusual sites (mesenteric, portal, hepatic veins)	CBC showing polycythaemia / thrombocytosis / leucocytosis; JAK2 mutation screening — especially for unusual-site thrombosis ^[14]; splenomegaly
Paroxysmal nocturnal haemoglobinuria (PNH)	Loss of GPI-anchored complement regulatory proteins (CD55, CD59) → complement-mediated haemolysis + complement activation on platelets → thrombosis (especially hepatic vein / Budd-Chiari syndrome)	Haemolytic anaemia (dark urine, elevated LDH, low haptoglobin), pancytopaenia; flow cytometry for CD55/CD59; very rare in Chinese ^[1]^[11]
Hyperhomocysteinaemia	Homocysteine damages endothelium → activates tissue factor pathway + impairs thrombomodulin/Protein C activation	Controversial ^[3] — observational data suggest association, but lowering homocysteine does not reduce VTE risk; no data in Chinese

Exam Pearl – APLS vs FVL

The key clinical differentiator between APLS and FVL:

APLS → both arterial AND venous thrombosis + recurrent miscarriage + thrombocytopenia + livedo reticularis
FVL → venous thrombosis only (DVT/PE), no thrombocytopenia, no livedo reticularis

Also: APLS can cause acquired APC resistance (via lupus anticoagulant interfering with phospholipid-dependent reactions), which can mimic FVL on a functional APCR assay → always confirm with FVL PCR if APCR is abnormal.

These are not true "thrombophilias" but are on the differential when evaluating why a patient developed VTE:

Provoking Factor	Virchow's Component	Why It Causes VTE
Surgery / Trauma	Endothelial injury + Stasis (immobilization)	Direct vascular damage exposes subendothelial collagen → triggers extrinsic pathway; post-op immobility → stasis
Prolonged immobilization (bed rest, long-haul travel > 6–8h)	Stasis	Loss of calf muscle pump → blood pools in deep veins → promotes clot formation
Central venous catheter	Endothelial injury	Catheter physically damages the endothelium of the cannulated vein
Obesity	Mixed	Chronic low-grade inflammation → endothelial dysfunction + reduced mobility → stasis + adipose tissue produces PAI-1 (plasminogen activator inhibitor) → impaired fibrinolysis
Smoking	Endothelial injury	Cigarette toxins damage endothelium directly

The APCR ratio is the functional screening test for FVL. An abnormal (low) APCR ratio means Factor Va in the patient's plasma resists inactivation by exogenous APC. But not all APC resistance is due to the FVL mutation:

Cause of APC Resistance	Genetic or Acquired?	Mechanism	How to Distinguish from FVL
Factor V Leiden (Arg506Gln)	Genetic	Cleavage site mutated → APC cannot cut Factor Va	Confirm with FVL PCR (gold standard)
Factor V Cambridge (Arg306Thr)	Genetic (very rare)	Alternative cleavage site mutated	FVL PCR negative; requires Factor V gene sequencing
Factor V Hong Kong (Arg306Gly)	Genetic (described in Chinese!)	Alternative cleavage site mutated; but clinical significance uncertain — may not significantly increase VTE risk	FVL PCR negative; gene sequencing
Pregnancy	Acquired (physiological)	Markedly elevated Factor VIII levels overwhelm APC capacity	Test after pregnancy; FVL PCR negative
OCP / HRT use	Acquired	Oestrogen increases pro-coagulant factors and decreases Protein S	Discontinue OCP, retest; FVL PCR negative
Antiphospholipid syndrome	Acquired	Lupus anticoagulant / anti-phospholipid antibodies interfere with APC-phospholipid interactions	APLS serology positive; FVL PCR negative
Elevated Factor VIII levels (any cause)	Acquired	Excess Factor VIII saturates APC's capacity to inactivate VIIIa; relative APC resistance	Factor VIII level elevated; FVL PCR negative
Other Factor V mutations	Genetic (rare)	Various point mutations affecting APC cleavage sites	Gene sequencing

Factor V Hong Kong — Relevant for HKU Exams?

Factor V Hong Kong (Arg306Gly) is an interesting entity described in ~5% of the Hong Kong Chinese population. It does cause APC resistance on functional assays, but its association with clinical VTE risk is uncertain and probably very low. It is NOT the same as Factor V Leiden. If an APCR assay comes back abnormal in a Chinese patient, FVL PCR will be negative — consider Factor V Hong Kong or acquired causes of APC resistance.

Framework 3: DDx When the Clinical Presentation Overlaps

Since FVL presents as VTE, the differential also includes non-thrombotic mimics of DVT and PE:

Differential	Key Distinguishing Features
Cellulitis	Bilateral erythema following skin entry point; fever, leucocytosis; skin breach/wound visible
Ruptured Baker's cyst	History of pre-existing knee arthritis (RA, OA); sudden onset posterior calf pain; ultrasound shows ruptured popliteal cyst
Muscle strain / haematoma	History of trauma or exertion; localized tenderness over muscle belly; no venous congestion pattern
Superficial thrombophlebitis	Palpable cord along superficial vein; erythema and tenderness localized to superficial vein
Lymphoedema	Non-pitting, chronic, bilateral (or unilateral if post-surgical/radiation); no acute tenderness
Chronic venous insufficiency	Bilateral, chronic, with skin changes (stasis dermatitis, lipodermatosclerosis); varicose veins
Lymphangitis	Red streaking along lymphatic channels; associated with infection proximally

Differential	Key Distinguishing Features
ACS (Acute Coronary Syndrome)	Central crushing chest pain, radiation to arm/jaw; ECG: ST changes / troponin rise
Pneumothorax	Sudden pleuritic pain + dyspnoea; absent breath sounds; CXR: visible pleural line
Aortic dissection	Tearing interscapular pain; BP discrepancy between arms; widened mediastinum on CXR
Pneumonia with pleurisy	Productive cough, fever, consolidation on CXR
Musculoskeletal chest pain	Reproducible on palpation; no cardiorespiratory compromise

High Yield – Thrombophilia DDx Summary for Exams

When approaching a patient with unprovoked VTE:

Always screen for malignancy — history, examination, CXR, age-appropriate cancer screening; "up to 10% of patients with unprovoked VTE have underlying malignancy" ^[3]
In Chinese patients: FVL is NOT on the DDx ^[1]^[2]^[11] — focus on Protein C/S, AT-III deficiency, APLS, and malignancy
In Caucasian patients: FVL is the most common inherited cause — screen with APCR, confirm with PCR
APLS can mimic FVL functionally (acquired APC resistance) — always confirm abnormal APCR with genetic testing
Pregnancy + OCP can cause acquired APC resistance — do not test APCR while on OCP or pregnant
Unusual-site thrombosis (mesenteric, portal, cerebral vein) → screen for JAK2 mutation (MPN) ^[14] in addition to standard thrombophilia panel

Active Recall - Factor V Leiden Differential Diagnosis

References

^[1] Senior notes: Ryan Ho Haemtology.pdf (Section 4.5.1 Thrombophilia Screening) — "Factor V Leiden: NOT found in Chinese"; inherited thrombophilia table ^[2] Senior notes: Maksim Medicine Notes.pdf (p.165, Thrombophilia screening section) — indications, tests, timing, Protein C/warfarin skin necrosis ^[3] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.1, 14, 16) — Virchow's triad, FVL mechanism, malignancy-associated VTE, "We Chinese clot less" ^[4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.612) — DDx of DVT ^[5] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p.965) — DDx of DVT ^[8] Lecture slides: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf ^[10] Senior notes: Ryan Ho Haemtology.pdf (p.131) — Clinical features and major differentials of VTE by site ^[11] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.397) — inherited thrombophilia table, "NOT found in Chinese" ^[12] Senior notes: Ryan Ho Rheumatology.pdf (p.73) — APLS revised Sapporo criteria ^[14] Senior notes: Block A - Splenomegaly: common causes of splenomegaly; myeloproliferative diseases.pdf (p.27–29) — MPN-associated thrombosis, JAK2

Diagnostic Criteria for Factor V Leiden

Factor V Leiden is a genetic diagnosis — there is no set of clinical criteria like the Sapporo criteria for APLS or the Duke criteria for endocarditis. Instead, the diagnostic approach involves:

Clinical suspicion → identifying patients who should be tested (i.e. indications for thrombophilia screening)
Functional screening test → Activated Protein C Resistance (APCR) assay
Confirmatory genetic test → Factor V Leiden PCR (the definitive diagnosis)

The "diagnostic criteria" are therefore best understood as criteria for when to test plus interpretation of the test results.

Not every patient with VTE needs thrombophilia screening. Screening is indicated in specific clinical scenarios ^[1]^[2]^[11]:

Indications for thrombophilia screen: ^[2]^[11]

Young patients with idiopathic (unprovoked) venous thrombosis

Recurrent venous thrombosis or superficial thrombophlebitis

Unusual sites of thrombosis (mesenteric, renal, portal vein, cerebral venous sinus)

Warfarin-induced skin necrosis (suspect Protein C/S deficiency)

Arterial thrombosis < 40 years

Recurrent miscarriage

Why these specific indications? Because they point toward an underlying, persistent hypercoagulable state rather than a one-off provoked event. A 70-year-old who develops DVT after hip replacement surgery has a clear provoking factor — testing for thrombophilia rarely changes management. But a 25-year-old with spontaneous DVT and a family history of clots? That's where finding FVL (or another thrombophilia) influences the duration and intensity of anticoagulation, family counselling, and decisions about OCP/pregnancy.

Timing of testing ^[2]^[11]:

Do NOT test at the time of acute VTE event

Do NOT test while patients are receiving anticoagulants

Withhold warfarin × 2 weeks (warfarin lowers Protein C and S → false positive for deficiency)

Withhold DOAC × at least 2 days

Heparin lowers Antithrombin III levels → false positive for AT-III deficiency

Acute thrombosis itself consumes natural anticoagulants (Protein C, S, AT-III) → falsely low levels ^[11]

Why Can't You Test During Acute Thrombosis?

During an acute thrombotic event, the coagulation cascade is maximally activated. The body consumes its natural anticoagulants (Protein C, Protein S, Antithrombin III) trying to brake the runaway clotting. If you measure these levels now, they will be falsely low, and you might wrongly diagnose a deficiency that doesn't exist. Similarly, anticoagulant drugs interfere with the assays: warfarin suppresses Protein C/S production (they're vitamin K-dependent), and heparin works by potentiating AT-III, so AT-III gets consumed faster. Wait until the acute event has settled and anticoagulants have been stopped for an adequate washout period.

Exception: APCR ratio and Factor V Leiden PCR are NOT affected by acute thrombosis or anticoagulants — these can technically be tested at any time. But since a full thrombophilia screen is usually sent together, the convention is to wait.

The following algorithm integrates the clinical decision-making process from suspicion through to definitive diagnosis of Factor V Leiden:

Investigation Modalities — Detailed Breakdown

Tier 1: The Core FVL Diagnostic Tests

What it is: A clotting-based assay that measures how well the patient's Factor Va responds to exogenous APC.

How it works (first principles):

You take the patient's plasma and measure the APTT (baseline clotting time)
You then add exogenous APC (activated Protein C) to the same plasma and measure the APTT again
In normal plasma: APC cleaves Factor Va and VIIIa → the coagulation cascade slows → the APTT prolongs significantly
In FVL plasma: APC cannot cleave Factor Va Leiden efficiently → the cascade doesn't slow as much → the APTT prolongs less

The APCR ratio:

$\text{APCR ratio} = \frac{\text{APTT with APC added}}{\text{APTT without APC (baseline)}}$

Result	Interpretation
APCR ratio > 2.0 (varies by lab)	Normal — APC effectively prolonged the APTT → Factor V responds normally
APCR ratio < 2.0	Abnormal — APC resistance present → suspect FVL, but must confirm with PCR

Second-generation APCR assay (modified): Uses Factor V-depleted plasma diluted with the patient's plasma before adding APC. This eliminates interference from other coagulation factor abnormalities and lupus anticoagulant, making it more specific for FVL (sensitivity ~99%, specificity ~98%).

High Yield – APCR Can Be Falsely Abnormal

Causes of acquired APC resistance (abnormal APCR ratio WITHOUT FVL mutation):

Pregnancy (↑Factor VIII overwhelms APC)
OCP / HRT (estrogen-driven coagulation factor increase)
Antiphospholipid syndrome / Lupus anticoagulant (interferes with phospholipid-dependent APC reaction)
Elevated Factor VIII (any cause — acute phase, post-exercise)
Factor V Hong Kong (Arg306Gly) — described in ~5% of HK Chinese; causes mild APC resistance but uncertain clinical significance

This is precisely why an abnormal APCR must always be confirmed by FVL PCR — you need to distinguish genetic FVL from acquired causes.

What it is: A DNA-based test that directly detects the G1691A point mutation in the F5 gene.

How it works:

Genomic DNA is extracted from the patient's blood (usually from leukocytes in an EDTA tube)
PCR amplifies the region around nucleotide 1691
Restriction fragment length polymorphism (RFLP) analysis or allele-specific PCR or sequencing identifies whether the G→A substitution is present
Modern labs may use real-time PCR with fluorescent probes

Result	Interpretation
Wild-type (G/G)	No FVL mutation — normal
Heterozygous (G/A)	One mutant allele — FVL carrier; 3–8× VTE risk
Homozygous (A/A)	Two mutant alleles — homozygous FVL; ~50–80× VTE risk

Key advantages of genetic testing over functional APCR:

Not affected by anticoagulants, pregnancy, OCP, or acute thrombosis — can theoretically be done anytime
100% specific for the FVL mutation (no false positives from acquired causes)
Provides genotype (het vs hom) which determines risk stratification
One-time test — the result never changes

The standard thrombophilia screen includes ^[2]^[11]:

Test	What It Measures	Key Findings Indicating Deficiency/Abnormality	Confounders
Protein C activity	Functional level of Protein C	Low activity → Protein C deficiency; associated with warfarin-induced skin necrosis ^[1]^[2]	Warfarin ↓ (vitamin K-dependent); consumed in acute thrombosis
Protein S activity (free and total)	Functional and antigenic levels of Protein S	Low free Protein S → Protein S deficiency	Warfarin ↓; pregnancy ↓; OCP ↓; acute inflammation ↓ (negative acute phase reactant-like behaviour)
Antithrombin activity	Functional level of AT-III	Low activity → AT-III deficiency; VTE resistant to normal doses of heparin ^[1]	Heparin use ↓; nephrotic syndrome ↓ (urinary loss); acute thrombosis ↓ (consumption)
APCR ratio	APC resistance (functional screen for FVL)	Low ratio → APC resistance	As above (pregnancy, OCP, APLS, ↑FVIII)
Factor V Leiden PCR	G1691A mutation	Heterozygous or homozygous	None — genetic test, always reliable
Prothrombin G20210A PCR	G20210A mutation in prothrombin gene	Heterozygous or homozygous	None — genetic test
Anti-cardiolipin Ab (IgG/IgM)	Antiphospholipid antibodies (immunoassay)	Moderate-to-high titre positive → suspect APLS	Must be positive on ≥2 occasions ≥12 weeks apart
Anti-β2-glycoprotein I Ab (IgG/IgM)	Antiphospholipid antibodies (immunoassay)	Positive → suspect APLS	Same as above
Lupus anticoagulant	Clotting-based detection of antiphospholipid antibodies	Positive → suspect APLS; classically causes prolonged APTT but paradoxically thrombotic (not bleeding) ^[7]^[15]	Anticoagulants interfere; in QMH lab, we use DRVVT (Dilute Russell's Viper Venom Time) ^[7]

High Yield – Lupus Anticoagulant Paradox

Lupus anticoagulant causes a prolonged APTT in vitro (because it interferes with phospholipid-dependent clotting reactions in the test tube), but clinically it causes thrombosis, not bleeding ^[7]^[15]. Why? Because in vivo, the antiphospholipid antibodies activate endothelial cells, platelets, and complement → pro-thrombotic state. The "anticoagulant" in the name refers only to its in vitro effect. This is a favourite exam question.

To differentiate lupus anticoagulant from a true factor deficiency causing prolonged APTT: mixing study — lupus anticoagulant will NOT correct after mixing with normal plasma (antibodies immediately attack the added phospholipids), whereas a factor deficiency WILL correct ^[7]^[15].

Tier 3: Investigations for VTE (When FVL Patient Presents with Acute Thrombosis)

When a patient with known or suspected FVL presents with acute VTE, the focus shifts to diagnosing and risk-stratifying the thrombotic event itself:

Investigation	Finding	Interpretation
D-dimer	Elevated (> 500 ng/mL, or age-adjusted: age × 10)	Sensitive but not specific ^[3]^[7]; high NPV — if negative, can essentially exclude VTE in low-risk patients ^[3]^[7]; useless in inpatients (many confounders: surgery, cancer, infection) ^[3]
Compression ultrasonography (duplex USG)	Non-compressibility of deep vein	Diagnostic for DVT; finding of non-compressibility with or without visible thrombus is the key criterion ^[10]
Contrast venography	Filling defect in deep vein	Former gold standard; now rarely used due to invasiveness

Clinical approach for DVT ^[10]:

Calculate Modified Wells score for pre-test probability
Low probability → D-dimer first → if negative, DVT excluded; if positive → duplex USG within 4 hours
High probability → duplex USG directly (skip D-dimer)

Investigation	Finding	Interpretation
D-dimer	Elevated	Same as above — rule-out test in low-probability patients
CXR	Usually normal; may show Hampton hump (peripheral wedge-shaped opacity from infarction), Westermark sign (focal oligaemia), Fleischner sign (enlarged pulmonary artery), pleural effusion	Non-specific but helps exclude other causes (pneumonia, pneumothorax) ^[6]
ECG	Sinus tachycardia (most common); S1Q3T3 (only ~15%); RV strain pattern (RBBB, RAD, P pulmonale, T-wave inversion V1–V4)	Not diagnostic — screens for and helps r/o MI; S1Q3T3 is classic but uncommon ^[6]
ABG	Type 1 respiratory failure (↓PaO2, normal/↓PaCO2); ↑A-a gradient; metabolic acidosis if massive PE with shock	Reflects V/Q mismatch and dead space
Cardiac enzymes (troponin, BNP)	Elevated troponin / BNP	Prognostic, not diagnostic — indicates RV strain/myocardial injury → risk stratification
CTPA (CT pulmonary angiogram)	Filling defect in pulmonary artery	Gold standard for PE diagnosis (Sn 91%, Sp 78%) ^[6]; must inform radiologist to time contrast for PA ^[6]; eGFR cutoff > 30 mL/min for contrast ^[16]
V/Q scan	Mismatched perfusion defect (normal ventilation, absent perfusion)	Alternative when CTPA contraindicated (renal impairment, contrast allergy) ^[6]^[16]; Sn 41%, Sp 97% ^[6]; radiologist gives probability score
Echocardiogram	RV dilatation, RV hypokinesis, tricuspid regurgitation, McConnell's sign	For haemodynamically unstable patients — bedside TTE to look for RV strain as presumptive diagnosis → start empirical thrombolysis without waiting for CTPA ^[6]
Lower limb duplex USG	DVT demonstrated	In pregnant patients who cannot have CTPA or V/Q scan — finding DVT supports PE diagnosis and justifies anticoagulation ^[16]

Risk stratification for PE — Wells Score "MarcoPolo Has NO STD" ^[6]:

Criterion	Points
Malignancy	+1.0
Previous PE/DVT	+1.5
Hemoptysis	+1.0
No other DDx	+3.0
Surgery / immobilization	+1.5
Tachycardia: HR > 100	+1.5
DVT signs	+1.5

Low probability (≤ 4): D-dimer → if negative, PE excluded; if positive → CTPA High probability (> 4): CTPA directly Haemodynamically unstable: Bedside echo ± LL USG → empirical thrombolysis → CTPA when stabilized ^[6]

For every patient with unprovoked VTE, screen for underlying malignancy ^[3]^[11]:

"In our clinic, more than 50% of our patients with a blood clot have an underlying tumour" ^[3] "Up to 10% of patients with unprovoked VTE were found to have an underlying malignancy" ^[3]

Investigation	Purpose
Thorough history	Constitutional symptoms (weight loss, night sweats, fatigue, anorexia)
Thorough physical examination	Lymphadenopathy, organomegaly, breast/rectal examination
CXR	Lung mass, mediastinal lymphadenopathy
Blood tests: CBC, serum Ca, LFT	Cytopaenias (bone marrow infiltration), hypercalcaemia (myeloma, bone mets), deranged LFT (liver mets)
Urinalysis	Haematuria (renal/bladder malignancy)
± CT abdomen/pelvis	If initial screen negative and suspicion persists (age > 40) ^[11]
± Mammogram (female > 40y)	Breast cancer screening ^[11]
Universal PET-CT screening	NOT recommended for unprovoked VTE per current guidelines ^[3]

This is important because FVL, by itself, does NOT alter standard clotting tests:

Test	Result in FVL	Why
PT	Normal	FVL does not affect the extrinsic pathway; Factor VII function is intact
APTT	Normal	FVL does not cause a factor deficiency — Factor V is present and functional as a pro-coagulant; the defect is only in its inactivation by APC, which is not measured by standard APTT
Platelet count	Normal	FVL is a coagulation pathway disorder, not a platelet disorder
Fibrinogen	Normal	No consumptive process in FVL per se
D-dimer	Normal (unless active VTE)	Elevated only if there is active clot formation and fibrinolysis
APCR ratio	Abnormal (low)	The specific screening test — demonstrates resistance to APC
FVL PCR	Positive (het or hom)	Definitive genetic diagnosis

Exam Trap – Normal Clotting Profile Does NOT Exclude Thrombophilia

A common mistake: seeing a normal PT, APTT, and platelet count and concluding there is no haemostatic abnormality. Factor V Leiden, Prothrombin G20210A, Protein C/S deficiency, and AT-III deficiency ALL have normal PT and APTT. Standard clotting tests only detect factor deficiencies or inhibitors that prolong clotting time. Thrombophilias are about failure of the braking system, not about the accelerator — the standard tests measure the accelerator (how fast you clot), not the brake (how effectively you stop clotting). You need specific thrombophilia assays to detect these conditions.

High Yield Summary – Diagnostics

FVL is diagnosed by genetic testing (FVL PCR), not by clinical criteria
APCR assay is the functional screening test — abnormal ratio (< 2.0) suggests APC resistance → must confirm with PCR
Standard clotting profile (PT, APTT) is NORMAL in FVL — thrombophilias are "braking system" failures, not measurable by standard clotting tests
Thrombophilia screen timing: not during acute VTE, off warfarin ≥2 weeks, off DOAC ≥2 days
Full screen includes: APCR, Protein C, Protein S, AT-III, FVL PCR, PT G20210A PCR, anti-cardiolipin, anti-β2-GPI, lupus anticoagulant
Always screen for occult malignancy in unprovoked VTE — history, examination, CXR, bloods, urinalysis
CTPA is gold standard for PE diagnosis; duplex USG for DVT; D-dimer for rule-out in low-risk patients
Lupus anticoagulant prolongs APTT in vitro but causes thrombosis in vivo — mixing study does NOT correct (unlike factor deficiency)

Active Recall - Factor V Leiden Diagnostics

^[1] Senior notes: Ryan Ho Haemtology.pdf (p.135–136) — inherited thrombophilia table, thrombophilia screening indications and workup ^[2] Senior notes: Maksim Medicine Notes.pdf (p.165) — thrombophilia screening indications, tests, timing ^[3] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.14, 16, 23) — FVL mechanism, malignancy-associated VTE, VTE investigations ^[6] Senior notes: Maksim Medicine Notes.pdf (p.288) — VTE investigations, Wells score, CXR/ECG findings, CTPA ^[7] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p.21, 23) — coagulation cascade interpretation, D-dimer, DRVVT for lupus anticoagulant, mixing study ^[10] Senior notes: Ryan Ho Haemtology.pdf (p.131) — DVT diagnostic evaluation, duplex USG, Wells score ^[11] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.398) — thrombophilia screening indications, timing, investigations ^[15] Senior notes: Maksim Medicine Notes.pdf (p.161) — clotting profile interpretation table, mixing study ^[16] Senior notes: Block A - Chest Pain - Department of Radiology.pdf — CTPA eGFR cutoff, V/Q scan alternative, DVT USG in pregnancy

Conceptual Framework: What Are We Actually Treating?

Before diving into specifics, understand what management of FVL involves. Factor V Leiden itself is a genetic mutation — you cannot "cure" it. Management therefore centres on:

Treating acute VTE when it occurs (identical to managing VTE from any cause)
Deciding duration of anticoagulation after a VTE event (where FVL genotype influences the decision)
Primary prevention in carriers who have never clotted (lifestyle, risk factor modification, situational prophylaxis)
Counselling (family screening, pregnancy planning, OCP avoidance)

The management is not "give lifelong anticoagulants to everyone with FVL." Most heterozygous carriers never clot. The art is in risk-stratifying who needs what, and when.

Treatment Modalities in Detail

1. Acute VTE Treatment (Same as Any VTE)

The treatment of acute DVT/PE in a patient with FVL is identical to standard VTE management. FVL does not change the acute treatment protocol — it may influence the duration of subsequent anticoagulation.

The goal is to immediately halt clot propagation and prevent embolisation.

Agent	Mechanism	Dose	Monitoring	When to Prefer
LMWH (e.g. enoxaparin)	Inhibits Factor Xa by potentiating antithrombin III	SC enoxaparin 1 mg/kg Q12h ^[6]^[17]	Anti-Xa levels (usually not needed unless obesity/renal impairment)	Standard first-line for most stable patients
UFH (unfractionated heparin)	Potentiates antithrombin III → inhibits both thrombin AND Factor Xa	IV 5000U bolus then 500–1500 U/hr infusion ^[6]^[17]	APTT Q6h, target 1.5–2.5× baseline ^[6]^[17]	Preferred if: (1) renal failure CrCl < 30, (2) pregnancy, (3) morbid obesity, (4) thrombolytic use considered — because UFH has short half-life (~1.5h) and can be acutely reversed by protamine ^[6]^[17]
DOAC loading	Direct inhibition of Factor Xa (rivaroxaban, apixaban, edoxaban) or thrombin (dabigatran)	See below	No routine monitoring	When oral route is feasible and no C/I

Why Is UFH Preferred When Thrombolysis Is Being Considered?

UFH has a half-life of only ~1.5 hours and can be immediately reversed with protamine sulfate. If a patient deteriorates and needs thrombolysis (which carries major bleeding risk), you need to be able to switch off anticoagulation quickly. LMWH has a longer half-life (~4 hours) and is only partially reversible with protamine. This is why for haemodynamically unstable PE patients where thrombolysis may be needed, UFH is the preferred initial anticoagulant ^[6]^[17].

Why does heparin work through Antithrombin III? Heparin is a naturally occurring glycosaminoglycan that binds to AT-III and causes a conformational change → dramatically accelerates AT-III's ability to inactivate thrombin and Factor Xa (by ~1000×). This has a key clinical implication:

In Antithrombin III deficiency, heparin is less effective ^[1] — because the drug depends on AT-III to work. These patients may need higher doses of LMWH (≥100 U/kg/day) or AT-III concentrate supplementation ^[1]. This does NOT apply to FVL — heparin works normally in FVL patients.

B. Long-Term Anticoagulation — Drug Options

After initial parenteral anticoagulation, the patient transitions to long-term oral anticoagulation:

Mechanism: Competitive inhibitor of vitamin K epoxide reductase (VKORC1) → reduces hepatic synthesis of vitamin K-dependent clotting factors (Factors II, VII, IX, X) and natural anticoagulants (Protein C, Protein S)
Monitoring: INR, target 2.0–3.0 for VTE ^[6]^[17]
Dosing: Start 5 mg daily for 2 days, 2 mg on 3rd day, then titrate to target INR ^[6]
Critical overlap rule: LMWH must be continued in parallel with warfarin for at least 5 days AND until INR 2–3 is reached ^[6]^[17]^[18]

Why the 5-day overlap? This is one of the most important concepts in anticoagulation:

Warfarin suppresses production of ALL vitamin K-dependent factors, including the anticoagulants Protein C and S
Protein C has a much shorter half-life (~8 hours) than pro-coagulant factors (Factor II ~60 hours)
So in the first few days of warfarin, Protein C drops rapidly while pro-coagulant factors are still circulating → paradoxical hypercoagulable state
This is why warfarin-induced skin necrosis occurs — particularly in patients with pre-existing Protein C deficiency ^[1]^[2] — the already-low Protein C drops to near zero, causing microvascular thrombosis in cutaneous vessels → necrosis
The 5-day overlap with LMWH/UFH "bridges" this dangerous window

Warfarin-Induced Skin Necrosis — NOT an FVL Complication

Warfarin-induced skin necrosis is associated with Protein C/S deficiency, NOT Factor V Leiden ^[1]^[2]. This is a common exam confusion. FVL patients can safely start warfarin with standard overlap protocols. Protein C deficiency patients are at risk because warfarin drops their already-deficient Protein C even further.

Pharmacogenomics of warfarin ^[19]:

Warfarin dosing is influenced by VKORC1 and CYP2C9 polymorphisms ^[19]. VKORC1 variants affect warfarin sensitivity (pharmacodynamic target), and CYP2C9 variants affect warfarin metabolism (pharmacokinetic clearance). Pharmacogenomic-guided dosing algorithms reduce time to stable INR and decrease bleeding complications compared to empirical dosing ^[19].

Warfarin Interactions — Key Exam Points
Contraindications	Pregnancy (crosses placenta → teratogenic in 1st trimester, fetal ICH in 3rd trimester); recent major surgery; uncontrolled hypertension; haemorrhagic stroke ^[6]^[17]
Side effects	Skin necrosis (Protein C/S deficiency); purple toe syndrome (cholesterol microembolisation); osteoporosis (long-term); bleeding ^[6]
Drug interactions	Extensively metabolised by CYP enzymes → many interactions; potentiated by amiodarone, metronidazole, fluconazole; reduced by rifampicin, carbamazepine, phenytoin

DOACs have largely replaced warfarin for VTE treatment in non-pregnant, non-APLS patients due to equivalent efficacy, reduced major bleeding, no INR monitoring, and fewer drug interactions.

DOAC	Mechanism	VTE Treatment Regimen	Key Points
Rivaroxaban	Direct Factor Xa inhibitor	15 mg BD for 21 days, then 20 mg OD ^[18]	Can be started without preceding LMWH (has its own loading)
Apixaban	Direct Factor Xa inhibitor	10 mg BD for 7 days, then 5 mg BD ^[18]	Can be started without preceding LMWH
Dabigatran	Direct thrombin (Factor IIa) inhibitor	At least 5 days of parenteral anticoagulant first, then 150 mg BD ^[18]	Requires LMWH lead-in; antidote: idarucizumab ^[17]
Edoxaban	Direct Factor Xa inhibitor	At least 5 days of parenteral anticoagulant first, then 60 mg OD ^[18]	Requires LMWH lead-in

DOAC antidotes ^[17]:

Idarucizumab ("I dare you sizumab") → specific reversal agent for dabigatran (monoclonal antibody fragment that binds dabigatran with high affinity)
Andexanet alfa → reversal agent for Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban); not fully registered in all centres; clinical benefit not well established ^[17]

Contraindications to DOACs ^[17]:

Valvular AF / Mechanical prosthetic heart valves → must use warfarin

Bioprosthetic valves → DOAC acceptable

Antiphospholipid syndrome → warfarin preferred (DOACs showed inferior outcomes in APLS trials)

Severe renal impairment → varies by agent; generally avoid or dose-reduce if CrCl < 30

Pregnancy → contraindicated (insufficient safety data)

High Yield – DOAC vs Warfarin Decision

DOACs are non-inferior to warfarin for VTE treatment with significantly reduced major bleeding ^[18]. They are now first-line in most guidelines. However, warfarin remains preferred in: (1) mechanical heart valves, (2) APLS, (3) ESRD (risk of calcified uraemic arteriopathy with warfarin but DOACs lack data in ESRD), (4) when cost is a barrier.

For FVL patients specifically, DOACs are perfectly appropriate and have no specific contraindication related to the FVL mutation.

Thrombolysis is indicated only when the clot is so massive it endangers life or limb ^[3]^[6]:

Indications for thrombolysis / embolectomy ^[3]:

Haemodynamic instability: shock, persistent hypotension (sBP < 90 or drop ≥ 40 mmHg)

Venous gangrene of the limbs → Phlegmasia cerulea dolens (complete blockage of venous drainage) ^[3]

Protocol ^[6]^[18]:

rtPA (alteplase) 100 mg IV over 2 hours → onset < 14 days
Follow with UFH infusion 500–1500 U/hr to keep APTT 1.5–2.5× control ^[6]
If tPA contraindicated or fails → catheter-directed embolectomy or surgical pulmonary thromboembolectomy ^[3]^[6]

Respiratory support in massive PE ^[17]:

Give high-flow nasal cannula oxygen rather than positive pressure ventilation — positive pressure ventilation increases intrathoracic pressure → reduces venous return → further compromises the already failing right ventricle ^[17]

Very limited role in VTE management ^[3]:

"Something she does not want us to use" — efficiency based on limited uncontrolled case series, no RCT data ^[3]

Indications ^[3]^[6]:

Patient has DVT with high PE risk but absolute contraindication to anticoagulation (e.g. active major bleed)
Temporary withholding of anticoagulation (e.g. patient needs major surgery soon — filter bridges the gap)
Recurrent PE despite adequate anticoagulation ^[6]

Key points ^[3]:

Plan for removal when bleeding risk decreases (usually within a month)
If left too long → filter endothelialises and cannot be removed → patient needs indefinite anticoagulation (filter itself can thrombose)
No role if patient already has PE — the horse has already bolted

This is where FVL genotype genuinely influences management. The decision framework:

Scenario	Recommended Duration	Rationale
First provoked VTE, FVL heterozygous	3–6 months ^[6]	Provoking factor (surgery, OCP, immobilisation) has resolved; heterozygous FVL alone is a relatively weak thrombophilia (3–8× risk); recurrence risk is low once trigger removed
First unprovoked VTE, FVL heterozygous	At least 3–6 months, then reassess ^[6]; consider indefinite if low bleeding risk	Unprovoked VTE has ~10% annual recurrence risk after stopping anticoagulation; FVL adds modest incremental risk; weigh bleeding vs recurrence
Recurrent VTE (any genotype)	Indefinite anticoagulation ^[6]	Two or more VTE events indicate a persistent prothrombotic tendency regardless of genotype
Homozygous FVL or compound heterozygous	Indefinite anticoagulation (after first unprovoked VTE)	~50–80× VTE risk is substantial; recurrence rate is high; benefit of continued anticoagulation outweighs bleeding risk
FVL + active malignancy	Continue anticoagulation > 6 months while cancer is active ^[10]; prefer LMWH or DOAC over warfarin for cancer-associated VTE ^[10]	Malignancy creates ongoing hypercoagulable state; warfarin has more drug interactions with chemotherapy
FVL + APLS	Indefinite warfarin (NOT DOAC) ^[10]	APLS requires indefinite anticoagulation; warfarin preferred over DOAC in APLS (DOACs showed inferior outcomes in trials)

Exam Pearl – Duration of Anticoagulation Decision Framework

Think of it as a balance:

Recurrence risk (what happens if I STOP anticoagulation?) — influenced by provoked vs unprovoked, genotype (het vs hom), additional thrombophilias
Bleeding risk (what happens if I CONTINUE anticoagulation?) — influenced by age, comorbidities, fall risk, concurrent medications

For most heterozygous FVL patients with a first provoked VTE: 3–6 months is sufficient. For unprovoked or recurrent VTE, or homozygous FVL: lean toward indefinite.

3. Primary Prevention in Asymptomatic FVL Carriers

Most FVL heterozygous carriers never need anticoagulation unless they have had a VTE. Management is about risk factor modification and situational prophylaxis:

Intervention	Why
Avoid combined OCP	OCP + FVL heterozygous ≈ 35× VTE risk — this synergistic interaction is dramatic; alternatives: progesterone-only contraception (much lower VTE risk), copper IUD, barrier methods
Avoid HRT with oestrogen	Same mechanism — exogenous oestrogen increases pro-coagulant factor production
Smoking cessation	Smoking damages endothelium → Virchow's triad
Maintain healthy weight	Obesity → chronic inflammation, impaired fibrinolysis, reduced mobility → stasis
Stay mobile	Avoid prolonged immobility; during long-haul travel (> 6–8 hours): regular calf exercises, adequate hydration, consider graduated compression stockings

FVL carriers should receive thromboprophylaxis in high-risk situations even without prior VTE:

Situation	Prophylaxis
Major surgery	Standard pharmacological prophylaxis with LMWH (e.g. enoxaparin 40 mg SC OD) + mechanical prophylaxis (graduated compression stockings, intermittent pneumatic compression)
Prolonged immobilisation / hospitalisation	LMWH prophylaxis as per standard protocols
Pregnancy (see below)	Risk-stratified approach
Long-haul travel (> 6–8h)	Hydration, calf exercises, compression stockings; LMWH prophylaxis generally NOT indicated for heterozygous carriers unless additional risk factors present

Pregnancy in FVL carriers requires special consideration because:

Pregnancy itself is a hypercoagulable state (↑Factors VII, VIII, X, fibrinogen; ↓Protein S)
Warfarin is contraindicated in pregnancy (crosses placenta → teratogenic in 1st trimester → nasal hypoplasia, chondrodysplasia punctata; risk of fetal ICH in 3rd trimester) ^[10]
DOACs are contraindicated in pregnancy (insufficient safety data)
LMWH is the anticoagulant of choice in pregnancy — does not cross the placenta

Scenario	Management
FVL carrier, no prior VTE	Antepartum: consider prophylactic LMWH especially if additional risk factors (obesity, family Hx of VTE, bed rest) or homozygous; postpartum: prophylactic LMWH for 6 weeks (highest VTE risk when blood returns from uterine vasculature) ^[10]
FVL carrier, prior VTE	Therapeutic LMWH throughout pregnancy → stop for delivery → restart postpartum for ≥6 weeks; can transition to warfarin postpartum once haemostasis secured (warfarin is safe in breastfeeding)
Timing switch	If previously on warfarin: switch to LMWH when pregnancy confirmed (1st trimester) to avoid teratogenicity; also stop LMWH at ≥36 weeks or before planned delivery to avoid postpartum haemorrhage; restart 6–12 hours postpartum ^[10]

Cover up to 6 weeks postpartum — this is the highest risk period as blood returns from the involuting uterus, and coagulation factors remain elevated ^[10].

Topic	Key Points
Who to screen?	First-degree relatives of confirmed FVL patients — particularly those who are young women of childbearing age (OCP and pregnancy implications)
What to tell carriers?	FVL is common in Caucasians; most carriers never clot; avoid OCP; inform all treating doctors of carrier status; seek prophylaxis in high-risk situations
Prenatal / preconception counselling	If both parents carry FVL → 25% chance of homozygous offspring (much higher VTE risk); discuss pregnancy management plan with haematologist

Modality	Indication	Contraindications / Cautions
LMWH	Initial VTE treatment; pregnancy; cancer-associated VTE	Reduce dose if CrCl < 30 ^[6]; caution in morbid obesity (poor SC absorption)
UFH	Initial VTE treatment when thrombolysis considered, renal failure, pregnancy, morbid obesity	HIT (heparin-induced thrombocytopenia and thrombosis); osteoporosis (long-term); hyperkalaemia (rare — aldosterone suppression) ^[6]
Warfarin	Long-term anticoagulation; mechanical valves; APLS	Pregnancy (teratogenic); skin necrosis (Protein C/S deficiency); drug interactions; requires INR monitoring
DOACs	Long-term VTE anticoagulation (non-pregnant, non-APLS)	Mechanical valves, APLS, pregnancy, severe renal impairment ^[17]; andexanet alfa availability limited
rtPA (thrombolysis)	Massive PE with haemodynamic instability; phlegmasia cerulea dolens	Recent major surgery; active bleeding; haemorrhagic stroke; intracranial neoplasm
Surgical / catheter-directed embolectomy	Massive PE when tPA contraindicated or fails	Requires cardiothoracic surgery or interventional radiology availability
IVC filter	C/I to anticoagulation + DVT with high PE risk; temporary bridge during surgery	No RCT evidence; must plan removal; endothelialisation if left in situ
Graduated compression stockings	Adjunctive in DVT management; prophylaxis in high-risk situations	Must be properly fitted; C/I in peripheral arterial disease (limb ischaemia)

High Yield Summary — Management of FVL

Acute VTE treatment is identical regardless of FVL status — LMWH/UFH initially → transition to warfarin or DOAC
FVL influences the DURATION of anticoagulation, not the choice of drug: heterozygous first provoked VTE → 3–6 months; unprovoked/recurrent/homozygous → consider indefinite
DOAC is non-inferior to warfarin with reduced bleeding ^[18] — now first-line for most VTE; but warfarin still preferred for mechanical valves, APLS
Warfarin requires 5-day overlap with LMWH until INR 2–3 (Protein C drops faster than pro-coagulant factors → paradoxical hypercoagulability)
Warfarin-induced skin necrosis = Protein C deficiency, NOT FVL
Thrombolysis only for massive PE (haemodynamic instability) or phlegmasia cerulea dolens
IVC filter has very limited role — no RCT evidence; only when anticoagulation absolutely contraindicated
Asymptomatic FVL carriers: avoid OCP, situational VTE prophylaxis, family screening
Pregnancy: LMWH throughout (warfarin/DOAC contraindicated); cover 6 weeks postpartum
Pharmacogenomics: VKORC1 and CYP2C9 influence warfarin dosing

Active Recall - Factor V Leiden Management

^[1] Senior notes: Ryan Ho Haemtology.pdf (p.135) — inherited thrombophilia treatment table (AT-III deficiency heparin resistance, Protein C/warfarin skin necrosis, Protein S prophylaxis) ^[2] Senior notes: Maksim Medicine Notes.pdf (p.165) — thrombophilia screening indications, timing ^[3] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.26) — thrombolysis indications, IVC filter, phlegmasia cerulea dolens ^[6] Senior notes: Maksim Medicine Notes.pdf (p.59, 289) — anticoagulant classes, MOA, dosing, side effects, VTE management protocol, duration ^[10] Senior notes: Ryan Ho Haemtology.pdf (p.132) — management principles, cancer-associated VTE, pregnancy anticoagulation, APLS warfarin preference ^[17] Senior notes: Block A - Clinical pharmacology of antiplatelets and anticoagulation.pdf (p.5) — DOAC antidotes (idarucizumab, andexanet alfa), DOAC contraindications, Factor XI inhibitors ^[18] Lecture slides: Handbook of Internal Medicine 2024.pdf (p.42) — DOAC VTE dosing regimens, thrombolysis protocol, IVC filter indications ^[19] Senior notes: Learning_Points_All_Lectures.txt — VKORC1/CYP2C9 pharmacogenomics for warfarin dosing

Complications of Factor V Leiden

Factor V Leiden, as a lifelong hypercoagulable state, gives rise to complications that can be understood through two lenses: (1) direct thrombotic complications from the mutation itself, and (2) complications of the treatment (anticoagulation). We will cover both systematically, explaining the pathophysiology from first principles for every complication.

A. Thrombotic Complications of Factor V Leiden

These are the consequences of the persistent hypercoagulable state caused by APC resistance. The unifying mechanism: Factor Va Leiden resists inactivation → prolonged thrombin generation → clot formation in the venous system.

Why does this happen? A DVT in the lower limb (especially proximal DVT — popliteal, femoral, or iliac vein) can fragment or propagate. Pieces of thrombus break off and travel through the venous system → right atrium → right ventricle → pulmonary arterial circulation → lodges where the vessel diameter becomes smaller than the embolus.

Severity	Pathophysiology	Clinical Consequence
Small/subsegmental PE	Occludes peripheral pulmonary artery branch → V/Q mismatch → hypoxaemia	Pleuritic chest pain, mild dyspnoea, haemoptysis (if pulmonary infarction occurs)
Submassive PE	Occludes lobar or multiple segmental arteries → increased pulmonary vascular resistance → RV strain without systemic hypotension	Dyspnoea, tachycardia, elevated troponin/BNP (RV injury markers), RV dilatation on echo
Massive PE	Saddle embolus at pulmonary artery bifurcation → near-complete obstruction of RV outflow → acute right ventricular failure → cardiogenic shock	Syncope, severe hypotension (sBP < 90), cardiac arrest, sudden death

Patients with PE usually die from right heart failure (cardiogenic shock) rather than hypoxaemia ^[4]^[5]

Risk in FVL: Heterozygous FVL carriers have approximately 2–3× increased risk of PE compared to the general population when they develop DVT. Homozygous carriers have substantially higher risk.

What is it? PTS develops in 20–50% of patients after a DVT, typically within 1–2 years.

Pathophysiology from first principles:

Acute DVT damages the venous valves in the deep veins → valvular incompetence
Even after the thrombus resolves (through fibrinolysis or recanalisation), the valves remain damaged
Damaged valves → chronic venous reflux → blood pools in the lower limb when standing
Additionally, residual thrombus or fibrotic changes can cause chronic venous outflow obstruction
Both mechanisms → sustained venous hypertension in the lower limb
Chronic venous hypertension → fluid transudation, tissue oedema, capillary leakage, inflammatory changes

Clinical features of PTS:

Feature	Pathophysiological Basis
Chronic leg swelling	Persistent venous hypertension → fluid transudation
Heaviness, aching, fatigue in the affected limb	Venous congestion → poor tissue perfusion + tissue oedema compressing nerve endings
Stasis dermatitis (brownish pigmentation, eczematous changes)	Chronic capillary leakage → extravasation of red blood cells → haemosiderin deposition in the skin → brown discolouration
Lipodermatosclerosis (hardening of subcutaneous tissue)	Chronic inflammation → fibrosis of subcutaneous fat and dermis
Venous ulceration (most severe form)	End-stage venous hypertension → tissue ischaemia from poor perfusion despite venous congestion → skin breakdown, ulcers typically around the medial malleolus (where perforating veins are most prominent)
Varicose veins	Chronic deep vein valve incompetence → blood diverts to superficial veins → dilatation

Why is PTS relevant to FVL? Patients with FVL are at increased risk of recurrent ipsilateral DVT, which markedly increases the risk of PTS. Each recurrence causes additional valve damage.

Prevention and management of PTS:

Early and adequate anticoagulation for DVT (prevents thrombus propagation → less valve damage)
Graduated compression stockings (though evidence from SOX trial has questioned benefit; still commonly used)
Exercise and leg elevation
Treatment of venous ulcers: compression bandaging, wound care

What is it? CTEPH develops in ~2–4% of patients after acute PE. It is essentially the pulmonary equivalent of post-thrombotic syndrome.

Pathophysiology:

After acute PE, most patients completely lyse the clot through endogenous fibrinolysis
In a subset of patients, the clot does NOT fully resolve → organises into fibrotic, endothelialised tissue within the pulmonary arteries
This creates chronic mechanical obstruction of the pulmonary vascular bed
Additionally, the chronic obstruction triggers secondary small-vessel arteriopathy (remodelling of the unobstructed pulmonary arteries due to flow redistribution and shear stress)
Progressive increase in pulmonary vascular resistance → pulmonary hypertension → right ventricular failure (cor pulmonale)

Clinical features:

Progressive exertional dyspnoea (months to years after the initial PE — there may be a "honeymoon period" of apparent recovery before symptoms emerge)
Exercise intolerance, fatigue
Signs of right heart failure: raised JVP, peripheral oedema, hepatomegaly, ascites
Loud P2, RV heave, TR murmur

Diagnosis: Echocardiogram at 3–6 months follow-up after PE to screen for CTEPH ^[6]

Relevance to FVL: FVL patients with recurrent PE are at increased risk. Lifelong anticoagulation for recurrent VTE also serves to prevent CTEPH.

Why? FVL is a permanent, irreversible risk factor. Unlike a provoked DVT from surgery (where the provoking factor resolves), the hypercoagulable state in FVL persists for life.

Heterozygous FVL: ~1.4× increased risk of recurrent VTE after a first event (modest increment, because the "second hit" risk factors may also resolve)
Homozygous FVL: significantly higher recurrence risk → this is a major driver for indefinite anticoagulation
Each recurrence compounds the damage: more valve destruction → worse PTS; more PE → higher CTEPH risk

The decision to continue or stop anticoagulation after the initial 3–6 months is largely driven by the estimated risk of recurrence (see Management section).

While FVL predominantly causes lower-limb DVT and PE, the persistent hypercoagulable state can also lead to thrombosis at unusual sites — particularly when combined with additional risk factors:

Site	Pathophysiology	Clinical Consequence
Cerebral venous sinus thrombosis (CVST)	Thrombosis of dural venous sinuses → impaired CSF absorption and venous drainage → raised intracranial pressure + venous infarction (which may become haemorrhagic)	Headache, papilloedema, seizures, focal deficits; classically in young women on OCP with FVL
Hepatic vein thrombosis (Budd-Chiari syndrome)	Thrombosis of hepatic veins → sinusoidal congestion → hepatocyte necrosis → portal hypertension	Hepatomegaly, ascites, abdominal pain, liver failure; FVL is one of many thrombophilic causes
Portal vein thrombosis	Thrombosis of portal vein → portal hypertension → collateral development	Abdominal pain, splenomegaly, variceal bleeding, ascites; majority clinically silent ^[20]; chronic → cavernous transformation
Mesenteric venous thrombosis	Venous congestion of bowel wall → oedema → ischaemia → potentially bowel infarction and necrosis	Severe abdominal pain (often out of proportion to exam findings), nausea, bloody diarrhoea
Renal vein thrombosis	Occlusion of renal vein → renal congestion → proteinuria, haematuria, flank pain	Particularly relevant when FVL coexists with nephrotic syndrome (where urinary loss of AT-III and Protein S ^[21]^[22] compounds the hypercoagulability)

Nephrotic Syndrome + FVL = Compounded Thrombosis Risk

Nephrotic syndrome causes hypercoagulability through: (1) urinary loss of antithrombin III and Protein S, (2) increased hepatic synthesis of clotting factors, and (3) haemoconcentration from hypovolaemia ^[21]^[22]. If a patient with nephrotic syndrome also has FVL, the thrombosis risk is multiplicative. Renal vein thrombosis and PE are the most feared thrombotic complications of nephrotic syndrome.

FVL increases the risk of adverse pregnancy outcomes through placental microvascular thrombosis.

Complication	Pathophysiology
Recurrent pregnancy loss	Micro-thrombosis in spiral arteries and intervillous spaces of the placenta → placental ischaemia and infarction → fetal demise; association strongest with late pregnancy loss (> 10 weeks)
Pre-eclampsia	Impaired trophoblast invasion + placental thrombosis → placental ischaemia → release of anti-angiogenic factors (sFlt-1) into maternal circulation → endothelial dysfunction → hypertension + proteinuria
Placental abruption	Thrombosis in decidual vessels → haemorrhage behind the placenta → premature separation
Intrauterine growth restriction (IUGR)	Chronic placental insufficiency from micro-thrombosis → inadequate nutrient and oxygen delivery to the fetus
VTE during pregnancy / puerperium	Pregnancy is already hypercoagulable (↑clotting factors, ↓Protein S, venous stasis from gravid uterus compressing IVC); FVL adds another layer; risk highest at 6 weeks postpartum ^[3]

"6 weeks postpartum is when the risk of thrombosis is highest" ^[3] — guidelines of management are written accordingly: LMWH prophylaxis continues through this high-risk period.

B. Complications of Anticoagulation Therapy

Since most symptomatic FVL patients require anticoagulation — sometimes indefinitely — the complications of treatment itself are important:

Severity	Examples	Risk Factors
Minor	Epistaxis, gum bleeding, easy bruising, menorrhagia	Over-anticoagulation (INR > 3 for warfarin), concurrent antiplatelet use
Major	GI haemorrhage, retroperitoneal haemorrhage	Falls, elderly, renal impairment, peptic ulcer disease, concurrent NSAIDs
Life-threatening	Intracranial haemorrhage	The most feared complication; risk ~0.3–0.5%/year on warfarin; lower on DOACs

Management of anticoagulant-related bleeding:

Warfarin: IV vitamin K (reversal in 6–12 hours) + fresh frozen plasma (immediate but transient) or prothrombin complex concentrate (PCC) for urgent reversal
UFH: Protamine sulfate (complete reversal)
LMWH: Protamine (only partial reversal, ~60%)
Dabigatran: Idarucizumab (specific monoclonal antibody antidote) ^[17]
Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban): Andexanet alfa (not universally available; clinical benefit not fully established) ^[17]; PCC as alternative

Pathophysiology:

Heparin binds to platelet factor 4 (PF4) on platelet surfaces → forms a heparin-PF4 complex
Some patients develop IgG antibodies against the heparin-PF4 complex
These antibodies bind to the complex → activate platelets via FcγRIIa receptors → platelet aggregation
Paradox: despite thrombocytopenia (platelets consumed in aggregation), the massive platelet activation creates a prothrombotic state → arterial and venous thrombosis

Clinical features:

Platelet drop > 50% from baseline, typically 5–14 days after starting heparin (or earlier if previous exposure)
Thrombosis (DVT, PE, limb ischaemia, stroke) — not bleeding
Skin necrosis at heparin injection sites

Management:

Stop ALL heparin immediately
Start non-heparin anticoagulant (e.g. argatroban, fondaparinux, bivalirudin)
Do NOT give warfarin until platelets recover (warfarin in HIT can cause venous limb gangrene via the Protein C mechanism)
Bridge to warfarin or DOAC once platelets normalise

Relevance to FVL: FVL patients who develop HIT are in a particularly dangerous situation — they have two prothrombotic states (FVL + HIT) simultaneously. Urgent switch to a non-heparin anticoagulant is critical.

This is a complication of warfarin therapy, NOT a complication of FVL per se — it is associated with Protein C deficiency ^[1]^[2]:

Occurs in the first few days of warfarin initiation
Warfarin suppresses Protein C (half-life ~8 hours) faster than pro-coagulant factors (Factor II half-life ~60 hours) → transient paradoxical hypercoagulable state
In patients with pre-existing Protein C deficiency, this is extreme → microvascular thrombosis → cutaneous necrosis, typically over fatty areas (breasts, thighs, buttocks)
Prevention: adequate heparin overlap during warfarin initiation (minimum 5 days)

Common Exam Trap

Warfarin-induced skin necrosis = Protein C/S deficiency, NOT Factor V Leiden. This distinction is repeatedly examined. FVL patients do not have an increased risk of warfarin-induced skin necrosis because their Protein C levels are normal.

Long-term UFH (rarely, LMWH) can cause osteoporosis by inhibiting osteoblast activity and increasing osteoclast activity
Warfarin inhibits vitamin K-dependent carboxylation of osteocalcin → impaired bone mineralisation
Relevant for FVL patients on indefinite anticoagulation, particularly if using these agents long-term
DOACs do NOT appear to have this effect — another advantage

Warfarin crosses the placenta → teratogenic in 1st trimester (warfarin embryopathy: nasal hypoplasia, chondrodysplasia punctata) → risk of fetal ICH in 2nd/3rd trimester ^[10]
This is why LMWH is mandatory in pregnancy for FVL patients who need anticoagulation

Often overlooked but important for holistic care:

Complication	Explanation
Anxiety about clotting	Knowing you carry a thrombophilia can cause significant psychological distress, particularly in young carriers who have witnessed family members with VTE
OCP restriction in young women	Being told to avoid combined OCP affects reproductive planning and quality of life; requires discussion of alternatives
Pregnancy anxiety	Fear of VTE during pregnancy and concern about adverse pregnancy outcomes; requires specialist antenatal care
Insurance and employment	In some jurisdictions, genetic diagnoses can affect life/health insurance; important to discuss
Family screening burden	Identification of an index case triggers testing of relatives, some of whom may not wish to know their genetic status

High Yield Summary — Complications of Factor V Leiden

Thrombotic Complications (Direct):

PE — most feared acute complication; massive PE → RV failure → cardiogenic shock → death
Post-thrombotic syndrome — chronic venous insufficiency after DVT (20–50%); stasis dermatitis → lipodermatosclerosis → venous ulceration
CTEPH — organised thrombus in pulmonary arteries → chronic pulmonary hypertension → cor pulmonale (2–4% post-PE); screen with echo at 3–6 months
Recurrent VTE — permanent risk factor means lifelong recurrence risk; drives decision for indefinite anticoagulation
Unusual-site thrombosis — CVST, Budd-Chiari, portal/mesenteric/renal vein thrombosis
Pregnancy complications — recurrent pregnancy loss, pre-eclampsia, placental abruption, IUGR, peripartum VTE (peak risk 6 weeks postpartum)

Treatment Complications: 7. Bleeding — universal risk of anticoagulation; ICH most feared; antidotes: protamine (heparin), vitamin K/PCC (warfarin), idarucizumab (dabigatran) 8. HIT — heparin-PF4 antibodies → paradoxical thrombosis + thrombocytopenia; stop all heparin, switch to non-heparin anticoagulant 9. Warfarin-induced skin necrosis = Protein C deficiency, NOT FVL 10. Osteoporosis — long-term heparin/warfarin 11. Teratogenicity — warfarin in pregnancy; use LMWH instead

Active Recall - Factor V Leiden Complications

References

^[1] Senior notes: Ryan Ho Haemtology.pdf (p.135) — inherited thrombophilia table, AT-III deficiency heparin resistance, Protein C/warfarin skin necrosis ^[2] Senior notes: Maksim Medicine Notes.pdf (p.165) — thrombophilia screening, warfarin-induced skin necrosis ^[3] Senior notes: Block A - Leg swelling and chest pain: deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p.6, 13, 19, 26) — inherited thrombophilia, pregnancy VTE risk, 6 weeks postpartum, IVC filter ^[4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.620, 622) — DVT complications (PE, chronic venous insufficiency), IVC filter, surgical treatment ^[5] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p.971, 973) — DVT complications, IVC filter placement ^[6] Senior notes: Maksim Medicine Notes.pdf (p.289) — VTE management, follow-up echocardiogram for CTEPH ^[10] Senior notes: Ryan Ho Haemtology.pdf (p.132, 134) — pregnancy anticoagulation, warfarin teratogenicity, secondary prevention measures ^[17] Senior notes: Block A - Clinical pharmacology of antiplatelets and anticoagulation.pdf (p.5) — DOAC antidotes (idarucizumab, andexanet alfa) ^[20] Senior notes: Block A - Abdominal distension: ascites and cirrhosis.pdf (p.19) — portal vein thrombosis, cavernous transformation, complications ^[21] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1024) — nephrotic syndrome hypercoagulability (AT-III/Protein S loss, clotting factor increase) ^[22] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.437) — nephrotic syndrome hypercoagulability mechanism, renal vein thrombosis

High Yield Summary

Factor V Leiden = most common inherited thrombophilia in Caucasians; point mutation G1691A → Arg506Gln → Factor Va resistant to APC cleavage → hypercoagulable state → VTE risk
Inheritance: Autosomal dominant, incomplete penetrance. Heterozygotes 3–8× VTE risk; homozygotes ~50–80× risk
NOT found in Chinese — in Hong Kong, the relevant inherited thrombophilias are Protein C, Protein S, and Antithrombin III deficiency; the most common cause of unprovoked VTE in HK is malignancy
Mechanism: Dual defect — (a) Factor Va Leiden resists APC inactivation, (b) loses its cofactor role in APC-mediated Factor VIIIa degradation
Clinical presentation: Predominantly venous thrombosis (DVT > PE > unusual sites). NOT arterial. Associated with pregnancy complications
OCP + FVL ≈ 35× VTE risk — classic exam scenario
Thrombophilia screening indications: young unprovoked VTE, recurrent VTE, unusual site, family history, warfarin-induced skin necrosis, recurrent miscarriage. Do NOT test during acute VTE or on anticoagulants
Tests: Functional APCR assay (screening) → FVL PCR (confirmatory/genetic test)
Warfarin-induced skin necrosis = Protein C deficiency, not FVL

High Yield Summary – Diagnostics

FVL is diagnosed by genetic testing (FVL PCR), not by clinical criteria
APCR assay is the functional screening test — abnormal ratio (< 2.0) suggests APC resistance → must confirm with PCR
Standard clotting profile (PT, APTT) is NORMAL in FVL — thrombophilias are "braking system" failures, not measurable by standard clotting tests
Thrombophilia screen timing: not during acute VTE, off warfarin ≥2 weeks, off DOAC ≥2 days
Full screen includes: APCR, Protein C, Protein S, AT-III, FVL PCR, PT G20210A PCR, anti-cardiolipin, anti-β2-GPI, lupus anticoagulant
Always screen for occult malignancy in unprovoked VTE — history, examination, CXR, bloods, urinalysis
CTPA is gold standard for PE diagnosis; duplex USG for DVT; D-dimer for rule-out in low-risk patients
Lupus anticoagulant prolongs APTT in vitro but causes thrombosis in vivo — mixing study does NOT correct (unlike factor deficiency)

High Yield Summary — Management of FVL

Acute VTE treatment is identical regardless of FVL status — LMWH/UFH initially → transition to warfarin or DOAC
FVL influences the DURATION of anticoagulation, not the choice of drug: heterozygous first provoked VTE → 3–6 months; unprovoked/recurrent/homozygous → consider indefinite
DOAC is non-inferior to warfarin with reduced bleeding ^[18] — now first-line for most VTE; but warfarin still preferred for mechanical valves, APLS
Warfarin requires 5-day overlap with LMWH until INR 2–3 (Protein C drops faster than pro-coagulant factors → paradoxical hypercoagulability)
Warfarin-induced skin necrosis = Protein C deficiency, NOT FVL
Thrombolysis only for massive PE (haemodynamic instability) or phlegmasia cerulea dolens
IVC filter has very limited role — no RCT evidence; only when anticoagulation absolutely contraindicated
Asymptomatic FVL carriers: avoid OCP, situational VTE prophylaxis, family screening
Pregnancy: LMWH throughout (warfarin/DOAC contraindicated); cover 6 weeks postpartum
Pharmacogenomics: VKORC1 and CYP2C9 influence warfarin dosing

High Yield Summary — Complications of Factor V Leiden

Thrombotic Complications (Direct):

PE — most feared acute complication; massive PE → RV failure → cardiogenic shock → death
Post-thrombotic syndrome — chronic venous insufficiency after DVT (20–50%); stasis dermatitis → lipodermatosclerosis → venous ulceration
CTEPH — organised thrombus in pulmonary arteries → chronic pulmonary hypertension → cor pulmonale (2–4% post-PE); screen with echo at 3–6 months
Recurrent VTE — permanent risk factor means lifelong recurrence risk; drives decision for indefinite anticoagulation
Unusual-site thrombosis — CVST, Budd-Chiari, portal/mesenteric/renal vein thrombosis
Pregnancy complications — recurrent pregnancy loss, pre-eclampsia, placental abruption, IUGR, peripartum VTE (peak risk 6 weeks postpartum)

Factor V Leiden

References

Definition

Epidemiology

Global Prevalence

VTE Risk by Genotype

Anatomy and Function: The Protein C Anticoagulant Pathway

Normal Coagulation Cascade (Relevant Portion)

Normal Protein C Anticoagulant Pathway (The "Brake")

What Goes Wrong in Factor V Leiden

Etiology

Genetic Etiology

Acquired APC Resistance (Not FVL, but Mimics It)

Pathophysiology

Why Not Everyone with FVL Gets a Clot

Classification

By Genotype

Classification Within the Broader Thrombophilia Framework

Clinical Features

Who Presents?

Symptoms (with Pathophysiological Basis)

1. Deep Vein Thrombosis (DVT) — The Most Common Presentation

2. Pulmonary Embolism (PE) — The Life-Threatening Complication

3. Unusual Site Thrombosis (Particularly Associated with Thrombophilia)

4. Pregnancy-Related Complications

Signs (with Pathophysiological Basis)

Signs of DVT

Signs of PE

Important Distinction: FVL vs Other Inherited Thrombophilias

Indications for Thrombophilia Screening

Active Recall - Factor V Leiden

References

Differential Diagnosis of Factor V Leiden

Framing the DDx Question Correctly

Framework 1: Differential Diagnosis of the Underlying Cause of VTE (Thrombophilia DDx)

A. Inherited Thrombophilias (Autosomal Dominant)

B. Acquired Thrombophilias

C. Non-Thrombophilia Causes of VTE (Provoked VTE)

Framework 2: Differential Diagnosis of APC Resistance (When APCR Assay is Abnormal)

Framework 3: DDx When the Clinical Presentation Overlaps

DDx of DVT (Clinical Mimics) [4][5][10]

DDx of PE [10]

Systematic Approach: Narrowing the DDx for a Patient with Suspected FVL

Active Recall - Factor V Leiden Differential Diagnosis

References

Diagnostic Criteria for Factor V Leiden

Important Conceptual Preface

Indications for Thrombophilia Screening (When to Suspect FVL)

Timing of Testing — Critical Pitfalls

Diagnostic Algorithm

Investigation Modalities — Detailed Breakdown

Tier 1: The Core FVL Diagnostic Tests

1. Activated Protein C Resistance (APCR) Assay — The Functional Screening Test

2. Factor V Leiden PCR — The Definitive Genetic Test

Tier 2: Complete Thrombophilia Screen (Sent Alongside FVL Testing)

Tier 3: Investigations for VTE (When FVL Patient Presents with Acute Thrombosis)

For Suspected DVT

For Suspected PE

Tier 4: Occult Malignancy Screen (For All Unprovoked VTE)

Summary: Interpretation of Clotting Profile in FVL

Putting It All Together: Complete Investigative Approach

Active Recall - Factor V Leiden Diagnostics

References

Management of Factor V Leiden

Conceptual Framework: What Are We Actually Treating?

Management Algorithm Overview

Treatment Modalities in Detail

1. Acute VTE Treatment (Same as Any VTE)

A. Initial Anticoagulation

B. Long-Term Anticoagulation — Drug Options

Warfarin (Vitamin K Antagonist)

Direct Oral Anticoagulants (DOACs)

C. Management of Haemodynamically Unstable PE (Massive PE)

D. IVC Filter

2. Duration of Anticoagulation — The Key FVL-Specific Decision

3. Primary Prevention in Asymptomatic FVL Carriers

A. Risk Factor Modification

B. Situational VTE Prophylaxis

4. Management During Pregnancy

5. Family Counselling and Genetic Screening