Microangiopathic Hemolytic Anemia (TTP/HUS/DIC)

Summary

Microangiopathic hemolytic anemia (MAHA) is a type of normocytic hemolytic anemia in which red blood cells are mechanically destroyed as they pass through small vessels blocked by platelet or fibrin thrombi. The result is the appearance of schistocytes (fragmented RBCs) on the peripheral smear.

Three classic causes share this same final pathway but differ in trigger and labs:

• TTP – ADAMTS13 deficiency → large vWF multimers → platelet microthrombi.
• HUS – Shiga toxin (E. coli O157:H7) → endothelial injury, mostly in kidneys.
• DIC – Systemic activation of coagulation → consumption of platelets + clotting factors → bleeding and clotting at the same time.

All three present with anemia + thrombocytopenia + schistocytes. The key to telling them apart is the clinical context and the coagulation panel (PT/PTT/fibrinogen): normal in TTP/HUS, deranged in DIC.

Definition

MAHA = intravascular hemolysis caused by mechanical shearing of RBCs as they pass through abnormal microvasculature (fibrin strands, platelet-rich thrombi, or damaged endothelium).

It is part of a larger group called thrombotic microangiopathies (TMAs), which all share:

• Hemolytic anemia with schistocytes
• Thrombocytopenia (platelets are consumed in microthrombi)
• End-organ ischemia (kidneys, brain, GI, etc.)

The main TMAs tested are TTP, HUS, and DIC. Less commonly: HELLP syndrome, malignant hypertension, scleroderma renal crisis, and mechanical heart valve hemolysis.

Pathophysiology of MAHA

The shared mechanism is simple — picture small vessels filled with sticky thrombi or fibrin strands. RBCs squeezing through get cut into fragments (schistocytes / helmet cells).

Two parallel consequences:

1. Intravascular hemolysis → ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, hemoglobinuria.
2. Platelet consumption in the thrombi → thrombocytopenia → petechiae, purpura, mucosal bleeding.

The trigger for the thrombi is what differs between conditions:

• TTP → uncleaved ultra-large vWF multimers (ADAMTS13 deficiency).
• HUS → Shiga toxin damages renal endothelium.
• DIC → systemic tissue factor release activates the whole clotting cascade.

Inline reference: see the classic peripheral smear with schistocytes — this finding alone tells you a TMA is happening; the rest of the workup tells you which one.

Thrombotic Thrombocytopenic Purpura (TTP)

Definition: A life-threatening TMA caused by deficiency of ADAMTS13, the metalloprotease that normally cleaves ultra-large von Willebrand factor (vWF) multimers.

Etiology

• Acquired (most common, ~95%) – autoantibody against ADAMTS13. Typical patient: adult woman, sometimes triggered by HIV, pregnancy, SLE, ticlopidine/clopidogrel, or quinine.
• Hereditary (Upshaw–Schulman syndrome) – ADAMTS13 gene mutation, presents in childhood.

Pathophysiology (one line)

↓ ADAMTS13 → uncleaved ultra-large vWF multimers stay on the endothelium → platelets stick to them → platelet-rich microthrombi all over the body (brain > kidney).

Clinical features – Classic pentad (FAT RN)

• Fever
• Anemia (MAHA, schistocytes)
• Thrombocytopenia (often <30,000)
• Renal failure (usually mild — unlike HUS)
• Neurologic changes (headache, confusion, seizures, focal deficits)

Important: Coagulation studies (PT, PTT, fibrinogen) are NORMAL — because the cascade isn't activated; only platelets are consumed.

Hemolytic Uremic Syndrome (HUS)

Definition: A TMA dominated by acute kidney injury, classically in a young child after bloody diarrhea.

Etiology

• Typical HUS (D+ HUS, ~90%) – Shiga-toxin-producing E. coli O157:H7 (undercooked beef, unpasteurized milk). Less commonly Shigella dysenteriae.
• Atypical HUS (aHUS) – complement dysregulation (Factor H mutations). No diarrhea prodrome.

Pathophysiology

Shiga toxin enters the blood → binds glycolipid receptors on renal endothelium → endothelial injury → platelet activation → microthrombi mostly in the kidney → MAHA + thrombocytopenia + AKI.

Clinical features – Classic triad

1. Microangiopathic hemolytic anemia (schistocytes)
2. Thrombocytopenia
3. Acute kidney injury (oliguria, ↑ BUN/Cr, hematuria)

Antecedent bloody diarrhea ~5–10 days before, in a child <5 years old.

Neurologic symptoms are uncommon (contrast with TTP). PT/PTT/fibrinogen are NORMAL.

Disseminated Intravascular Coagulation (DIC)

Definition: A secondary syndrome of widespread, uncontrolled activation of the coagulation cascade → simultaneous thrombosis and bleeding. Always look for the underlying cause.

Etiology – "STOP Making New Thrombi"

• Sepsis (especially gram-negative)
• Trauma / burns / heat stroke
• Obstetric – abruptio placentae, amniotic fluid embolism, retained dead fetus, HELLP
• Pancreatitis (acute)
• Malignancy – especially acute promyelocytic leukemia (APL/M3), mucin-secreting adenocarcinomas
• Nephrotic syndrome / snake bites
• Transfusion reactions

Pathophysiology

Massive tissue factor release → systemic activation of thrombin → fibrin deposition throughout microvasculature → RBC shearing (schistocytes) + organ ischemia. At the same time, platelets and clotting factors are consumed faster than they can be made → bleeding from every site (IV lines, gums, GI, GU).

Clinical features

• Sick patient (sepsis, post-trauma, post-delivery)
• Bleeding from multiple sites + evidence of microthrombi (organ failure, purpura fulminans, digital ischemia)
• Oozing from venipuncture sites is a classic clue

Labs – the deranged ones

• ↓ Platelets
• ↑ PT and PTT (factors consumed)
• ↓ Fibrinogen (consumed)
• ↑↑ D-dimer / fibrin split products (fibrinolysis)
• Schistocytes on smear

This abnormal coagulation panel is what distinguishes DIC from TTP and HUS.

Comparison TTP vs HUS vs DIC

The fastest way to separate the three: look at the coagulation panel.

• Normal PT/PTT/fibrinogen → TTP or HUS (decide by patient profile — adult with neuro vs child with diarrhea/AKI).
• Abnormal PT/PTT, low fibrinogen, high D-dimer → DIC.

Quick comparison reference: HUS vs TTP vs ITP differential · Lab findings across major coagulopathies.

Diagnosis

Step 1 – Recognize MAHA

• CBC: normocytic anemia + thrombocytopenia
• Peripheral smear: schistocytes (helmet cells, triangular fragments) — see fragmented RBCs on smear
• Hemolysis labs: ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, ↑ reticulocytes
• Coombs test: NEGATIVE (this is mechanical hemolysis, not autoimmune)

Step 2 – Identify which TMA

• Coagulation panel (PT, PTT, fibrinogen, D-dimer):
  • Normal → TTP or HUS
  • ↑ PT/PTT, ↓ fibrinogen, ↑↑ D-dimer → DIC
• Renal function (BUN/Cr, urinalysis): severely abnormal → favor HUS
• Clinical context:
  • Child + bloody diarrhea + AKI → HUS
  • Adult + neurologic signs ± fever → TTP
  • Sepsis / OB emergency / cancer + bleeding from everywhere → DIC

Step 3 – Confirmatory tests

• TTP: ADAMTS13 activity < 10% confirms. Do NOT wait for results — start treatment on clinical suspicion. PLASMIC score can stratify pre-test probability.
• HUS: stool culture / Shiga toxin PCR for E. coli O157:H7.
• DIC: ISTH DIC score (platelets, fibrinogen, D-dimer, PT prolongation).

Management

TTP – Medical emergency

• Plasma exchange (plasmapheresis) — first-line, urgent. Removes autoantibody, replaces ADAMTS13. Mortality without it ~90%; with it <20%.
• Glucocorticoids (in acquired/autoimmune TTP)
• Caplacizumab (anti-vWF nanobody) — newer adjunct
• Rituximab — for refractory or relapsing disease
• AVOID platelet transfusion unless life-threatening bleeding (worsens microthrombi)

HUS – Mostly supportive

• Fluid and electrolyte management
• RBC transfusion if severe anemia
• Dialysis for severe AKI
• Avoid antibiotics & antimotility agents in Shiga-toxin HUS
• Atypical HUS: eculizumab (anti-C5 complement inhibitor)

DIC – Treat the underlying cause

• #1 priority: treat the trigger (sepsis → antibiotics; OB cause → deliver/evacuate; APL → ATRA)
• Supportive blood products for bleeding patients:
  • FFP — replaces clotting factors
  • Cryoprecipitate — for fibrinogen < 100 mg/dL
  • Platelets — if < 20,000 or bleeding
  • RBCs — as needed
• Heparin — controversial; used in chronic DIC of malignancy or predominantly thrombotic DIC

Complications

• TTP – stroke, seizures, myocardial ischemia, death if untreated. Relapse in ~30–50% of acquired cases.
• HUS – chronic kidney disease, hypertension, end-stage renal failure; rarely colonic necrosis, pancreatitis, CNS involvement.
• DIC – multi-organ failure (ARDS, AKI, hepatic failure), purpura fulminans, digital gangrene, life-threatening hemorrhage.

Mnemonics