Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

Quick Answer

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS) are thrombotic microangiopathies (TMAs) characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and end-organ damage. TTP results from severe ADAMTS13 deficiency (below 10%), leading to accumulation of ultra-large von Willebrand factor (UL-VWF) multimers and platelet-rich microthrombi. HUS is classified as typical (STEC-associated, Shiga toxin-mediated) or atypical (complement-mediated). Treatment differs fundamentally: TTP requires urgent plasma exchange, corticosteroids, rituximab, and caplacizumab; atypical HUS requires complement inhibition with eculizumab. Platelet transfusion is contraindicated in TTP unless life-threatening bleeding occurs. Early recognition and treatment are critical—untreated TTP mortality exceeds 90%, but appropriate therapy reduces this to 10-20%.

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CICM Second Part Exam Focus

High-Yield Topics for CICM Second Part

Core Knowledge:

• ADAMTS13 pathophysiology and the "molecular scissors" concept
• PLASMIC score calculation and interpretation (≥5 = high probability TTP)
• Differential diagnosis of thrombotic microangiopathies in ICU
• Plasma exchange mechanism and urgency (Rock 1991 landmark trial)
• Caplacizumab mechanism and HERCULES trial outcomes
• Distinction between typical HUS (STEC) and atypical HUS (complement)
• Eculizumab for aHUS and meningococcal vaccination requirements

Critical Management Points:

• Platelet transfusion is contraindicated unless life-threatening bleeding
• Start plasma exchange empirically before ADAMTS13 results return
• Corticosteroids and rituximab reduce anti-ADAMTS13 antibodies
• Avoid antibiotics in typical STEC-HUS (may increase toxin release)
• Pregnancy-associated TMA differential: HELLP vs TTP vs HUS

SAQ/Viva Themes:

• Approach to thrombocytopenia with MAHA in ICU patient
• Indications for plasma exchange vs complement inhibition
• ICU complications and prognostic factors in TTP
• Post-transplant TMA management

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Key Points

1. TTP is defined by severe ADAMTS13 deficiency (below 10%) - this distinguishes it from other TMAs and predicts response to plasma exchange
2. PLASMIC score ≥5 has high probability of TTP - use to guide empiric plasma exchange before ADAMTS13 results
3. Plasma exchange is life-saving in TTP - reduces mortality from greater than 90% to 10-20% (Rock 1991 landmark trial)
4. Caplacizumab (anti-VWF nanobody) accelerates platelet recovery by 1.55x and reduces TTP-related death/recurrence by 74% (HERCULES trial)
5. Typical HUS (STEC) is triggered by Shiga toxin (E. coli O157:H7); avoid antibiotics as they may worsen disease
6. Atypical HUS (aHUS) results from complement dysregulation and requires eculizumab, not plasma exchange
7. Platelet transfusion is contraindicated in TTP - associated with 2x increase in mortality, MI, and stroke
8. Pregnancy-associated TMA requires careful differentiation of HELLP, TTP, and HUS—timing and ADAMTS13 are key

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Section 1: Overview and Classification

1.1 Definition and Terminology

Thrombotic microangiopathies (TMAs) are a group of disorders characterized by the clinical triad of:

• Microangiopathic hemolytic anemia (MAHA): mechanical destruction of red blood cells (schistocytes)
• Thrombocytopenia: consumption of platelets in microthrombi
• End-organ damage: most commonly affecting brain, kidneys, and heart

The two primary TMAs encountered in the ICU are TTP and HUS, but the differential diagnosis extends to several secondary causes. [1,2]

1.2 Classification of Thrombotic Microangiopathies

1.3 The Classic Pentad (Historical)

The classic TTP pentad is rarely seen in modern practice due to earlier diagnosis:

1. Thrombocytopenia - present in greater than 95% of cases
2. Microangiopathic hemolytic anemia - schistocytes, elevated LDH, low haptoglobin
3. Neurological symptoms - confusion, headache, seizures, focal deficits
4. Renal impairment - typically mild in TTP (severe suggests HUS)
5. Fever - present in only 25% of cases at presentation

Modern Diagnostic Approach: Do NOT wait for the full pentad. The presence of MAHA and thrombocytopenia without an alternative explanation should prompt urgent evaluation for TTP/HUS. Less than 10% of patients present with all five features. [3]

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Section 2: Pathophysiology

2.1 TTP: The ADAMTS13-VWF Axis

Normal Physiology: Von Willebrand factor (VWF) is synthesized in endothelial cells and stored as ultra-large multimers (UL-VWF) in Weibel-Palade bodies. Upon release, these UL-VWF multimers are highly adhesive and must be cleaved into smaller, less prothrombotic fragments by ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13). [4]

TTP Pathogenesis: In TTP, ADAMTS13 activity is severely reduced (below 10% of normal), leading to:

1. Persistence of UL-VWF multimers on the endothelial surface
2. Spontaneous platelet adhesion to UL-VWF via GPIb/IX/V receptor
3. Formation of platelet-rich microthrombi in the microcirculation
4. Mechanical shearing of RBCs through narrowed vessels (schistocytes)
5. Organ ischemia (brain, heart, kidneys) [5,6]

Types of TTP:

2.2 HUS: Typical (STEC) vs Atypical (Complement-Mediated)

Typical HUS (STEC-HUS):

• Caused by Shiga toxin-producing Escherichia coli (STEC), most commonly O157:H7
• Shiga toxin (Stx1, Stx2) binds to globotriaosylceramide (Gb3) receptors on glomerular endothelial cells
• Results in endothelial cell apoptosis, pro-inflammatory cytokine release, and microvascular thrombosis
• Classically follows bloody diarrhea by 5-10 days [7,8]

Atypical HUS (aHUS):

• Results from uncontrolled activation of the alternative complement pathway
• Associated with genetic mutations in complement regulatory proteins:
  • CFH (Complement Factor H) - 20-30% of cases
  • CFI (Complement Factor I) - 5-10%
  • MCP/CD46 (Membrane Cofactor Protein) - 10-15%
  • C3, CFB (Complement Factor B) - 2-10%
  • THBD (Thrombomodulin) - rare
• May also be caused by anti-CFH autoantibodies (5-10%) [9,10]

ADAMTS13 Structure and Function

ADAMTS13 is a 1427-amino acid metalloprotease primarily synthesized in hepatic stellate cells. Its structure includes:

• Metalloprotease domain: catalytic activity
• Disintegrin-like domain: substrate recognition
• Thrombospondin type 1 repeats: VWF binding
• CUB domains: regulatory function

The enzyme cleaves VWF at the Tyr1605-Met1606 bond within the A2 domain, which is only exposed when VWF is unfolded under shear stress. This explains why TTP predominantly affects high-shear microvasculature. [11]

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Section 3: Clinical Presentation

3.1 TTP Presentation

Demographics:

• Peak incidence: 30-50 years
• Female predominance (2:1)
• More common in African Americans (3-4x higher incidence)
• Pregnancy is a recognized trigger (especially postpartum) [12]

Clinical Features:

Cardiac Involvement is Underappreciated: Troponin elevation occurs in up to 50% of TTP patients and is an independent predictor of mortality. Always obtain troponin in suspected TTP. [13]

3.2 HUS Presentation

Typical HUS (STEC-HUS):

• Prodromal bloody diarrhea (5-10 days before HUS onset)
• Severe acute kidney injury (oliguria/anuria, often requiring dialysis)
• Neurological complications in 20-50% (encephalopathy, seizures)
• Predominantly affects children below 5 years
• Seasonal (summer months, associated with food outbreaks) [14]

Atypical HUS:

• No diarrheal prodrome (though may be triggered by infection)
• Severe, rapidly progressive renal failure
• May present at any age (can occur in adults)
• High recurrence rate (especially CFH mutations)
• Family history in 20% [15]

3.3 Pregnancy-Associated TMA

Pregnancy-associated TMA represents a diagnostic challenge as HELLP syndrome, TTP, and HUS can present similarly. [16]

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Section 4: Investigations

4.1 Laboratory Diagnosis

Blood Film:

• Schistocytes (fragmented RBCs) - greater than 1% on blood film is significant
• Polychromasia (reticulocytosis)
• Nucleated RBCs
• Absent platelet clumps (unlike EDTA-induced pseudothrombocytopenia)

Haemolysis Markers:

4.2 ADAMTS13 Testing

ADAMTS13 Activity:

• below 10% is diagnostic for TTP
• 10-20% is indeterminate (consider other causes)
• greater than 20% essentially excludes TTP

ADAMTS13 Antibodies:

• Present in immune TTP (iTTP)
• Titre may correlate with disease severity and relapse risk

Do NOT Wait for ADAMTS13 Results: ADAMTS13 assays may take 24-72 hours to return. If TTP is clinically suspected (MAHA + thrombocytopenia + no alternative explanation), initiate plasma exchange empirically. [17]

4.3 The PLASMIC Score

The PLASMIC score predicts the probability of severe ADAMTS13 deficiency and guides empiric management while awaiting results. [18]

Interpretation:

• Score 0-4: Low probability of ADAMTS13 below 10% (consider alternative diagnoses)
• Score 5: Intermediate probability (~57%)
• Score 6-7: High probability (~85-96%)

Validation: The PLASMIC score was validated in a cohort of 214 patients and demonstrated high discriminative ability for identifying patients with severe ADAMTS13 deficiency (AUC 0.96). [18]

4.4 Additional Investigations

For TTP:

• Troponin (cardiac involvement)
• ECG (arrhythmias, ischemia)
• CT/MRI brain (if neurological symptoms)
• HIV, Hepatitis B/C serology (associated conditions)
• Autoimmune screen (ANA, anti-dsDNA)

For HUS:

• Stool culture for STEC (O157:H7 and non-O157 serotypes)
• Shiga toxin PCR
• Complement studies (C3, C4, CH50)
• Genetic testing for complement mutations (if aHUS suspected)
• Anti-CFH antibodies

To Exclude Secondary TMA:

• DIC screen (PT, aPTT, fibrinogen, D-dimer)
• Pregnancy test
• Drug history (see Drug-Induced TMA section)
• Bone marrow biopsy (if malignancy suspected)

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Section 5: Differential Diagnosis

5.1 Thrombotic Microangiopathies in the ICU

5.2 Drug-Induced Thrombotic Microangiopathy (DITMA)

Common causative agents: [19,20]

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Section 6: Management of TTP

6.1 Principles of TTP Management

1. Plasma Exchange (TPE): Cornerstone of therapy - removes UL-VWF and anti-ADAMTS13 antibodies, replaces ADAMTS13
2. Immunosuppression: Corticosteroids and rituximab reduce antibody production
3. Caplacizumab: Anti-VWF nanobody prevents platelet-VWF interaction
4. Supportive Care: Avoid platelet transfusion, manage organ dysfunction
5. ADAMTS13 Monitoring: Guides treatment intensity and duration

6.2 Plasma Exchange: The Landmark Evidence

The Rock et al. (1991) randomized controlled trial established plasma exchange as superior to plasma infusion for TTP. [21]

Rock 1991 Trial (Canadian Apheresis Study Group)

• Design: RCT, 102 patients, plasma exchange vs plasma infusion
• Results:
  • "Day 9 platelet normalization: 47% (PEX) vs 25% (PI)"
  • "Mortality: 3.9% (PEX) vs 17.6% (PI) during first cycle"
• Conclusion: Plasma exchange is superior and became standard of care
• PMID: 2067330

Plasma Exchange Protocol:

• Volume: 1.0-1.5 plasma volumes (40-60 mL/kg) per session
• Replacement fluid: Fresh frozen plasma (FFP) or cryo-poor plasma
• Frequency: Daily until sustained platelet count greater than 150 × 10⁹/L for ≥2 days
• Access: Large-bore central venous catheter (dialysis catheter)
• Duration: Typically 7-14 days; may require longer if refractory

6.3 Caplacizumab: HERCULES Trial

Caplacizumab is a nanobody that binds to the A1 domain of VWF, blocking its interaction with platelet GPIb. [22]

HERCULES Trial (Scully 2019)

• Design: Phase 3 RCT, 145 patients, caplacizumab vs placebo + standard care
• Results:
  • "Time to platelet normalization: 1.55x faster with caplacizumab (pbelow 0.001)"
  • "Composite endpoint (TTP death, recurrence, thromboembolic event): 12% vs 49% (74% reduction)"
  • No patients developed refractory TTP (vs 3 in placebo)
  • Shorter ICU and hospital stays
• Safety: Increased mucocutaneous bleeding (65% vs 48%)
• PMID: 30625082

Caplacizumab Dosing:

• Loading: 10 mg IV before first plasma exchange
• Maintenance: 10 mg subcutaneous daily during TPE and for 30 days after
• Extension: Continue if ADAMTS13 activity remains below 10%

6.4 Corticosteroids

• Methylprednisolone: 1 mg/kg IV daily (or 1g IV daily for 3 days in severe cases)
• Prednisone: 1 mg/kg oral daily, then taper over 4-6 weeks
• Mechanism: Reduce anti-ADAMTS13 antibody production

6.5 Rituximab

Rituximab (anti-CD20 monoclonal antibody) depletes B-cells and reduces anti-ADAMTS13 antibody production. [23,24]

Indications:

• Refractory TTP (no platelet response after 4-7 days of TPE)
• Relapsed TTP
• Upfront in severe cases (neurological/cardiac involvement)
• Preemptive for falling ADAMTS13 activity during remission

Dosing:

• 375 mg/m² IV weekly × 4 doses (standard)
• Alternative: 1000 mg fixed dose × 2 (days 1 and 15)

Evidence: Rituximab added early in acute iTTP reduces plasma exchange duration, hospital length of stay, and relapse rates. [23]

6.6 Platelet Transfusion: Contraindicated

Platelet transfusion in TTP is associated with significant harm due to the "fuel to the fire" phenomenon—transfused platelets are immediately consumed by UL-VWF, exacerbating microvascular thrombosis. [25]

Goel et al. (2015) - National Inpatient Sample Analysis

• Design: Retrospective analysis, 10,124 TTP hospitalizations
• Results: Platelet transfusion associated with:
  • "In-hospital mortality: OR 2.0"
  • "Acute myocardial infarction: OR 2.0"
  • "Stroke: OR 2.0"
• Conclusion: Platelet transfusion should be avoided unless life-threatening hemorrhage
• PMID: 25524614

Exceptions (life-threatening bleeding only):

• Intracranial hemorrhage
• Massive GI bleeding
• Before invasive procedures with high bleeding risk

6.7 Red Cell Transfusion

• Transfuse if symptomatic anemia (Hb below 70-80 g/L)
• No evidence of harm (unlike platelet transfusion)
• Use irradiated products if rituximab therapy planned

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Section 7: Management of HUS

7.1 Typical HUS (STEC-HUS)

Management is primarily supportive, as there is no specific treatment proven to benefit. [7,14]

Supportive Care:

• Fluid Management: Early aggressive isotonic IV fluids during diarrheal phase may reduce HUS severity
• Renal Replacement Therapy: Required in 50-60% of cases
• Transfusion: PRBCs as needed; avoid platelet transfusion
• Neurological Monitoring: CNS involvement in 20-50%

What to AVOID:

Antibiotics and STEC-HUS: The seminal study by Wong et al. (2000) demonstrated that antibiotic treatment during E. coli O157:H7 infection significantly increased the risk of developing HUS. Avoid antibiotics unless sepsis is suspected. [26] PMID: 10873096

Neurological Complications:

• Encephalopathy, seizures, focal deficits occur in 20-50%
• Leading cause of mortality in acute phase
• MRI may show basal ganglia/thalamic involvement
• Eculizumab has been used compassionately in severe neurological cases [27]

7.2 Atypical HUS (aHUS)

Atypical HUS is a complement-mediated TMA requiring targeted complement inhibition. [28,29]

First-Line Therapy: Eculizumab

Eculizumab is a humanized monoclonal antibody against complement C5, preventing formation of the membrane attack complex (MAC).

Legendre et al. (2013) - Phase 2 Trials

• Design: Two phase 2 trials in adults and adolescents with aHUS
• Results:
  • Significant increase in platelet counts
  • Improvement in eGFR
  • Sustained TMA-free status
• Conclusion: Eculizumab is effective and well-tolerated for aHUS
• PMID: 23782178

Eculizumab Dosing:

• Induction: 900 mg IV weekly × 4 weeks
• Maintenance: 1200 mg IV at week 5, then every 2 weeks

Critical Requirement: Meningococcal Vaccination Complement inhibition dramatically increases risk of Neisseria meningitidis infection (1000-2000x increased risk). [30]

• Vaccinate with MenACWY and MenB at least 2 weeks before starting therapy
• If urgent treatment needed, give prophylactic antibiotics (penicillin VK 500 mg BD or ciprofloxacin)
• Continue prophylaxis until 2 weeks after vaccination

Long-Term Considerations:

• Duration of therapy is controversial
• Discontinuation possible in some patients but carries 20-30% relapse risk
• Higher relapse risk with CFH mutations
• ADAMTS13 monitoring not applicable (normal in aHUS)

7.3 Plasma Exchange in HUS

Typical HUS: Not routinely recommended Atypical HUS: May be used as bridging therapy while awaiting eculizumab, but does not address underlying complement dysregulation Coexisting anti-CFH antibodies: Plasma exchange may be beneficial to remove autoantibodies

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Section 8: ICU Management Considerations

8.1 Indications for ICU Admission

• Severe neurological impairment (GCS below 13, seizures, focal deficits)
• Cardiac involvement (troponin elevation, arrhythmias, heart failure)
• Respiratory failure requiring ventilatory support
• Multi-organ dysfunction
• Need for urgent plasma exchange and central venous access
• Renal failure requiring dialysis
• Severe bleeding complications

8.2 Prognosis and Mortality

TTP ICU Outcomes:

• Modern ICU mortality: 10-22% with appropriate therapy
• Untreated mortality: greater than 90%
• Key prognostic factors: [31,32]

Mechanical Ventilation: Patients requiring mechanical ventilation have mortality rates exceeding 40-50%, often due to:

• Status epilepticus
• Coma from cerebral ischemia
• Cardiac failure
• Hospital-acquired complications (sepsis, VAP)

8.3 Monitoring in ICU

Daily Monitoring:

• Platelet count (primary marker of response)
• LDH (correlates with hemolysis)
• Haemoglobin/reticulocyte count
• Creatinine/urea
• Neurological assessment
• Troponin (if cardiac involvement suspected)

Response Criteria:

• Complete response: Platelet count greater than 150 × 10⁹/L for ≥2 consecutive days
• Exacerbation: Recurrence within 30 days of stopping TPE
• Relapse: Recurrence greater than 30 days after stopping TPE
• Refractory: No platelet response after 4-7 days of daily TPE

8.4 Complications of Plasma Exchange

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Section 9: Special Populations

9.1 Pregnancy-Associated TMA

Timing Clues:

• TTP can occur at any gestation; aHUS predominantly postpartum (79%)
• HELLP syndrome occurs in late pregnancy

ADAMTS13 Testing:

• Essential to differentiate TTP from HELLP
• ADAMTS13 below 10% = TTP requiring plasma exchange
• ADAMTS13 normal = consider HELLP or aHUS [16,33]

Management:

• If below 34 weeks with suspected TTP: plasma exchange + steroids; delivery timing individualized
• If HELLP: expedite delivery
• If postpartum and no improvement after delivery: consider aHUS, start eculizumab

9.2 Post-Transplant TMA

Risk Factors:

• Calcineurin inhibitor use (cyclosporine, tacrolimus)
• Conditioning regimen toxicity
• GVHD
• Infections (CMV, adenovirus)

Management:

• Reduce/discontinue CNI
• Switch to alternative immunosuppression (sirolimus, belatacept)
• Consider eculizumab for refractory cases
• Distinguish from GVHD and sepsis-associated coagulopathy [34]

9.3 HIV-Associated TTP

• TTP may be presenting feature of HIV or occur during immune reconstitution
• ADAMTS13 activity typically below 10%
• Responds to standard TPE + steroids
• Antiretroviral therapy is essential

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Section 10: Long-Term Considerations

10.1 ADAMTS13 Monitoring and Relapse Prevention

Relapse Risk:

• Occurs in 20-50% of iTTP patients
• Higher risk with persistent ADAMTS13 below 10% or detectable anti-ADAMTS13 antibodies

Surveillance Protocol:

• ADAMTS13 activity every 3 months after acute episode
• If ADAMTS13 falls below 20%: preemptive rituximab to prevent clinical relapse [24]

10.2 Long-Term Complications

TTP Survivors:

• Cognitive impairment (memory, concentration)
• Depression and anxiety
• Fatigue
• Increased cardiovascular risk
• Relapse risk (20-50%) [35]

HUS Survivors:

• Chronic kidney disease (common in aHUS)
• Hypertension
• Proteinuria
• Risk of ESRD (higher with CFH mutations)

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Section 11: Evidence Summary

11.1 Landmark Trials

11.2 Current Guidelines

• ISTH 2020: Guidelines on diagnosis and management of TTP (PMID: 32832960)
• KDIGO 2012: Clinical practice guidelines for glomerulonephritis (includes HUS)
• BSH 2012: Guidelines for diagnosis and management of TTP

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SAQ Practice Questions

SAQ 1: Approach to Thrombocytopenia with MAHA

Question: A 35-year-old woman is admitted to the ICU with confusion, platelet count 18 × 10⁹/L, Hb 68 g/L, LDH 2400 U/L, undetectable haptoglobin, and creatinine 120 μmol/L. Blood film shows numerous schistocytes.

a) What is the most likely diagnosis and why? (3 marks) b) Calculate the PLASMIC score and interpret its significance. (4 marks) c) Outline your immediate management priorities. (5 marks) d) The intern asks whether platelets should be transfused. Explain your response. (3 marks)

Model Answer:

a) Most likely diagnosis (3 marks)

• Thrombotic Thrombocytopenic Purpura (TTP) (1 mark)
• Features supporting diagnosis:
  • "MAHA: schistocytes, elevated LDH, undetectable haptoglobin (1 mark)"
  • Thrombocytopenia with neurological involvement (confusion) (0.5 mark)
  • Relatively preserved renal function (creatinine only mildly elevated) - distinguishes from HUS (0.5 mark)

b) PLASMIC score calculation (4 marks)

• Estimated score: 6-7 (2 marks)
• Interpretation: High probability (85-96%) of severe ADAMTS13 deficiency (below 10%) (1 mark)
• Supports empiric initiation of plasma exchange before ADAMTS13 results (1 mark)

c) Immediate management priorities (5 marks)

1. Urgent plasma exchange - 1.0-1.5 plasma volumes daily (1 mark)
2. Central venous access - large-bore dialysis catheter for TPE (0.5 mark)
3. Corticosteroids - methylprednisolone 1 mg/kg IV daily (1 mark)
4. Caplacizumab - 10 mg IV before first TPE, then 10 mg SC daily (1 mark)
5. Send ADAMTS13 activity and antibody - do not delay treatment (0.5 mark)
6. Rituximab - consider early if severe neurological involvement (0.5 mark)
7. Supportive care - RBC transfusion for symptomatic anemia (0.5 mark)

d) Platelet transfusion advice (3 marks)

• Platelet transfusion is contraindicated in TTP (1 mark)
• Mechanism: "Fuel to the fire"
• transfused platelets aggregate on UL-VWF multimers, worsening microvascular thrombosis (1 mark)
• Evidence: Goel et al. (2015) demonstrated 2-fold increase in mortality, MI, and stroke with platelet transfusion (PMID: 25524614) (0.5 mark)
• Only indication: life-threatening hemorrhage (intracranial, massive GI bleeding) (0.5 mark)

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SAQ 2: Atypical HUS Management

Question: A 28-year-old woman presents 10 days postpartum with severe acute kidney injury (creatinine 580 μmol/L), platelet count 45 × 10⁹/L, LDH 1800 U/L, and schistocytes on blood film. She had an uncomplicated vaginal delivery and no diarrhea. Her blood pressure is 165/95 mmHg.

a) What is the differential diagnosis? List 3 conditions. (3 marks) b) What investigations would help differentiate these conditions? (4 marks) c) Her ADAMTS13 returns at 68%. Stool PCR for Shiga toxin is negative. What is the most likely diagnosis and what treatment is required? (4 marks) d) What preventive measure is critical before initiating definitive treatment? (2 marks) e) What is the relapse risk if treatment is discontinued, and which genetic factors increase this risk? (2 marks)

Model Answer:

a) Differential diagnosis (3 marks)

1. Atypical HUS (complement-mediated) - postpartum timing, severe AKI, no diarrhea (1 mark)
2. TTP - MAHA + thrombocytopenia, requires ADAMTS13 testing (1 mark)
3. Postpartum HELLP/atypical preeclampsia - can persist postpartum, check liver enzymes (1 mark)

(Other acceptable: malignant hypertension, drug-induced TMA)

b) Differentiating investigations (4 marks)

• ADAMTS13 activity and antibody - below 10% = TTP (1 mark)
• Liver function tests - elevated in HELLP, normal in aHUS (0.5 mark)
• Stool culture and Shiga toxin PCR - positive in typical HUS (0.5 mark)
• Complement studies - C3, C4, CH50; low C3 may suggest complement activation (1 mark)
• Anti-CFH antibodies - present in autoimmune aHUS (0.5 mark)
• Genetic testing - CFH, CFI, MCP, C3, CFB mutations (0.5 mark)

c) Diagnosis and treatment (4 marks)

• Diagnosis: Atypical HUS (complement-mediated TMA) (1 mark)

  • ADAMTS13 68% (excludes TTP)
  • Shiga toxin negative (excludes typical HUS)
  • Postpartum presentation classic for aHUS

• Treatment: Eculizumab (2 marks)

  • "Induction: 900 mg IV weekly × 4 weeks"
  • "Maintenance: 1200 mg IV at week 5, then every 2 weeks"

• Plasma exchange may be used as bridging therapy while awaiting eculizumab but does not address underlying pathophysiology (1 mark)

d) Critical preventive measure (2 marks)

• Meningococcal vaccination (1 mark)
  • MenACWY and MenB vaccines
  • Ideally 2 weeks before starting eculizumab
• If urgent treatment needed: prophylactic antibiotics (penicillin VK 500 mg BD or ciprofloxacin) until 2 weeks after vaccination (1 mark)

e) Relapse risk (2 marks)

• Relapse risk if discontinued: 20-30% (1 mark)
• Highest risk genetic factors (1 mark):
  • CFH (Complement Factor H) mutations - highest relapse risk
  • CFI mutations
  • C3 gain-of-function mutations
  • "Lower risk: MCP mutations (expressed on cell membrane, not replaced by therapy)"

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Viva Scenarios

Viva 1: Refractory TTP in the ICU

Scenario: You are the ICU registrar called to review a 42-year-old woman who was admitted 5 days ago with TTP. She has received daily plasma exchange and methylprednisolone but her platelet count remains at 22 × 10⁹/L (admission 15 × 10⁹/L). She has developed worsening confusion and is now GCS 12.

Examiner Questions:

Q1: How do you define refractory TTP and what is the prognosis?

Expected Answer:

• Definition: Failure of platelet count to respond after 4-7 days of daily therapeutic plasma exchange
• Also consider refractory if:
  • Persistent or worsening neurological symptoms
  • New organ dysfunction despite treatment
  • LDH fails to trend down
• Prognosis: ICU mortality approaches 40% in refractory cases
• Differential considerations:
  • Ensure adequate TPE volume (1.0-1.5 plasma volumes)
  • Exclude incorrect diagnosis (check ADAMTS13 result)
  • Consider congenital TTP (would not respond to immunosuppression)

Q2: What additional therapies would you institute?

Expected Answer:

1. Rituximab - 375 mg/m² weekly × 4 doses

   • B-cell depletion reduces anti-ADAMTS13 antibody production
   • May take 1-2 weeks for effect

2. Caplacizumab - if not already started

   • 10 mg IV loading, then 10 mg SC daily
   • Immediate effect on platelet recovery

3. Intensify plasma exchange

   • Increase volume to 1.5-2 plasma volumes
   • Consider twice-daily TPE

4. Consider alternative immunosuppression

   • Cyclophosphamide (if no response to rituximab)
   • Bortezomib, vincristine (case reports only)

5. CT brain - exclude intracranial pathology given neurological deterioration

Q3: The ADAMTS13 result returns showing activity of 45%. How does this change your management?

Expected Answer:

• ADAMTS13 greater than 10% effectively excludes TTP as the primary diagnosis

• Reconsider differential diagnosis:

  • Atypical HUS (aHUS) - would explain renal involvement if present
  • Drug-induced TMA - review medications carefully
  • Malignancy-associated TMA - consider CT staging
  • Secondary TMA from sepsis
  • DIC with microangiopathic features

• Investigation priorities:

  • Complement studies (C3, C4, CH50)
  • Anti-CFH antibodies
  • Drug history review
  • Consider malignancy screen

• Treatment modification:

  • "If aHUS suspected: initiate eculizumab"
  • May discontinue TPE if an alternative diagnosis is confirmed
  • Continue supportive care including renal replacement therapy if required

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Viva 2: STEC-HUS with Neurological Complications

Scenario: A 6-year-old child is transferred to your ICU from a regional hospital with bloody diarrhea for 7 days, followed by oliguria and generalized tonic-clonic seizures. Blood tests show: Hb 72 g/L, platelets 28 × 10⁹/L, creatinine 450 μmol/L, LDH 2800 U/L. Stool PCR confirms Shiga toxin-producing E. coli O157:H7.

Examiner Questions:

Q1: What is the diagnosis and what are the key principles of management?

Expected Answer:

• Diagnosis: Typical HUS (STEC-HUS) with neurological complications

• Key management principles:

  1. Supportive care - this is the mainstay
  2. Renal replacement therapy - CVVHDF given oliguria and elevated creatinine
  3. Seizure management - antiepileptic therapy (levetiracetam or phenytoin)
  4. Fluid balance - careful attention to avoid overload
  5. Blood pressure control - target age-appropriate BP

• What to AVOID:

  • Antibiotics - may increase toxin release
  • Anti-motility agents - prolong toxin exposure
  • Platelet transfusion - unless life-threatening bleeding

Q2: The child has ongoing seizures and develops focal neurological signs. The neurology team is asking about eculizumab. What is your response?

Expected Answer:

• Eculizumab is NOT routinely recommended for typical STEC-HUS

• Rationale:

  • Primary pathology is Shiga toxin-mediated endothelial injury, not complement dysregulation
  • Limited evidence for benefit in typical HUS
  • Risk of meningococcal infection

• However, compassionate use has been reported in severe neurological cases:

  • Some case series suggest possible benefit in CNS-dominant STEC-HUS
  • Complement activation may contribute to neurological injury

• My approach:

  • This is a critically ill child with life-threatening neurological complications
  • Would discuss with haematology, nephrology, and neurology as multidisciplinary case
  • If all standard supportive measures failing and prognosis poor, compassionate use could be considered after meningococcal vaccination/prophylaxis
  • Decision should involve family discussion about experimental nature

• Reference: Case series of eculizumab in severe neurological STEC-HUS (PMID: 32371911)

Q3: What are the long-term renal and neurological outcomes of STEC-HUS?

Expected Answer:

• Renal outcomes:

  • Majority (60-70%) have full renal recovery
  • 15-25% develop chronic kidney disease
  • 3-5% progress to ESRD
  • "Risk factors for poor renal outcome: prolonged oliguria, need for dialysis greater than 7 days"

• Neurological outcomes:

  • CNS involvement is the leading cause of mortality in acute phase
  • 25-40% of those with initial neurological symptoms have long-term sequelae
  • "Sequelae include:"
    • Cognitive impairment
    • Epilepsy
    • Fine motor deficits
    • Behavioural changes
  • Basal ganglia and thalamic lesions on MRI associated with poorer prognosis

• Follow-up requirements:

  • Long-term nephrology surveillance (blood pressure, proteinuria, eGFR)
  • Neurodevelopmental assessment
  • Psychological support

---

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23. Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118(7):1746-1753. PMID: 21673346

24. Jestin M, Benhamou Y, Schelpe AS, et al. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018;132(20):2143-2153. PMID: 30213873

25. Goel R, Ness PM, Takemoto CM, et al. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood. 2015;125(9):1470-1476. PMID: 25524614

26. Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000;342(26):1930-1936. PMID: 10873096

27. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, et al. Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med. 2011;364(26):2561-2563. PMID: 21612462

28. 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. PMID: 23782178

29. 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. PMID: 25651366

30. McNamara LA, Topaz N, Wang X, et al. 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. PMID: 28704346

31. Benhamou Y, Assié C, Boelle PY, et al. Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Haematologica. 2012;97(8):1181-1186. PMID: 22307545

32. Coppo P, Bubenheim M, Azoulay E, et al. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP. Blood. 2021;137(6):733-742. PMID: 33103729

33. Scully M, Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome. Br J Haematol. 2014;164(6):759-766. PMID: 24387053

34. Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11(8):571-575. PMID: 16041306

35. Lewis QF, Lanneau MS, Mathias SD, et al. Long-term deficits in health-related quality of life after recovery from thrombotic thrombocytopenic purpura. Transfusion. 2009;49(1):118-124. PMID: 18954400

36. Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89(3):701-711. PMID: 26805378

37. Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016;31(1):15-39. PMID: 25754438

38. Zheng XL. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura. Annu Rev Med. 2015;66:211-225. PMID: 25587650

39. Swisher KK, Terrell DR, Vesely SK, et al. Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura. Transfusion. 2009;49(5):873-887. PMID: 19175771

40. 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. PMID: 22624596

41. Coppo P, Schwarzinger M, Cuker A, 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. PMID: 20424340

42. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347(8):589-600. PMID: 12192020

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44. Joly BS, Vanhoorelbeke K, Veyradier A. Understanding therapeutic targets in thrombotic thrombocytopenic purpura. Intensive Care Med. 2017;43(9):1398-1400. PMID: 28401271

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Appendix A: Additional Viva Scenarios

Viva 3: TTP with Cardiac Involvement

Scenario: A 48-year-old man is admitted via the emergency department with chest pain, platelet count 28 × 10⁹/L, Hb 82 g/L, and schistocytes on blood film. His troponin T is 850 ng/L (normal below 14). ECG shows diffuse ST segment depression in leads V2-V6. PLASMIC score is 6.

Examiner Questions:

Q1: How common is cardiac involvement in TTP and what are its manifestations?

Expected Answer:

• Incidence: Cardiac involvement occurs in 25-50% of TTP patients
• Subclinical myocardial injury (troponin elevation) is underappreciated

Manifestations:

• Prognostic significance: Troponin elevation is an independent predictor of mortality
• Reference: French TMA Reference Center (PMID: 22307545)

Q2: Would you perform coronary angiography in this patient?

Expected Answer:

• Generally NOT recommended in the acute phase of TTP with suspected myocardial involvement

Reasons:

1. High bleeding risk - severe thrombocytopenia makes arterial access hazardous
2. Mechanism is different - cardiac injury is due to microvascular thrombosis, not epicardial coronary occlusion
3. Antiplatelet/anticoagulation - standard post-PCI therapy would be dangerous
4. Priority is TTP treatment - plasma exchange will address the underlying pathology

Alternative approach:

• Urgent plasma exchange - will treat the underlying cause
• Continuous ECG monitoring
• Serial troponin monitoring
• Echocardiogram to assess LV function
• Cardiology consultation for arrhythmia management
• Avoid platelet transfusion even with ECG changes (unless cardiogenic shock)

When angiography might be considered:

• Post-recovery from TTP if residual symptoms
• If clinical picture strongly suggests concurrent ACS (prior CAD, STEMI pattern)

Q3: The patient develops ventricular tachycardia during his second plasma exchange session. How do you manage this?

Expected Answer: Immediate Management:

1. Assess haemodynamic stability

   • If unstable (hypotension, altered consciousness): DC cardioversion 120-200J biphasic
   • If stable: pharmacological management

2. Pause plasma exchange temporarily if patient unstable

3. Check and correct electrolytes

   • Citrate anticoagulation during TPE causes hypocalcemia
   • Give calcium gluconate 10 mL of 10% IV
   • Check and correct potassium, magnesium

4. Antiarrhythmic therapy

   • First-line: Amiodarone 300 mg IV over 20-60 mins
   • Alternative: Lidocaine if contraindication to amiodarone
   • Avoid beta-blockers in acute setting if cardiogenic shock

5. Continue TTP treatment

   • Resume plasma exchange once stabilized
   • Consider caplacizumab if not already started
   • Cardiac involvement indicates severe disease - consider early rituximab

6. ICU monitoring

   • Continuous cardiac monitoring
   • Invasive blood pressure monitoring
   • Consider inotropic support if cardiogenic shock develops

---

Viva 4: Drug-Induced TMA

Scenario: A 62-year-old woman with metastatic pancreatic cancer has received 6 cycles of gemcitabine over the past 8 months. She presents with fatigue, Hb 72 g/L, platelets 55 × 10⁹/L, creatinine 380 μmol/L (baseline 90), and LDH 1200 U/L. Blood film shows schistocytes.

Examiner Questions:

Q1: What is the most likely diagnosis and what is the mechanism?

Expected Answer:

• Diagnosis: Gemcitabine-induced thrombotic microangiopathy (GiTMA)

Mechanism:

• Dose-dependent, cumulative endothelial toxicity (NOT immune-mediated)
• Risk increases with:
  • Prolonged therapy (greater than 7 cycles or greater than 8 months)
  • Higher cumulative dose (greater than 20,000 mg/m²)
  • Combination with other nephrotoxic agents

Key distinguishing features from TTP:

• ADAMTS13 activity typically greater than 10% (normal or mildly reduced)
• More prominent renal involvement
• Temporal relationship with drug exposure
• Severe AKI often irreversible

Other drugs causing DITMA by similar mechanism:

• Mitomycin C
• Cyclosporine/Tacrolimus (calcineurin inhibitors)
• VEGF inhibitors (bevacizumab, sunitinib)

Reference: Al-Nouri et al. Blood 2015 (PMID: 26202490)

Q2: How does management of drug-induced TMA differ from immune TTP?

Expected Answer: Key Differences in Management:

Management of GiTMA:

1. Immediate cessation of gemcitabine - most important step
2. Supportive care:
   • Renal replacement therapy if required
   • Blood transfusion for symptomatic anemia
   • Blood pressure control
3. Plasma exchange: May be tried but evidence limited; not routinely recommended
4. Eculizumab: Case reports of benefit, but not established therapy
5. Oncology discussion: Alternative chemotherapy regimens

Prognosis:

• GiTMA often causes permanent renal damage
• Up to 50% may require long-term dialysis
• Mortality approximately 15-25%

---

Appendix B: Management Algorithms

Algorithm 1: Approach to Suspected TTP in ICU

┌─────────────────────────────────────────────────────────────┐
│     MAHA (schistocytes, ↑LDH, ↓haptoglobin) +              │
│     Thrombocytopenia with no obvious cause                  │
└─────────────────────────────────────────────────────────────┘
                              │
                              ▼
┌─────────────────────────────────────────────────────────────┐
│     Calculate PLASMIC Score                                  │
│     Send ADAMTS13 activity (do NOT wait for result)         │
└─────────────────────────────────────────────────────────────┘
                              │
          ┌───────────────────┼───────────────────┐
          ▼                   ▼                   ▼
    Score 0-4            Score 5           Score 6-7
    Low probability    Intermediate     High probability
          │                   │                   │
          ▼                   ▼                   ▼
    Consider other      Consider TPE      Urgent TPE +
    diagnoses:          based on          Corticosteroids +
    - DIC               clinical          Caplacizumab
    - HUS               severity          
    - HELLP                              +/- Rituximab if
    - Malignant HTN                      severe/neurological

Algorithm 2: TTP vs HUS Differentiation

┌────────────────────────────────────────────────────────────┐
│              MAHA + Thrombocytopenia + Organ Damage         │
└────────────────────────────────────────────────────────────┘
                              │
                              ▼
         ┌────────────────────┴────────────────────┐
         │                                          │
    ADAMTS13 below 10%                           ADAMTS13 greater than 10%
         │                                          │
         ▼                                          ▼
       TTP                               ┌──────────┴──────────┐
         │                               │                      │
         ▼                          Diarrhea?                   │
    Plasma Exchange                      │                      │
    Steroids                     ┌───────┴───────┐              │
    Caplacizumab                 │               │              │
    +/- Rituximab               Yes             No              │
                                 │               │              │
                                 ▼               ▼              │
                          Typical HUS      Atypical HUS        │
                          (STEC)           (Complement)        │
                                 │               │              │
                                 ▼               ▼              │
                          Supportive      Eculizumab           │
                          NO antibiotics  Meningococcal vax    │

---

Appendix C: Quick Reference Tables

Table C1: Laboratory Features Comparison

Table C2: Treatment Summary

Table C3: Plasma Exchange Prescription

Table C4: Caplacizumab Dosing and Monitoring

Monitoring:

• Weekly ADAMTS13 activity during treatment
• Bleeding assessment (mucocutaneous bleeding common)
• Withhold if severe bleeding; reinitiate when controlled

---

Appendix D: CICM Exam Tips

Key Points for Written Exam (SAQ)

1. Always mention ADAMTS13 - this is the defining test for TTP
2. PLASMIC score - know how to calculate and interpret
3. Rock 1991 - landmark trial establishing plasma exchange
4. HERCULES - know the key outcomes for caplacizumab
5. Platelet transfusion contraindication - high-yield safety point

Common Viva Questions

1. "How do you differentiate TTP from HUS from DIC?"
2. "What is the role of rituximab in TTP?"
3. "When would you give platelet transfusion in TTP?"
4. "What are the complications of plasma exchange?"
5. "How do you manage refractory TTP?"

Pitfalls to Avoid

• Don't wait for ADAMTS13 results before starting plasma exchange
• Don't forget meningococcal vaccination before eculizumab
• Don't transfuse platelets unless life-threatening bleeding
• Don't give antibiotics in STEC-HUS unless sepsis suspected
• Don't assume normal ADAMTS13 excludes TMA (may be HUS or secondary)

Integration Points

• Haematology: MAHA diagnosis, coagulation testing, transfusion
• Nephrology: Dialysis in HUS, complement testing, genetic workup
• Neurology: Encephalopathy, seizure management, stroke mimics
• Cardiology: Troponin elevation, arrhythmia management
• Obstetrics: Pregnancy-associated TMA differentiation

---

Appendix E: Clinical Pearls Summary

1. "If you think TTP, start TPE" - don't wait for ADAMTS13 results in high-probability cases

2. The pentad is rare - only 10% present with all 5 features; MAHA + thrombocytopenia is enough to suspect

3. Renal spares, brain impairs - TTP typically has mild renal involvement but prominent neurological features; reverse suggests HUS

4. Platelets fuel the fire - transfusion in TTP worsens microvascular thrombosis

5. Antibiotics amplify Shiga toxin - avoid in suspected STEC infection

6. Postpartum + severe AKI = think aHUS - 79% of pregnancy-associated aHUS is postpartum

7. Meningococcal risk is 2000x higher - always vaccinate before eculizumab

8. ADAMTS13 below 10% + antibodies = immune TTP - guides treatment with rituximab

9. Troponin elevation = high risk - cardiac involvement indicates severe disease

10. Caplacizumab works fast - 1.55x faster platelet normalization than standard therapy

---

Appendix F: Patient and Family Information

What is TTP/HUS?

TTP (Thrombotic Thrombocytopenic Purpura) and HUS (Hemolytic Uremic Syndrome) are rare blood disorders where small blood clots form throughout the body's tiny blood vessels. This causes:

• Low blood platelet count (bruising and bleeding risk)
• Destruction of red blood cells (anemia, fatigue)
• Damage to vital organs (brain, kidneys, heart)

How is it treated?

TTP:

• Plasma exchange (similar to dialysis but exchanges your blood plasma)
• Medications to suppress the immune system
• New medications that prevent blood clots from forming

HUS:

• Supportive care and kidney dialysis if needed
• For atypical HUS: medication that blocks part of the immune system

What to expect in ICU?

• Close monitoring of blood tests (often multiple times daily)
• Large IV line in neck or groin for plasma exchange
• Plasma exchange sessions lasting 2-3 hours daily
• Possible dialysis if kidneys affected
• Neurological checks for any brain involvement

Long-term outlook

With prompt treatment, most patients with TTP survive (80-90%). Regular follow-up is essential as the condition can recur. For HUS, kidney function may be permanently affected in some patients.

When to seek urgent help after discharge

• Unusual bleeding or bruising
• Confusion or severe headache
• Fever (especially if on eculizumab)
• Dark-coloured urine
• Extreme fatigue

---

Appendix G: Nursing Considerations

Pre-Plasma Exchange Checklist

Patient Preparation:

• Confirm consent obtained
• Large-bore central venous catheter in situ and patent
• Baseline observations recorded (BP, HR, SpO2, GCS, temperature)
• Recent blood results available (FBC, coag, biochemistry, calcium)
• Calcium gluconate at bedside (for citrate toxicity)
• Antihistamine and hydrocortisone available for allergic reactions

Equipment Check:

• Apheresis machine set up and primed
• Fresh frozen plasma thawed and available (volume as prescribed)
• Emergency trolley nearby
• Cardiac monitor with defibrillator available

During Plasma Exchange

Observations:

• Continuous cardiac monitoring
• Blood pressure every 15 minutes (or more frequently if unstable)
• Neurological observations hourly
• Symptoms of citrate toxicity: perioral tingling, muscle cramps, tetany
• Signs of allergic reaction: urticaria, bronchospasm, hypotension

Common Complications:

Post-Plasma Exchange

• Document total volume exchanged and any complications
• Repeat observations for 1 hour post-procedure
• Check calcium level 1 hour post if symptomatic during procedure
• Continue neurological observations
• Document response (any improvement in neurological status)

---

Appendix H: Pharmacology Quick Reference

Caplacizumab (Cablivi)

Mechanism: Humanized bivalent nanobody that binds VWF A1 domain, inhibiting interaction with platelet GPIb-IX-V receptor

Dosing:

• Loading: 10 mg IV before first TPE
• Maintenance: 10 mg SC daily

Duration:

• Continue during TPE and for 30 days after last TPE
• Extend if ADAMTS13 activity remains below 10%

Side Effects:

• Mucocutaneous bleeding (65%)
• Epistaxis, gingival bleeding, bruising
• Serious bleeding rare but reported

Contraindications:

• Active major bleeding
• Hypersensitivity to caplacizumab

Drug Interactions:

• Caution with anticoagulants/antiplatelets (increased bleeding)

---

Eculizumab (Soliris)

Mechanism: Humanized monoclonal antibody against complement C5, prevents formation of membrane attack complex (MAC)

Dosing for aHUS:

• Week 1-4: 900 mg IV weekly
• Week 5 onwards: 1200 mg IV every 2 weeks

Preparation:

• Dilute in 0.9% saline to final concentration 5 mg/mL
• Infuse over 25-45 minutes

Black Box Warning:

• Serious meningococcal infections (2000x increased risk)
• Must vaccinate MenACWY + MenB at least 2 weeks before
• If urgent, give prophylactic antibiotics

Side Effects:

• Headache (44%)
• Upper respiratory infection
• Diarrhea, nausea
• Infusion reactions (rare)

Monitoring:

• Meningococcal vaccination status
• Signs of meningitis (educate patient)
• LDH, platelet count, renal function

---

Rituximab (Rituxan/MabThera)

Mechanism: Chimeric anti-CD20 monoclonal antibody, depletes B-lymphocytes

Dosing for TTP:

• Standard: 375 mg/m² IV weekly × 4 doses
• Alternative: 1000 mg fixed dose days 1 and 15

Premedication:

• Paracetamol 1g PO
• Diphenhydramine 50 mg IV (or equivalent antihistamine)
• Methylprednisolone 100 mg IV

Infusion Protocol:

• First infusion: Start 50 mg/hr, increase by 50 mg/hr every 30 min to max 400 mg/hr
• Subsequent: Start 100 mg/hr, increase to max 400 mg/hr

Side Effects:

• Infusion reactions (fever, chills, rigors) - usually first infusion
• Infection (immunosuppression)
• Progressive multifocal leukoencephalopathy (PML) - rare but serious

Monitoring:

• B-cell count (CD19+, CD20+)
• Immunoglobulin levels (especially IgG)
• Signs of infection

---

Appendix I: Coding and Classification

ICD-10 Codes

SNOMED CT Codes

AR-DRG Classification (Australia)

• DRG: Q60A/Q60B - Blood disorders with/without complications
• Plasma exchange adds significant complexity weighting