How do I treat heparin-induced thrombocytopenia?

1.

Abrams, Charles S. (2024). In Goldman-Cecil Medicine (pp. 1170). DOI: 10.1016/B978-0-323-93038-3.00158-1

If the patient has thrombocytopenia but no thrombosis, anticoagulation is usually given for 4 to 6 weeks. Because patients rarely become profoundly thrombocytopenic as a result of HIT alone, platelet transfusions are typically not required and may actually precipitate thrombotic complications.If low-molecular-weight heparin is used for prophylaxis instead of unfractionated heparin, the risk of HIT is much lower. However, low-molecular-weight heparins should never be used in the treatment of HIT because this drug can cross-react with the pathologic HIT antibodies.

If a patient is suspected of having HIT, all heparin should be stopped immediately. This includes subcutaneous injections of “minidose” heparin, heparin flushes of intravenous lines, and low-molecular-weight heparin; even heparin-coated intravenous catheters should be withdrawn. Alternative anticoagulation, such as the direct thrombin inhibitor argatroban, should be used (Chapter 70). Although not as well studied (nor FDA approved), both bivalirudin and fondaparinux appear to be viable alternatives. Accumulating evidence also suggests that the direct-acting oral anticoagulants (Table 70-6) can be used in patients with HIT,using doses similar to what are used for the treatment of an acute venous thromboembolism but with a higher dose administered at the beginning of therapy (e.g., rivaroxaban 15 mg twice daily with food for 21 days then 20 mg with food once per day). Warfarin should not be used initially in cases of acute HIT because of its delayed therapeutic effect and its association with venous limb gangrene. However, when the platelet count has returned to a normal level as the acute episode of HIT starts to resolve, warfarin can be slowly introduced at a dose of 5 mg or less daily while an alternative anticoagulant such as argatroban is still being used. The warfarin dose can be gradually increased to achieve an international normalized ratio (INR) of 2 to 3. If the patient has had an acute thrombosis attributable to their HIT, they should be treated for a minimum of 3 months of anticoagulation. If the patient has thrombocytopenia but no thrombosis, anticoagulation is usually given for 4 to 6 weeks.

2.

Elsevier ClinicalKey Derived Clinical Overview

• For patients with a moderate or high pretest probability from 4Ts, discontinue all heparin exposure. Even if the patient does not have a clinically evident thrombosis, there is a significant risk of developing an incident clot within the subsequent 30 days. Thus, the patient must be started on an alternative anticoagulant. • Two agents, both direct thrombin inhibitors, are approved for this indication (Table E4): 1.000000000000000e+00 Argatroban (preferred agent in renal failure and in hemodialysis patients; avoid in liver dysfunction). 2.000000000000000e+00 Bivalirudin (approved only for patients with HIT or at risk of HIT who are undergoing PCI; dose adjustment is required in renal failure). • Note: Lepirudin is no longer available. Outside of the U.S., the factor Xa inhibitor danaparoid may be used. • Platelet transfusion in the absence of life-threatening hemorrhage or extreme thrombocytopenia should be avoided. Risk of bleeding is low, and platelet transfusions in HIT can increase risk of arterial thrombosis. • In patients with critical illness, high risk of bleeding, need for urgent procedures, or HIT that is complicated by life- or limb-threatening venous thromboembolism (VTE), argatroban and bivalirudin are recommended due to their shorter duration of action. • For relatively stable patients with average risk of bleeding, direct oral anticoagulants (DOACs) and fondaparinux may be considered. • Warfarin should not be initiated until after platelet counts recover to >150 × 109/L because there is increased risk of warfarin-induced skin necrosis and venous limb gangrene. In a patient who is diagnosed with HIT while on warfarin, vitamin K should be administered with concomitant initiation of nonheparin anticoagulant.

TABLE E5Treatment Schedules for Danaparoid and FondaparinuxHIT,Heparin-induced thrombocytopenia;IV,intravenous.From Hoffman R et al:Hematology: basic principles and practice,ed 7, Philadelphia, 2018, Elsevier.AnticoagulantTherapeutic Dosing Protocol for HIT-Associated ThrombosisAnticoagulant MonitoringClearanceHalf-Life (h)CommentDanaparoidInitial bolus, 2250 unitsIV; accelerated infusion (400 units/hr × 4 h, 300 units/hr × 4 h; then 200 units/h IV, subsequently adjusted by antifactor Xa levels)Antifactor Xa levels (target, 0.5-0.8 units/ml)Renal (minor)25Widely approved for HIT treatment (although not in the U.S.); not available in the U.S.; low risk for in vivo cross-reactivity; prophylactic-dose therapymay be appropriate when clinical suspicion for HIT is low.Fondaparinux7.5 mgsubcutaneous once dailyAnti–Xa factor levels (target levels not well established)Renal (major)17Not approved for HIT treatment (although increasingly used as off-label therapy). Prophylactic-dose therapymay be appropriate when clinical suspicion for HIT is low, or if there is renal insufficiency.aTherapeutic dosing is usually appropriate for strongly suspected or confirmed HIT (including “isolated” HIT, i.e., HIT without apparent thrombosis), or when thrombosis is documented.bAdjust IV danaparoid bolus for body weight: <60 kg, 1500 units; 60-75 kg, 2250 units; 75-90 kg, 3000 units; >90 kg, 3750 units.cProphylactic-dose regimen, 750 units subcutaneous every 8 h (for renal failure, reduce to 750 units every 12 h).

3.

Weitz, Jeffrey I. (2022). In Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine (pp. 1766). DOI: 10.1016/B978-0-323-72219-3.00095-5

This test involves quantification of serotonin release after exposure of washed platelets loaded with labeled serotonin to patient serum in the absence or presence of various concentrations of heparin. If the patient's serum contains HIT antibody, the addition of heparin induces platelet activation and subsequent serotonin release. To manage HIT, heparin therapy should be stopped in patients with suspected or documented HIT, and an alternative anticoagulant should be administered to prevent or treat thrombosis (Table 95.6).The agents most often used for this indication are parenteral direct thrombin inhibitors, such as argatroban or bivalirudin, or factor Xa inhibitors, such as fondaparinux, rivaroxaban or apixaban. Patients with HIT, particularly those with associated thrombosis, often have evidence of increased thrombin generation, which can lead to consumption of protein C. If these patients receive warfarin without a concomitant parenteral anticoagulant, the further decrease in protein C levels induced by the vitamin K antagonist can trigger skin necrosis. To avoid this problem, patients with HIT require treatment with a direct thrombin inhibitor, fondaparinux, rivaroxaban, or apixaban until the platelet count returns to normal levels. At this point, low-dose warfarin therapy can be introduced, and the thrombin inhibitor or fondaparinux can be discontinued when the anticoagulant response to warfarin has been therapeutic for at least 2 days.

4.

Goldhaber, Samuel Z., Piazza, Gregory (2022). In Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine (pp. 1635). DOI: 10.1016/B978-0-323-72219-3.00087-6

When HIT is diagnosed, UFH or LMWH should be discontinued immediately, and patients should not receive platelet transfusions. Heparin “flushes” of intravenous lines should also be discontinued. For HIT with thrombosis, a parenteral direct thrombin inhibitor such as argatroban or bivalirudin should be used.

5.

Food and Drug Administration (DailyMed).

Publish date: January 1, 2022.

Warnings And Cautions Once HIT or HITT is diagnosed or strongly suspected, discontinue all heparin sources (including heparin flushes) and use an alternative anticoagulant. Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin, or platelet activation induced by heparin. Obtain platelet counts at baseline and periodically during heparin administration. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin in heparin–naive individuals and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin initiation), especially in patients with a recent exposure to heparin (i.e., previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT. Monitor any degree of thrombocytopenia closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Evaluate patients presenting with thrombocytopenia or thrombosis after discontinuation of HEPARIN SODIUM IN SODIUM CHLORIDE (heparin sodium) for HIT or HITT. 5.3 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy.

6.

Food and Drug Administration (DailyMed).

Publish date: March 2, 2024.

Warnings And Cautions HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition known as HITT. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Once HIT or HITT is diagnosed or strongly suspected, discontinue all heparin sources (including heparin flushes) and use an alternative anticoagulant. Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin, or platelet activation induced by heparin. Obtain platelet counts at baseline and periodically during heparin administration. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin in heparin-naïve individuals and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin initiation), especially in patients with a recent exposure to heparin (i.e., previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT. Monitor thrombocytopenia of any degree closely. If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy.

7.

Food and Drug Administration (DailyMed).

Publish date: July 2, 2019.

Clinical Studies AT-BAT Trial (NCT# 00043940) This was a single-arm open-label study in which 51 patients with heparin-induced thrombocytopenia (HIT) or heparin induced thrombocytopenia and thrombosis syndrome (HITTS) underwent PCI. The majority of patients achieved adequate ACT at the time of device activation and no major bleeding was reported. Evidence for the diagnosis of HIT/HITTS was based on a clinical history of a decrease of platelets in patients after heparin administration [new diagnosis or history of clinically suspected or objectively documented HIT/HITTS defined as either: 1) HIT: positive heparin-induced platelet aggregation (HIPA) or other functional assay where the platelet count has decreased to <100,000/mL (minimum 30% from prior to heparin), or has decreased to <150,000/mL (minimum 40% from prior to heparin), or has decreased as above within hours of receiving heparin in a patient with a recent, previous exposure to heparin; 2) HITTS: thrombocytopenia as above plus arterial or venous thrombosis diagnosed by physician examination/laboratory and/or appropriate imaging studies]. Patients ranged in age from 48 to 89 years (median 70); weight ranged from 42 to 123 kg (median 76); 50% were male and 50% were female. Bivalirudin for injection was administered as either 1 mg/kg bolus followed by 2.5 mg/kg/h (high dose in 28 patients) or 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion (lower dose in 25 patients) for up to 4 hours. Ninety-eight percent of patients received aspirin, 86% received clopidogrel and 19% received GPIs. The median ACT values at the time of device activation were 379 sec (high dose) and 317 sec (lower dose). Following the procedure, 48 of the 51 patients (94%) had TIMI grade 3 flow and stenosis <50%.