HIT

**Definition:** Heparin-induced thrombocytopenia (HIT, Type II) is a prothrombotic, antibody-mediated drug reaction. Do not confuse with Type I HIT (non-immune), a mild, early (days 1–4) benign platelet drop from direct heparin-induced platelet clumping that resolves spontaneously without stopping heparin.

**Pathophysiology (Type II, hypersensitivity type II reaction):** 1. Heparin binds platelet factor 4 (PF4, released from platelet α-granules), forming PF4–heparin complexes. 2. This exposes neoepitopes, and the body produces IgG antibodies against the complex. 3. IgG–PF4–heparin immune complexes bind platelet FcγIIa receptors, causing platelet activation and aggregation, release of procoagulant microparticles, and thrombin generation. 4. Result: platelet consumption (thrombocytopenia) plus a hypercoagulable state (thrombosis).

**Timing:** - Typical onset 5–10 days after heparin start. - Rapid onset (<24 hours) if there was prior exposure in the last ~30–100 days (preformed antibodies). - Delayed-onset HIT can occur after heparin is stopped.

**Risk factors:** - Unfractionated heparin (UFH) carries a higher risk than LMWH. - Surgical patients (especially cardiac and orthopedic) carry a higher risk than medical patients.

**Clinical features:** - Platelet count falls >50% from baseline (usually nadir 20–60K; rarely <10K, and spontaneous bleeding is uncommon despite thrombocytopenia). - Thrombosis: DVT/PE (most common), arterial thrombosis (limb ischemia, stroke, MI), cerebral venous sinus thrombosis, adrenal hemorrhagic infarction. - Skin necrosis at heparin injection sites. - Acute systemic reaction after an IV heparin bolus. - Warfarin-induced venous limb gangrene if warfarin is started during acute HIT (protein C depletion).

**Diagnosis:** - Pretest probability by the **4Ts score**: Thrombocytopenia, Timing, Thrombosis, oTher causes of thrombocytopenia (absence of). - Low 4Ts score effectively rules out HIT (high NPV). - Intermediate/high score: immunoassay (PF4–heparin ELISA; high sensitivity, lower specificity), then confirm with functional assay (serotonin release assay, SRA, the gold standard).

**Management:** 1. Stop ALL heparin: UFH, LMWH, heparin flushes, heparin-coated catheters. 2. Start a non-heparin anticoagulant even without thrombosis, since the thrombotic risk is high: - Direct thrombin inhibitors: argatroban (hepatic clearance; use in renal failure), bivalirudin. - Fondaparinux (indirect factor Xa inhibitor); DOACs (e.g., rivaroxaban, apixaban) are also used in stable patients. 3. Avoid platelet transfusions (may fuel thrombosis). 4. Avoid warfarin until platelets recover (>150K) and the patient is therapeutically anticoagulated with a non-heparin agent (overlap ≥5 days). If already on warfarin, give vitamin K.

**High-yield boards points:** - Paradoxical thrombosis with low platelets. - Platelets fall 5–10 days after heparin start. - Mechanism: IgG against PF4–heparin complex. - Treat with argatroban or bivalirudin (argatroban if renal impairment, bivalirudin if hepatic impairment). - Heparin's anticoagulant effect is via antithrombin activation (↑ inhibition of thrombin and factor Xa); monitor UFH with aPTT, LMWH with anti-Xa. - The reversal agent for heparin is protamine sulfate, which is not useful for HIT itself. - Differential: DIC, TTP/HUS (do not give platelets in TTP; 4Ts helps differentiate), ITP, sepsis, drug-induced thrombocytopenia. - In the Step 1 context, "HIT" is a classic type II hypersensitivity reaction.

**Other meaning (for context):** HIT can also refer to "high-intensity training" or "HIV-associated…" in other contexts, but on USMLE it almost always means heparin-induced thrombocytopenia.