Thrombocytopenia ITP, TTP, HUS, HIT

Summary

Overview & Initial Approach to Thrombocytopenia

Thrombocytopenia = platelet count <150,000/mm³. Bleeding risk is threshold-driven:

• <50,000/mm³ → bleeding with trauma/surgery; petechiae, purpura, easy bruising.
• <20,000/mm³ → risk of spontaneous bleeding.
• <10,000/mm³ → risk of spontaneous severe / intracranial bleeding.

Signs are mucocutaneous (vs the deep joint/muscle bleeds of coagulation-factor disorders): petechiae, purpura, epistaxis, gum bleeding, menorrhagia, and easy bruising.

Initial approach — three questions

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

This lesson covers the four most exam-tested causes — ITP (isolated, immune destruction), TTP and HUS (thrombotic microangiopathies with MAHA), and HIT (drug-induced, paradoxically pro-thrombotic). For the broader differential, refer to the common causes of thrombocytopenia by mechanism for the bone-marrow vs splenic vs peripheral-destruction breakdown.

Isolated Thrombocytopenia: Immune Thrombocytopenic Purpura (ITP)

Definition: Acquired autoimmune disorder in which IgG autoantibodies against platelet surface glycoproteins (GpIIb/IIIa) opsonize platelets for destruction by splenic macrophages.

Pathophysiology

• Antibody-coated platelets are cleared in the spleen → isolated thrombocytopenia.
• Marrow compensates → increased megakaryocytes and release of large/young platelets (megathrombocytes) into the blood.

Presentation — child vs adult

• Children: acute, self-limited; follows a viral infection (URI, EBV, varicella) by 1–4 weeks. Resolves in most within weeks.
• Adults: chronic; women > men. May be associated with SLE, HIV, HCV, CLL, or H. pylori — screen for these.
• Sudden mucocutaneous bleeding; patient otherwise looks well — no fever, no organomegaly, no neurologic signs.

Diagnosis (diagnosis of exclusion)

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

The clinical features of immune thrombocytopenia (ITP) lays out the antecedent viral trigger, the isolated-thrombocytopenia lab pattern, and the bleeding-severity-based treatment thresholds.

Tiered management

• Platelets >30,000/mm³ & no bleeding → observe (especially children).
• Platelets <30,000 or bleeding → corticosteroids (prednisone) first-line.
• Severe bleeding / 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 Microangiopathies: TTP & HUS

TTP and HUS are thrombotic microangiopathies — platelet-rich microthrombi in small vessels consume platelets and shear passing RBCs, producing MAHA (schistocytes, ↑LDH, ↑indirect bilirubin, ↓haptoglobin, negative Coombs). Key shared rule: PT/PTT/fibrinogen are normal — this separates them from DIC. The discriminator is the question "neuro or renal predominant?"

Schistocytes (helmet cells, triangular fragments) are the hallmark smear finding for both TTP and HUS.

TTP — ADAMTS13 deficiency (neuro-predominant)

• Mechanism: deficiency of ADAMTS13 (autoantibody = acquired; or genetic = Upshaw-Schulman) → uncleaved ultra-large vWF multimers → platelet-rich microthrombi.
• Patient: adult woman 30–50 y. Triggers: pregnancy, HIV, drugs (clopidogrel, quinine, cyclosporine).
• Clinical: neurologic signs predominate — confusion, headache, focal deficits, seizures; plus fever, jaundice, fatigue.
• Diagnosis: severe thrombocytopenia + MAHA; confirmatory ADAMTS13 activity <10%. Normal PT/PTT/fibrinogen.
• Management: urgent plasma exchange (plasmapheresis) — start immediately on clinical suspicion (replaces ADAMTS13, removes autoantibody). Add corticosteroids ± rituximab; caplacizumab (anti-vWF) in refractory cases. Avoid platelet transfusion.

The TTP pathophysiology, clinical features, and management summary lays out the ADAMTS13 mechanism and the plasma-exchange protocol.

HUS — Shiga toxin (renal-predominant)

• Mechanism: Typical (90%) = Shiga toxin-producing E. coli O157:H7 (also Shigella) binds Gb3 receptors on renal endothelium → injury → microthrombi. ADAMTS13 is normal. Atypical = complement dysregulation (factor H mutation), no diarrhea.
• Patient: child <5 y with bloody diarrhea 5–10 days earlier (undercooked beef, unpasteurized milk).
• Clinical: the classic triad = MAHA + thrombocytopenia + acute kidney injury (oliguria, hematuria, hypertension, edema). Neuro signs less prominent than TTP.
• Diagnosis: schistocytes + hemolysis labs; ↑BUN/creatinine; stool Shiga-toxin PCR. Normal PT/PTT/fibrinogen.
• Management: supportive (IV fluids, electrolytes, dialysis if needed, RBC transfusion). Avoid antibiotics and anti-motility agents in STEC-HUS (increase toxin release). Atypical HUS → eculizumab. Plasma exchange is not first-line for typical HUS.

The HUS etiology and clinical-features summary details the Shiga-toxin mechanism and the MAHA + thrombocytopenia + AKI triad.

Drug-Induced Thrombocytopenia: Heparin-Induced Thrombocytopenia (HIT)

Definition: Immune-mediated, drug-induced thrombocytopenia from IgG antibodies against the heparin–platelet factor 4 (PF4) complex. Platelets are activated, not merely destroyed — so HIT causes thrombosis, not bleeding.

Type I vs Type II

• 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" refers to.

Pathophysiology — the paradoxical clot (Type II)

The sequence:

1. Heparin binds PF4 → heparin–PF4 complex.
2. IgG antibodies form against the 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 (nadir often 30,000–70,000) 5–10 days after starting heparin (rapid <24 h if heparin exposure within 100 days).
• Thrombosis (~50%): DVT, PE, arterial limb ischemia, stroke, MI, skin necrosis at injection sites.
• More common with unfractionated heparin than LMWH.

Diagnosis

• Start with the 4T score (pretest probability): Thrombocytopenia magnitude, Timing of platelet fall, Thrombosis/sequelae, oTher causes excluded.
• Score 4–8 (intermediate/high) → test for anti-PF4 antibodies by ELISA (sensitive screen).
• Serotonin release assay (SRA) — gold-standard confirmatory test (high specificity).

Use the 4T score for pretest probability of HIT for the point values across the four criteria, and the clinical features of type 2 HIT for the diagnostic and treatment pathway.

Urgent management

1. Step 1: Stop ALL heparin immediately — including flushes and LMWH.
2. Step 2: Start a non-heparin anticoagulant: argatroban (direct thrombin inhibitor, continuous IV 2 µg/kg/min, titrate to aPTT 1.5–3× baseline; preferred in renal failure), bivalirudin, or fondaparinux (7.5 mg SC daily; 5 mg if <50 kg, 10 mg if >100 kg).
3. Step 3: Once platelets recover to >150,000, overlap and transition to warfarin. Never give warfarin alone early.

Master Comparison & Management Principles

This is the single most important review for thrombocytopenia questions — most stems are solved by matching the patient profile + smear finding to one column.

Absolute management rules

• Never transfuse platelets in TTP, HUS, or HIT (except life-threatening bleeding) — it fuels microthrombosis. In ITP, transfuse only for life-threatening bleeding (platelets destroyed rapidly).
• TTP → start plasma exchange immediately on suspicion — do not wait for ADAMTS13 results.
• STEC-HUS → supportive only; no antibiotics, no anti-motility agents (increase Shiga-toxin release). Atypical HUS → eculizumab.
• HIT → stop all heparin (including flushes/LMWH), start argatroban or fondaparinux; never warfarin alone (skin necrosis).
• DIC distinction → prolonged PT/PTT + low fibrinogen = DIC, not TTP/HUS (which have normal coagulation studies). See the laboratory characteristics of coagulopathies for the platelet/PT/PTT/fibrinogen/smear pattern across vWD, ITP, TTP-HUS, and DIC.
• Pseudothrombocytopenia → recheck in a citrate tube before any workup.

For a focused side-by-side of the three microvascular/immune destruction causes, the HUS vs TTP vs ITP differential compares prodrome, fever, neurologic changes, MAHA, AKI, and ADAMTS13 activity.