DESCRIPTION ã…¡ There are two types of heparin-induced thrombocytopenia (HIT)...
- Type 1: Isolated HIT develops early in heparin therapy and is benign. No resultant bleeding or thrombotic complications. HIT type 1 NOT mediated by the immune system (passive heparin binding to platelets resulting in a modest shortening of the platelet life span). The platelet count rarely falls below 100 × 109/L.
- Type 2: Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is associated with severe thrombocytopenia and paradoxically thrombotic episodes instead of hemorrhagic complications. Occurs in patients receiving heparin for more than 5 days; may occur within 1 day if prior heparin therapy exposure < 100 days.
Frequency varies widely depending on type of heparin used and the patient group: (1) Unfractionated heparin is associated with a higher frequency of HIT than fractionated heparin. (2) Surgical patients have a higher frequency of HIT than either medical or obstetric patients with the same heparin exposure. (3) Postoperative orthopedic patients receiving unfractionated heparin have the highest HIT frequency (<5%) and require more intense platelet count monitoring. (4) Pregnant women receiving LMWH have an almost negligible risk.
PATHOPHYSIOLOGY
Heparin exposure can induce the formation of pathogenic IgG antibodies that can cause platelet activation by recognizing complexes of platelet factor 4 (PF4) and heparin on platelet surfaces. Platelet activation results in further release of PF4 and the appearance of platelet microparticles in circulation, both of which magnify the procoagulant state of HIT. PF4 complex binding to endothelial cells stimulates thrombin release. There is an increased clearance of platelets with resultant thrombocytopenia and venous and/or arterial thrombus formation with the potential for severe organ damage (loss of limbs, stroke, MI) and unusual sites of thrombosis (adrenal, portal vein, skin). Potential for severe organ damage (loss of limbs, stroke, MI) and unusual sites of thrombosis (adrenal, portal vein, skin). See, figure (1). Pathophysiology of HIT.
In rare cases, targets other than PF4 are involved (NAP-2, IL8). The risk of heparin-induced thrombosis is far lower than the incidence of antibody formation. Fewer than 10% of those who develop an antibody to the heparin–PF4 complex will exhibit a thrombotic event. PF4 antibodies usually decline to undetectable levels within a few weeks or months of an episode of HIT, and there is no anamnestic response.
DIAGNOSIS
LABORATORY INVESTIGATIONS — Testing should be performed when HIT is clinically suspected. HIT antibodies are detected using either PF4-dependent antigen immunoassays (PF4–heparin antibody ELISA) or functional assays (serotonin release assay) of platelet activation and aggregation. Both tests are very sensitive but specificity is poor. Clinically insignificant HIT antibodies are common in patients who have received heparin 5–100 days earlier. In the ICU setting, HIT is uncommon, whereas thrombocytopenia from other causes is very common.
CLINICAL DIAGNOSIS — The diagnosis of HIT should be based on clinical abnormalities (thrombocytopenia with or without thrombosis) and a positive test for HIT antibodies.
- HITTS has an incidence of < 1% of patients receiving heparin. Platelet counts as low as 20 × 109/L can result in arterial and venous thrombosis, with an incidence of morbidity and mortality of 20% of the patients who develop HITTS.
- About 25% of HIT patients receiving a heparin bolus develop signs or symptoms — fever, chills, respiratory distress, or hypertension. Transient global amnesia and cardiorespiratory arrest have also been reported. About 5–15% of HIT patients develop decompensated DIC.
- Thrombocytopenia does not usually develop until days 5–10 of heparin treatment and reaches a median nadir of 55 × 109/L. The platelet counts falls below 150 × 109/L in 90% of HIT cases.
- Hemorrhage and platelet counts below 10 × 109/L suggest an alternative cause such as posttransfusion purpura.
- Patients who have received heparin within the last 100 days may have a fall in platelet counts within 1 day of heparin reexposure.
MANAGEMENT
| Table (1). Doses of common used anticoagulants | |||
|---|---|---|---|
| Anticoagulant | Dosing (therapeutic range) | Pharmacokinetics (t1/2) | Comment |
| Danaparoid sodium (Orgaran) |
Bolus (adjust for body weight):
Infusion: 400 U/h × 4 h, then 300 U/h × 4 h, and then 200 U/h, with monitoring by anti–factor Xa levels (0.5–0.8 anti-Xa U/mL) |
Renal metabolism 25 h anti–factor Xa activity 2–4 h anti–factor IIa activity |
Approved for use in countries outside of the United States Withdrawn from the US market because of potential for in vivo cross-reactivity (rare, not predictable by in vitro testing) |
| Anticoagulant monitoring not always necessary; preferred for very small or large patients, renal failure patients, and those with life- or limb-threatening thrombosis | |||
| Lepirudin (Refludan) |
Bolus: 0.4 mg/kg Infusion: 0.15 mg/kg/h (target aPTT range 1.5–2.5 times baseline) In the absence of life-threatening thrombosis or when treating isolated HIT, may be prudent to omit the initial bolus and to aim for aPTT of 1.5–2 times baseline |
Renal excretion: 80 min |
Approved by FDA for the treatment of HIT-related thrombosis t1/2 rises considerably in renal failure patients High rate of antihirudin antibodies (40–60%) that are not usually significant Anaphylaxis reported after lepirudin especially with a repeat treatment course |
| Argatroban (Novastan) | 2 μg/kg/min without an initial bolus (target aPTT range 1.5–3 times baseline) | Hepatobiliary excretion 40–50 min |
FDA approved for prevention and treatment of HIT-related thrombosis (identical therapeutic dose regimens used for both indications) Argatroban increases the INR, so a higher therapeutic range is reported during overlapping of argatroban and warfarin |
Stop heparin immediately. See, (figure (2). Treatment of HITTS), and do not readminister in patients who develop thrombocytopenia to 100 × 109/L or if the original platelet counts falls by 50%. Platelet counts should return to normal within 4–6 days. As HIT is associated with thrombosis, an alternative anticoagulant should be initiated, initially with a parenteral agent, and then with warfarin:
- Direct thrombin inhibitors, lepirudin and argatroban and the heparinoid danaparoid (not approved in the United States) may be used. HIT patients can cross-react to danaparoid sodium (10% in vitro, less common in vivo). DTI administration should be continued until the platelet count has recovered to 100 × 109/L (at which point treatment with warfarin may be initiated) and until INR of 2–3 achieved with warfarin.
- Bivalirudin and fondaparinux are investigational agents for the treatment of HIT: Fondaparinux is a pentasaccharide that potentiates antithrombin and has anti-Xa activity. Despite being a synthetic heparin derivative, it does not generate HIT antibodies and has been used safely in those with suspected or confirmed HIT.
- No antidote: bleeding that may occur with these treatments may not be easily corrected. Direct thrombin inhibitors have short plasma half-lives, so their effects resolve relatively quickly.
- There is a 5–20% frequency of new thrombosis despite treatment of HIT patients with an alternative anticoagulant.
Prophylactic platelet transfusions are relatively contraindicated. Oral anticoagulants should only be used while direct thrombin inhibitors are administered as well. Patients with HIT, particularly those with associated thrombosis, often have evidence of increased thrombin generation that can lead to consumption of protein C. If these patients are given warfarin without a concomitant parenteral anticoagulant to inhibit thrombin or thrombin generation, the further decrease in protein C levels induced by the vitamin K antagonist can worsen thrombosis and trigger skin necrosis. Warfarin should be continued for at least 30 days, due to a persistent risk of thrombosis even after the platelet count has recovered. In patients in whom thrombosis has been documented, anticoagulation with warfarin should continue for at least 3 months
| Table (2). Investigational Agents for the Treatment of HIT | |||
|---|---|---|---|
| Bivalirudin (Angiomax) | 0.15–0.2 mg/kg/h without an initial bolus (target aPTT range 1.5–2.5 times baseline) | Enzymatic > renal 25 min if normal renal function 57 min if severe renal insufficiency |
Approved in the United States for anticoagulation during PCI (non-HIT) Short t1/2 and enzymatic metabolism are theoretical advantages over lepirudin for cardiac surgery in patients with HIT (current investigation) |
| Fondaparinux (Arixtra) | Uncertain | Renal 17–20 h | Approved for DVT prophylaxis after orthopedic surgery Theoretically, lack of in vitro cross-reactivity with HIT antibodies suggests that it may be efficacious in patients with HIT (not yet studied for this indication) |
REFERENCES
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Otis, S.A. and Zehnder, J.L. (2010). Heparin-induced thrombocytopenia: Current status and diagnostic challenges. American Journal of Hematology, 85(9), pp.700–706. Available at: https://pubmed.ncbi.nlm.nih.gov/20665476
Shantsila, E., Lip, G.Y.H. and Chong, B.H. (2009). Heparin-induced thrombocytopenia. A contemporary clinical approach to diagnosis and management. Chest, [online] 135(6), pp.1651–1664. Available at: https://pubmed.ncbi.nlm.nih.gov/19497901
Hassell, K. (2005). The Management of Patients With Heparin-Induced Thrombocytopenia Who Require Anticoagulant Therapy. Chest, 127(2), pp.1S-8S. Available at: https://pubmed.ncbi.nlm.nih.gov/15706025