Heparin-induced thrombocytopenia

Background

• Pathologic activation / consumption of platelets due to antibodies against heparin-platelet complex
• Can be caused by unfractionated heparin or LMWH (10 times more common in unfractionated)
• Occurs in 0.5-5% of patients treated with heparin
• Thrombosis occurs in 35-75% of patients ; 20-30% die within 1 month
• HYPER-coagulable, despite low platelet count
  • activated platelets bound in clot, thus low platelet count
  • bleeding is unusual

Type 1 HIT

• Onset within 48h of initiating heparin
• Drop in platelet count due to platelet activation by heparin
• Platelet count usually normalizes in a few days with continued heparin treatment

Type 2 HIT

• Immune-mediated process
• Onset typically 5-10 days after exposure to heparin
• Complicated by thrombosis

Clinical Features

Gangrenous right hand and left foot in a patient with antibody-confirmed HIT.

Ischaemic changes in the right hand (A), right foot (B), and left food (C) from HIT.

Lower extremity gangrene secondary to both arterial and venous thrombosis.

• The 4 T's: (formal scoring system below)
  • Thrombocytopenia
  • Timing (5-14d)
  • Thrombosis
  • No oTher cause

Immediate Symptoms

• Flushing
• Tachycardia
• Hypotension
• Dyspnea

Delayed Symptoms

• >50% decrease in platelet count (median nadir is ~60K; rarely <20K)
• DVT or PE
• Cerebral vein or adrenal vein thrombosis
• Limb arterial occlusion
• CVA
• MI
• Skin necrosis

Differential Diagnosis

Thrombocytopenia

Decreased production

• Marrow infiltration (tumor or infection)
• Viral infections (rubella, HIV)
• Marrow suppression (commonly chemotherapy or radiation)
• Congenital thrombocytopenia
  • Fanconi anemia
  • Alport syndrome
  • Bernand Soulier
• Vitamin B12 and/or folate deficiency

Increased platelet destruction or use

• Idiopathic thrombocytopenic purpura
• Thrombotic Thrombocytopenic Purpura (TTP)
• Hemolytic Uremic Syndrome (HUS)
• Disseminated Intravascular Coagulation (DIC)
• Viral infections (HIV, mumps, varicella, EBV)
• Drugs (heparin, protamine)
• Postransfusion or Posttransplantation
• Autoimmune destruction (SLE or Sarcoidosis)
• Mechanical destruction
  • Artificial valves
  • ECMO
• HELLP syndrome
• Excessive hemorrhage
• Hemodialysis, extracorporeal circulation
• Splenic Sequestration
  • Occurs in Sickle cell disease and Cirrhosis

Drug Induced

• sulfa antibiotics, ETOH, ASA, thiazide diuretics/furosemide

Comparison by Etiology

	ITP	TTP	HUS	HIT	DIC
↓ PLT	Yes	Yes	Yes	Yes	Yes
↑PT/INR	No	No	No	+/-	Yes
MAHA	No	Yes	Yes	No	Yes
↓ Fibrinogen	No	No	No	No	Yes
Ok to give PLT	Yes	No	No	No	Yes

Microangiopathic Hemolytic Anemia (MAHA)

• Disseminated Intravascular Coagulation (DIC)
• Thrombotic Thrombocytopenic Purpura (TTP)
• Hemolytic Uremic Syndrome (HUS)
• HELLP syndrome
• Heparin-Induced Thrombocytopenia (HIT)
• Hereditary spherocytosis
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Malignant hypertension
• Scleroderma
• Antiphospholipid Syndrome (APS)
• Other medical causes: malignancy, renal allograft rejection, vasculitides like polyarteritis nodosa and Wegener's granulomatosis
• Drugs: chemotherapy; Clopidogrel (Plavix) associated with TTP
• Nonvascular causes: prosthetic valve (more common with mechanical, more common at aortic valve), LVAD, TIPS, coil embolization, patched AV shunt, AVM

Evaluation

• Serotonin release assay (SRA) = gold standard
• Anti-PF4 plus SRA has combined sensitivity of 99%
• Positivity determined by optical density (OD) reported with assay (same concept as a titer)
  • OD <1 = <5% chance of HIT
  • OD 1.4 = 50% chance of HIT
  • OD >2 = 90% chance of HIT

Pre-test Probability Scoring (The 4 T Score)

• Thrombocytopenia
  • 2 points: platelets > 50% fall AND nadir > 20k
  • 1 points: patient 30-50% fall OR nadir 10-19k
• Timing
  • 2 points: clear onset 5-10 days OR platelet fall < 1 day with prior heparin exposure within 30 days
  • 1 point: likely onset 5-10 days OR fall < 1 day with prior heparin exposure 30-100 days
• Thrombosis
  • 2 points: new thrombosis or skin necrosis at injection sites
  • 1 point: suspected thrombosis or progressive/recurrent thrombosis
• Likelihood of other causes
  • 2 points: none apparent
  • 1 point: possible
• Scoring
  • ≤3 is low risk and do not require further testing or heparin discontinuation
  • ≥4 should have serologic testing performed, heparin discontinued, and alternative anticoagulation started

Management

• Discontinue all heparin products
• Do not give platelets (may precipitate thrombosis)
• Start anticoagulation with no heparin based compound such as a direct thrombin inhibitor: [lepirudin (unless renal failure), argatroban (unless hepatobiliary disease), bivalirudin] or direct Xa inhibitor (fondaparinux, danaparoid)
  • 4T Score ≥4 with/without thrombosis and average bleeding risk should receive therapeutic dose
  • 4T Score ≥4 with/without thrombosis and high bleeding risk should receive prophylactic dose
• Avoid warfarin until platelets >100K-150K
  • Those already on warfarin should receive vitamin K to restore protein C & S levels

Disposition

• Admit (with hematology consult)

Calculators

4Ts Score for HIT

4Ts Score for Heparin-Induced Thrombocytopenia

Criteria	0 Points	1 Point	2 Points
Thrombocytopenia	1 <30% fall or nadir <10	30–50% fall or nadir 10–19	>50% fall and nadir ≥20
Timing of platelet fall	1 <4 days without recent heparin	Consistent but unclear; or fall after day 10	5–10 days; or ≤1 day if recent heparin
Thrombosis or other sequelae	1 None	Progressive/recurrent or suspected	Confirmed new thrombosis or skin necrosis
Other causes for thrombocytopenia	1 Definite other cause present	Possible other cause	No other cause apparent
4Ts Score	/ 8

Interpretation — Pretest Probability for HIT

0–3	Low probability (~5% risk of HIT). HIT antibody testing usually not needed.
4–5	Intermediate probability (~14% risk). Send HIT antibody; consider alternative anticoagulation.
6–8	High probability (~64% risk). Start alternative anticoagulant; send confirmatory testing.

References

Lo GK, et al. Evaluation of pretest clinical score (4 Ts) for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost. 2006;4(4):759-765. PMID 16634744.

See Also

• Unfractionated heparin
• Low molecular weight heparin
• Coagulopathy (main)
• Hirudins