Thrombotic Thrombocytopenic Purpura and Haemolytic Uraemic Syndrome in Adults

Overview

Thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) are life-threatening thrombotic microangiopathies (TMAs) characterised by the clinical triad of microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, and organ dysfunction. These conditions represent medical emergencies requiring immediate recognition and treatment to prevent mortality and long-term morbidity.

TTP is caused by severe deficiency of ADAMTS13, a von Willebrand factor (VWF)-cleaving protease, leading to accumulation of ultra-large VWF multimers that trigger spontaneous platelet aggregation and microvascular thrombosis, predominantly affecting the brain and other organs. Without treatment, mortality exceeds 90%, but with prompt plasma exchange and adjunctive therapies including caplacizumab, mortality is reduced to 10-20%.[1,2]

HUS is divided into two main forms: typical (Shiga toxin-associated) HUS (STEC-HUS), predominantly affecting children following infection with Shiga toxin-producing Escherichia coli, and atypical HUS (aHUS), caused by dysregulation of the complement alternative pathway, affecting all ages with predominant renal involvement. The management strategies differ fundamentally: TTP requires emergency plasma exchange, STEC-HUS requires supportive care only, and aHUS responds to complement inhibition with eculizumab.[3,4]

Recognition of these conditions depends on identifying the combination of MAHA (evidenced by schistocytes on blood film, elevated LDH, low haptoglobin) with thrombocytopenia in the absence of another clear cause. The key principle is to start treatment for suspected TTP immediately without waiting for ADAMTS13 results, as delays in plasma exchange directly correlate with increased mortality and morbidity.

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Epidemiology

TTP

Incidence: TTP has an annual incidence of 2-6 cases per million population, with regional variations.[1,5] The incidence appears to be increasing, possibly due to improved recognition and reporting rather than true epidemiological changes.

Demographics:

• Age: Peak incidence occurs between ages 30-50 years, with a median age at presentation of approximately 40 years
• Sex: Female predominance with a female-to-male ratio of 2-3:1 for acquired TTP
• Ethnicity: Higher incidence in Black populations compared to White populations (9-fold increased risk in some studies), possibly related to genetic factors affecting ADAMTS13 or immune response patterns[6]

Acquired vs Hereditary:

• Acquired (autoimmune) TTP accounts for approximately 90% of cases
• Hereditary TTP (Upshaw-Schulman syndrome) is rare, caused by homozygous or compound heterozygous ADAMTS13 gene mutations, typically presenting in infancy or childhood but occasionally diagnosed in adulthood

Mortality Trends: Before the introduction of plasma exchange in the 1970s-1980s, mortality from TTP exceeded 90%. With modern treatment including plasma exchange, corticosteroids, rituximab, and caplacizumab, mortality has decreased to 10-20% in developed healthcare settings.[1,2]

Atypical HUS

Incidence: aHUS has an estimated incidence of 0.5-2 cases per million population annually, though this may be underestimated due to diagnostic challenges.[3,7]

Demographics:

• Age: Can occur at any age, with approximately 40% of cases presenting in childhood and 60% in adulthood
• Sex: Slight female predominance in some series
• Genetics: 50-60% of patients have identifiable mutations in complement regulatory genes (factor H, factor I, MCP, C3, factor B, thrombomodulin)

Triggers: While aHUS is driven by underlying complement dysregulation, acute episodes are often triggered by:

• Infections (particularly respiratory and gastrointestinal)
• Pregnancy and postpartum period
• Medications
• Malignancy
• Autoimmune diseases

Typical (STEC) HUS

Incidence: STEC-HUS is the most common form of HUS, with an incidence of 1-3 per 100,000 children under 5 years annually in developed countries. It is rare in adults, accounting for less than 5% of all HUS cases in adult populations.[8]

Epidemiology:

• Peak age: Children under 5 years
• Seasonal variation: Peak in summer months (June-September) in temperate climates
• Outbreaks: Associated with contaminated food (undercooked beef, unpasteurised milk, contaminated vegetables) and water

Causative organisms:

• E. coli O157:H7 is the most common serotype (accounts for > 50% of cases)
• Other serotypes: O111, O103, O26, O145
• Shigella dysenteriae type 1 (less common, more prevalent in developing countries)

Geographic and Temporal Trends

Regional variations:

• Higher incidence of STEC-HUS in regions with intensive cattle farming
• aHUS has no clear geographic predilection but varies with genetic background
• TTP incidence is generally consistent across developed healthcare systems with standardised diagnostic criteria

Seasonal patterns: STEC-HUS shows clear summer predominance, while TTP and aHUS show no consistent seasonal variation.

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Aetiology & Pathophysiology

TTP: ADAMTS13 Deficiency Mechanism

Normal VWF Processing: Under physiological conditions, ultra-large von Willebrand factor (ULVWF) multimers are secreted from endothelial cells. The metalloprotease ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 motif, member 13) cleaves the Tyr1605-Met1606 bond in the VWF A2 domain, reducing ULVWF multimers to smaller, less thrombogenic forms.[9]

ADAMTS13 Deficiency Pathophysiology:

1. Severe deficiency (activity less than 10%) results from either:

   • Acquired: IgG autoantibodies against ADAMTS13 (90% of adult-onset TTP cases), typically directed against the spacer and cysteine-rich domains
   • Hereditary: Homozygous or compound heterozygous mutations in ADAMTS13 gene (chromosome 9q34), causing congenital deficiency

2. ULVWF accumulation: Without adequate ADAMTS13 activity, ULVWF multimers persist in circulation, particularly in high shear stress areas

3. Spontaneous platelet aggregation: ULVWF multimers bind platelet GPIb receptors with high affinity under shear stress, triggering platelet adhesion and aggregation without requiring platelet activation

4. Microvascular thrombosis: Platelet-rich microthrombi form spontaneously in small arterioles and capillaries throughout the body, with particular predilection for:

   • Brain: Explains high frequency of neurological symptoms
   • Heart: Myocardial ischaemia and troponin elevation
   • Kidneys: Usually mild-moderate AKI (distinguishes from HUS)
   • Other organs: Pancreas, adrenals, GI tract

5. Mechanical haemolysis:

   • Red blood cells are fragmented as they traverse fibrin strands in microthrombi
   • Shear stress-induced RBC membrane damage creates schistocytes (helmet cells, fragmented RBCs)
   • Intravascular haemolysis releases haemoglobin → haptoglobin depletion, elevated unconjugated bilirubin, elevated LDH

6. Platelet consumption: Ongoing platelet incorporation into microthrombi causes thrombocytopenia despite normal/increased platelet production

Triggering Factors (in acquired TTP):

• Pregnancy and postpartum period (accounts for ~10-25% of TTP cases)
• Infections (HIV, influenza, other viral infections)
• Medications (quinine, ticlopidine, clopidogrel - though rare with clopidogrel)
• Autoimmune diseases (SLE, Sjögren's syndrome)
• Malignancy
• Pancreatitis
• Often no identifiable trigger

Atypical HUS: Complement Dysregulation

Normal Complement Regulation: The complement alternative pathway is continuously activated at low levels on cell surfaces ("tick-over"). Healthy endothelium expresses complement regulatory proteins (factor H, MCP/CD46, thrombomodulin) that prevent amplification and protect from complement-mediated damage.[3,10]

Pathophysiology of aHUS:

1. Genetic abnormalities (50-60% of cases):

   • Loss-of-function mutations in complement regulatory genes:
     • Factor H (CFH): Most common (20-30% of aHUS), impaired regulation of C3 convertase
     • Membrane cofactor protein (MCP/CD46): 10-15%, impaired surface regulation
     • Factor I (CFI): 5-10%, impaired C3b degradation
     • Thrombomodulin (THBD): Rare, impaired cofactor activity for factor H
   • Gain-of-function mutations in:
     • C3: Resistant to factor H regulation
     • Factor B (CFB): Increased C3 convertase stability

2. Acquired abnormalities:

   • Anti-factor H antibodies: Account for ~5-10% of aHUS, more common in children
   • Associated with CFHR1-CFHR3 deletion (homozygous)

3. Complement activation cascade:

   • Uncontrolled alternative pathway → C3 convertase (C3bBb) formation
   • Amplification → massive C3b deposition on endothelial surfaces
   • Formation of C5 convertase → C5a (anaphylatoxin) + C5b
   • Terminal pathway → C5b-9 membrane attack complex (MAC)

4. Endothelial injury:

   • MAC insertion causes endothelial cell lysis and activation
   • Release of prothrombotic factors (tissue factor, VWF)
   • Loss of anticoagulant surface (thrombomodulin, heparan sulfate)
   • Exposure of subendothelial collagen

5. Thrombotic microangiopathy:

   • Platelet adhesion and activation
   • Fibrin deposition
   • Microvascular thrombosis predominantly affecting renal microvasculature
   • Mechanical haemolysis (schistocyte formation)

6. Renal-predominant injury:

   • Glomerular endothelial swelling and detachment
   • Mesangiolysis
   • Arteriolar and capillary thrombosis
   • Progressive to cortical necrosis in severe cases

Triggers for aHUS Episodes: Even with genetic predisposition, aHUS episodes are often triggered by:

• Infections (particularly upper respiratory and gastroenteritis)
• Pregnancy and postpartum
• Medications (calcineurin inhibitors, chemotherapy)
• Surgery or trauma
• Many patients have no identifiable trigger for first presentation

Penetrance: Genetic mutations have incomplete penetrance (~50%), meaning not all carriers develop aHUS, suggesting additional genetic or environmental factors are required.

Typical (STEC) HUS: Shiga Toxin Mechanism

Infection Phase:

1. Infection with Shiga toxin-producing E. coli (most commonly O157:H7)
2. Colonisation of large intestine
3. Bloody diarrhoea develops (due to direct toxin effect on intestinal mucosa)

Toxin-Mediated Injury:

1. Shiga toxin subtypes: Stx1 and Stx2 (Stx2 associated with more severe disease and HUS)

2. Toxin structure: AB5 toxin

   • A subunit: Enzymatically active
   • B subunit pentamer: Binds to globotriaosylceramide (Gb3) receptors

3. Target cells:

   • Gb3 highly expressed on renal glomerular endothelium, tubular epithelium
   • Also present on intestinal epithelium, CNS endothelium

4. Cellular mechanism:

   • Toxin binds Gb3 → endocytosis
   • A subunit cleaves 28S ribosomal RNA
   • Inhibition of protein synthesis
   • Endothelial cell death and activation

5. Thrombotic microangiopathy:

   • Direct endothelial toxicity (primary mechanism)
   • Release of ULVWF multimers
   • Decreased ADAMTS13 activity (relative, not absolute deficiency)
   • Platelet adhesion and microthrombi formation
   • Mechanical haemolysis

Systemic Manifestations:

• Predominantly renal (HUS develops in ~10-15% of STEC infections)
• Neurological involvement in severe cases (5-10%)
• Gastrointestinal complications (ischaemic colitis, perforation rare)

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Clinical Presentation

TTP: Classic and Modern Presentations

Historical TTP Pentad (now recognised in only 5-10% of cases at presentation):

1. Microangiopathic haemolytic anaemia (MAHA) - 100%
2. Thrombocytopenia - 100%
3. Neurological symptoms - 50-90%
4. Renal impairment - 50-80% (usually mild-moderate)
5. Fever - 25-50%

Modern Recognition: The triad of MAHA + thrombocytopenia + any organ dysfunction should prompt consideration of TTP, with ADAMTS13 testing and urgent plasma exchange initiation.[1,11]

Symptom Patterns and Frequencies:

Neurological Manifestations in Detail:

• Fluctuating nature: Symptoms may wax and wane over hours, distinguishing from static stroke
• Confusion/altered mental status: Most common neurological feature (40-60%)
• Headache: 25-40%, can be severe and migraine-like
• Seizures: 10-20%, focal or generalised
• Transient ischaemic attacks (TIAs): Recurrent, affecting different vascular territories
• Stroke: 10-15%, may be multifocal
• Visual disturbances: Cortical blindness, scotomas, diplopia
• Aphasia, dysarthria: Indicating focal ischaemia
• Coma: 5-10%, indicates severe disease with poor prognosis

Severity Indicators:

• Platelet count less than 30 × 10⁹/L
• Troponin elevation (associated with increased mortality)
• Severe neurological symptoms (coma, stroke)
• Creatinine > 250 μmol/L (suggests possible aHUS or severe TTP)

PLASMIC Score: Risk Stratification for TTP

The PLASMIC score is a validated clinical prediction tool to estimate the probability of severe ADAMTS13 deficiency (less than 10%) before laboratory results are available.[12]

PLASMIC Score Components (1 point each):

Score Interpretation:

Limitations of PLASMIC Score:

• Developed in populations with suspected TTP (pre-test probability already elevated)
• Does not replace clinical judgment
• Should not delay treatment in clinically suspected TTP
• Less validated in pregnancy-associated TMA

Clinical Application:

• PLASMIC score 6-7: High probability of TTP → start plasma exchange without delay
• PLASMIC score 5: Intermediate risk → discuss urgently with haematology, consider starting plasma exchange depending on clinical suspicion
• PLASMIC score 0-4: Low probability BUT if clinical suspicion remains high (e.g., classic presentation), still send ADAMTS13 and consider empiric treatment

Atypical HUS Presentation

Predominant Features:

• Renal-predominant disease: Distinguishes from TTP
• Acute kidney injury (often severe, 50-70% require dialysis at presentation)
• MAHA and thrombocytopenia (as in TTP, but usually less severe thrombocytopenia)
• Less prominent neurological symptoms compared to TTP (though can occur in 10-20%)

Clinical Patterns:

Presentation Contexts:

1. De novo presentation: No prior history, often with identifiable trigger
2. Relapsing disease: 50-60% of patients experience recurrent episodes without eculizumab treatment
3. Pregnancy-associated: Can present during pregnancy or postpartum (distinguish from HELLP, pre-eclampsia)
4. Post-transplant: 50-90% recurrence in renal transplant if underlying genetic defect present and not on eculizumab

Age-Related Patterns:

• Children: Often present with severe AKI requiring dialysis, may have preceding diarrhoea (can be confused with STEC-HUS)
• Adults: May have more insidious onset, history of "unexplained" AKI episodes

Typical (STEC) HUS Presentation

Prodromal Phase (5-10 days before HUS):

1. Diarrhoeal illness: Initially non-bloody, becomes bloody in 70-90%
2. Abdominal pain: Cramping, severe
3. Nausea and vomiting
4. Low-grade fever (in ~30%)

HUS Phase (develops in ~10-15% of STEC infections):

1. Timing: Typically 5-10 days after onset of diarrhoea, often as diarrhoea is resolving
2. Acute kidney injury: Oliguria, anuria, fluid overload
3. MAHA: Pallor, fatigue, jaundice
4. Thrombocytopenia: Petechiae, bruising
5. Neurological involvement (5-10% of STEC-HUS): Seizures, altered consciousness, stroke (poor prognostic sign)

Severity Indicators:

• White blood cell count > 20 × 10⁹/L (associated with worse outcomes)
• Severe neurological involvement
• Prolonged anuria
• Very young age (less than 2 years)

Differential Diagnosis: Distinguishing TTP, aHUS, and STEC-HUS

Red Flag Features Requiring Immediate Action

🚨 CRITICAL RED FLAGS:

• Schistocytes on blood film + thrombocytopenia = Assume TMA, consider TTP
• Confusion/altered consciousness + thrombocytopenia = Highly suspicious for TTP → initiate plasma exchange immediately
• Seizures with thrombocytopenia and anaemia = TTP until proven otherwise
• Platelet count dropping rapidly (> 50% decline in 24-48 hours)
• Haemoglobin less than 80 g/L with schistocytes
• LDH > 1000 U/L (usually > 2x upper limit normal in TTP)
• Troponin elevation (indicates cardiac involvement, worse prognosis)
• Oliguria/anuria with haemolysis + thrombocytopenia (suggests HUS)

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Clinical Examination

General Inspection

Appearance:

• Pallor: Severe anaemia (Hb often 60-90 g/L at presentation)
• Jaundice: Unconjugated hyperbilirubinaemia from haemolysis (mild scleral icterus)
• Petechiae and purpura: Particularly on dependent areas, oral mucosa
• Bruising: Easy bruising from thrombocytopenia
• Distress level: Confusion, agitation (neurological involvement)

Vital Signs

• Temperature: Low-grade fever in 25-50% of TTP
• Heart rate: Tachycardia (anaemia, hypovolaemia)
• Blood pressure:
  • May be elevated in HUS (especially aHUS)
  • May be low in severe haemolysis with hypovolaemia
• Respiratory rate: Increased if anaemia severe or fluid overload
• Oxygen saturation: Usually normal unless severe anaemia or cardiac involvement

Neurological Examination (Critical in TTP)

Mental Status:

• Level of consciousness: Alert, confused, drowsy, or comatose
• Orientation: Fluctuating disorientation common in TTP
• Attention and concentration: Impaired in microvascular brain ischaemia

Focal Neurological Signs:

• Cranial nerves: Visual field defects, diplopia, facial weakness
• Motor: Hemiparesis, monoparesis (focal ischaemia)
• Sensory: Hemisensory loss
• Reflexes: May be asymmetric with focal lesions
• Plantar responses: Upgoing (upper motor neuron lesion)
• Speech: Dysarthria, aphasia

Seizure Activity:

• Observe for ongoing seizure activity
• Post-ictal state

Fluctuating Nature:

• Key feature: symptoms may change dramatically over hours
• Document serial examinations

Cardiovascular Examination

• Inspection: JVP (fluid status, may be elevated if AKI with fluid overload)
• Palpation: Apex beat (displaced if heart failure)
• Auscultation:
  • Systolic flow murmur (anaemia)
  • Signs of heart failure (S3 gallop)
  • Pericardial rub (rare)

Respiratory Examination

• Inspection: Respiratory distress (pulmonary oedema if severe AKI)
• Auscultation: Crackles if fluid overload

Abdominal Examination

Inspection: Distension (rare)

Palpation:

• Tenderness (STEC-HUS with colitis, pancreatitis in TTP)
• Hepatomegaly (mild, from haemolysis)
• Splenomegaly (not typical, consider alternative diagnosis if present)

Percussion: Usually normal

Auscultation: Bowel sounds (may be reduced with ileus)

Skin and Mucous Membranes

Petechiae and Purpura:

• Non-blanching
• Distribution: Dependent areas, pressure points
• Oral mucosa, conjunctivae

Bruising: Ecchymoses at venepuncture sites, spontaneous

Bleeding:

• Rare unless platelets less than 10-20 × 10⁹/L
• Gingival bleeding
• Epistaxis
• Major bleeding uncommon (distinguishes from DIC)

Fluid Status Assessment

• Hypovolaemia: If severe diarrhoea (STEC-HUS), vomiting, reduced oral intake
• Fluid overload: If severe AKI with oliguria/anuria
• Assess: Mucous membranes, skin turgor, JVP, peripheral oedema, lung bases

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Investigations

Immediate Bedside Tests

Urine Dipstick:

• Haematuria: Present in TTP/HUS from microvascular injury
• Proteinuria: Often 1-3+, may be nephrotic range in aHUS
• No leucocytes/nitrites (distinguishes from UTI)

ECG:

• Indications: All patients (assess for cardiac ischaemia)
• Findings:
  • Tachycardia (anaemia)
  • ST-T changes (microvascular ischaemia, troponin elevation in 10-30%)
  • Arrhythmias (rare)

Essential Laboratory Tests (BEFORE Plasma Exchange)

Critical Principle: Send ADAMTS13 and complement studies BEFORE starting plasma exchange or eculizumab, as these therapies interfere with test interpretation. However, DO NOT DELAY treatment while awaiting results.

Full Blood Count

Blood Film: THE KEY DIAGNOSTIC TEST

Critical Features:

• Schistocytes (fragmented RBCs):
  • Helmet cells, triangle cells, fragmented cells
  • > 1% RBCs = significant (normal less than 0.5%)
  • Indicates mechanical haemolysis from microangiopathic process
  • MAHA diagnosis requires schistocytes
• Polychromasia: Indicates reticulocytosis (marrow response)
• Nucleated RBCs: May be present (stress erythropoiesis)
• Normal platelet morphology: Large platelets (young), not clumped
• Absence of blasts or dysplasia: Excludes leukaemia/MDS

Reporting: Request urgent review by senior haematology laboratory staff or consultant haematologist

Haemolysis Screen

Interpretation:

• MAHA requires: Schistocytes + elevated LDH + low haptoglobin + negative DAT
• DAT positive = consider autoimmune haemolytic anaemia (AIHA), Evans syndrome, or mixed picture

Coagulation Studies

Clinical Significance: Normal coagulation studies (PT, APTT, fibrinogen) distinguish TMA from disseminated intravascular coagulation (DIC). This is critical for differential diagnosis.

Renal Function

Urine Output Monitoring: Essential in HUS (oliguric AKI common)

Cardiac Biomarkers

Other Baseline Tests

• Liver function tests: Mild transaminitis (haemolysis, ischaemia), elevated bilirubin (unconjugated)
• Bone profile: Calcium, phosphate (may be deranged in AKI)
• Blood cultures: If fever present (exclude sepsis as alternative/concurrent diagnosis)
• Pregnancy test: All women of childbearing age (pregnancy-associated TMA)

Diagnostic Tests: ADAMTS13 and Complement Studies

ADAMTS13 Testing: THE DEFINITIVE TEST FOR TTP

Send BEFORE plasma exchange (plasma exchange falsely elevates ADAMTS13 activity)

Components:

1. ADAMTS13 activity:

   • Measures enzymatic function
   • less than 10% = severe deficiency = TTP diagnosis[1,11]
   • 10-20% = possible TTP or partial deficiency

   • 20% = TTP unlikely (consider aHUS, other TMA)

2. ADAMTS13 inhibitor (IgG autoantibody):

   • Measured if activity less than 10%
   • Quantified in Bethesda Units (BU)
   • > 0.5-2 BU = positive (acquired TTP)
   • Negative = hereditary TTP (gene sequencing needed)
   • Titre correlates with relapse risk

Timing Issues:

• Results typically take 24-72 hours (reference laboratory test)
• DO NOT WAIT for results before starting plasma exchange
• False elevations if sample taken after plasma exchange started
• If plasma exchange already started, interpret results cautiously (may need repeat after remission)

Interpretation:

Complement Studies (for aHUS Diagnosis)

Send BEFORE eculizumab (eculizumab blocks C5, interfering with assays)

Serum Complement Levels:

• C3: Low in 30-50% of aHUS (alternative pathway consumption)
• C4: Normal (classical pathway not involved)
• Pattern: Low C3 + Normal C4 = alternative pathway activation

Functional Assays:

• Factor H level: Low if CFH mutation or anti-FH antibodies
• Factor I level: Low if CFI mutation
• Factor B level: May be elevated if gain-of-function CFB mutation

Autoantibody Testing:

• Anti-factor H antibodies: Present in ~5-10% of aHUS (more common in children)
• Associated with CFHR1-CFHR3 homozygous deletion
• Usually good response to immunosuppression + plasma exchange

Genetic Testing (send but takes weeks):

• Genes tested: CFH, CFI, MCP, C3, CFB, THBD, DGKE
• Timing: Send acutely but results not available for acute management
• Yield: Mutations found in 50-60% of aHUS patients
• Clinical utility:
  • Confirms diagnosis
  • Informs prognosis (e.g., MCP mutations better prognosis)
  • Guides transplant counselling (high recurrence risk with CFH/CFI mutations)
  • Family screening and genetic counselling

Interpretation:

Stool Studies (if STEC-HUS Suspected)

Indications:

• Diarrhoeal prodrome (especially bloody diarrhoea)
• Children or young adults with HUS presentation
• Outbreak setting or food exposure history

Tests:

1. Stool culture for E. coli O157:H7:

   • Requires sorbitol-MacConkey agar
   • Positive in ~50% by time HUS develops (organism cleared)

2. Stool PCR for Shiga toxin genes (stx1, stx2):

   • More sensitive than culture
   • Detects stx genes even if organism cleared

3. Enzyme immunoassay (EIA) for Shiga toxin:

   • Detects toxin directly
   • Rapid turnaround

4. Serology: Anti-LPS antibodies to E. coli O157

   • Useful if stool negative but HUS developed

Timing: Send immediately, but often negative by time HUS manifests (organism cleared during diarrhoeal phase)

PLASMIC Score Calculation (Clinical Prediction Tool)

Calculate at bedside using available tests:[12]

1. Platelet count less than 30 × 10⁹/L = 1 point
2. LDH/AST ratio > 20 = 1 point (indicates haemolysis)
3. No active cancer = 1 point
4. No transplant history = 1 point
5. MCV less than 90 fL = 1 point
6. INR less than 1.5 = 1 point
7. Creatinine less than 176 μmol/L = 1 point

Score 6-7: 62-82% chance of ADAMTS13 less than 10% → High risk TTP → Start plasma exchange immediately

Imaging Studies

Not routinely required for diagnosis, but may be indicated for complications:

CT/MRI Brain (if neurological symptoms):

• Indications: Focal deficits, seizures, persistent confusion, coma
• Findings in TTP:
  • Often normal (small vessel disease)
  • Multifocal T2/FLAIR hyperintensities (cortical, subcortical)
  • Acute infarcts (may be multiple, different territories)
  • Haemorrhage (rare, but possible)
• Purpose: Exclude alternative causes (ICH, mass lesion, large vessel stroke)

CT Abdomen (if severe abdominal pain):

• STEC-HUS: May show colitis (bowel wall thickening, thumbprinting)
• TTP: May show pancreatitis (rare), mesenteric ischaemia (rare)

Renal Ultrasound:

• Usually shows normal-sized kidneys (acute process)
• Excludes obstruction
• Assess cortical thickness and echogenicity

Chest X-ray:

• Assess for pulmonary oedema (if severe AKI with fluid overload)
• Exclude infection

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Management

General Principles

1. TTP is a medical emergency: Mortality > 90% without treatment, 10-20% with treatment
2. Start treatment immediately: Do NOT wait for ADAMTS13 results
3. Plasma exchange is life-saving: Reduces mortality from 90% to 10-20%
4. Avoid platelet transfusions: May worsen thrombosis ("fuel for the fire")
5. Differentiate TTP from HUS early: Treatment strategies differ fundamentally

TTP: Emergency Management Protocol

Initial Resuscitation and Assessment (First 30-60 minutes)

ABC Approach:

• Airway: Assess if GCS reduced (protect if GCS less than 8)
• Breathing: Oxygen if hypoxic, assess for pulmonary oedema
• Circulation: IV access (large-bore for plasma exchange), fluid resuscitation if hypovolaemic

Immediate Actions:

1. ✅ Senior haematology consult (within 30 minutes)
2. ✅ Urgent blood tests (as above, including ADAMTS13 BEFORE plasma exchange)
3. ✅ Cross-match blood (anticipate RBC transfusions)
4. ✅ Activate plasma exchange service (within 4-8 hours of diagnosis)
5. ✅ Central venous catheter insertion (for plasma exchange access)
6. ✅ Admit to HDU/ICU if severe neurological symptoms or organ dysfunction
7. ✅ Neurology consult if seizures or focal deficits
8. ✅ Commence monitoring: Continuous cardiac monitoring (troponin elevation risk), neuro observations hourly

Supportive Care:

• Fluid management: Cautious IV fluids (risk of fluid overload if renal impairment)
• Seizure management: Benzodiazepines (lorazepam 4 mg IV), then loading with levetiracetam or phenytoin
• Antiemetics: For nausea/vomiting
• Analgesia: Paracetamol, avoid NSAIDs (renal impairment, bleeding risk)

Plasma Exchange (Plasmapheresis): First-Line Treatment

Mechanism:

• Removes ADAMTS13 autoantibodies and ULVWF multimers
• Replaces with ADAMTS13-containing plasma
• Provides exogenous ADAMTS13 activity

Timing: Within 4-8 hours of suspected diagnosis[1,2]

• Delays associated with increased mortality and morbidity
• Start empirically if high clinical suspicion even without ADAMTS13 result

Procedure Details:

Remission Criteria (all must be met for 2-3 consecutive days):

1. Platelet count > 150 × 10⁹/L for 2-3 days
2. LDH normalising or less than 1.5× upper limit normal
3. Schistocytes resolving on blood film
4. Neurological symptoms resolved
5. Haemoglobin stabilising

Typical Duration: 5-14 days (median ~7-9 days)

Tapering:

• Once remission achieved, some centres taper to alternate day for 2-3 sessions (to prevent rebound)
• Others stop abruptly and monitor closely

Complications of Plasma Exchange:

• Central line complications: Infection (5-10%), thrombosis, pneumothorax (if IJ/subclavian)
• Citrate toxicity: Hypocalcaemia (perioral tingling, tetany), give calcium gluconate
• Allergic reactions to FFP: Urticaria (give antihistamines), anaphylaxis (rare, stop and treat)
• Fluid shifts: Hypotension, pulmonary oedema
• Plasma-transmitted infections: Extremely rare with modern screening

Monitoring During Plasma Exchange:

• Vital signs every 15-30 minutes during procedure
• Ionised calcium (citrate chelation causes hypocalcaemia)
• Platelet count, LDH, Hb daily
• Neurological observations every 4 hours

Caplacizumab: Anti-VWF Nanobody Therapy

Mechanism:

• Humanised bivalent nanobody targeting VWF A1 domain
• Blocks interaction between VWF and platelet GPIb receptor
• Prevents VWF-mediated platelet aggregation
• Does NOT remove autoantibodies (still need plasma exchange/immunosuppression)

Evidence Base:

• TITAN Trial (Phase 2, 2016)[13]: Faster platelet recovery, reduced recurrence during treatment
• HERCULES Trial (Phase 3, 2019)[2]:
  • 74% reduction in TTP-related death or recurrence during treatment
  • 67% reduction in composite endpoint (death, recurrence, major thromboembolic event)
  • "Time to platelet normalisation: 2.69 vs 2.88 days (modest difference)"
  • "Recurrence during treatment period: 12% vs 38% (placebo)"
  • Increased bleeding events (particularly epistaxis, gingival bleeding)

Indications (as per guidelines and trial data):[1]

• Acquired TTP (immune-mediated, ADAMTS13 less than 10%)
• Use in conjunction with plasma exchange and immunosuppression
• Consider in all patients with acquired TTP if available and no contraindications

Dosing Protocol:

Monitoring Requirements:

1. ADAMTS13 activity and inhibitor every 7 days during treatment
2. Continuation criteria:
   • After 30-day post-PEX period, check ADAMTS13 activity
   • If ADAMTS13 less than 10% or inhibitor present → continue caplacizumab
   • If ADAMTS13 ≥20% and inhibitor absent → stop caplacizumab
3. Maximum duration: Usually stop by 6 months (reassess if still requiring)

Contraindications:

• Active bleeding (relative contraindication, assess risk vs benefit)
• Known hypersensitivity to caplacizumab

Side Effects:

• Bleeding (10-15%): Epistaxis, gingival bleeding, menorrhagia, bruising
  • Usually mild, manage conservatively
  • "Severe bleeding: STOP caplacizumab, consider platelet transfusion"
• Headache (5-10%)
• Injection site reactions
• Antibodies to caplacizumab: Rare, usually not clinically significant

Special Considerations:

• Cost: Extremely expensive (>£200,000 per treatment course), but cost-effective analyses support use
• Availability: May not be available in all centres, discuss with tertiary haematology

Corticosteroids: Immunosuppression

Rationale: Suppress autoantibody production against ADAMTS13

Regimens:

High-dose pulsed regimen (preferred by many):

• Methylprednisolone 10 mg/kg IV daily (max 1 g) for 3 days
• Then prednisolone 1 mg/kg PO daily (max 60-80 mg)
• Taper over 4-6 weeks once remission achieved

Alternative regimen:

• Prednisolone 1 mg/kg PO daily from outset
• Continue during plasma exchange
• Taper over 4-6 weeks after remission

Tapering Schedule (example):

• Week 1-2 post-remission: 60 mg daily
• Week 3: 40 mg daily
• Week 4: 30 mg daily
• Week 5: 20 mg daily
• Week 6: 10 mg daily, then stop

Monitoring:

• Blood glucose (steroid-induced hyperglycaemia)
• Blood pressure
• Gastric protection: PPI (e.g., lansoprazole 30 mg daily)
• Bone protection: Consider calcium/vitamin D
• Pneumocystis prophylaxis: Co-trimoxazole 480 mg daily or dapsone 100 mg 3×/week if prolonged high-dose steroids

Rituximab: Anti-CD20 Monoclonal Antibody

Mechanism: Depletes B-cells, reducing autoantibody production

Indications:

1. Refractory TTP: Not responding to plasma exchange after 4-7 days (platelets not rising, ongoing neurological symptoms)
2. Severe TTP: High inhibitor titre, very low ADAMTS13
3. Relapsing TTP: History of previous TTP episodes
4. Adjunctive in first episode: Increasingly used upfront to reduce relapse risk[14]

Evidence:

• Reduces relapse rate from 50% to ~10% in observational studies
• Faster ADAMTS13 recovery
• Allows earlier cessation of plasma exchange in some studies
• No RCTs, but strong observational evidence

Dosing:

• Standard regimen: 375 mg/m² IV weekly × 4 doses
• Alternative: 375 mg/m² IV at presentation, then weekly during plasma exchange

Pre-Medication:

• Paracetamol 1 g PO
• Chlorphenamine 10 mg IV
• Hydrocortisone 100 mg IV (if not already on high-dose steroids)

Monitoring:

• Infusion reactions (first infusion): Fever, rigors, hypotension (slow/stop infusion, give chlorphenamine, hydrocortisone)
• Infections: Increased risk (hypogammaglobulinaemia)
• B-cell counts: Check CD19+ count at 3-6 months (expect depletion)
• Hepatitis B reactivation risk: Check HBsAg, anti-HBc before rituximab (reactivation can be fatal)

Contraindications:

• Active hepatitis B (unless on antiviral prophylaxis)
• Severe active infection

Red Blood Cell Transfusion

Indications:

• Haemoglobin less than 70 g/L (liberal threshold)
• Symptomatic anaemia: Chest pain, dyspnoea, reduced GCS
• Higher threshold if cardiac ischaemia: Consider less than 80 g/L

Precautions:

• Anticipate need for multiple units (Hb often 60-80 g/L at presentation)
• Use leucodepleted blood
• Transfuse slowly if risk of fluid overload (renal impairment)

Platelet Transfusion: CONTRAINDICATED

DO NOT transfuse platelets in TTP except:

• Life-threatening bleeding (ICH, major GI bleed)
• Invasive procedure with high bleeding risk (neurosurgery, major surgery)

Rationale:

• Platelets provide "substrate" for ongoing microthrombosis
• Historical reports of clinical deterioration after platelet transfusion
• Thrombocytopenia in TTP is due to consumption, not production failure
• Bleeding is uncommon even with very low platelets (microthrombi consume platelets and factors locally, less systemic bleeding risk)

Exception: If platelets less than 10 × 10⁹/L AND active bleeding, discuss with senior haematologist (risk vs benefit)

Anticoagulation: Generally NOT Recommended

Avoid therapeutic anticoagulation unless specific indication (e.g., confirmed DVT/PE, AF)

Rationale:

• Increased bleeding risk with thrombocytopenia
• Microthrombotic process, not macrothrombosis
• No evidence of benefit

VTE prophylaxis:

• Avoid pharmacological prophylaxis if platelets less than 30-50 × 10⁹/L
• Use mechanical prophylaxis (compression stockings, intermittent pneumatic compression)
• Consider low-dose LMWH if platelets > 50 × 10⁹/L and immobile

Monitoring During Treatment

Daily Monitoring:

• FBC (Hb, platelets, WCC)
• Blood film review (schistocytes)
• LDH
• Renal function
• Troponin (if initially elevated)

Twice-Weekly:

• ADAMTS13 activity (if available rapidly)
• Inhibitor titre

Clinical Monitoring:

• Neurological observations every 4 hours (or more frequently if severe)
• Fluid balance (risk of overload if renal impairment)
• Cardiac monitoring (if troponin elevated)
• Temperature, BP, HR every 4-6 hours

Response Markers (expect improvement within 3-5 days):

• Platelet count rising (should double within 7 days if responding)
• LDH falling
• Schistocytes decreasing
• Neurological symptoms improving

Refractory TTP: Escalation Strategies

Definition: Failure to respond after 4-7 days of plasma exchange (platelets not rising, persistent symptoms)

Escalation Options:

1. Increase plasma exchange volume: 1.5 plasma volumes or twice-daily plasma exchange
2. Add rituximab (if not already given)
3. Immunosuppression escalation:
   • Ciclosporin 3-5 mg/kg/day PO (target trough 100-200 ng/mL)
   • Cyclophosphamide 500 mg/m² IV
   • Vincristine 1-2 mg IV weekly
   • Bortezomib (proteasome inhibitor, case reports)
4. Splenectomy: Historical option, rarely used now (rituximab preferred)
5. Check compliance with caplacizumab (if prescribed)
6. Consider alternative diagnosis: Is this definitely TTP? Could it be aHUS, secondary TMA?

Atypical HUS: Complement Inhibition Strategy

Eculizumab: Anti-C5 Monoclonal Antibody (First-Line for aHUS)

Mechanism:

• Binds complement C5
• Prevents cleavage to C5a and C5b
• Blocks formation of C5b-9 membrane attack complex (MAC)
• Stops terminal complement-mediated endothelial injury

Evidence Base:

• Legendre et al. (2013), NEJM[3]:
  • "Complete TMA response: 65%"
  • eGFR improvement: median +28 mL/min/1.73m²
  • "Dialysis-free: 80%"
  • Marked superiority over historical controls (50% progressed to ESRD without eculizumab)
• Licht et al. (2015): Long-term treatment prevents recurrence, maintains renal function

Indications (as per guidelines):[7]

• Confirmed or highly suspected aHUS (low C3, normal ADAMTS13, no Shiga toxin)
• May be used empirically in TMA if TTP vs aHUS uncertain and ADAMTS13 results pending
• Prophylaxis in renal transplant if underlying genetic defect (prevents recurrence)

Dosing Protocol:

Administration:

• IV infusion over 35 minutes
• Pre-medication usually not required
• Monitor for infusion reactions

Duration of Treatment:

• Usually lifelong (ongoing complement dysregulation)
• Stopping risks: 50-60% recurrence of aHUS within weeks-months
• Exceptions: May consider stopping after prolonged remission (> 12-24 months) in:
  • MCP/THBD mutations (better prognosis)
  • Anti-factor H antibody-associated aHUS after antibody eradicated
  • Trigger-associated aHUS (e.g., pregnancy) if trigger resolved
• Monitor closely if stopping: Weekly FBC, U&E, LDH for 12 weeks

Monitoring:

• Pre-treatment:
  • Confirm diagnosis (complement studies, ADAMTS13)
  • MANDATORY meningococcal vaccination (see below)
  • Baseline FBC, U&E, LDH, complement
• During treatment:
  • "FBC, U&E, LDH: Daily initially, then weekly, then every 2-4 weeks once stable"
  • "Complement C3: May normalise"
  • "Platelet count, Hb, schistocytes: Should normalise within 1-4 weeks"
  • "Renal function: Gradual improvement over weeks-months"

Meningococcal Vaccination and Prophylaxis: CRITICAL SAFETY REQUIREMENT

Rationale: Eculizumab blocks C5, preventing MAC formation, which is essential for killing Neisseria meningitidis. Risk of invasive meningococcal disease increases 1000-2000 fold.[15]

MANDATORY Vaccination Protocol:

Ideally (if time permits, i.e., NOT emergency):

• Vaccinate ≥2 weeks before starting eculizumab
• Vaccines required:
  1. MenACWY (quadrivalent conjugate vaccine, e.g., Menveo, Nimenrix)
  2. MenB (e.g., Bexsero) - two doses 1 month apart
  3. Consider pneumococcal (PCV13 + PPSV23) and Haemophilus influenzae type b

In Emergency Situations (cannot wait 2 weeks):

• Give vaccines immediately (same day as first eculizumab dose if necessary)
• PLUS initiate antibiotic prophylaxis until 2 weeks post-vaccination:
  • Penicillin V 500 mg PO twice daily (first-line), OR
  • Azithromycin 500 mg PO daily (if penicillin allergy)
• Some centres continue prophylaxis indefinitely during eculizumab therapy (varies by local protocol)

Booster Vaccinations:

• MenACWY: Every 5 years
• MenB: Consider booster every 2-3 years (no firm guidelines)

Patient Education:

• ⚠️ Seek immediate medical attention for fever, headache, neck stiffness, rash, confusion
• Carry emergency card identifying eculizumab use
• Inform all healthcare providers
• Awareness of early meningococcal symptoms

Management of Suspected Meningococcal Infection:

• MEDICAL EMERGENCY
• Immediate IV antibiotics (ceftriaxone 2 g IV stat)
• Blood cultures, LP if safe
• Inform infectious diseases/microbiology immediately
• Consider stopping eculizumab temporarily (discuss with haematology)

Plasma Exchange in aHUS: Limited Role

Rationale:

• Historically used before eculizumab availability
• May remove antibodies (if anti-FH antibodies) or provide complement regulators
• HOWEVER: May worsen by removing complement regulatory proteins
• Inferior to eculizumab

Current Role:

• While awaiting eculizumab (if delay in obtaining drug)
• Anti-factor H antibody-associated aHUS: Plasma exchange + immunosuppression may be effective
• Uncertain TTP vs aHUS: May use both plasma exchange + eculizumab empirically until ADAMTS13 result available

If Used:

• Daily plasma exchange with FFP replacement
• 1-1.5 plasma volumes
• Transition to eculizumab as soon as available

Immunosuppression for Anti-Factor H Antibody aHUS

If anti-factor H antibodies detected:

• Plasma exchange (removes antibodies)
• Corticosteroids: Prednisolone 1 mg/kg daily
• Rituximab: 375 mg/m² weekly × 4 doses
• Mycophenolate mofetil: 500-1000 mg twice daily (some protocols)
• Monitor antibody titres: Continue treatment until undetectable
• May be able to stop eculizumab once antibodies eradicated and sustained remission

Typical (STEC) HUS: Supportive Care ONLY

Critical Principle:

• NO plasma exchange (not effective, may worsen)
• NO antibiotics during acute diarrhoeal phase (may increase Shiga toxin release, worsen HUS)
• NO antimotility agents (e.g., loperamide) - may prolong bacterial contact time

Supportive Management:

Fluid and Electrolyte Management:

• Aggressive early hydration during diarrhoeal phase may reduce HUS risk (evidence from outbreak data)
• Once HUS develops: Careful fluid balance (risk of oliguria, fluid overload)
• IV fluids: Isotonic saline initially
• Monitor: Urine output, weight, JVP, peripheral oedema
• Restrict fluids if oliguric/anuric and fluid overloaded

Renal Replacement Therapy:

• Indications:
  • Severe hyperkalaemia (> 6.5 mmol/L, ECG changes)
  • Metabolic acidosis (pH less than 7.2, bicarbonate less than 10)
  • Fluid overload with pulmonary oedema
  • Symptomatic uraemia
• Modality: Haemodialysis or peritoneal dialysis (PD often preferred in children)
• Duration: 30-50% of children with STEC-HUS require dialysis, median duration 7-10 days
• Recovery: Most recover renal function (80-90%), though may have reduced GFR long-term

RBC Transfusion:

• Threshold Hb less than 70 g/L
• Anticipate need (Hb often 60-80 g/L)
• Avoid over-transfusion (risk of fluid overload if anuric)

Platelet Transfusion:

• Avoid unless life-threatening bleeding (same principle as TTP)

Nutrition:

• Maintain nutrition (enteral if possible, PN if prolonged ileus)
• Protein restriction NOT necessary

Hypertension Management:

• Common (60-80%)
• Target BP less than 95th percentile for age (children) or less than 140/90 (adults)
• Agents: Amlodipine, labetalol, hydralazine (IV if severe)

Seizure Management (if CNS involvement):

• Benzodiazepines acutely
• Maintenance anticonvulsants if recurrent
• Investigate: CT/MRI brain (exclude haemorrhage, oedema, infarction)

Monitoring:

• Daily: FBC, U&E, LDH, creatinine
• Fluid balance strictly
• Blood pressure
• Neurological observations

Prognosis:

• Mortality: 3-5% (mainly from CNS complications)
• Renal recovery: 80-90% recover renal function
• Long-term: 25-30% develop CKD, hypertension, proteinuria (require long-term follow-up)

Antibiotic Considerations:

• Avoid during acute diarrhoeal phase (may increase Shiga toxin release)
• May use if secondary bacterial infection (e.g., pneumonia, line sepsis) AFTER HUS established
• Evidence mixed: Some studies show increased HUS risk with antibiotics, others neutral

Experimental Therapies (not standard, investigational):

• Eculizumab: Some case reports in severe STEC-HUS with neurological involvement, but not routinely recommended
• Shiga toxin-binding agents: Investigational

Secondary TMA: Treat Underlying Cause

If TMA associated with:

• Pregnancy (HELLP, pre-eclampsia): Delivery of placenta
• Drugs (calcineurin inhibitors, chemotherapy, quinine): STOP offending drug
• Malignancy: Treat underlying cancer
• Bone marrow transplant: Reduce immunosuppression if possible, supportive care
• HIV: Antiretroviral therapy
• Autoimmune disease (SLE): Immunosuppression for underlying condition

Plasma exchange role: May be used empirically if uncertain diagnosis or severe TMA

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Complications

Acute Complications During TMA Episode

Treatment-Related Complications

Plasma Exchange Complications:

• Central line infection: 5-10%, line care protocols, remove if infected
• Central line thrombosis: 5%, may require anticoagulation, removal
• Pneumothorax: 1-5% (if IJ/subclavian insertion), CXR post-insertion
• Citrate toxicity: Hypocalcaemia (tingling, tetany), give calcium gluconate 10 mL 10% IV
• Allergic reactions to FFP: Urticaria (10%), anaphylaxis (less than 1%), pre-medicate, slow/stop infusion
• Fluid overload: Monitor fluid balance, diuretics if needed

Caplacizumab Complications:

• Bleeding: 10-15% (epistaxis, gingival bleeding, menorrhagia), usually mild, manage conservatively
• Severe bleeding: STOP drug, platelet transfusion if life-threatening

Eculizumab Complications:

• Invasive meningococcal disease: 0.5-1% per patient-year (1000× general population), MANDATORY vaccination, prophylactic antibiotics, patient education
• Other infections: Encapsulated organisms (pneumococcus, Haemophilus), vaccinate
• Infusion reactions: Rare, slow infusion if occurs

Corticosteroid Complications:

• Hyperglycaemia, hypertension, gastritis, mood changes, osteoporosis (if prolonged)
• Manage: Glucose monitoring, PPI, bone protection, taper ASAP

Rituximab Complications:

• Infusion reactions (first dose), infections, hypogammaglobulinaemia, hepatitis B reactivation (check serology pre-treatment)

Long-Term Complications and Sequelae

Neurocognitive Impairment (25-50% of TTP survivors):

• Cognitive deficits: Memory, executive function, attention, processing speed
• Emotional: Depression (30-40%), anxiety, PTSD
• Fatigue: Persistent, debilitating
• Assessment: Neuropsychological testing
• Management: Cognitive rehabilitation, psychiatric support, occupational therapy

Chronic Kidney Disease:

• TTP: 10-15% develop CKD (usually mild-moderate)
• aHUS without eculizumab: 50% progress to ESRD
• aHUS with eculizumab: 20% still develop CKD (some irreversible damage pre-treatment)
• STEC-HUS: 25-30% develop CKD, proteinuria, hypertension
• Monitoring: Annual eGFR, urine ACR, BP
• Management: ACE-I/ARB for proteinuria, BP control, CKD management protocols

Hypertension:

• Frequency: 25% (TTP), 60% (HUS)
• Mechanism: Renal injury, endothelial dysfunction
• Management: Lifestyle, antihypertensives (ACE-I first-line if proteinuria)

Cardiovascular Disease:

• Increased long-term risk (endothelial injury, traditional risk factors)
• Monitor: BP, lipids, diabetes screening
• Prevention: Statin, aspirin (once platelet count normal), lifestyle

Relapse of TTP:

• Frequency: 30-50% over 10 years (without rituximab), ~10% (with rituximab)
• Timing: Can occur months to years later
• Triggers: Infection, pregnancy, no identifiable trigger
• Monitoring: ADAMTS13 activity every 3 months × 2 years, then annually
• Predictors of relapse: Persistent low ADAMTS13 (less than 10%), high inhibitor titre, African ancestry
• Management of relapse: Repeat plasma exchange + caplacizumab + rituximab, usually responds well

Quality of Life:

• Significantly reduced vs general population
• Domains affected: Physical function, mental health, fatigue, cognitive function
• Supportive interventions: Patient support groups, rehabilitation, psychological support

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Prognosis & Outcomes

TTP Prognosis

Acute Mortality:

• Untreated TTP: > 90% mortality (historical)
• With plasma exchange alone: 20-30% mortality
• With plasma exchange + caplacizumab + immunosuppression: 10-20% mortality[1,2]

Factors Associated with Increased Mortality:

• Delayed treatment (> 24-48 hours from presentation)
• Severe neurological symptoms (coma, stroke)
• Cardiac involvement (troponin elevation, arrhythmias)
• Advanced age (> 60 years)
• High creatinine at presentation (> 250 μmol/L suggests severe disease or possible aHUS)

Remission Rates:

• First-line plasma exchange: 70-85% achieve remission
• Refractory TTP (not responding to plasma exchange): 15-30%, requires escalation (rituximab, increased PEX)

Relapse Risk:

• Overall: 30-50% within 10 years
• With rituximab in first episode: ~10%
• Risk factors for relapse:
  • Persistent ADAMTS13 less than 10%
  • High inhibitor titre
  • African ancestry (3-4× higher relapse rate)
  • Multiple prior episodes

Time to Relapse:

• Median time to first relapse: 1-3 years
• Can occur months to decades later
• Requires lifelong monitoring

Long-Term Survival:

• 10-year survival: 70-80% (includes relapses)
• Standardised mortality ratio vs general population: ~3× (due to acute episodes, cardiovascular disease)

Atypical HUS Prognosis

Without Eculizumab (historical data):

• 50% progress to end-stage renal disease (ESRD) or die within 1 year of diagnosis
• 65-70% ESRD or death at 3-5 years
• Recurrence rate: 50-60%

With Eculizumab:[3,7]

• Complete TMA response: 60-70%
• Dialysis independence: 80% (if started early)
• eGFR improvement: Median +20-30 mL/min/1.73m²
• Prevention of recurrence: > 90% if on continuous eculizumab
• Long-term renal function: Depends on degree of irreversible injury pre-treatment
  • "Early treatment (within days): Excellent renal recovery"
  • "Delayed treatment (weeks): Partial recovery, residual CKD common"

Genotype-Specific Prognosis (with eculizumab):

Pregnancy-Associated aHUS:

• High risk of recurrence in subsequent pregnancies (> 50%)
• Prophylactic eculizumab recommended for subsequent pregnancies if prior episode

Transplant Outcomes:

• Without eculizumab: Recurrence in 50-90% (depending on genotype), graft loss common
• With eculizumab prophylaxis: Recurrence rate less than 10%, excellent graft survival
• Recommendation: Lifelong eculizumab if transplanted with genetic aHUS

STEC-HUS Prognosis

Acute Mortality: 3-5%

• Deaths mainly from CNS complications (cerebral oedema, stroke, seizures)

Renal Recovery:

• Complete recovery: 65-70%
• Partial recovery (residual CKD): 25-30%
• ESRD requiring long-term dialysis: 5%

Long-Term Renal Outcomes (10-year follow-up):

• 25-30% have reduced GFR, proteinuria, hypertension
• 5-10% progress to ESRD
• Risk factors for poor renal outcome: Anuria > 7 days, severe neurological involvement, need for dialysis

Neurological Outcomes:

• Most neurological symptoms resolve
• 5-10% have long-term deficits (cognitive impairment, motor deficits, epilepsy)

Recurrence:

• Extremely rare (unless recurrent STEC exposure)

Monitoring: All children with STEC-HUS require long-term follow-up (annual BP, urinalysis, eGFR)

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Prevention & Screening

TTP Prevention Strategies

Primary Prevention: Not possible (autoimmune condition, unpredictable triggers)

Secondary Prevention (preventing relapse in patients with prior TTP):

1. ADAMTS13 monitoring:

   • Measure ADAMTS13 activity every 3 months for 2 years, then annually
   • If ADAMTS13 drops to less than 10% or 10-20% with rising inhibitor → high relapse risk
   • Consider pre-emptive rituximab if ADAMTS13 less than 10% even without symptoms (emerging practice, not universal)

2. Rituximab for relapse prevention:

   • Evidence: Reduces 3-year relapse risk from 50% to ~10%[14]
   • Consider in all patients after first episode (increasingly common practice)
   • Alternative: Reserve for high-risk patients (African ancestry, high inhibitor, prior relapse)

3. Patient education:

   • Recognize early symptoms (petechiae, confusion, fatigue, dark urine)
   • Seek immediate medical attention
   • Carry medical alert card/bracelet identifying TTP history
   • Inform all healthcare providers

4. Avoid triggers (if identifiable):

   • Medication review (avoid quinine, ticlopidine if possible)
   • Infection prevention (vaccinations, hygiene)
   • Pregnancy counselling (see below)

Pregnancy in Women with Prior TTP:

• Risk of TTP relapse/recurrence during pregnancy or postpartum: 10-25%
• Monitoring protocol:
  • ADAMTS13 activity monthly during pregnancy, weekly in third trimester and 6 weeks postpartum
  • FBC, blood film, LDH every 1-2 weeks in third trimester
• Prophylactic strategies (no consensus):
  • "Option 1: Monitor closely, treat if relapse occurs"
  • "Option 2: Prophylactic plasma infusion (10-15 mL/kg every 1-2 weeks) if ADAMTS13 less than 10%"
  • "Option 3: Prophylactic rituximab pre-conception (then wait 6-12 months)"
• Delivery planning: Multidisciplinary (haematology, obstetrics, anaesthetics), tertiary centre

aHUS Prevention Strategies

Genetic Counselling:

• If genetic mutation identified → family screening
• Siblings, children: Test for mutation
• Penetrance incomplete (~50%), so carriers may never develop aHUS
• Awareness of triggers (infection, pregnancy) if carrier identified

Prophylactic Eculizumab:

• Renal transplant recipients with genetic aHUS: Start eculizumab before or at time of transplant (prevents recurrence)
• Pregnancy in women with prior aHUS: Consider prophylactic eculizumab during pregnancy and postpartum (high recurrence risk 20-30%)
• Carriers undergoing high-risk surgery: Discuss with haematology/nephrology (case-by-case basis)

Infection Prevention:

• Vaccination: Up-to-date (influenza, pneumococcal, COVID-19)
• Prompt treatment of infections

Meningococcal Prevention (if on eculizumab): As detailed above (vaccination, prophylactic antibiotics)

STEC-HUS Prevention Strategies

Public Health Measures:

1. Food safety:
   • Cook beef to internal temperature > 70°C (particularly ground beef)
   • Avoid unpasteurised milk and juices
   • Wash vegetables thoroughly
   • Avoid cross-contamination (separate raw meat from other foods)
2. Water safety: Chlorination of water supplies, boil water advisories during outbreaks
3. Hand hygiene: Especially in childcare settings, farms
4. Outbreak investigation: Public health notification for clusters

Individual Prevention:

• Hand hygiene after handling raw meat, farm animals, before eating
• Safe food handling practices
• Avoid swallowing water in lakes, rivers (potential contamination)

Secondary Prevention (after STEC infection):

• Avoid antibiotics during acute diarrhoeal phase (may increase HUS risk, though evidence conflicting)
• Avoid antimotility agents (loperamide)
• Early aggressive hydration: Some evidence that IV fluids during diarrhoeal phase may reduce HUS progression (outbreaks data)

No vaccine currently available for Shiga toxin-producing E. coli

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Key Guidelines

International and National Guidelines

1. British Society for Haematology (BSH) Guideline on TTP and TMAs (2019)[1]

   • Comprehensive UK guideline covering diagnosis, treatment, monitoring
   • Recommends urgent plasma exchange for suspected TTP
   • Supports use of caplacizumab and rituximab
   • ADAMTS13 testing mandatory but not to delay treatment

2. International Society on Thrombosis and Haemostasis (ISTH) Guidelines for TTP (2020)[11]

   • Global consensus on ADAMTS13 testing and interpretation
   • Diagnostic criteria for TTP: ADAMTS13 less than 10%
   • Treatment recommendations: Plasma exchange, caplacizumab, corticosteroids, rituximab

3. European TTP Working Party Consensus Statements

   • Rituximab use in TTP
   • ADAMTS13 monitoring protocols
   • Relapse prevention strategies

4. Kidney Disease: Improving Global Outcomes (KDIGO) - TMA in Transplant Recipients

   • Management of transplant-associated TMA
   • Eculizumab use in aHUS transplant recipients

5. American Society of Hematology (ASH) - Educational Materials on TTP

   • Evidence-based reviews
   • Clinical practice updates

Key Guideline Recommendations Summary

Diagnosis:

• Send ADAMTS13 in all suspected TMA cases
• Do NOT wait for results before starting treatment if TTP clinically suspected
• Blood film review for schistocytes essential
• Differentiate from DIC (normal PT, APTT, fibrinogen in TMA)

TTP Treatment:

• Plasma exchange within 4-8 hours (first-line)
• Caplacizumab (add to plasma exchange, strong recommendation)
• Corticosteroids (adjunctive)
• Rituximab (refractory cases, consider upfront)
• Avoid platelet transfusions except life-threatening bleeding

aHUS Treatment:

• Eculizumab first-line (strong recommendation)
• Meningococcal vaccination mandatory before eculizumab (or urgent vaccination + prophylactic antibiotics)
• Lifelong treatment usually required

STEC-HUS Treatment:

• Supportive care only
• No plasma exchange, no antibiotics during acute diarrhoea

Monitoring:

• ADAMTS13 activity every 3-6 months for 2 years post-TTP, then annually
• Long-term renal monitoring for all HUS patients

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Viva Points & Exam Focus

Opening Statement for TTP

"Thrombotic thrombocytopenic purpura is a life-threatening haematological emergency characterised by microangiopathic haemolytic anaemia, thrombocytopenia, and organ dysfunction, caused by severe deficiency of ADAMTS13, a von Willebrand factor-cleaving protease. Mortality exceeds 90% without treatment but is reduced to 10-20% with prompt plasma exchange, caplacizumab, and immunosuppression."

Key Facts for Viva

✅ Triad of TMA: MAHA (schistocytes, elevated LDH, low haptoglobin, negative DAT) + Thrombocytopenia + Organ dysfunction

✅ TTP Mechanism: ADAMTS13 less than 10% → ultra-large VWF multimers → spontaneous platelet aggregation → microvascular thrombosis (brain, heart, kidneys)

✅ Classic Pentad (only 5-10% have all): MAHA, thrombocytopenia, neurological symptoms, renal impairment, fever

✅ PLASMIC Score 6-7: 62-82% chance of ADAMTS13 less than 10% → start plasma exchange immediately

✅ TTP vs aHUS Differentiation:

• TTP: ADAMTS13 less than 10%, neurological predominance, mild-moderate renal
• aHUS: Normal ADAMTS13, low C3, severe renal, complement mutations

✅ Emergency Treatment: Plasma exchange within 4-8 hours + caplacizumab 10 mg IV then SC daily + corticosteroids

✅ Caplacizumab: Anti-VWF A1 domain nanobody, reduces recurrence by 74% (HERCULES trial)

✅ Eculizumab for aHUS: Anti-C5 monoclonal, 65% complete response, 80% dialysis-free, MANDATORY meningococcal vaccination

✅ STEC-HUS: Supportive care ONLY, NO plasma exchange, NO antibiotics

✅ Platelet transfusion: CONTRAINDICATED (except life-threatening bleeding) - "fuel for the fire"

✅ Relapse Risk: TTP 30-50% without rituximab, ~10% with rituximab

Common Viva Questions with Model Answers

Q1: A 35-year-old woman presents with confusion, thrombocytopenia (platelets 18 × 10⁹/L), and anaemia (Hb 72 g/L). Blood film shows schistocytes. What is your differential diagnosis and immediate management?

Model Answer: "This presentation of confusion with thrombocytopenia and schistocytes strongly suggests a thrombotic microangiopathy, most likely thrombotic thrombocytopenic purpura, which is a medical emergency.

Differential diagnosis: The key differentials for TMA are:

1. TTP (most likely given neurological predominance)
2. Atypical HUS (less likely as usually renal-predominant)
3. DIC (but would expect abnormal coagulation)
4. HELLP syndrome (if pregnant)
5. Malignant hypertension (check BP)
6. Drug-induced TMA (e.g., quinine)

Immediate investigations:

• FBC, blood film review (confirm schistocytes)
• Haemolysis screen: LDH (expect elevated), haptoglobin (expect undetectable), bilirubin, reticulocyte count, DAT (expect negative)
• Coagulation: PT, APTT, fibrinogen (expect normal - distinguishes from DIC)
• Renal function, electrolytes
• ADAMTS13 activity and inhibitor (send BEFORE plasma exchange but do NOT wait for result)
• Complement studies (C3, C4) if aHUS considered
• Pregnancy test
• PLASMIC score calculation

In this case, PLASMIC score would likely be 6-7 (platelets less than 30, likely elevated LDH, neurological symptoms) indicating high probability of TTP.

Immediate management:

1. Urgent haematology consult within 30 minutes
2. Activate plasma exchange within 4-8 hours (do NOT wait for ADAMTS13 result)
3. Caplacizumab: 10 mg IV bolus before first plasma exchange, then 10 mg SC daily
4. Corticosteroids: Methylprednisolone 1 g IV daily × 3, then prednisolone 1 mg/kg PO
5. Supportive care: IV fluids cautiously, neurological observations hourly, cardiac monitoring
6. Avoid platelet transfusions unless life-threatening bleeding
7. Central line insertion for plasma exchange access
8. Consider HDU/ICU admission given neurological symptoms

Plasma exchange reduces mortality from 90% to 10-20%, so urgent initiation is critical."

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Q2: What is the PLASMIC score and how do you interpret it?

Model Answer: "The PLASMIC score is a validated clinical prediction tool that estimates the probability of severe ADAMTS13 deficiency (less than 10%) before laboratory results are available, helping guide urgent treatment decisions in suspected TTP.

Components (7 points, 1 for each):

• Platelets less than 30 × 10⁹/L
• Haemolysis (LDH/AST ratio > 20, or indirect bilirubin/LDH elevated)
• Absence of active cancer
• Absence of transplant
• MCV less than 90 fL
• INR less than 1.5
• Creatinine less than 176 μmol/L (2.0 mg/dL)

Interpretation:

• Score 0-4 (Low risk): less than 5% probability of ADAMTS13 less than 10%
  • Consider alternative diagnoses, but still send ADAMTS13
• Score 5 (Intermediate): 5-24% probability
  • TTP possible, discuss with haematology urgently
• Score 6-7 (High risk): 62-82% probability of ADAMTS13 less than 10%
  • Highly suggestive of TTP, initiate plasma exchange immediately

Limitations:

• Does not replace clinical judgment
• Developed in populations with suspected TTP (pre-test probability already elevated)
• Less validated in pregnancy-associated TMA

Clinical application: If PLASMIC score 6-7 and clinical presentation fits, I would start plasma exchange immediately without waiting for ADAMTS13 results, as delays increase mortality."

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Q3: How do you differentiate TTP from atypical HUS?

Model Answer: "Differentiating TTP from atypical HUS is critical as they require different treatments - plasma exchange for TTP versus eculizumab for aHUS.

Key differences:

Clinical approach when uncertain: If ADAMTS13 results are delayed and presentation is severe TMA, I would discuss with haematology and consider:

• Starting both plasma exchange AND eculizumab empirically
• Once ADAMTS13 result available:
  • If less than 10% → continue plasma exchange, stop eculizumab
  • If normal → continue eculizumab, stop plasma exchange

This dual approach prevents delays in definitive treatment for either condition."

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Q4: A patient with TTP is starting eculizumab for possible aHUS. What critical safety measure must you implement?

Model Answer: "The critical safety requirement before starting eculizumab is meningococcal vaccination and prophylaxis.

Rationale: Eculizumab is an anti-C5 monoclonal antibody that blocks the terminal complement pathway by preventing C5 cleavage. This prevents formation of the C5b-9 membrane attack complex, which is essential for killing Neisseria meningitidis. Without terminal complement function, the risk of invasive meningococcal disease increases 1000-2000 fold.

Vaccination protocol:

Ideally (if time permits):

• Vaccinate at least 2 weeks before starting eculizumab
• Required vaccines:
  • MenACWY (quadrivalent conjugate vaccine covering serotypes A, C, W, Y)
  • MenB vaccine (e.g., Bexsero) - two doses 1 month apart
  • Also consider pneumococcal (PCV13 + PPSV23) and Haemophilus influenzae type b

In emergency situations (cannot delay treatment):

• Give vaccines immediately (same day as starting eculizumab if necessary)
• PLUS start prophylactic antibiotics until 2 weeks post-vaccination:
  • Penicillin V 500 mg PO twice daily (first-line), OR
  • Azithromycin 500 mg PO daily (if penicillin allergy)
• Some centres continue antibiotic prophylaxis indefinitely during eculizumab therapy

Booster vaccinations:

• MenACWY: Every 5 years
• MenB: Consider every 2-3 years

Patient education (critical):

• ⚠️ Seek immediate medical attention for fever, headache, neck stiffness, rash, confusion
• Carry emergency card identifying eculizumab use
• Inform all healthcare providers

If suspected meningococcal infection develops:

• Medical emergency
• Immediate IV antibiotics (ceftriaxone 2 g IV stat) without waiting for LP
• Blood cultures, LP if safe
• Inform infectious diseases immediately

Failure to vaccinate before eculizumab is a serious safety error that significantly increases mortality risk from preventable infection."

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Q5: Why should you avoid platelet transfusions in TTP?

Model Answer: "Platelet transfusions are contraindicated in TTP except for life-threatening bleeding or high-risk invasive procedures, for several important reasons:

Mechanism of harm:

1. 'Fuel for the fire': In TTP, the underlying problem is spontaneous platelet aggregation driven by ultra-large VWF multimers. Transfusing platelets provides additional substrate for ongoing microthrombosis, potentially worsening organ ischaemia.

2. Historical evidence: Case reports from the pre-plasma exchange era documented clinical deterioration, increased neurological symptoms, and death following platelet transfusions in TTP.

3. Thrombocytopenia mechanism: The low platelet count in TTP is due to consumption in microthrombi, not production failure. The bone marrow is producing platelets appropriately; they are simply being consumed peripherally.

4. Bleeding risk is lower than expected: Despite very low platelet counts (often less than 20 × 10⁹/L), spontaneous bleeding is uncommon in TTP. This is because:

   • Microthrombi consume platelets and coagulation factors locally
   • Less systemic bleeding tendency
   • Unlike ITP where platelets are low but VWF/coagulation normal

Exceptions (when platelet transfusion acceptable):

• Life-threatening bleeding: Intracranial haemorrhage, major GI bleeding
• High-risk invasive procedure: Emergency neurosurgery, major surgery where bleeding would be catastrophic
• Even then, transfuse minimally and only after discussing with senior haematologist

Alternative approach:

• Treat the underlying disease: Plasma exchange + caplacizumab rapidly reduces microthrombosis
• Caplacizumab blocks VWF-platelet interaction, allowing platelet count to recover (usually within 2-5 days)
• Monitor closely: Transfuse RBCs if needed, but avoid platelets

In summary: Platelet transfusion in TTP risks worsening microthrombosis and clinical deterioration. The priority is urgent plasma exchange and caplacizumab to address the underlying pathophysiology, allowing platelets to recover naturally."

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Q6: What is caplacizumab and what is the evidence for its use?

Model Answer: "Caplacizumab is a humanised bivalent nanobody that targets the A1 domain of von Willebrand factor, blocking the interaction between VWF and platelet GPIb receptors, thereby preventing VWF-mediated platelet aggregation in TTP.

Mechanism:

• Binds to VWF A1 domain (the site that binds platelet GPIb)
• Prevents platelet adhesion to ultra-large VWF multimers
• Does NOT remove autoantibodies or increase ADAMTS13 activity
• Therefore used in addition to plasma exchange and immunosuppression, not instead of

Evidence base:

TITAN Trial (Phase 2, 2016):

• 75 patients with acquired TTP
• Caplacizumab vs placebo, both with plasma exchange
• Results: Faster platelet normalisation, trend towards reduced recurrence

HERCULES Trial (Phase 3, 2019) - the definitive trial:

• 145 patients with acquired TTP
• Caplacizumab + standard care vs placebo + standard care
• Key results:
  • 74% reduction in TTP-related death or recurrence during treatment period (12% vs 38%, pless than 0.001)
  • 67% reduction in composite endpoint (death, recurrence, major thromboembolic event)
  • "Time to platelet normalisation: 2.69 days vs 2.88 days (modest difference, not clinically significant)"
  • "Reduced plasma exchange requirements: Median 5 vs 7 days"
  • "Recurrence during treatment: 12% vs 38%"
• Safety: Increased bleeding events (mainly minor: epistaxis, gingival bleeding), but severe bleeding rare

Guideline recommendations:

• BSH 2019: Recommend caplacizumab in addition to plasma exchange for acquired TTP
• ISTH 2020: Supports use in immune-mediated TTP

Dosing:

• 10 mg IV bolus before first plasma exchange
• Then 10 mg SC daily during plasma exchange
• Continue 10 mg SC daily for 30 days after stopping plasma exchange
• Extend if ADAMTS13 remains less than 10% or inhibitor present

Clinical impact:

• Reduces recurrence risk significantly
• Allows earlier cessation of plasma exchange
• Reduces thromboembolic complications
• Now considered standard of care for acquired TTP in many centres (though cost is significant consideration)

Cost-effectiveness: Despite high cost (>£200,000 per course), health economic analyses support use due to reduction in complications, ICU stays, and recurrence."

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Common Exam Mistakes to Avoid

❌ Waiting for ADAMTS13 results before starting plasma exchange ✅ Send ADAMTS13, but start plasma exchange immediately if clinical suspicion high

❌ Transfusing platelets in TTP ✅ Avoid unless life-threatening bleeding

❌ Using plasma exchange for STEC-HUS ✅ Supportive care only for STEC-HUS

❌ Starting eculizumab without meningococcal vaccination ✅ Vaccinate (or give vaccine + antibiotics if urgent)

❌ Assuming normal ADAMTS13 rules out TMA ✅ Consider aHUS, STEC-HUS, secondary TMA

❌ Diagnosing MAHA without seeing schistocytes ✅ Blood film review is essential

❌ Missing DIC in differential (similar presentation) ✅ Check coagulation studies (PT, APTT, fibrinogen normal in TMA, abnormal in DIC)

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Patient & Family Information

What is TTP?

"I need to explain a serious but treatable blood condition called TTP - thrombotic thrombocytopenic purpura.

What's happening in your body: Your immune system has made antibodies against a protein called ADAMTS13, which normally prevents your blood from clotting when it shouldn't. Without this protein working, tiny clots form in your small blood vessels throughout your body.

These tiny clots cause three main problems:

1. Low platelets: The clots use up your platelets (the cells that stop bleeding), which is why your platelet count is very low and you might bruise easily.
2. Anaemia: As your red blood cells squeeze through these tiny clots, they get damaged and break apart, causing anaemia (low blood count), making you feel tired and weak.
3. Organ problems: The clots can reduce blood flow to important organs, especially your brain, which is why you might feel confused or have headaches.

Why this is serious: Without treatment, TTP is life-threatening. However, with treatment, we can reverse this condition in most people.

Treatment plan:

1. Plasma Exchange (Plasmapheresis) - our main treatment:

• This is similar to dialysis
• We remove your blood plasma (the liquid part that contains the harmful antibodies)
• We replace it with healthy plasma from donors
• Takes 2-4 hours daily
• Usually needed for 5-14 days
• A tube (central line) will be placed in a vein in your neck or groin

2. Caplacizumab - a new medication:

• Injection under your skin once daily
• Blocks the clotting process
• Significantly reduces risk of the condition coming back
• Continue for at least 30 days after plasma exchange stops
• Side effect: Slightly increased bleeding risk (nosebleeds, gum bleeding - usually mild)

3. Steroids - to calm your immune system:

• Tablets or IV
• Help stop your body making more antibodies
• Gradually reduced over 4-6 weeks

What to expect:

During treatment:

• You'll likely feel better within a few days
• Platelet count usually starts rising within 3-7 days
• Most people achieve full remission (no more tiny clots) within 1-2 weeks
• You'll need daily blood tests to monitor progress

Risks and side effects:

• Central line: Small risk of infection or clot in the vein
• Plasma exchange: Tingling around mouth (low calcium - easily treated), allergic reactions (rare)
• Caplacizumab: Mild bleeding (nosebleeds, bruising)
• Steroids: Blood sugar changes, mood changes, increased appetite

After treatment:

Recovery: Most people (80-90%) recover completely from the first episode.

Follow-up:

• Blood tests every 3 months for 2 years, then annually
• Monitor for recurrence (blood test called ADAMTS13)

Risk of recurrence:

• TTP can come back in 30-50% of people over 10 years
• With additional treatment (rituximab), this drops to about 10%
• If it recurs, it usually responds well to the same treatment

Warning signs to watch for (seek immediate medical attention):

• New bruising or petechiae (small red spots on skin)
• Confusion or difficulty thinking clearly
• Severe headache
• Dark urine
• Shortness of breath
• Unusual fatigue

Long-term outlook:

• Most people return to normal activities
• Some experience long-term fatigue or mild memory problems (we can provide support)
• Regular monitoring to catch any recurrence early

Support:

• TTP patient support groups available (e.g., TTP Network UK)
• We'll provide written information
• Specialist TTP clinic for follow-up

Questions you might have:

Can I have children? Yes, but pregnancy increases risk of recurrence. We'd monitor you very closely with a specialized team.

Is it genetic? The acquired form (what you have) is not inherited. A very rare inherited form exists but that's not what you have.

Will I need this treatment forever? No, once in remission, most people don't need ongoing plasma exchange. However, you'll need long-term monitoring and possibly medication to prevent recurrence.

When can I go home? Usually after your platelet count has been normal for 2-3 days and all symptoms have resolved, typically 1-2 weeks.

Do you have any questions?"

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References

1. Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158(3):323-335. doi:10.1111/j.1365-2141.2012.09167.x. PMID: 22624596. Updated 2019 (Scully M, et al. Br J Haematol. 2019;184(4):542-558. PMID: 30512199).

2. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346. doi:10.1056/NEJMoa1806311. PMID: 30625070.

3. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368(23):2169-2181. doi:10.1056/NEJMoa1208981. PMID: 23738544.

4. Jokiranta TS. HUS and atypical HUS. Blood. 2017;129(21):2847-2856. doi:10.1182/blood-2016-11-709865. PMID: 28416507.

5. Kremer Hovinga JA, Coppo P, Lämmle B, et al. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers. 2017;3:17020. doi:10.1038/nrdp.2017.20. PMID: 28382967.

6. Deford CC, Reese JA, Schwartz LH, 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. doi:10.1182/blood-2013-04-496752. PMID: 23838348.

7. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(17):1676-1687. doi:10.1056/NEJMra0902814. PMID: 19846853.

8. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365(9464):1073-1086. doi:10.1016/S0140-6736(05)71144-2. PMID: 15781103.

9. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2496-2502. doi:10.1111/jth.15010. PMID: 32914582.

10. Goodship THJ, Cook HT, Fakhouri F, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539-551. doi:10.1016/j.kint.2016.10.005. PMID: 27989322.

11. Coppo P, Schwarzinger M, Buffet M, et al. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS One. 2010;5(4):e10208. doi:10.1371/journal.pone.0010208. PMID: 20436664.

12. Bendapudi PK, Hurwitz S, Fry A, 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. doi:10.1016/S2352-3026(17)30026-1. PMID: 28259520.

13. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016;374(6):511-522. doi:10.1056/NEJMoa1505533. PMID: 26863353.

14. Westwood JP, Webster H, McGuckin S, McDonald V, Machin SJ, Scully M. Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse. J Thromb Haemost. 2013;11(3):481-490. doi:10.1111/jth.12114. PMID: 23297868.

15. McNamara LA, Topaz N, Wang X, Hariri S, Fox L, MacNeil JR. High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine. MMWR Morb Mortal Wkly Rep. 2017;66(27):734-737. doi:10.15585/mmwr.mm6627e1. PMID: 28704348.

16. Fakhouri F, Roumenina L, Provot F, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21(5):859-867. doi:10.1681/ASN.2009070706. PMID: 20203157.

17. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654-666. doi:10.1056/NEJMra1312353. PMID: 25119609.

18. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846. doi:10.1182/blood-2016-10-709857. PMID: 28416506.

19. Licht C, Greenbaum LA, Muus P, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015;87(5):1061-1073. doi:10.1038/ki.2014.423. PMID: 25648470.

20. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325(6):393-397. doi:10.1056/NEJM199108083250604. PMID: 2062330.

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Last updated: 2025-01-07 Evidence level: High Citation count: 20 Target examination: MRCP, Haematology postgraduate examinations