Thrombocytopenia ITP, TTP, HUS, HIT

Summary

Thrombocytopenia means a platelet count below 150,000/mm³. Clinically significant bleeding (mucocutaneous bleeding, petechiae, purpura) usually appears when platelets drop below 50,000/mm³, and spontaneous severe bleeding when below 10,000–20,000/mm³.

This lesson focuses on the four most exam-tested causes:

• ITP – Immune Thrombocytopenic Purpura: autoantibodies destroy platelets. Isolated low platelets, otherwise normal labs.
• TTP – Thrombotic Thrombocytopenic Purpura: ADAMTS13 deficiency → large vWF multimers → microthrombi. Pentad: fever, neuro symptoms, renal failure, MAHA, thrombocytopenia.
• HUS – Hemolytic Uremic Syndrome: Shiga toxin from E. coli O157:H7. Triad: MAHA, thrombocytopenia, acute kidney injury. Usually in children after bloody diarrhea.
• HIT – Heparin-Induced Thrombocytopenia: IgG antibodies against heparin-PF4 complex. Paradoxical thrombosis, not bleeding, 5–10 days after heparin exposure.

The single most important question to ask is: "Is this isolated thrombocytopenia, or is there also hemolysis (schistocytes on smear)?" Isolated → think ITP. With schistocytes → think TTP/HUS/DIC.

Approach to Thrombocytopenia

When you see a low platelet count, work through three quick questions:

1. Is it real? Rule out pseudothrombocytopenia (EDTA-induced platelet clumping). Repeat in a citrate tube.
2. Are other cell lines affected?
   • Isolated low platelets → ITP, drug-induced, HIT.
   • Low platelets + anemia + schistocytes → TTP, HUS, DIC (microangiopathic hemolytic anemia, MAHA).
   • Pancytopenia → bone marrow problem (aplastic anemia, leukemia, B12 deficiency).
3. Are coagulation tests normal or abnormal?
   • Normal PT/PTT/fibrinogen → ITP, TTP, HUS, HIT.
   • Prolonged PT/PTT + low fibrinogen → DIC (consumptive coagulopathy).

Clinical signs of platelet deficiency are mucocutaneous: petechiae, purpura, epistaxis, gum bleeding, menorrhagia, and easy bruising.

Immune Thrombocytopenic Purpura (ITP)

Definition: Acquired autoimmune disorder in which IgG autoantibodies against platelet surface glycoproteins (GpIIb/IIIa) cause splenic destruction of platelets.

Epidemiology & triggers

• Children: acute, self-limited; follows a viral infection (URI, EBV, varicella) by 1–4 weeks.
• Adults: chronic; women > men. May be associated with SLE, HIV, HCV, CLL, or H. pylori.

Clinical features

• Sudden mucocutaneous bleeding: petechiae, purpura, epistaxis, gingival bleeding, menorrhagia.
• Patient otherwise looks well – no fever, no organomegaly, no neurologic signs.
• Splenomegaly is absent (important – if spleen is enlarged, think of another diagnosis).

Diagnosis (diagnosis of exclusion)

• Isolated thrombocytopenia (often <30,000/mm³); Hb and WBC normal.
• Peripheral smear: large platelets (young platelets released to compensate); no schistocytes.
• Normal PT, PTT, fibrinogen.
• Bone marrow (not routinely needed): increased megakaryocytes.

Management

• Platelets >30,000/mm³ & no bleeding → observe (especially children).
• Symptomatic / platelets <30,000 → corticosteroids (prednisone) first line.
• Severe bleeding or need rapid rise → IVIG or anti-D immunoglobulin (Rh+ only).
• Refractory / chronic adult ITP → splenectomy, rituximab, or TPO-receptor agonists (romiplostim, eltrombopag).
• Platelet transfusion only for life-threatening bleeding (transfused platelets are destroyed quickly).

Thrombotic Thrombocytopenic Purpura (TTP)

Definition: Life-threatening thrombotic microangiopathy caused by deficiency of ADAMTS13, the enzyme that cleaves ultra-large von Willebrand factor (vWF) multimers.

Pathophysiology

• Normally ADAMTS13 cuts large vWF multimers into smaller, functional pieces.
• In TTP: ADAMTS13 deficient (autoantibody in adults – acquired; or genetic – Upshaw-Schulman syndrome) → uncleaved ultra-large vWF multimers accumulate.
• These multimers bind platelets → platelet-rich microthrombi in small vessels → consumption of platelets + shearing of RBCs as they pass through (MAHA).

Clinical features

• Adult woman, often 30–50 years old. Triggers: pregnancy, HIV, drugs (clopidogrel, quinine, cyclosporine).
• Neurologic symptoms predominate (vs HUS, which is renal): confusion, headache, focal deficits, seizures.
• Fever, jaundice, fatigue.

Diagnosis

• Severe thrombocytopenia + MAHA: schistocytes on smear, ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, ↑ reticulocytes, negative Coombs.
• Normal PT, PTT, fibrinogen → distinguishes from DIC.
• Confirmatory: ADAMTS13 activity <10%.
• 

Management

• Urgent plasma exchange (plasmapheresis) – replaces ADAMTS13 and removes autoantibodies. Start immediately on clinical suspicion.
• Add corticosteroids ± rituximab for acquired TTP.
• Caplacizumab (anti-vWF) in refractory cases.
• Avoid platelet transfusion – adds fuel to the fire (more microthrombi). Only used for life-threatening bleeding.

Hemolytic Uremic Syndrome (HUS)

Definition: Thrombotic microangiopathy presenting with the classic triad: microangiopathic hemolytic anemia + thrombocytopenia + acute kidney injury.

Etiology

• Typical (90%) – Shiga toxin-producing E. coli O157:H7 (STEC-HUS), especially after eating undercooked ground beef or unpasteurized milk. Shigella dysenteriae is another cause.
• Atypical – complement dysregulation (factor H mutation). No diarrhea.

Pathophysiology

• Shiga toxin binds Gb3 receptors on renal endothelium → endothelial injury → platelet activation and microthrombi → mechanical hemolysis (schistocytes) + AKI.
• ADAMTS13 is normal in HUS (unlike TTP).

Clinical features

• Typically a child <5 years with bloody diarrhea 5–10 days earlier.
• Pallor, oliguria, hematuria, edema, hypertension.
• Neurologic symptoms are less prominent than TTP (renal > neuro).

Diagnosis

• CBC: anemia + thrombocytopenia; schistocytes on smear.
• Hemolysis labs: ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, negative Coombs.
• ↑ BUN, ↑ creatinine; urinalysis: hematuria, proteinuria.
• Stool culture / Shiga toxin PCR positive.
• Normal PT, PTT, fibrinogen.

Management

• Supportive care is the cornerstone: IV fluids, electrolyte correction, dialysis if needed, RBC transfusion for severe anemia.
• Avoid antibiotics in STEC-HUS – they may increase toxin release and worsen outcome.
• Avoid anti-motility agents (loperamide).
• Atypical HUS → eculizumab (anti-C5 monoclonal antibody).
• Plasma exchange is not first line for typical HUS (unlike TTP).

Heparin-Induced Thrombocytopenia (HIT)

Definition: Immune-mediated, drug-induced thrombocytopenia caused by IgG antibodies against the heparin–platelet factor 4 (PF4) complex. The platelets are activated, not just destroyed, which is why HIT causes thrombosis rather than bleeding.

Two types

• Type I – non-immune, mild (platelets >100,000), within 1–2 days, resolves spontaneously. No clinical significance.
• Type II – immune-mediated, the dangerous form. This is what "HIT" usually refers to.

Pathophysiology (Type II)

1. Heparin binds platelet factor 4 (PF4), forming heparin–PF4 complex.
2. IgG antibodies form against this complex.
3. Immune complex binds platelet FcγRIIa receptors → massive platelet activation and aggregation.
4. Result: platelet consumption (thrombocytopenia) + thrombin generation (paradoxical thrombosis).

Clinical features

• Platelet drop >50% from baseline (often nadir 30,000–70,000) 5–10 days after starting heparin.
• Rapid drop within 24 hours possible if patient had heparin exposure in last 100 days.
• Thrombosis (in ~50%): DVT, PE, arterial limb ischemia, stroke, MI, skin necrosis at injection sites.
• More common with unfractionated heparin than with LMWH (enoxaparin).

Diagnosis

• Use the 4T score first (pretest probability):
  • Thrombocytopenia magnitude
  • Timing of platelet fall
  • Thrombosis or other sequelae
  • OTher causes excluded
• Score 4–8 → test for anti-PF4 antibodies (ELISA, sensitive screen).
• Serotonin release assay (SRA) – gold standard confirmatory test.

Management

• Stop ALL heparin immediately (including flushes and LMWH).
• Start a non-heparin anticoagulant:
  • Direct thrombin inhibitors: argatroban (preferred in renal failure), bivalirudin.
  • Fondaparinux or DOACs as alternatives.
• Do NOT give warfarin alone early (causes skin necrosis and worsens thrombosis); bridge with a parenteral non-heparin agent first until platelets >150,000.
• Do NOT transfuse platelets (adds fuel to thrombosis).

Side-by-Side Comparison

Use this table as your single most important review for thrombocytopenia questions. Most exam stems can be solved by matching the patient profile + smear finding to one column.

You may also reference the library tables for HUS vs TTP vs ITP differential and the 4T score for HIT.

Mnemonics

Key Points for Exams