American Society of Hematology

Ask the Hematologist: January-February 2012

Kenneth A. Bauer, MD

Published on: January 25, 2012

Professor of Medicine, Harvard Medical School, Boston, MA

Dr. Bauer has served as a consultant to GSK, Bayer Healthcare, and Johnson & Johnson.

Editor’s Note: This question was submitted through the Consult-a-Colleague program. Dr. Bauer was asked to respond.

The Question

How do you manage a patient with heparin-induced thrombocytopenia (HIT) being treated with argatroban who has persistent thrombocytopenia? The patient is a 45-year-old man with laboratory evidence of HIT (positive serotonin release assay) without thrombosis who has been treated with argatroban for 10 days. The platelet count was 52,000 per microliter at the time of diagnosis and increased to 95,000 per microliter during the first five days of therapy. However, over the past five days, no significant increase in the platelet count has been observed.

  • Is there a platelet threshold at which you recommend starting warfarin? If so, what evidence supports that determination? Would your recommendation change if the patient had HIT with thrombosis (HITT)?
  • If the recommended platelet threshold is not reached, is there a point at which you feel it is safe to start treatment with warfarin? For example, in this patient who has been on argatroban for 10 days, is it acceptable to start warfarin even though his platelet count is less than 100,000 per microliter? Would your recommendation change if the patient had HIT with thrombosis?
  • Does fondaparinux play a role in management of HIT in this setting?
  • Is there a role for the new oral anticoagulants (dabigatran and rivaroxaban) in this setting?

My Response

HIT is a clinical-pathological syndrome that is typically characterized by the onset of thrombocytopenia (≥50% fall from baseline) within five to 10 days of drug initiation. The mean platelet count in patients with this disorder is 60,000 per microliter. Thrombosis occurs in approximately 50 percent of patients and clusters in the first few days following onset of thrombocytopenia (termed HITT). It is mediated by antibodies against platelet factor 4 (PF4)-heparin complexes that activate platelets leading to excessive thrombin generation. Prompt recognition and appropriate treatment of HIT is required to reduce the risk of serious thrombotic events and complications including limb loss. Paradoxically, a major problem with HIT today is its over-diagnosis. Enzyme immunoassays (EIAs) for antibodies against PF4-heparin complexes are currently widely applied for making the diagnosis of HIT; while highly sensitive (>99%), only some antibodies have strong platelet-activating properties in the serotonin-release assay, one of the “gold standard” platelet-activation assays used for diagnostic confirmation. As results of serotonin release assays are rarely available for clinical decision making early in the course of HIT, it is best not to order ELISA tests in patients with low pretest probability scores for HIT (4T score: Thrombocytopenia, Timing of platelet count fall, Thrombosis, oTher causes of thrombocytopenia).1 Also, many labs do not report the optical densities (OD) of positive EIAs; in such instances, it is useful to request this information, as it can be useful diagnostically since the strength of a positive EIA (OD) predicts for a positive SRA.2

After stopping heparin administration in patients with HIT, the median time to achieving a platelet count of >150,000 per microliter is about four days. However, in patients with more severe HIT, the platelet count can take longer (up to two weeks or more) to recover. It is important to keep in mind, however, that patients with HIT often have concurrent medical problems or are on other medications contributing to thrombocytopenia. The recommendation in the 8th Edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines is as follows3: “For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K-antagonist (VKA) therapy until after the platelet count has substantially recovered (i.e., usually to at least 150 × 109/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low, maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) rather than with higher initial doses (Grade 1B); and that the non-heparin anticoagulant (e.g., lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the INR has reached the intended target, and after a minimum overlap of at least five days between non-heparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B).”

Despite a platelet count that has only risen to 95,000 per microliter, I would transition this patient with HIT without thrombosis (termed isolated HIT) off a parenteral direct thrombin inhibitor (i.e., argatroban) after 10 days of therapy. Management options for this patient include: 1) initiation of warfarin carefully under the cover of continued IV argatroban; 2) initiation of fondaparinux alone at therapeutic doses (provided the patient’s creatinine clearance is greater than 30 mL/min) in lieu of argatroban; or 3) initiation of an oral direct thrombin or factor Xa inhibitor (either dabigatran etexilate or rivaroxaban) at therapeutic doses.

The initiation of warfarin causes a rapid decline in protein C levels and a slower decline in the levels of longer-lived vitamin K-procoagulant factors (especially prothrombin) augmenting the preexistent hypercoagulable state due to HIT. This mechanism is contributory to the development of venous limb gangrene, which is estimated to occur in 12 percent of patients with HITT4; its frequency is likely less in patients with isolated HIT. Fondaparinux, a synthetic pentasaccharide that selectively inhibits factor Xa after binding to antithrombin, has an attractive profile for the treatment of HIT based on in vitro studies; it is administered subcutaneously once daily. Small case series indicate generally favorable outcomes with initial use of this agent in HIT; in a recent retrospective series of 16 patients with the diagnosis confirmed by serotonin-release assay, nine of whom had thrombosis, none developed new or recurrent thrombosis.5 However, fondaparinux is not approved for this indication; it is approved in the United States for the prophylaxis of VTE following major orthopedic and general surgery and the initial treatment of VTE.

If the continuation of argatroban is the only reason for continued hospitalization, I would employ fondaparinux alone at this juncture provided the patient could self-inject the medication and drug acquisition was not a problem (i.e., inability to gain insurance approval or prohibitive out-of-pocket cost). The total duration of anticoagulant treatment has not been defined by prospective studies, but I would treat isolated HIT for a minimum of six weeks given the high risk of thrombosis within the first 30 days after diagnosis. The use of fondaparinux to complete treatment would obviate the use of warfarin entirely and the burden of INR monitoring with attendant dose adjustments. Alternatively, warfarin could be initiated after the platelet count had risen to more than 150,000 per microliter under the cover of fondaparinux overlap for a minimum of five days until the INR reached the target range of 2-3. This would also circumvent complexities relating to INR monitoring during argatroban therapy if this option were chosen.3 For patients with HITT, I would treat with anticoagulation for three to six months.

It should be pointed out that the efficacy of non-heparin anticoagulants for HIT and their approval by the U.S. FDA was not based on prospective, randomized controlled clinical trials. Vitamin K antagonists have been used for the treatment of HIT for many years and adopted by evidence-based guidelines after initial treatment with a non-heparin anticoagulant, as they have up until recently been the only class of oral anticoagulants available. Based on our mechanistic understanding of venous-induced limb gangrene in HIT, a strong case can be made that we should be moving away from using warfarin in the initial phase of HITT (and HIT) treatment (up until 30 days after diagnosis) given that alternative oral anticoagulants that do not lower protein C levels are available.6 These oral agents selectively target thrombin or factor Xa, have a rapid onset of action, and do not require coagulation monitoring; however, there is not yet any reported experience with these agents in this patient population, and they have no specific antidote. Dabigatran and rivaroxaban have gained FDA approval for stroke prevention in atrial fibrillation7, 8 and rivaroxaban is approved for the prophylaxis of VTE following total hip or knee replacement9; they have shown promising result for the treatment of symptomatic VTE but have not yet been approved for this indication in the United States. Thus, caution should be exercised if either dabigatran or rivaroxaban is used in a patient such as this; if chosen, they should be used at therapeutic doses and limited to adult patients with satisfactory renal function (creatinine clearance > 30 mL/min). Furthermore, given that HIT can result in serious complications including limb loss and subsequent litigation against health-care providers, hematologists choosing to use any of the new anticoagulants (dabigatran, rivaroxaban, or fondaparinux) should carefully document in the medical record their rationale for choosing the new agent.

Both the infrequent occurrence of HIT confirmed by validated platelet-activation assays and the clinical heterogeneity of affected patients make it difficult to perform trials of new agents in HIT. It is therefore unlikely that the new oral anticoagulants will be studied in controlled trials so as to gain FDA approval for management of this disorder in the near future. Hopefully, the reporting of well-characterized cohorts of patients with HIT (or HITT) treated with these agents will lead to favorable outcomes that will improve, as well as simplify, management of this disorder.

  1. Lo GK, Juhl D, Warkentin TE , et al. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-765.
  2. Warkentin TE, Sheppard JI, Moore JC, et al. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6:1304-1312.
  3. Warkentin TE, Greinacher A, Koster A, et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:340S-380S
  4. Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Int Med. 1997;127:804-812.
  5. Warkentin TE, Pai M, Sheppard JI, et al. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost. 2011;9:2389-2396.
  6. Krauel K, Hackbarth C, Fürll B, et al. Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies. Blood. 2011. Epub ahead of print.
  7. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Eng J Med. 2009;361:1139-1151.
  8. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.
  9. Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011;105:444-453.
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