• Female sex (especially of childbearing age)
• Black ethnicity
• Obesity (BMI > 30 — association with increased autoimmune TTP risk)
• Underlying autoimmune conditions (SLE, RA, Sjögren syndrome — these patients have a dysregulated immune system prone to producing autoantibodies, including anti-ADAMTS13 antibodies)

Secondary causes of acquired TTP include: ^[1]

May be further precipitated by conditions associated with decreased ADAMTS13 activity, e.g. sepsis, cardiac surgery, pancreatitis, liver disease ^[2]

1. Synthesis: vWF is synthesised by endothelial cells and megakaryocytes. It is stored in:
   • Weibel-Palade bodies in endothelial cells
   • α-granules in platelets
2. Release: Upon endothelial activation (by injury, inflammation, high shear stress), vWF is released as ultra-large vWF multimers (UL-vWF) — these are extremely long, "string-like" glycoprotein chains that unfurl from the endothelial surface into the flowing blood
3. Function of UL-vWF: These ultra-large multimers are the most biologically active form of vWF — they are hyperadhesive and bind platelets avidly via the platelet receptor GPIb-IX-V complex (= platelet adhesion)
4. Role of ADAMTS13: Under normal circumstances, ADAMTS13 circulates in the plasma and rapidly cleaves UL-vWF multimers at a specific peptide bond (Tyr1605-Met1606 in the A2 domain). This cleavage:
   • Occurs optimally under high shear stress conditions (shear stress unfolds the vWF A2 domain, exposing the cleavage site)
   • Converts hyperadhesive UL-vWF into smaller, less thrombogenic multimers
   • This is a constitutive, ongoing process — it is the body's way of preventing spontaneous platelet adhesion in the microvasculature

Microthrombi form preferentially where shear stress is highest:

• Arterioles and capillaries (smaller diameter = higher shear stress by Poiseuille's law)
• Organs with rich microvascular beds: brain (CNS), kidneys, heart, skin, GI tract ^[2]
• This explains the clinical manifestations: neurological symptoms, renal impairment, cardiac ischaemia, purpura, and abdominal pain

• Produced primarily by hepatic stellate cells (not hepatocytes — this is why liver disease can decrease ADAMTS13 levels but does not abolish it entirely)
• Also produced by endothelial cells, podocytes, and megakaryocytes (minor contribution)
• Plasma half-life: ~2–3 days
• Normal plasma ADAMTS13 activity: 50–150%
• TTP is defined by severe ADAMTS13 deficiency: activity ≤ 10%

This is the core concept. Let's walk through it from first principles:

Step 1: ADAMTS13 Deficiency

• Whether from autoantibodies (acquired) or genetic mutations (hereditary), ADAMTS13 activity falls to ≤ 10% of normal

Step 2: Accumulation of Ultra-Large vWF Multimers

• Without ADAMTS13 cleavage, UL-vWF multimers released from endothelial cells persist on the endothelial surface and in the circulation
• These UL-vWF strings are hyperadhesive — they readily capture circulating platelets

Step 3: Platelet Adhesion and Aggregation at Sites of High Shear Stress

• Platelets bind to UL-vWF via GPIb-IX-V → platelet activation → further platelet recruitment
• This occurs preferentially in arterioles and capillaries where shear stress is highest (shear stress unfurls vWF, exposing binding sites)
• Result: formation of platelet-rich microthrombi (these are "white thrombi" — composed predominantly of platelets and vWF, with relatively little fibrin)

This is a crucial distinction: TTP thrombi are platelet-rich (white thrombi), whereas DIC thrombi are fibrin-rich (red thrombi). This is why the clotting profile (PT, aPTT, fibrinogen) is typically normal in TTP — the coagulation cascade is NOT primarily activated. Clotting profile: normal (rule out DIC) ^[3].

Step 4: Thrombocytopenia

• Platelets are consumed in the microthrombi → severe thrombocytopenia (mean platelet count ~10 × 10⁹/L at presentation ^[2])
• This consumption is the reason for the low platelet count — it is NOT immune-mediated destruction as in ITP

Step 5: Microangiopathic Haemolytic Anaemia (MAHA)

• Red blood cells are forced through the narrowed, thrombus-laden microvasculature
• The mechanical shearing of RBCs against platelet-fibrin strands creates fragmented red cells = schistocytes (including helmet cells, triangular cells)
• This is intravascular haemolysis → elevated LDH, elevated unconjugated bilirubin, reduced haptoglobin, reticulocytosis
• The DAT (direct antiglobulin/Coombs test) is negative ^[3] — this is NOT immune-mediated haemolysis

Step 6: Organ Ischaemia and Injury

• Microvascular thrombotic occlusion → downstream tissue ischaemia
• Typical sites: kidneys, CNS, heart, skin, GI tract ^[2]
• The clinical manifestations depend on which organs are affected

An important concept: many patients with acquired TTP have low-level anti-ADAMTS13 antibodies or mildly reduced ADAMTS13 activity for some time before their acute episode. TTP generally only becomes symptomatic with additional factors that trigger decreased ADAMTS13 activity, e.g. sepsis ^[2]. This is the "two-hit":

1. First hit: Underlying severe ADAMTS13 deficiency (autoantibody or genetic)
2. Second hit: A precipitating event that either:
   • Further decreases ADAMTS13 activity (e.g., increased vWF release from endothelial activation during infection/inflammation overwhelms the already-depleted ADAMTS13)
   • Increases endothelial vWF release (surgery, pregnancy, infection)
   • Activates the complement system or endothelium

It is critical to understand where TTP sits among other TMAs, as the management differs drastically:

Clotting profile is normal in TTP (use this to rule out DIC) ^[3]. This is because TTP thrombi are platelet-rich, not fibrin-rich — the coagulation cascade is not activated to the same degree as in DIC.

The classical pentad of TTP is a historical description that is present in only ~35% of cases at diagnosis ^[3]. Modern practice is to initiate treatment well before the full pentad develops. The pentad consists of:

1. Fever
2. Anaemia (MAHA)
3. Thrombocytopenia → petechiae
4. Renal impairment → microthrombi in kidney
5. Neurological fluctuating signs → microthrombi in brain ^[3]

Bleeding in TTP is generally minor despite severe thrombocytopenia ^[2]. Major overt bleeding is rare. This is because:

• The thrombi are consuming the platelets but the remaining haemostatic system (coagulation cascade, fibrinogen) remains intact
• The platelet count is very low, but enough to prevent major haemorrhage in most cases
• However, petechiae and purpura are seen in approximately 54% of patients ^[2]
• Major overt bleeding is rare ^[2]

TTP is primarily a THROMBOTIC condition, not a bleeding condition. Despite the severe thrombocytopenia, the main risk is organ damage from microvascular thrombosis, not haemorrhage. The name "purpura" is somewhat misleading.

Cardiac ischaemia is a significant cause of morbidity and mortality in TTP:

• Troponin elevation is found in up to 50–60% of TTP episodes
• ECG changes (ST-segment changes, arrhythmias) are common
• Sudden cardiac death can occur
• Mechanism: microthrombi in coronary microvasculature → patchy myocardial ischaemia

• Onset over days ^[2] — not a hyperacute presentation; symptoms typically develop and escalate over several days
• Without treatment: progressive multiorgan failure and death (> 90% mortality)
• With treatment (plasma exchange): mortality ~10–20%; but relapse is common (~30–50%)

In DIC, excessive activation of the coagulation cascade leads to: (1) too much thrombin → too much fibrin formation → fibrin clots block blood vessels; (2) excessive consumption of coagulation factors → bleeding tendency; (3) fibrin clots trap and consume platelets → thrombocytopenia; (4) fibrin strands shear RBCs → MAHA ^[5]. The key difference is that in TTP, the coagulation cascade is not primarily activated — the clotting profile is normal.

Terminology can be overlapping and confusing in MAHA: (1) MAHA = non-immune haemolysis due to intravascular RBC fragmentation; causes include TMA, prosthetic heart valve, LVAD, DIC. (2) TMA = pathological diagnosis of abnormalities in vessel wall of arterioles/capillaries leading to microvascular thrombosis; primary: TTP, HUS, drug-induced TMA, complement-mediated TMA; secondary: HELLP, malignant HTN, SLE, scleroderma, APS. (3) DIC = intravascular activation of coagulation with loss of localisation; usually associated with MAHA and microvascular thrombosis predominantly RBCs/fibrin instead of platelets and vWF in TMA ^[2].

The systematic approach to thrombocytopenia is to classify by mechanism:

Causes of MAHA ^[2]:

If you see schistocytes on blood film with normal platelets, think of macrovascular causes (e.g. prosthetic heart valve) rather than TMA ^[9]. The platelets are normal because the issue is not a consumptive process causing microthrombi, but rather mechanical shearing by a large artificial surface.

Approach to petechiae/purpura ^[3]:

• Non-palpable petechiae:
  • Thrombocytopenic: ITP, HUS, TTP, DIC, leukaemia ^[3]
  • Coagulopathy: vWD, haemophilia ^[3]
  • Disrupted vessel integrity: meningococcal sepsis, trauma ^[3]
• Palpable petechiae:
  • Vasculitis: roundish purpura ^[3]
    • Small vessel disease: blisters/ulcers ^[3]
    • Medium vessel disease: network-like rash ^[3]
  • Vasculopathy: angulated purpura; usually poorer prognosis ^[3]
    • Livedo vasculopathy, APLS, calciphylaxis (ESRD), purpura fulminans (DIC) ^[3]

If the patient has haemolysis and the DAT is NEGATIVE, consider ^[10]:

• TTP or other thrombotic microangiopathy (TMA) ^[10]
• G6PD deficiency ^[10]
• Other non-immune causes: mechanical (prosthetic valve), infections (malaria, Clostridium), PNH, Wilson disease

If the DAT is positive, the haemolysis is immune-mediated → think of warm AIHA, cold AIHA, Evans syndrome (AIHA + ITP), drug-induced immune haemolysis — NOT TTP.

• Evans syndrome = AIHA + ITP (autoimmune haemolytic anaemia coexisting with immune thrombocytopenia)
• Can mimic TTP because patient has both anaemia (with haemolysis markers) and thrombocytopenia
• Key distinction: DAT is positive in Evans syndrome (immune haemolysis) vs negative in TTP (mechanical haemolysis); no schistocytes in Evans syndrome
• If a patient with ITP also has anaemia due to haemolysis, consider Evans syndrome (AIHA + ITP) or TMA (MAHA + TTP) ^[4]

• Immune-mediated: anti-PF4/heparin antibodies → platelet activation → thrombosis + thrombocytopenia
• Can mimic TTP due to thrombocytopenia + thrombosis
• Key distinction: History of heparin exposure (typically 5–10 days); no MAHA/schistocytes; platelet drop is usually moderate (nadir ~50–80 × 10⁹/L, rarely < 20); 4T score for pre-test probability; anti-PF4 antibody testing

• Essential thrombocythaemia with very high platelets ( > 1000 × 10⁹/L) can consume vWF → acquired vWD → paradoxical bleeding ^[11]
• This is the opposite end of the spectrum from TTP: too many platelets consuming vWF rather than vWF being uncleaved
• Key distinction: Platelet count is elevated (not low); vWF activity/antigen reduced; ADAMTS13 normal

Pregnancy complicates the DDx of TMA significantly because multiple conditions causing MAHA + thrombocytopenia can occur:

• TTP (can occur any trimester; ADAMTS13 ≤ 10%)
• HELLP syndrome (typically 3rd trimester; elevated LFTs; responds to delivery)
• Pre-eclampsia with severe features (hypertension, proteinuria)
• Acute fatty liver of pregnancy (hypoglycaemia, coagulopathy, liver failure)
• Typical or atypical HUS (postpartum)

ADAMTS13 activity is the critical differentiator: if ≤ 10%, it is TTP regardless of pregnancy status and requires plasma exchange, not just delivery.

The threshold for initiating empirical plasma exchange is deliberately low because untreated TTP has > 90% mortality. You treat first, confirm later.

Minimum requirements to suspect TTP and initiate treatment:

1. Thrombocytopenia — unexplained, typically severe (mean platelet count ~10 × 10⁹/L at presentation ^[2])
2. MAHA — evidenced by:
   • Schistocytes (including helmet cells, triangular cells) on peripheral blood smear ^[2]
   • Haemolysis markers: ↑unconjugated bilirubin, ↑LDH, ↓haptoglobin ^[2]
   • Negative DAT (direct antiglobulin test) — ruling out immune-mediated haemolysis ^[3][10]
3. No alternative explanation — particularly, clotting profile should be normal (to rule out DIC) ^[3]
4. ± Organ involvement — neurological signs, renal impairment, fever, cardiac ischaemia

Severely reduced ADAMTS13 activity < 10% during an acute episode is the hallmark of acquired TTP ^[1][12]

This is the gold-standard confirmatory test. It distinguishes TTP from other TMAs (HUS, complement-mediated TMA, drug-induced toxic TMA) where ADAMTS13 is normal ( > 10%).

Additional confirmatory data:

• Presence of autoantibodies (inhibitor) against ADAMTS13 ^[12] — confirms acquired (immune-mediated) TTP
• If inhibitor is negative but ADAMTS13 < 10%, consider hereditary TTP (Upshaw-Schulman syndrome) → genetic testing for ADAMTS13 mutations

Classical pentad (present in only ~35%) ^[3]:

1. Fever
2. Anaemia (MAHA)
3. Thrombocytopenia → petechiae
4. Renal impairment → microthrombi in kidney
5. Neurological fluctuating signs → microthrombi in brain

CBC: key findings are anaemia + thrombocytopenia ^[3]. Note that the WCC and differential are usually unremarkable in TTP.

This is the single most important "bedside" investigation. It must be ordered urgently.

These tests confirm that haemolysis is occurring and quantify its severity:

Immediately differentiating haemolysis: LDH is the quickest marker — if high, indicates high turnover/haemolysis ^[13].

If patient had schistocytes + haemolysis but a negative DAT, need to start thinking of TTP or other TMA, or G6PD deficiency ^[10].

Clotting profile: should be NORMAL except in severe organ ischaemia causing secondary DIC ^[12]. The normal clotting profile is the single most useful test for distinguishing TTP from DIC.

Useful investigations for exclusion of DIC: peripheral blood film (fragmented red cells), clotting profile (↑PT and aPTT, ↑D-dimer, ↓fibrinogen) ^[8].

This is the definitive diagnostic test for TTP.

Practical points:

• Turnaround time: ADAMTS13 activity testing is a specialised assay, often sent to reference laboratories. Turnaround can be 24–72 hours or longer. This is why empirical treatment must not be delayed.
• Timing: Must be drawn BEFORE the first plasma exchange session (the replacement fluid contains donor ADAMTS13, which will raise the patient's ADAMTS13 level artifactually)
• Methods: FRETS-vWF73 assay (fluorescence resonance energy transfer), chromogenic assay, or ELISA-based methods

Once TTP is confirmed, search for underlying triggers:

Bone marrow biopsy is NOT routinely required in TTP. It may be considered if:

• The diagnosis is uncertain (to rule out leukaemia, MDS, myelofibrosis, aplastic anaemia as causes of thrombocytopenia)
• Indications for BM exam in thrombocytopenia: uncertain diagnosis, prior to splenectomy, poor treatment response ^[4]
• BM findings in consumptive thrombocytopenia: normal cellularity with increased megakaryocytes ^[8] — this reflects the marrow's attempt to compensate for peripheral platelet consumption

• Not routinely performed in TTP (diagnosis is made on blood tests)
• May be indicated if there is diagnostic uncertainty, particularly if significant renal impairment is present and HUS or other renal TMA is suspected
• Vascular diseases — e.g. thrombotic microangiopathy — are an indication for renal biopsy ^[14]
• Histological findings in TMA: arteriolar/capillary thrombi, endothelial swelling, fibrinoid necrosis of vessel walls

This is the cornerstone of TTP treatment and the single intervention that transformed mortality from > 90% to ~10–20%.

Daily plasma exchange with plasma or cryo-reduced plasma (CRP) should be commenced immediately ^[15]

How it works — from first principles:

Plasmapheresis removes large vWF multimers + replaces with FFP containing ADAMTS13 / cryo-reduced plasma ^[3]

Let's break this down into what is removed and what is replaced:

Replacement fluid options:

Plasmapheresis: remove large vWF multimers + replace by FFP (ADAMTS13) / cryo-reduced plasma (CRP) ^[3]

Practical details:

• Volume: 1–1.5 plasma volumes per session (approximately 3–4 litres of plasma exchanged per session for a 70 kg adult)
• Frequency: Daily until platelet count stabilises > 150 × 10⁹/L for ≥ 2 consecutive days ^[15]
• Access: Requires a large-bore double-lumen central venous catheter (e.g., Vascath in internal jugular or femoral vein)
• Duration: Typically 7–14 days, but variable; guided by platelet response
• Tapering: Once sustained platelet normalisation achieved, may taper PEX to every other day before stopping, although this practice varies by centre

Why PEX is superior to simple plasma infusion:

• Simple plasma infusion can provide ADAMTS13 but cannot remove the autoantibody efficiently
• PEX achieves both removal of pathogenic material (autoAb, UL-vWF) AND replenishment of ADAMTS13
• In acute acquired TTP, the autoantibody titre is often high → simple infusion cannot overcome the inhibitor; you must physically remove it
• However, in hereditary TTP (Upshaw-Schulman syndrome), there is no autoantibody — simple FFP infusion (10–15 mL/kg every 2–3 weeks) may be sufficient for prophylaxis because you are simply replacing the missing enzyme

Complications of PEX:

• Citrate toxicity (anticoagulant used in the apheresis circuit) → hypocalcaemia → perioral tingling, cramps, arrhythmias; prophylactic calcium supplementation is given
• Central line complications: infection, pneumothorax, thrombosis
• Allergic reactions to donor plasma
• Hypotension during the procedure
• Coagulopathy: removal of patient's own clotting factors (partially replaced by donor plasma, but transient deficiency possible)

Steroid: Prednisolone 1 mg/kg/day or pulse Methylprednisolone 1g/day × 3 days ^[15]

Why steroids?

• Acquired TTP is an autoimmune condition — IgG autoantibodies against ADAMTS13
• Steroids suppress B-cell antibody production and T-cell helper function → reduce anti-ADAMTS13 autoantibody formation
• They also have general anti-inflammatory effects that may reduce endothelial activation

Regimen options:

Duration: Typically continued for several weeks and tapered gradually once sustained platelet remission is achieved. Abrupt cessation risks relapse.

Immunosuppressants: high-dose steroids + rituximab ^[3] — rituximab is added upfront in many centres now (see below).

What it is: Rituximab is a chimeric monoclonal antibody targeting CD20 on B lymphocytes → B-cell depletion → reduced autoantibody (anti-ADAMTS13 IgG) production.

"Rituximab" → "ritu" from rituximab (chimeric), "xi" = chimeric antibody suffix, "mab" = monoclonal antibody.

Indications:

1. Refractory TTP: no adequate platelet response to PEX + steroids after ~5–7 days
2. Upfront (frontline) use: increasingly used in combination with PEX + steroids from the start, especially in severe presentations (e.g., neurological involvement, very high inhibitor titre)
3. Relapse prevention: when ADAMTS13 activity remains < 10% during remission (even without clinical symptoms) → pre-emptive rituximab to prevent clinical relapse
4. Relapsing TTP: at the time of each relapse

Regimen: Standard dosing is 375 mg/m² IV weekly × 4 doses

Onset of action: B-cell depletion begins within days, but clinical effect (reduction in autoantibody titre and rise in ADAMTS13) takes 1–3 weeks. This is why rituximab alone is not sufficient for acute treatment — PEX is needed to bridge the gap.

Why rituximab + steroids but not rituximab alone?

• Rituximab takes time to deplete B cells and reduce antibody production
• Steroids provide immediate immunosuppression
• PEX provides immediate mechanical removal of antibody and UL-vWF
• All three together cover immediate, short-term, and long-term aspects of treatment

What it is: Caplacizumab is a humanised, bivalent nanobody (single-domain antibody fragment) that targets the A1 domain of vWF — the exact domain that binds to platelet GPIb-IX-V. By blocking this interaction, caplacizumab immediately prevents platelet adhesion to UL-vWF multimers → stops microthrombi formation.

"Caplacizumab" → "caplaci" = targeting a specific molecule, "zumab" = humanised monoclonal antibody.

Mechanism — why it works from first principles:

• The fundamental problem in TTP is: UL-vWF → binds platelets via A1 domain–GPIb interaction → microthrombi
• Caplacizumab physically blocks the A1 domain of vWF → platelets cannot bind → no new microthrombi form
• This is a direct, immediate, mechanistic intervention at the exact molecular interaction driving TTP

Evidence: The HERCULES trial (2019) showed that caplacizumab added to PEX + steroids significantly:

• Reduced time to platelet count normalisation
• Reduced incidence of TTP-related death, recurrence, or major thromboembolic events
• Reduced duration of PEX and hospital stay

Dosing: 11 mg IV bolus before first PEX, then 11 mg SC daily for 30 days after last PEX (or until ADAMTS13 activity normalises)

Side effects: Increased bleeding risk (because blocking vWF–platelet interaction impairs primary haemostasis); mucocutaneous bleeding (epistaxis, gum bleeding) is the most common adverse effect

Current status (2024–2026): Recommended by ISTH 2020 guidelines and BSH 2024 guidelines as part of standard frontline treatment for acquired TTP in combination with PEX and immunosuppression. However, it is expensive and may not be universally available in all centres, including some public hospitals in Hong Kong.

Platelet transfusion is contraindicated ^[15] C/I to platelet transfusion: add to clot formation ^[3] TTP: classically described as harmful (precipitate thrombosis) ^[4]

Why — from first principles:

• The microvasculature in TTP is flooded with uncleaved UL-vWF multimers that are actively capturing any platelets they encounter
• Transfusing additional platelets provides more substrate for UL-vWF → more platelet-vWF microthrombi → worsening organ ischaemia (brain, heart, kidneys)
• This is "adding fuel to the fire"
• Clinical reports have documented neurological deterioration and death following platelet transfusion in TTP

The ONLY exception: If the patient has life-threatening haemorrhage (e.g., intracranial haemorrhage, massive GI bleed) where the bleeding itself is immediately lethal, then the risk-benefit calculation shifts and platelet transfusion may be considered as a rescue measure. But this is exceedingly rare in TTP (major overt bleeding is uncommon despite the severely low platelet count).

Defined as no platelet response (or worsening) after 5–7 days of daily PEX + steroids.

Options:

1. Rituximab (if not already started) — 375 mg/m² weekly × 4 doses
2. Twice-daily PEX — increases the volume of antibody/UL-vWF removal
3. Caplacizumab (if not already started)
4. Other immunosuppressants (very rare, salvage settings):
   • Cyclophosphamide
   • Vincristine
   • Cyclosporin A
   • Bortezomib (proteasome inhibitor — targets plasma cells producing anti-ADAMTS13 Ab)
5. Splenectomy — last resort; spleen is a site of autoantibody production and platelet sequestration. Historically performed for refractory cases, but now rare due to rituximab efficacy

~30–50% of acquired TTP patients will relapse. Relapse risk is highest in the first 2 years.

Monitoring in remission:

• ADAMTS13 activity measured every 3–6 months for at least 2 years
• If ADAMTS13 falls to < 10% during remission (even without symptoms) → pre-emptive rituximab to prevent clinical relapse (this is based on observational evidence that persistent severe ADAMTS13 deficiency predicts relapse)

Treatment of clinical relapse:

• Same as initial episode: PEX + steroids + rituximab ± caplacizumab

• No autoantibody to remove → PEX is not the first-line approach (though can be used in acute episodes)
• FFP infusion (10–15 mL/kg every 2–3 weeks) is the mainstay — simply replaces the missing ADAMTS13 enzyme
• During acute episodes: PEX or FFP infusion to rapidly replenish ADAMTS13
• Recombinant ADAMTS13 (TAK-755 / BAX930): under development as a targeted replacement therapy; not yet widely available but represents the future of hereditary TTP management
• No role for rituximab (no autoantibody to suppress)

• TTP in pregnancy is a complex situation because the differential includes HELLP, pre-eclampsia, atypical HUS
• If ADAMTS13 ≤ 10% → treat as TTP: PEX + steroids
• Rituximab is generally avoided in pregnancy (anti-CD20 crosses placenta → fetal B-cell depletion)
• Caplacizumab safety data in pregnancy is limited
• After delivery: standard TTP management can be resumed
• Women with hereditary TTP may present for the first time during pregnancy (physiological decrease in ADAMTS13 during pregnancy unmasking the genetic deficiency) → prophylactic FFP infusion during future pregnancies

• Immune-mediated (ticlopidine, clopidogrel, quinine): Stop the offending drug + treat as acquired TTP with PEX + steroids ± rituximab. These patients have anti-ADAMTS13 autoantibodies and respond to standard TTP treatment
• Direct endothelial toxicity (cyclosporin, tacrolimus, gemcitabine, mitomycin C): Stop the offending drug. PEX is generally NOT effective because ADAMTS13 is normal and the mechanism is direct toxicity. Supportive care is the mainstay

Neurological injury is the most characteristic and most dangerous complication of TTP. It is the principal cause of acute morbidity and the feature that most distinguishes TTP from HUS.

CNS involvement: headache, confusion, seizure, stroke, coma ^[2]. Neurological complications are the leading cause of death in the acute phase of TTP.

Why TTP has more neurological involvement than HUS: In HUS, the Shiga toxin has tropism for renal endothelial cells (high Gb3 receptor expression), concentrating damage in the kidneys. In TTP, UL-vWF accumulates wherever shear stress is high — and the cerebral microvasculature is a high-shear system with extensive capillary beds, making it particularly vulnerable. The kidney is also affected in TTP but the brain bears the brunt.

Long-term neurological sequelae: Even after successful treatment, some TTP survivors experience persistent cognitive deficits (impaired memory, attention, executive function), depression, and reduced quality of life. MRI studies show residual white matter changes in some patients. This is thought to result from cumulative microvascular ischaemic injury during the acute episode.

Kidney: severe AKI common in TMA (except TTP) ^[2] — the renal impairment in TTP is characteristically milder than in HUS, but it is still present and should be monitored.

Cardiac involvement is an underrecognised but critically important complication. It is a significant cause of sudden death in TTP.

Despite the very low platelet count, TTP is primarily a thrombotic condition, not a bleeding condition. The microthrombi cause organ damage. Major spontaneous haemorrhage is uncommon because the coagulation cascade is intact (normal fibrinogen, normal PT/aPTT). The risk of bleeding increases if DIC develops secondarily to severe organ ischaemia.

• Incidence: ~30–50% of acquired TTP patients will relapse, with highest risk in the first 1–2 years after the initial episode
• Risk factors for relapse: Persistently low ADAMTS13 activity during remission (especially < 10%), presence of persistent anti-ADAMTS13 antibodies, Black ethnicity, higher BMI
• Why relapse occurs: In many patients, the autoimmune process (anti-ADAMTS13 autoantibodies) is not permanently eradicated by a single course of treatment. B-cell memory and long-lived plasma cells can regenerate the antibody response
• Prevention: ADAMTS13 activity monitoring every 3–6 months for at least 2 years; pre-emptive rituximab if ADAMTS13 falls < 10% in remission (even without clinical symptoms)
• Management of relapse: Same as initial episode (PEX + steroids + rituximab ± caplacizumab)

• Defined as a decline in platelet count after initial improvement, occurring while still on treatment or within 30 days of stopping PEX
• Distinguished from relapse (which occurs > 30 days after achieving complete remission)
• Suggests inadequate control of the autoimmune process → intensify treatment (add rituximab if not already given, increase PEX frequency)

• Defined as failure to achieve platelet normalisation after 5–7 days of standard therapy (daily PEX + steroids)
• Associated with very high antibody titres, severe organ damage, or misdiagnosis (the patient may not have TTP)
• Carries significantly higher mortality
• Requires escalation: rituximab, twice-daily PEX, caplacizumab, or salvage agents (bortezomib, cyclophosphamide)

• Women with a history of acquired TTP are at risk of relapse during subsequent pregnancies (pregnancy is a physiological trigger that increases vWF levels and reduces ADAMTS13 activity)
• Pregnancy accounts for 5–25% of all cases of TTP ^[1] — some of these are first presentations, others are relapses
• Women with hereditary TTP (Upshaw-Schulman syndrome) may only manifest during pregnancy for the first time
• Complications include: relapse of TTP, fetal growth restriction, pre-eclampsia, stillbirth
• Management: close monitoring with regular ADAMTS13 levels during pregnancy; prophylactic FFP infusion (hereditary TTP) or close surveillance for relapse (acquired TTP)

• Historically: > 90% mortality if untreated
• With modern treatment (PEX + steroids ± rituximab ± caplacizumab): ~10–20% mortality during acute episodes
• Causes of death:
  • Cardiac: sudden cardiac death from arrhythmia or massive myocardial infarction (microthrombi in coronary microvasculature)
  • Neurological: massive ischaemic stroke, cerebral oedema, intracranial haemorrhage
  • Multiorgan failure: cumulative ischaemic damage to multiple organs
  • Sepsis: immunosuppression-related (steroids, rituximab) + central line infection during PEX
  • Refractory TTP: progressive organ damage despite maximal therapy