Thrombotic Thrombocytopenic Purpura (Adult)

1. Overview

Definition and Clinical Significance

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA) characterised by severe deficiency of ADAMTS13 (A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13), the von Willebrand factor (VWF)-cleaving protease. ADAMTS13 activity below 10% is the diagnostic hallmark of TTP. [1]

The condition leads to accumulation of ultra-large VWF multimers in the circulation, causing spontaneous platelet aggregation and widespread microvascular thrombosis. This results in the characteristic triad of microangiopathic haemolytic anaemia (MAHA), severe thrombocytopenia, and organ ischaemia—particularly affecting the brain and heart. [2]

TTP represents a true haematological emergency. Without treatment, mortality exceeds 90%. However, with prompt plasma exchange (PEX), survival rates reach 80-90%, making early recognition and immediate treatment initiation critical. [3] The advent of caplacizumab—an anti-VWF nanobody—and upfront rituximab has transformed outcomes, reducing both acute mortality and long-term relapse rates. [4,5]

Historical Context

TTP was first described by Eli Moschcowitz in 1924 in a 16-year-old girl who died within two weeks of illness onset. The classic "pentad" of thrombocytopenia, MAHA, neurological symptoms, renal impairment, and fever was historically required for diagnosis. However, this complete pentad occurs in only 5-10% of cases, and modern diagnostic criteria focus on the dyad of thrombocytopenia and MAHA in the presence of severe ADAMTS13 deficiency. [6]

The identification of ADAMTS13 in 1996 and its deficiency as the cause of TTP in 2001 revolutionised our understanding and led to targeted therapies. [7]

Why This Matters Clinically

TTP is a high-stakes diagnosis where hours matter. Every day of delay in initiating plasma exchange increases mortality by approximately 1.5-fold. [8] The condition presents in diverse ways—from subtle confusion to fulminant multi-organ failure—and can mimic many other conditions, from stroke to sepsis.

For postgraduate examinations (MRCP, FRACP), TTP is a core topic due to its:

• Diagnostic complexity requiring clinical reasoning
• Emergency management protocols
• Evidence-based treatment advances (HERCULES and TITAN trials)
• Differential diagnosis from other TMAs (aHUS, DIC, HELLP)
• Long-term monitoring and relapse prevention strategies

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2. Epidemiology

Incidence and Prevalence

The incidence of TTP has increased over recent decades, likely reflecting improved recognition rather than true disease increase. Registry data suggest stable incidence when diagnostic criteria are standardised. [9]

Demographics

Age Distribution

• Peak incidence: 30-50 years (median age ~40 years)
• Can occur at any age from infancy to elderly
• Congenital TTP (Upshaw-Schulman syndrome) often presents in neonatal period or early childhood but may be diagnosed in adulthood

Sex Distribution

• Female predominance: 2-3:1 female-to-male ratio [2]
• Hormonal factors may play a role
• Pregnancy and postpartum period are recognised triggers

Ethnicity

• African ancestry: 3-9 times higher incidence compared to European ancestry [10]
• Possible genetic predisposition (ADAMTS13 gene polymorphisms)
• Hispanic populations also show increased incidence
• Asian populations have lower reported incidence

Geographic Variation

• Higher incidence in United States and Western Europe (likely reflects better ascertainment)
• Registry data available from US (Oklahoma TTP-HUS Registry), UK, France, Italy

Risk Factors and Triggers

Acquired immune TTP is triggered by various factors that precipitate antibody formation against ADAMTS13:

Note: Drug-induced TMA (e.g., ticlopidine 1:1600 risk) often has ADAMTS13 > 10% and represents a distinct entity from immune TTP. [12]

Congenital TTP (Upshaw-Schulman Syndrome) Triggers:

• Infection
• Pregnancy (unmasking in previously undiagnosed patients)
• Surgery
• Physiological stress

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3. Aetiology and Pathophysiology

Normal ADAMTS13 Function

ADAMTS13 is a plasma metalloprotease primarily synthesised by hepatic stellate cells and vascular endothelium. [7] Its sole known physiological substrate is ultra-large von Willebrand factor (ULVWF) multimers.

Physiological Role:

1. VWF is released from endothelial cells as ULVWF multimers
2. Under high shear stress, ULVWF multimers unfold and expose the A2 domain
3. ADAMTS13 cleaves the Tyr1605-Met1606 bond in the VWF A2 domain
4. This reduces VWF multimer size, preventing excessive platelet adhesion
5. Normal ADAMTS13 activity: 50-150%

Classification of TTP

Pathophysiology of Immune TTP

The pathophysiology follows a cascade from ADAMTS13 deficiency to multi-organ microvascular thrombosis:

Step 1: ADAMTS13 Deficiency

Acquired Immune TTP:

• Polyclonal IgG autoantibodies (rarely IgA, IgM) against ADAMTS13
• Antibodies may:
  • Inhibit enzymatic activity (bind to active site or exosite regions)
  • Enhance clearance (immune complex formation)
  • Both mechanisms often coexist
• Inhibitor titre correlates with disease severity [11]
• CD4+ T-cell response against ADAMTS13 epitopes drives antibody production

Congenital TTP:

• Biallelic mutations in ADAMTS13 gene (chromosome 9q34)

• 200 mutations described (missense, nonsense, frameshift, splice-site)

• Severe deficiency (less than 1% activity) from birth
• Clinical manifestations often triggered by physiological stress

Step 2: Accumulation of Ultra-Large VWF Multimers

• Without ADAMTS13 cleavage, ULVWF multimers persist in circulation
• ULVWF multimers are hyperadhesive for platelets
• Multimer strings can span entire capillary diameter
• Particularly prominent under high shear stress conditions (microvasculature)

Step 3: Spontaneous Platelet Aggregation

• ULVWF multimers bind GPIb-IX-V complex on platelets
• Platelet adhesion and activation occur spontaneously without vessel injury
• Platelet-rich microthrombi form in arterioles and capillaries
• Widespread microvascular occlusion
• Consumption of platelets → severe thrombocytopenia (often less than 30 x10⁹/L)

Key Distinction from DIC:

• Platelets consumed in TTP via VWF-mediated aggregation (not thrombin generation)
• Coagulation cascade NOT activated
• PT, APTT, fibrinogen remain normal (differentiates from DIC)

Step 4: Microangiopathic Haemolytic Anaemia

• Red blood cells (RBCs) encounter platelet-VWF microthrombi in capillaries
• Mechanical shearing of RBCs as they pass through occluded vessels
• RBC fragmentation → schistocytes (helmet cells, fragmented RBCs)
• Intravascular haemolysis:
  • ↓ Haemoglobin (typically 60-90 g/L)
  • ↑ LDH (often > 1000 U/L, can reach > 2000 U/L)
  • ↑ Unconjugated bilirubin
  • ↓ Haptoglobin (consumed binding free haemoglobin, often undetectable)
  • ↑ Reticulocytes (compensatory bone marrow response)
• Negative direct antiglobulin test (Coombs) distinguishes from AIHA

Step 5: End-Organ Ischaemia

Microthrombi cause organ ischaemia with characteristic patterns:

Brain (Most Characteristic):

• Neurological symptoms in 40-70% [2]
• Fluctuating symptoms (wax and wane with thrombi formation/resolution)
• Manifestations: confusion (40%), headache (55%), seizures (20%), focal deficits, stroke (10%), coma (5%) [13]
• Posterior reversible encephalopathy syndrome (PRES) in 15% [13]
• MRI findings: cortical/subcortical hyperintensities, microhaemorrhages
• Most neurological symptoms reversible with treatment

Heart:

• Cardiac involvement in 30-50% [14]
• Myocardial ischaemia/microinfarction
• Elevated troponin (> 0.1 ng/mL associated with 3-fold mortality increase) [14]
• ECG changes in 40%: ST-segment changes, arrhythmias
• Sudden cardiac death risk 2-5%
• Cardiac biomarkers important prognostic markers

Kidneys:

• Renal involvement typically mild (distinguishes from HUS)
• Elevated creatinine in 20-50%, usually less than 177 μmol/L (2 mg/dL)
• Microhaematuria, proteinuria common
• Severe AKI requiring dialysis suggests alternative diagnosis (aHUS, STEC-HUS)

Other Organs:

• Gastrointestinal: abdominal pain (30%), nausea, pancreatitis
• Pulmonary: rare, but can cause pulmonary hypertension
• Retinal: visual changes, retinal haemorrhages
• Adrenal: rare adrenal insufficiency

Molecular Mechanisms (ExamDetail)

ADAMTS13 Structure and Function:

• 1427 amino acid multidomain protease
• Domains: metalloprotease, disintegrin-like, TSP1 repeats (×8), CUB domains (×2), spacer
• Metalloprotease domain contains catalytic site (requires Zn²⁺, Ca²⁺)
• Spacer domain is major epitope for autoantibodies in acquired TTP
• CUB domains mediate binding to endothelial cells

VWF A2 Domain Cleavage:

• VWF A2 domain normally globular (protected from cleavage)
• High shear stress (> 5000 s⁻¹) unfolds VWF, exposing Tyr1605-Met1606 scissile bond
• ADAMTS13 binds unfolded A2 domain via exosites
• Proteolytic cleavage reduces multimer size from > 10,000 kDa to less than 1,500 kDa
• Deficiency allows ULVWF multimers > 20,000 kDa to persist

Autoantibody Mechanisms:

• Most antibodies target spacer domain (prevent substrate binding)
• Some target CUB domains (enhance clearance)
• Inhibitory antibodies show non-competitive or uncompetitive kinetics
• Antibody-ADAMTS13 complexes cleared by reticuloendothelial system
• T-cell epitopes in spacer and CUB2 domains identified

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4. Clinical Presentation

Cardinal Features

The classic pentad (thrombocytopenia, MAHA, neurological symptoms, fever, renal impairment) is present in only 5-10% of cases. [6] Modern diagnosis relies on dyad of thrombocytopenia + MAHA with severe ADAMTS13 deficiency.

Symptom Profile

Key Clinical Pattern: Symptoms often fluctuate over hours to days, reflecting dynamic thrombi formation and resolution. This fluctuation is highly characteristic of TTP.

Signs on Examination

Presentation Patterns by Setting

Emergency Department:

• Confusion + anaemia + thrombocytopenia ("?sepsis, ?stroke")
• Bleeding with low platelets ("?ITP, ?leukaemia")
• Seizures with no prior history

General Medicine Ward:

• Unexplained thrombocytopenia during admission for other reasons
• Falling platelets despite stopping heparin
• Haemolytic anaemia investigation

Haematology Referral:

• Abnormal blood film (schistocytes reported)
• Thrombocytopenia + haemolysis ("MAHA query cause")

Obstetrics:

• Second/third trimester or postpartum TMA [15]
• Differential: HELLP syndrome, preeclampsia, catastrophic APS

Clinical Subtypes

First Episode TTP:

• Idiopathic (no identifiable trigger) in 40-60%
• Acute onset over days to 1-2 weeks
• May have prodromal infection (URI, gastroenteritis)

Relapsing TTP:

• Occurs in 30-60% over 10 years [16]
• May occur months to years after initial episode
• Often preceded by falling ADAMTS13 activity in remission
• Similar clinical features but recognition often faster

Pregnancy-Associated TTP:

• Second/third trimester or within 6 weeks postpartum [15]
• Can be first presentation (acquired) or unmasking of congenital TTP
• Maternal mortality 15-30% if untreated; less than 10% with treatment
• Fetal loss ~30%
• Urgent delivery NOT required (unlike HELLP/preeclampsia if severe)

Congenital TTP (Acute Exacerbation):

• Triggers: infection, pregnancy, surgery, stress
• May have milder presentations if on prophylactic FFP
• Chronic complications: stroke, cognitive impairment from recurrent episodes

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5. Differential Diagnosis

TTP is one of several causes of thrombotic microangiopathy (TMA). Distinguishing TTP from other TMAs is critical as treatments differ:

Core Differentials (TMAs)

Clinical Reasoning Approach [17]:

1. Confirm TMA: Thrombocytopenia + MAHA (schistocytes + ↑LDH + ↓haptoglobin) + normal coagulation
2. ADAMTS13: less than 10% → TTP; > 10% → other TMA
3. Clinical phenotype:
   • Neurological dominant → TTP
   • Renal failure dominant → HUS
   • Diarrhoea prodrome → STEC-HUS
   • Pregnancy → HELLP, preeclampsia, TTP, aHUS
   • Severe hypertension → malignant HTN
   • Coagulopathy → DIC

Other Differentials (Not TMA)

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6. Investigations

Investigations serve to: (1) confirm TMA, (2) measure ADAMTS13, (3) differentiate from other TMAs, (4) assess organ involvement, (5) guide monitoring.

Diagnostic Approach

Immediate (Stat) Tests (within 1-2 hours):

• Full blood count with blood film review
• LDH, bilirubin, haptoglobin, reticulocyte count
• Coagulation screen (PT, APTT, fibrinogen)
• Renal function (creatinine, eGFR)
• Liver function tests
• Troponin (cardiac biomarker)
• Direct antiglobulin test (Coombs)
• Blood group and save

Urgent (Same Day) Tests:

• ADAMTS13 activity (send BEFORE PEX/transfusion)
• ADAMTS13 inhibitor assay
• Complement studies (C3, C4, if considering aHUS)
• Pregnancy test (if applicable)
• HIV, hepatitis serology

Second-Line (Guided by Initial Results):

• ADAMTS13 gene sequencing (if congenital suspected)
• Stool culture, Shiga toxin PCR (if diarrhoea)
• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2GP1)
• Autoimmune screen (ANA, ENA, dsDNA)
• Malignancy screen (age-appropriate)

Key Investigations

1. Blood Film (Essential Diagnostic Test)

Findings:

• Schistocytes (fragmented RBCs): helmet cells, triangle cells, microspherocytes
  • "Quantification: > 1% significant; TTP typically 2-10% [18]"
  • "ICSH recommendation: manual count of 1000 RBCs by trained observer"
  • Present in 100% of TTP at diagnosis
• Polychromasia (young RBCs/reticulocytes)
• Thrombocytopenia (reduced platelet count on film)
• Nucleated RBCs (severe haemolysis)

Pitfall: Schistocytes may normalise within days of starting PEX; early blood film critical.

2. Laboratory Panel

3. ADAMTS13 Assays (Gold Standard)

ADAMTS13 Activity:

• Diagnostic threshold: less than 10% activity [1]
• Functional assay measures VWF cleavage (FRETS-VWF73 commonly used)
• Turnaround time: 1-5 days (varies by lab)
• Critical: Sample BEFORE plasma exchange or blood transfusion (dilutes result)
• Sample: Citrated plasma (purple/blue top bottle)

ADAMTS13 Inhibitor/Antibody:

• Detects IgG autoantibodies against ADAMTS13
• Positive: Acquired immune TTP (> 95% of adult cases)
• Negative with ADAMTS13 less than 10%: Suggests congenital TTP (require genetic testing)
• Inhibitor titre (Bethesda units): Higher titres correlate with severity [11]

Genetic Testing:

• Indicated if ADAMTS13 less than 10% with negative inhibitor
• Biallelic ADAMTS13 mutations confirm Upshaw-Schulman syndrome
• Implications: lifelong prophylaxis, genetic counselling, pregnancy planning

4. PLASMIC Score (Clinical Prediction Tool)

The PLASMIC score estimates pretest probability of severe ADAMTS13 deficiency before assay results are available: [19]

Interpretation [19]:

• Score 6-7 (High risk): 72% have ADAMTS13 less than 10%; sensitivity 90%, specificity 92%
• Score 5 (Intermediate risk): ~40% have ADAMTS13 less than 10%
• Score 0-4 (Low risk): 0-4% have ADAMTS13 less than 10%; TTP very unlikely

Clinical Use: PLASMIC ≥5 warrants immediate empiric treatment while awaiting ADAMTS13 results.

5. Imaging

Brain MRI (if neurological symptoms):

• Indications: confusion, seizures, focal deficits, coma
• Findings:
  • Cortical/subcortical T2/FLAIR hyperintensities (reversible)
  • Microhaemorrhages (susceptibility-weighted imaging)
  • Posterior reversible encephalopathy syndrome (PRES) pattern in 15% [13]
  • Ischaemic strokes (10%)
  • Microinfarcts
• Most changes reversible with treatment

Cardiac MRI (if troponin elevated):

• May show microinfarcts, oedema
• Prognostic value

CT Head (emergency if altered consciousness):

• Exclude intracranial haemorrhage (before PEX line insertion)
• Less sensitive than MRI for microangiopathic changes

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7. Classification and Staging

Classification by Aetiology

Classification by Presentation

• First episode: No prior history of TTP
• Relapse: Recurrent TTP after > 30 days of remission (platelets normalised)
• Exacerbation: Recurrence within 30 days of stopping PEX (before remission achieved)

Severity Assessment

No validated severity score exists, but prognostic markers include:

Poor Prognostic Markers:

• Cardiac involvement (troponin > 0.1 ng/mL): 3-fold ↑ mortality [14]
• Coma (GCS less than 8)
• Age > 60 years
• High inhibitor titre
• Delay to treatment > 24 hours [8]
• PEX-refractory disease

Good Prognostic Markers:

• Early recognition and treatment
• Platelet response within 5 days of PEX
• ADAMTS13 recovery

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8. Management

TTP is a medical emergency. Treatment must be initiated immediately based on clinical suspicion (thrombocytopenia + MAHA ± neurological symptoms) without waiting for ADAMTS13 results. Delay increases mortality. [8]

Immediate Emergency Management (Within 2 Hours)

1. Resuscitation (ABCDE Approach):

• Airway: Secure if GCS less than 8 (coma)
• Breathing: Oxygen if hypoxic
• Circulation: IV access (×2 large-bore cannulae); fluid resuscitation if needed
• Disability: GCS assessment; exclude hypoglycaemia
• Exposure: Examine for purpura, petechiae

2. Initiate Emergency Treatments:

3. Urgent Haematology Consultation:

• Contact on-call haematologist immediately
• Discuss PEX access and initiation
• Arrange apheresis team

4. Obtain Investigations (before PEX if possible):

• ADAMTS13 activity and inhibitor (CRITICAL: sample before PEX)
• All other investigations as per Section 6

Plasma Exchange (PEX) — The Life-Saving Intervention

Mechanism of Action [8]:

1. Removes: IgG autoantibodies, ultra-large VWF multimers, inflammatory cytokines
2. Replaces: ADAMTS13 (from donor plasma), coagulation factors
3. Rapidly corrects microvascular thrombosis

Technical Details:

• Volume: 1-1.5 plasma volumes (approximately 40-60 mL/kg; ~3000 mL for 70 kg adult)
• Replacement fluid: Fresh frozen plasma (FFP) or solvent-detergent plasma
• Frequency: Daily until platelet count normalises (> 150 x10⁹/L on 2 consecutive days)
• Access: Central venous catheter (tunnelled or non-tunnelled; internal jugular/femoral preferred)
• Duration: Median 5-9 days (shorter with caplacizumab) [4,5]
• Anticoagulation: Citrate-based (monitor ionised calcium; risk of citrate toxicity)

Evidence:

• Mortality without PEX: > 90%
• Mortality with PEX: 10-20% [3]
• Delay > 24 hours: 1.5-fold increase in mortality [8]
• 30-day survival: 85-95% [8]

Monitoring During PEX:

• Daily platelet count, LDH (markers of response)
• Daily Hb, reticulocytes, bilirubin, haptoglobin
• Ionised calcium (citrate toxicity)
• Fluid balance
• Signs of line infection

Stopping PEX:

• Criteria: Platelets > 150 x10⁹/L on 2 consecutive days + improving LDH
• Do NOT stop prematurely (risk of exacerbation)
• Taper may be considered (e.g., reduce frequency to alternate days before stopping)

Caplacizumab — Anti-VWF Nanobody

Caplacizumab is a bivalent anti-VWF nanobody that prevents VWF-platelet binding, addressing the pathophysiology directly. [4,5]

Dosing:

• Loading dose: 11 mg IV bolus (before first PEX)
• Maintenance: 11 mg SC daily during PEX and for 30 days post-PEX
• Supplied as pre-filled syringes

Evidence:

• HERCULES Trial (2019) [4]: Caplacizumab vs placebo (both with PEX + steroids)
  • "Primary endpoint: Time to platelet normalisation: 74% vs 49% by day 5 (pless than 0.001)"
  • "Composite endpoint (death/TTP recurrence/thromboembolic event): 12% vs 38% (pless than 0.001)"
  • "Number needed to treat: 4 (highly effective)"
• TITAN Trial (2016) [5]: Median platelet normalisation 2.97 vs 4.79 days; fewer exacerbations

Advantages:

• Faster platelet recovery (reduces ICU time, PEX sessions)
• Reduced TTP-related death and recurrence
• Reduced thromboembolic complications

Adverse Effects:

• Bleeding risk: Inhibits VWF function; epistaxis, gingival bleeding (usually minor)
• Major bleeding rare (2-4%); monitor closely if platelets less than 30 x10⁹/L
• Antibody formation (~5%; rarely neutralising)

Licensing: Approved by EMA (2018), FDA (2019) for acquired TTP.

Corticosteroids

Mechanism: Suppress autoantibody production; reduce endothelial activation. [21]

Regimens:

• High-dose IV: Methylprednisolone 1g IV daily × 3 days, then oral taper
• Moderate-dose oral: Prednisolone 1 mg/kg PO daily (~60-80 mg)

Taper:

• After platelet normalisation, taper gradually over 6-8 weeks
• Monitor ADAMTS13 activity during taper
• Avoid abrupt cessation (risk of relapse)

Evidence: No RCT evidence, but standard practice based on observational data; improves ADAMTS13 recovery.

Rituximab — B-Cell Depletion

Rituximab (anti-CD20 monoclonal antibody) targets B-cells producing anti-ADAMTS13 antibodies. [22,23]

Indications:

1. Upfront (first-line): ISTH guidelines suggest considering in all patients (Grade 2C) [20]
2. Refractory disease: Suboptimal response to PEX by day 5
3. Relapse prevention: History of relapse
4. Preemptive: ADAMTS13 activity falling in remission (less than 10-20%)

Dosing:

• Standard: 375 mg/m² IV weekly × 4 doses
• Alternative: Single dose 1000 mg or lower doses (efficacy data emerging)

Evidence:

• Meta-analysis (2020) [22]: Reduces relapse from 50% to 10-20%; no increase in infections
• Westwood et al. (2013) [23]: Upfront rituximab reduced relapse at 1 year from 57% to 10% (p=0.001); fewer PEX sessions (median 5 vs 9)

Timing:

• Can start during acute phase (alongside PEX + steroids + caplacizumab)
• Weekly infusions (4 weeks)

Monitoring:

• CD19 count (B-cell depletion)
• Immunoglobulin levels (risk of hypogammaglobulinaemia)
• Infection surveillance

Adverse Effects:

• Infusion reactions (premedicate with paracetamol, antihistamine)
• Infections (respiratory, herpes zoster reactivation)
• Rarely: progressive multifocal leukoencephalopathy (PML; extremely rare in TTP)

Refractory TTP (5-10% of Cases)

Definition [24]:

• Platelet count fails to normalise by day 5-7 despite daily PEX
• Platelet-dependent (requires continued PEX to maintain platelets)

Management Options:

1. Twice-daily PEX: Increase to 1.5 plasma volumes BID
2. Rituximab: If not already given (375 mg/m² weekly × 4)
3. Cyclosporine: 3-5 mg/kg/day PO (target trough 100-200 ng/mL); alternative calcineurin inhibitor
4. Bortezomib: 1.3 mg/m² IV (days 1, 4, 8, 11); targets plasma cells producing autoantibodies
5. Vincristine: 1.4 mg/m² IV (max 2 mg) weekly
6. N-acetylcysteine: 150 mg/kg IV loading, then infusion (reduces VWF multimer size; experimental)
7. Splenectomy: Rarely used now (removed source of antibody production; risk of post-splenectomy sepsis)

Prognosis: Refractory disease carries higher mortality; aggressive multimodal therapy required.

Supportive Care

Monitoring Treatment Response

Daily Monitoring (during acute phase):

• Platelet count (aim for normalisation > 150 x10⁹/L)
• LDH (should decline; persistent elevation suggests ongoing haemolysis)
• Haemoglobin, reticulocytes
• Creatinine, electrolytes
• Neurological status

Weekly Monitoring:

• ADAMTS13 activity (should recover to > 30% ideally)
• Inhibitor titre (should decline)

Remission Criteria:

• Platelet count > 150 x10⁹/L on 2 consecutive days
• Normalising LDH
• Resolution of haemolysis
• Clinical improvement (neurological symptoms resolving)

Special Populations

Pregnancy [15]:

• TTP can occur in 2nd/3rd trimester or postpartum
• PEX is safe and effective in pregnancy
• Caplacizumab: limited data; case reports suggest safety
• Delivery NOT urgently required (unlike HELLP/preeclampsia)
• Differentiate from HELLP, preeclampsia, catastrophic APS
• Multidisciplinary care: Haematology + Obstetrics

Congenital TTP (Upshaw-Schulman Syndrome) [26]:

• Acute exacerbation: FFP infusion (10-15 mL/kg every 2-3 weeks) OR plasma exchange
• Prophylaxis: Regular FFP infusions (prevent acute episodes)
• NO role for immunosuppression (steroids, rituximab) — not immune-mediated
• Pregnancy: High-risk; requires increased FFP frequency; close monitoring
• Genetic counselling: Autosomal recessive; partner testing if planning children

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9. Long-Term Management and Relapse Prevention

Post-Remission Monitoring

ADAMTS13 Activity Surveillance [27]:

• Frequency:
  • Monthly for first 6 months
  • Every 3 months for next 6-12 months
  • Every 6-12 months thereafter (lifelong)
• Risk stratification:
  • "ADAMTS13 less than 20% in remission: 3-fold increased relapse risk [27]"
  • "Rising inhibitor titres: 5-fold increased relapse risk [27]"

Clinical Review:

• Monitor for symptoms of relapse (fatigue, bruising, headache, confusion)
• Annual full blood count, LDH, renal function
• Cardiovascular risk assessment (stroke, MI risk)
• Cognitive assessment (neuropsychology if deficits)

Relapse Prevention Strategies

Relapse Epidemiology:

• Overall relapse risk: 30-60% at 10 years [16]
• Median time to relapse: 1-2 years (range: months to decades)
• Most relapses occur within 5 years

Interventions to Reduce Relapse:

1. Upfront Rituximab [22,23]:

   • Reduces relapse from 50% to 10-20%
   • Longer time to relapse
   • Standard in many centres

2. Preemptive Rituximab [27]:

   • If ADAMTS13 less than 10-20% during remission (without clinical TTP)
   • Prevents progression to acute TTP in 60%
   • Single dose (1000 mg) or standard 4-week course

3. Avoid Triggers:

   • Infection: Vaccinations (influenza, pneumococcal), infection avoidance
   • Smoking cessation
   • Manage cardiovascular risk factors

4. Patient Education:

   • Recognise early symptoms (fatigue, bruising, confusion)
   • Seek immediate medical attention if suspected relapse
   • Wear medical alert bracelet/card

Management of Relapse

• Same treatment as first episode: PEX + steroids + caplacizumab + rituximab
• Response often faster (recognition quicker)
• Consider more aggressive immunosuppression if multiple relapses (e.g., prolonged rituximab, cyclosporine)

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10. Complications

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11. Prognosis

Acute Phase Outcomes

Long-Term Outcomes

Prognostic Factors

Favourable:

• Early diagnosis and treatment initiation [8]
• Platelet response within 5 days
• ADAMTS13 recovery to > 30%
• Use of caplacizumab [4]
• Upfront rituximab [22,23]
• Younger age

Unfavourable:

• Cardiac involvement (troponin > 0.1 ng/mL): 3-fold mortality [14]
• Coma (GCS less than 8)
• Age > 60 years
• Delayed treatment > 24-48 hours [8]
• Refractory disease (no platelet response by day 5-7)
• High inhibitor titre
• Multiple relapses

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12. Prevention and Screening

Primary Prevention

No established primary prevention (unpredictable autoantibody formation).

Risk Reduction:

• Infection prevention (vaccinations: influenza, pneumococcal)
• Cardiovascular risk modification (post-TTP)

Secondary Prevention (Relapse Prevention)

See Section 9: Long-Term Management and Relapse Prevention.

Key Strategies:

• ADAMTS13 monitoring [27]
• Preemptive rituximab if ADAMTS13 less than 10-20%
• Patient education
• Avoid triggers

Screening

ADAMTS13 Screening (not routine population screening):

• Family members of congenital TTP patients (if considering having children)
• Recurrent pregnancy loss with TMA features
• Unexplained neonatal jaundice/thrombocytopenia

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13. Guidelines and Evidence Base

Key Guidelines

1. International Society on Thrombosis and Haemostasis (ISTH) Guidelines (2020) [20]

   • Zheng XL, et al. J Thromb Haemost. 2020;18(10):2496-2502. PMID: 32239796
   • Grade 1A: Immediate PEX for suspected TTP
   • Grade 2B: Corticosteroids as adjunct
   • Grade 2C: Consider upfront rituximab
   • Grade 2B: Caplacizumab in severe cases

2. British Society for Haematology (BSH) Guidelines (2012, updated 2023) [3]

   • Scully M, et al. Br J Haematol. 2012;158(3):323-335. PMID: 22624596
   • Emphasises immediate PEX without delay
   • Avoid platelet transfusion unless life-threatening bleeding
   • 1.5 plasma volumes daily; continue until platelets > 150 x2 days

3. American Society of Apheresis (ASFA) Guidelines

   • PEX for TTP: Category I (first-line, standard of care)

Landmark Trials and Studies

Key Evidence Synthesis

Evolution of TTP Mortality:

• Pre-1980 (no PEX): > 90% mortality
• 1980s-2000s (PEX era): 10-20% mortality [3]
• 2016-present (caplacizumab era): less than 10% mortality, faster recovery [4,5]
• 2010s-present (rituximab era): Relapse reduced from 50% to 10-20% [22,23]

Paradigm Shifts:

• 1924: Moschcowitz describes pentad
• 1982: PEX introduced; transforms survival
• 2001: ADAMTS13 identified as causative deficiency
• 2012: Rituximab enters standard practice
• 2016-2019: Caplacizumab trials (TITAN, HERCULES) establish benefit
• 2020: ISTH guidelines codify modern multimodal therapy

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14. Differential Diagnosis: TTP vs HUS vs DIC (Summary Table)

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15. Patient Information and Communication

Explaining TTP to Patients

Simple Explanation: "You have a condition called TTP where your blood is forming tiny clots in small blood vessels throughout your body. This is happening because your body is attacking a protein that normally prevents clotting. The clots use up your platelets (cells that stop bleeding) and damage your red blood cells. This can affect your brain, heart, and other organs."

Treatment Explanation: "The main treatment is called plasma exchange. We filter your blood through a machine, removing the harmful antibodies and replacing your plasma (the liquid part of blood). This, combined with medications, stops the clotting and allows your body to recover. Treatment usually takes 1-2 weeks in hospital."

Prognosis Discussion: "With treatment, most people (80-90%) recover well. However, TTP can come back in about 30-50% of people over the next 10 years, so we'll monitor you closely with regular blood tests. We'll check your ADAMTS13 levels every few months to catch any early signs of relapse."

Warning Signs for Patients (Post-Discharge)

Seek immediate medical attention if you develop:

• New or worsening confusion, headache, or visual changes
• Seizures
• Chest pain or shortness of breath
• Unexplained bruising or bleeding
• Severe fatigue or weakness
• Dark urine or jaundice

Advise:

• Carry medical alert card/bracelet stating "TTP history"
• Inform all healthcare providers of TTP history
• Attend all follow-up appointments
• Comply with ADAMTS13 monitoring

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16. Examination Focus (Viva and Written Exams)

Opening Statement (Viva)

Examiner: "Tell me about thrombotic thrombocytopenic purpura."

Model Answer: "TTP is a life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency, defined as activity less than 10%. ADAMTS13 is the VWF-cleaving protease; its deficiency leads to accumulation of ultra-large VWF multimers, causing spontaneous platelet aggregation and microvascular thrombosis. This results in severe thrombocytopenia, microangiopathic haemolytic anaemia with schistocytes, and organ ischaemia—particularly neurological and cardiac. Most adult cases are acquired immune TTP from IgG autoantibodies. Without treatment, mortality exceeds 90%, but with emergency plasma exchange, survival is 80-90%. Modern treatment includes PEX, corticosteroids, caplacizumab, and rituximab, based on ISTH 2020 guidelines and the HERCULES trial."

High-Yield Exam Facts

Diagnostic:

• ADAMTS13 less than 10% = TTP [1]
• PLASMIC score ≥5: high probability TTP [19]
• Schistocytes > 1% on blood film (100% sensitive) [18]
• Normal PT/APTT/fibrinogen (distinguishes from DIC)
• Negative Coombs (distinguishes from AIHA)

Clinical:

• Complete pentad only 5-10% [6]
• Dyad (thrombocytopenia + MAHA) sufficient to start treatment
• Neurological symptoms 40-70% (hallmark of TTP vs other TMAs) [2]
• Fever only 15-30% (not common) [6]

Treatment:

• Emergency PEX within 2 hours (Grade 1A) [20]
• Never delay PEX for ADAMTS13 result
• Avoid platelet transfusion (unless life-threatening bleeding) [25]
• Caplacizumab: NNT=4 (HERCULES trial) [4]
• Rituximab reduces relapse 50% → 10-20% [22]

Outcomes:

• Troponin > 0.1: 3-fold mortality [14]
• Delay > 24 h: 1.5-fold mortality [8]
• Relapse 30-60% at 10 years [16]

Common Exam Questions

1. "How do you differentiate TTP from HUS?"

   • ADAMTS13 (less than 10% in TTP, normal in HUS)
   • Neurological dominant (TTP) vs renal dominant (HUS)
   • Adults (TTP) vs children (STEC-HUS)
   • Severe AKI/dialysis suggests HUS, not TTP

2. "Why do you not give platelets in TTP?"

   • Historical teaching: platelets "add fuel to fire" and worsen microthrombosis
   • Retrospective data suggest possible increased mortality/neurological events [25]
   • Current guidelines: avoid unless life-threatening bleeding (ICH, massive GI bleed)
   • If given, use lowest dose necessary

3. "What is the PLASMIC score?"

   • Clinical prediction tool for ADAMTS13 less than 10% before lab results available [19]
   • 7 variables (platelets less than 30, haemolysis, no cancer, no transplant, MCV less than 90, INR less than 1.5, Cr less than 177)
   • Score ≥5: 72% have ADAMTS13 less than 10%; sensitivity 90%, specificity 92%
   • Use to justify empiric PEX while awaiting ADAMTS13

4. "Describe the evidence for caplacizumab."

   • HERCULES trial (2019): 145 patients, RCT, caplacizumab vs placebo [4]
   • 74% vs 49% platelet normalisation less than 5 days (pless than 0.001)
   • 12% vs 38% composite endpoint (death/recurrence/TE) (pless than 0.001)
   • NNT = 4; licenced EMA 2018, FDA 2019

5. "What is your approach to a patient with thrombocytopenia, anaemia, and schistocytes?"

   • Confirm TMA: blood film (schistocytes), LDH (high), haptoglobin (low), Coombs (negative), coagulation (normal)
   • Calculate PLASMIC score
   • Send ADAMTS13 activity and inhibitor (before PEX)
   • If PLASMIC ≥5 or high clinical suspicion: start PEX immediately (do not wait for ADAMTS13)
   • Add steroids, caplacizumab, rituximab
   • Avoid platelet transfusion
   • Daily monitoring: platelets, LDH
   • Continue PEX until platelets > 150 x2 days

Common Mistakes (What Fails Candidates)

❌ Waiting for ADAMTS13 result before starting PEX → Delays treatment; increases mortality ❌ Transfusing platelets routinely → Worsens thrombosis (avoid unless life-threatening bleeding) ❌ Diagnosing TTP with ADAMTS13 > 10% → Not TTP; investigate other TMA ❌ Confusing TTP with HUS → Different treatments (PEX vs eculizumab) ❌ Missing cardiac involvement → Troponin is critical prognostic marker [14] ❌ Forgetting to send ADAMTS13 before PEX → Dilutes sample; false-normal result ❌ Stopping PEX too early → Risk of exacerbation; need platelets > 150 x2 days

Viva Anchors (Key Phrases to Use)

• "ADAMTS13 less than 10% is diagnostic"
• "Emergency plasma exchange is life-saving and should not be delayed"
• "PLASMIC score guides empiric treatment"
• "Neurological features distinguish TTP from HUS"
• "Normal coagulation distinguishes TTP from DIC"
• "Caplacizumab has a number needed to treat of 4 based on HERCULES trial"
• "Rituximab reduces relapse from 50% to 10-20%"
• "Troponin elevation predicts 3-fold increased mortality"
• "Avoid platelet transfusion unless life-threatening bleeding"

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17. References

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2. Joly BS, et al. Thrombotic thrombocytopenic purpura: a contemporary review. Blood Rev. 2022;54:100927. PMID: 35316270

3. Scully M, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158(3):323-335. PMID: 22624596

4. Scully M, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346. PMID: 30625035

5. Peyvandi F, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016;374(6):511-522. PMID: 26833331

6. Joly BS, et al. Clinical presentation of TTP: the changing pentad. Semin Hematol. 2014;51(3):236-242. PMID: 25264959

7. Lenting PJ, et al. ADAMTS13 biology and disease. J Thromb Haemost. 2021;19(2):348-359. PMID: 33909823

8. Azoulay E, et al. Therapeutic plasma exchange in critically ill patients with thrombotic thrombocytopenic purpura. Intensive Care Med. 2019;45(8):1153-1155. PMID: 31292116

9. Joly BS, et al. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846. PMID: 28416507

10. Deford CC, et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood. 2013;122(12):2023-2029. PMID: 23838348

11. Lenting PJ, et al. An emerging view on inhibitory antibodies in hemophilia A: it takes two to tango. J Thromb Haemost. 2015;13(Suppl 1):S44-52. PMID: 26149048

12. Al-Nouri ZL, et al. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015;125(4):616-618. PMID: 25414441

13. Miller JB, et al. Neurological manifestations of thrombotic thrombocytopenic purpura. J Neurol Sci. 2020;414:116843. PMID: 32405340

14. Benhamou Y, et al. Cardiac involvement is frequent in patients with thrombotic thrombocytopenic purpura and is associated with an adverse outcome. Circulation. 2019;140(13):1065-1067. PMID: 31570614

15. Moatti-Cohen M, et al. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood. 2012;119(24):5888-5897. PMID: 22547583

16. Han B, et al. Long-term outcomes and quality of life of patients with thrombotic thrombocytopenic purpura. Blood Adv. 2021;5(3):781-790. PMID: 33508122

17. George JN, et al. Distinguishing thrombotic thrombocytopenic purpura from other microangiopathies. Blood Rev. 2021;48:100792. PMID: 34265830

18. Lesesve JF, et al. Schistocytes in disseminated intravascular coagulation. Int J Lab Hematol. 2014;36(4):439-443. PMID: 24750675

19. Bendapudi PK, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol. 2017;4(4):e157-e164. PMID: 28259520

20. Zheng XL, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2496-2502. PMID: 32239796

21. Li J, et al. The role of corticosteroids in thrombotic thrombocytopenic purpura. Ther Apher Dial. 2019;23(6):507-515. PMID: 30498037

22. Hie M, et al. Rituximab in thrombotic thrombocytopenic purpura: a systematic review of the literature. Autoimmun Rev. 2020;19(10):102650. PMID: 32909630

23. Westwood JP, et al. Rituximab prophylaxis to prevent thrombotic thrombocytopenic purpura relapse: outcome and evaluation of dosing regimens. Blood. 2017;130(15):1746-1751. PMID: 28835437

24. Patriquin CJ, et al. Bortezomib in the treatment of refractory thrombotic thrombocytopenic purpura. Br J Haematol. 2016;173(5):779-785. PMID: 26992003

25. Sayani FA, et al. Platelet transfusion in TTP: harmful or helpful? Transfus Med Rev. 2016;30(3):96-102. PMID: 27056995

26. Fujimura Y, et al. Congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome): molecular pathogenesis, classification, diagnosis, and management. Semin Thromb Hemost. 2019;45(5):447-457. PMID: 30952310

27. Roose E, et al. ADAMTS13 and von Willebrand factor assessment in the diagnosis of thrombotic thrombocytopenic purpura and monitoring of patients in clinical remission. J Thromb Haemost. 2021;19(5):1158-1170. PMID: 33945620

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