Fragmentation Hemolysis: MAHA, TMA, TTP, and HUS - A Clear Overview

The Terminology, Untangled

Schistocytes on smear
       ↓
MAHA (the clinical syndrome)
       ↓
TMA (the pathological mechanism)
     /       \
  TTP        HUS (typical & atypical)

• Schistocytes - fragmented RBCs (helmet cells, triangular cells) seen on peripheral blood smear. This is the finding - not a diagnosis.
• MAHA (Microangiopathic Hemolytic Anemia) - the syndrome of mechanical intravascular hemolysis producing schistocytes. It is not a specific diagnosis but demands an explanation.
• TMA (Thrombotic Microangiopathy) - the pathological process: endothelial injury in small vessels with platelet-fibrin thrombi causing mechanical RBC destruction and thrombocytopenia. TMA is the mechanism behind MAHA in the TTP/HUS family.
• TTP (Thrombotic Thrombocytopenic Purpura) - a specific TMA disease caused by ADAMTS13 deficiency.
• HUS (Hemolytic Uremic Syndrome) - a TMA disease dominated by renal failure, subdivided into typical (Shiga toxin) and atypical (complement dysregulation).

MAHA: The Overarching Syndrome

TMA: The Pathologic Process

1. Platelet consumption → thrombocytopenia
2. Mechanical RBC shearing → MAHA / schistocytes
3. Downstream ischemia → organ dysfunction (brain, kidneys, heart)

• Harrison's Principles of Internal Medicine 22E, p. 2488

TTP (Thrombotic Thrombocytopenic Purpura)

Pathophysiology

• iTTP (immune-mediated) - acquired autoantibody (IgG/IgM) against ADAMTS13. This is the common form. Incidence ~2.9/million in the US, median age 40, female:male ~3:1, markedly higher in Black patients.
• cTTP (congenital) - ADAMTS13 gene mutation, also known as Upshaw-Schulman syndrome. Can present in infancy or first emerge in pregnancy/adulthood.

Classic Presentation

• Cardiac ischemia (~25%)
• Abdominal pain / mesenteric ischemia (~35%)
• Predominantly neurological and cardiac involvement (contrasting HUS which is predominantly renal)

HUS (Hemolytic Uremic Syndrome)

Typical HUS (STEC-HUS / "D+ HUS")

• Prodrome: bloody diarrhea (hemorrhagic colitis) 5-10 days before onset
• Predominantly affects children (most common cause of acute renal failure in children)
• Triad: MAHA + Thrombocytopenia + Acute kidney injury (oliguria, elevated creatinine)
• CNS involvement is less prominent than in TTP
• Typically self-limiting

Atypical HUS (aHUS / "D- HUS")

• Factor H (CFH) mutations - most common (~25-30%)
• Factor I, MCP (CD46), C3, factor B mutations
• Anti-factor H autoantibodies (DEAP-HUS - associated with deletion of CFHR1 and CFHR3)

• Can occur at any age
• No diarrheal prodrome
• Severe acute kidney injury (often progresses to ESRD)
• Recurrent episodes
• Can be triggered by pregnancy, infection, complement-activating drugs

Quick Comparison Table

Diagnosis

Step 1 - Confirm MAHA

• Peripheral blood smear: schistocytes (helmet cells, triangular fragments)
• LDH: elevated (hemolysis marker)
• Haptoglobin: low or undetectable
• Indirect bilirubin: elevated
• Coombs test: negative (mechanical, not immune hemolysis - distinguishes from autoimmune hemolytic anemia)
• Platelet count: low (thrombocytopenia)
• Coagulation screen: helps exclude DIC (PT/APTT usually normal in TMA, abnormal in DIC)

Step 2 - Use the PLASMIC Score to Stratify TTP Risk

Step 3 - Specific Tests

• ADAMTS13 activity: Send before plasma exchange begins. Activity <5-10% confirms iTTP. Normal ADAMTS13 with TMA picture points toward HUS.
• Shiga toxin stool PCR/culture: If prodromal diarrhea
• Complement panel: If aHUS suspected (C3, C4, CH50, anti-factor H antibodies, genetic panel)
• Creatinine / urinalysis: Proteinuria and hematuria indicate renal TMA
• Pregnancy test in women of childbearing age

Management (with 2025 ISTH Guidelines)

iTTP (Immune TTP)

1. Therapeutic Plasma Exchange (TPE/PEX) - started immediately. Removes anti-ADAMTS13 autoantibody and UL-vWF multimers; replenishes functional ADAMTS13 via donor plasma. Before PEX was available, mortality was >90%; now ~80% survive. Continue daily until platelet count >150×10⁹/L for ≥2 consecutive days.
2. Corticosteroids - prednisone 1 mg/kg/day PO (or methylprednisolone 1 g IV daily x3 for severe/neurological cases). Immunosuppresses the anti-ADAMTS13 autoantibody.
3. Caplacizumab - anti-vWF nanobody (11 mg IV initial dose, then 11 mg SC daily during and for 30 days post-PEX). Blocks the A1 domain of vWF, preventing platelet-vWF aggregation. Approved for iTTP in conjunction with PEX and immunosuppression. Reduces time to platelet recovery, thromboembolic events, and death. - Harrison's 22E, p. 2489

• Rituximab (anti-CD20) - depletes B cells producing the anti-ADAMTS13 antibody. Used in refractory disease or for relapse prevention. Twice-daily PEX with rituximab for refractory cases.
• Bortezomib - proteasome inhibitor targeting plasma cells; emerging data for refractory disease (PMID 37571963).

2025 ISTH Guideline Update (Key Points)

• For iTTP: No change from 2020 recommendations. PEX + steroids + caplacizumab remains the standard.
• For cTTP in remission (Upshaw-Schulman): New strong recommendation for recombinant ADAMTS13 over fresh frozen plasma (where accessible). Recombinant ADAMTS13 provides the most favorable benefit-risk balance. FFP remains an option where recombinant ADAMTS13 is not accessible.
• Shared decision-making should incorporate patient burden of care and cost considerations.

Typical STEC-HUS

• IV fluids (early volume resuscitation)
• Dialysis if needed (renal support)
• No plasma exchange - not effective for STEC-HUS
• No antibiotics in children with E. coli O157:H7 - increases HUS risk
• No antimotility agents
• Azithromycin may reduce bacterial shedding duration in adults

Atypical HUS (aHUS)

• Eculizumab (anti-C5 monoclonal antibody) - approved first-line treatment; blocks terminal complement cascade activation; aborts MAHA and improves renal function
• Ravulizumab - engineered from eculizumab with extended half-life (dosing every 4-8 weeks vs 2 weeks); FDA-approved for aHUS
• Mandatory pre-treatment vaccination: Neisseria meningitidis (A, C, W, Y and B), Haemophilus influenzae, Streptococcus pneumoniae - Harrison's 22E
• Plasma exchange used as a bridge until eculizumab is initiated
• Genetic/complement workup guides duration of treatment and transplant decisions

Drug-Induced TMA

• Stop the offending drug immediately
• If refractory: trial of C5 inhibitors (eculizumab)
• Plasma exchange is not effective for drug-induced endothelial TMA (unlike iTTP)

A Simple Clinical Flow

Schistocytes + Thrombocytopenia + Hemolysis
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        Calculate PLASMIC Score
        Send ADAMTS13 activity, stool Shiga toxin Cx
              ↓
Score 6-7 OR severe/neurological symptoms?
→ START PLASMA EXCHANGE + STEROIDS + CAPLACIZUMAB NOW
  (do not wait for ADAMTS13 result)
              ↓
ADAMTS13 <5%? → Confirm iTTP, continue treatment
ADAMTS13 normal + prior diarrhea? → STEC-HUS: STOP PEX, supportive care
ADAMTS13 normal + no diarrhea? → Suspect aHUS: complement workup, start eculizumab