Heparin-induced thrombocytopenia

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Heparin-induced thrombocytopenia (HIT; formerly called type 2 HIT) is an immune-mediated prothrombotic disorder characterized by a sudden drop in platelet count (typically > 50% from baseline) in a patient receiving heparin-containing products. It typically occurs within 5–10 days of heparin initiation, but it can occur earlier in patients with recent prior heparin exposure. The disorder is mediated by platelet-activating autoantibodies and frequently leads to significant thromboembolic complications. Bleeding, on the other hand, is rare. HIT should be suspected in any patient with recent heparin exposure who develops thrombocytopenia, venous or arterial thrombosis, skin necrosis at heparin injection sites, DIC, or an anaphylactoid reaction to heparin. HIT should be differentiated from the more common nonimmune heparin-associated thrombocytopenia (formerly called type 1 HIT), which is a transient and clinically insignificant mild to moderate thrombocytopenia that can be managed with serial monitoring of platelet counts and does not require discontinuation of heparin. Empirical management of HIT should be initiated immediately in any patient with an intermediate or high pretest probability of HIT (i.e., 4Ts score ≥ 4) while confirmatory HIT-specific diagnostic testing is pursued. Management consists of the immediate cessation of heparin therapy and treatment with a nonheparin anticoagulant at least until the resolution of thrombocytopenia (longer if concurrent thrombosis is present). Lifetime avoidance of heparin-containing products is indicated following recovery from HIT.

Heparin-induced thrombocytopenia (HIT; formerly called type 2 HIT) is an antibody-mediated response to heparin leading to thrombocytopenia and an increased risk of thrombosis.

• Isolated heparin-induced thrombocytopenia (isolated HIT): acute HIT in the absence of thrombosis
• Heparin-induced thrombocytopenia with thrombosis (HITT): acute HIT complicated by thrombosis and/or thromboembolism

Unlike other drug-induced immune thrombocytopenias, HIT leads to thrombosis in 25-50% of affected patients.

• Occurs in 0.1–7% of patients receiving heparin products ^[2]
• Incidence varies significantly based on the patient group and exposure type.
  • The incidence is highest (5%) in patients undergoing major surgery who are exposed to heparin.
  • Higher rates (1–3%) are seen in patients receiving unfractionated heparin (UFH).
  • The lowest risk is in medical patients receiving LMWH.

Epidemiological data refers to the US, unless otherwise specified.

• An immune-mediated adverse drug reaction to heparin (see “Pathophysiology”)
• Risk factors for HIT include: ^[2][3][4]
  • Female sex
  • Surgery (involving the use of cardiopulmonary bypass in particular)
  • Major trauma
  • Use of unfractionated heparin
  • Longer duration of heparin exposure (> 5 days)

Heparin treatment, especially with unfractionated heparin (UFH), often causes thrombocytopenia. For this reason, a baseline check and regular monitoring of platelet counts are required.

• Heparin and platelet factor 4 (PF4) form a complex → production of IgG antibodies against the heparin/PF4 complex → IgG antibody-heparin/PF4 immunocomplex binds on platelet surface → platelet activation and aggregation → consumption of platelets (thrombocytopenia) and arterial/venous thrombosis
• Thrombocytopenia also occurs due to phagocytosis of IgG antibody-heparin/PF4 immunocomplex-bound platelets by macrophages in the spleen, liver, and bone marrow.

Overview

• HIT is primarily a prothrombotic disorder, with venous and/or arterial thrombosis developing in 25–50% of affected patients.
• Clinical features of thrombocytopenia are uncommon because HIT rarely causes platelet counts to decrease below 20,000 platelets/mm³. ^[3][5]

HIT more commonly manifests with symptoms of thrombosis than with bleeding or other clinical features of thrombocytopenia.

Thrombotic manifestations

• Venous thrombosis occurs most frequently; manifestations include:
  • Acute chest pain and dyspnea from PE
  • Calf swelling and pain from lower extremity DVT
• Arterial thrombosis occurs less commonly; manifestations include:
  • Abdominal pain from acute mesenteric ischemia
  • New-onset neurological deficits from stroke
  • Chest pain from myocardial infarction
  • Limb pain and pallor from acute limb ischemia

Other manifestations

• Localized skin necrosis at heparin injection sites (seen in 10–20% of cases) ^[3]
• Clinical features of DIC (seen in up to 20% of cases) ^[3]
• Bleeding at unusual sites (e.g., adrenal hemorrhage, cerebral bleed) ^[6][7]
• Anaphylactoid reactions from IV heparin

Overview ^[2]

• Suspect HIT in all individuals with current or recent heparin exposure who develop thrombocytopenia and/or thrombosis.
• Obtain routine laboratory studies (e.g., CBC, peripheral blood smear).
  • Mild or nonsustained thrombocytopenia
    • Consider alternative diagnoses of HIT. (e.g., nonimmune heparin-associated thrombocytopenia).
    • Continue heparin and monitor CBC.
  • Significant or sustained thrombocytopenia: Calculate the 4Ts score to determine the pretest probability (PTP) of HIT.
• Further management depends on the PTP of HIT.

Intermediate or high PTP for HIT (4Ts score ≥ 4 points) ^[2]

• Immediate steps
  • Stop all heparin exposure.
  • Initiate empirical management of HIT.
  • Obtain PF4 heparin immunoassay (HIT-specific diagnostic test).
    • Positive immunoassay: HIT is likely; consider functional platelet activation assay (if available).
    • Negative immunoassay: HIT is unlikely.
• HIT confirmed
  • Screen for associated thrombosis (see “Imaging” in “Diagnostics”).
  • Continue treatment for HIT.
• HIT ruled out/unlikely
  • Consider alternative diagnoses.
  • Monitor CBC/PLT count and recalculate 4Ts score as needed.
  • Consider resuming heparin, if indicated.
  • Stop nonheparin anticoagulant (if initiated empirically).

Low PTP for HIT (4Ts score ≤ 3 points) ^[2]

• Evaluate for other causes of thrombocytopenia.
• HIT-specific diagnostic tests are not recommended (unless the score is inaccurate).
• Continue heparin.
• Monitor clinical features and CBC/PLT count at frequent intervals.
• Recalculate 4Ts score if PLT drops and/or clinical features of HIT develop.

Initial diagnostics

• CBC: PLT < 50% of the baseline count at heparin initiation
  • Timing of PLT decline: usually within 5–7 days of heparin initiation ; can occur rapidly (within 1–3 days) ^[3][5][8]
  • Typical PLT nadir: 40,000–80,000 mm^{3 [5]}
• Coagulation studies: ↑ PTT, ↑ INR, and ↓ fibrinogen may be seen in DIC or massive thrombosis.
• Tests to rule out differential diagnoses
  • Peripheral blood smear: to exclude pseudothrombocytopenia and other findings consistent with an alternative diagnosis
  • Renal function tests: may be abnormal in other causes of thrombocytopenia (e.g., HUS and TTP)
  • Liver chemistries: may be abnormal in other causes of thrombocytopenia (e.g., chronic alcohol abuse, cirrhosis, HELLP syndrome)

A rapidly falling platelet count in a patient with recent heparin exposure should raise concern for HIT, even if the platelet count is still within the normal range.

HIT rarely causes platelet counts to decrease below 20,000 platelets/mm³. ^[5]

Determination of the pretest probability of HIT

Calculate the 4Ts score in any patient with current or recent heparin exposure who develops significant thrombocytopenia and/or thrombosis. ^[2][5]

Do not wait for diagnostic confirmation; start empirical treatment of HIT immediately in patients with an intermediate or high 4Ts score!

Confirmatory diagnostic studies (HIT-specific diagnostic tests) ^[2][3][5]

Confirmatory testing is indicated in patients with an intermediate or high PTP of HIT and is a two-stage process. ^[2]

Step one: Order PF4 heparin immunoassay (e.g., ELISA).

• Goal: to detect antibodies against heparin/PF4 complexes
• Findings and further management
  • Negative: HIT is unlikely (see “HIT ruled out/unlikely” in the “Management” section).
  • Positive: HIT is possible; proceed to step two.
• Important consideration: In patients with a high PTP of HIT and a strongly positive heparin immunoassay , the diagnosis of HIT may be established without further testing. ^[2]

Step two: Order functional platelet activation assay (e.g., serotonin release assay).

• Goal: to identify clinically significant anti-heparin/PF4 antibodies (i.e., those that cause platelet activation)
• Findings and further management
  • Negative: HIT is unlikely (see “Hit ruled out/unlikely” in the “Management” section).
  • Positive: HIT is confirmed.
• Important consideration
  • As false-negatives may occur, a diagnosis of HIT may still be considered in patients with a high PTP of HIT and a strongly positive heparin immunoassay. ^[2]
  • Results may take days ; continue empirical treatment of HIT while awaiting results.

Imaging

Screening for asymptomatic deep vein thrombosis (DVT) ^[2]

• Indication: confirmed or strongly suspected HIT
• Modalities
  • All patients: bilateral lower extremity venous compression ultrasonography
  • Patients with central venous catheters: upper extremity venous compression ultrasonography on side with catheter

Additional imaging based on clinical suspicion ^[5]

• Indications: suspected thrombosis or hemorrhage due to HIT
• Examples
  • Abdominal imaging : in patients with acute abdominal pain or hypotension
  • CT pulmonary angiography (CTPA) to rule out pulmonary embolism in patients with acute chest pain, dyspnea, and/or hypoxia
  • MRI or CT head to rule out cerebral venous thrombosis or stroke in patients with new onset headache, seizure, and/or neurological deficit

Initiate empirical management of HIT in all patients with intermediate or high PTP for HIT, without waiting for diagnostic confirmation (see “Management” section above for initial steps). The key features of management include immediate discontinuation of heparin and preventing and treating complications such as thrombosis.

Empirical management of HIT ^[2][10]

• Stop all heparin exposure immediately (including heparin flushes and heparin-coated catheters).
• Patients on vitamin K antagonists (e.g., warfarin): Stop the medication and consider reversal with vitamin K.
• Consult hematology.
• Screen for associated thrombosis (see “Imaging” in “Diagnostics”).
• Initiate nonheparin anticoagulation; the choice of anticoagulant depends on the severity of illness and/or the presence of thrombosis.
• Consider platelet transfusion only for significant bleeding or patients at high risk of bleeding (e.g., during invasive procedures).

Nonheparin anticoagulation ^[2][5]

General principles

• Choice of anticoagulant
  • Initiate fondaparinux or oral anticoagulation in clinically stable patients.
  • Initiate parenteral anticoagulation before transitioning to oral therapy in the following instances:
    • Critically ill patients
    • Increased risk of bleeding
    • Life- or limb-threatening thrombosis (e.g., venous limb gangrene, massive pulmonary embolus)
    • Need for an urgent invasive procedure
• Dosing: A therapeutic dose should be used to counteract the large amounts of thrombin generated during HIT in all patients.
• Duration of nonheparin anticoagulation: The duration of therapy depends on the presence or absence of thrombosis.
  • HITT: ≥ 3 months ^[2]
  • Isolated HIT
    • Patients with platelet recovery (platelets ≥ 150,000/mm³): maximum duration of 3 months
    • Patients with persistent thrombocytopenia due to HIT: Continue nonheparin anticoagulation until platelet recovery (optimal duration unknown).

A significantly increased risk of bleeding is the main side effect of all anticoagulants.

Parenteral therapy ^[2]

• Intravenous direct thrombin inhibitors
  • Preferred in critical illness and in patients with increased risk of bleeding or potential need for urgent procedure
  • Options: argatroban or bivalirudin
• Subcutaneous synthetic heparin: fondaparinux

Oral therapy ^[2][11]

• First line: DOACs
  • Can be started immediately in clinically stable patients
  • In unstable patients, DOACs may be started as soon as the patient is stable (platelet count recovery not required), with no need for overlap with parenteral anticoagulation.
  • Options: rivaroxaban , apixaban , or dabigatran ^[2]
• Second line: warfarin
  • Should not be used in the acute management of HIT
  • Transition to warfarin only once platelet count has recovered (usually to ≥ 150,000/mm³).
  • Overlap warfarin therapy with ongoing anticoagulants for at least 5 days and until the target INR (typically 2–3) is reached. ^[10]

Ongoing management

• Lifetime avoidance of heparin-containing products
  • Ensure patient awareness and medical record documentation.
  • Use nonheparin anticoagulants for VTE treatment/prophylaxis in all patients with a prior history of HIT. ^[2]
• Patients who were on VKA before HIT: Restart VKA once the platelet count has recovered.

• Calculate the 4Ts score in all heparin-exposed patients who develop new-onset thrombocytopenia and/or thrombosis.
• A score ≥ 4 indicates that HIT is likely. Initiate the following urgently.
• Immediately discontinue all heparin products.
• Discontinue vitamin K antagonists and consider reversal with vitamin K.
• Initiate a nonheparin anticoagulant.
• Obtain HIT-specific diagnostic tests.
• Obtain venous compression sonography to screen for asymptomatic DVT in the lower extremities and in any upper extremity with a central venous catheter.
• Consider a hematology consult.

• Nonimmune heparin-associated thrombocytopenia (formerly called type 1 HIT)
  • A transient and clinically insignificant mild to moderate thrombocytopenia, usually occurring within 5 days of heparin initiation
  • Caused by a direct effect of heparin on platelet activation
  • Not associated with an increased risk of thrombosis
• See also “Differential diagnosis of platelet disorders.”

The differential diagnoses listed here are not exhaustive.