Lessening the Punch of Heparin-Induced Thrombocytopenia

Abstract

While bleeding remains the most common serious complication of heparin use, heparin is also a common cause of drug-related thrombocytopenia.1Hirsh J Warkentin TE Shaughnessy SG et al.Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.Chest. 2001; 119: 64S-94SAbstract Full Text Full Text PDF PubMed Scopus (1220) Google Scholar Heparin-induced thrombocytopenia (HIT) occurs either as an acute, transient, and innocuous phenomenon due to nonimmunologic heparin effects (type I HIT), or as a morbid syndrome that usually occurs after a week of heparin therapy and is associated with platelet activation and a high rate of thromboembolism (type II, commonly termed “HIT”).2Singer RL Mannion JD Bauer TL et al.Complications from heparin-induced thrombocytopenia in patients undergoing cardiopulmonary bypass.Chest. 1993; 104: 1436-1440Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Heparin-associated thrombocytopenia and heparin-associated thrombocytopenia with thrombosis are older classifications now folded into the rubric HIT. Thrombocytopenia usually denotes < 100 × 109 platelets per liter. HIT often is described in the context of antiheparin antibodies in patients with > 100 × 109 platelets per liter, if they have a falling platelet count and/or thrombotic events. A decrease in platelets during illness is usually not due to concomitant heparin therapy.3Bonfiglio MF Traeger SM Kier KL et al.Thrombocytopenia in intensive care patients: a comprehensive analysis of risk factors in 314 patients.Ann Pharmacother. 1995; 29: 835-842Crossref PubMed Scopus (74) Google Scholar Sepsis, disseminated intravascular coagulation, bone marrow suppression by drugs or illness, hypersplenism, or platelet consumption from pulmonary embolism, cardiac bypass, and orthopedic surgery can all decrease platelet counts acutely.4Warkentin TE Levine MN Hirsh J et al.Heparin-induced thrombocytopenia in patients treated with low-molecular- weight heparin or unfractionated heparin.N Engl J Med. 1995; 332: 1330-1335Crossref PubMed Scopus (2145) Google Scholar HIT has a relatively low incidence of 1 to 3% in patients treated with unfractionated heparin (UFH). When do we need to suspect HIT? In this issue of CHEST (see page 37), we are provided with a study that increases our diagnostic accuracy of HIT. Lubenow and colleagues undertook a retrospective chart review of HIT onset in relation to the start of heparin therapy. They used a database of 119 surgical and medical patients with HIT who were enrolled in a prospective multicenter clinical trial of lepirudin therapy as an alternative anticoagulant. They defined HIT as thrombocytopenia < 100 × 109 platelets per liter in the presence of circulating antiheparin antibodies, whether thrombosis was present or not. Chiefly, they found that HIT is uncommon in the first 5 days of heparin therapy, unless heparin was administered in the preceding 3 months. HIT occurred similarly whether heparin was administered subcutaneously or IV. Heparin-reexposed patients (n = 46) had HIT develop at an average of 5 days of therapy (many on day 2), while heparin-na i˙˙ve patients (n = 79) had HIT develop at an average of 12 days (only 6% before day 6). Of the heparin-reexposed patients, only those who received heparin in the past 3 months were likely to get HIT before day 5 of heparin. Most HIT cases from heparin reexposure still occurred “late,” after 5 days of heparin. Few HIT cases involved low-molecular-weight heparin (LMWH). Whether this discrepancy was due to limited use of LMWH at the participating centers or due to the lower immunogenicity of LMWH is unclear. However, the preponderance of HIT cases among UFH-treated patients is consistent with two prospective studies of heparin prophylaxis in orthopedic patients,6Leyvraz PF Bachmann F Hoek J et al.Prevention of deep vein thrombosis after hip replacement: randomized comparison between unfractionated heparin and low molecular weight heparin.BMJ. 1991; 303: 543-548Crossref PubMed Scopus (216) Google Scholar which revealed significantly less HIT in the LMWH-treated patients compared to those treated with UFH.4Warkentin TE Levine MN Hirsh J et al.Heparin-induced thrombocytopenia in patients treated with low-molecular- weight heparin or unfractionated heparin.N Engl J Med. 1995; 332: 1330-1335Crossref PubMed Scopus (2145) Google Scholar How can the study of Lubenow and colleagues help us improve our early diagnosis of HIT? HIT antibody test results may take days. Stopping heparin while awaiting assay results may be unnecessary. Using the findings of Lubenow and colleagues, decreasing platelet counts are likely not due to HIT for a heparin-na i˙˙ve patient in the first 5 days of heparin treatment for an acute thrombosis. However, deciding whether a patient is heparin na i˙˙ve may not be simple. Heparin from hemodialysis, IV catheter flushes, and even on heparin-coated central venous catheters7Feinberg BI LaMantia KR Addonizio VP et al.Pulmonary artery catheter-associated thrombocytopenia: effect of heparin coating.Mt Sinai J Med. 1987; 54: 147-149Google Scholar can cause HIT. In heparin-na i˙˙ve patients, platelet monitoring would be of little value before day 5 of heparin, yet should be instituted daily for patients exposed to any heparin in the prior 3 months. If one cannot rule out recent heparin exposure, monitor platelet counts early. The conclusions of this study are consistent with those of another retrospective study8Warkentin TE Kelton JG Temporal aspects of heparin-induced thrombocytopenia.N Engl J Med. 2001; 344: 1286-1292Crossref PubMed Scopus (788) Google Scholar of the temporal aspects of HIT with a different definition of thrombocytopenia (> 50% fall in platelet count). HIT must be considered in all heparin-treated patients with a significant fall (> 30%) in platelet count, even in the absence of thromboembolism or actual thrombocytopenia. While most HIT patients in the lepirudin trial database had < 100 × 109 platelets per liter, thromboembolic events due to HIT in that and other studies clearly can occur with platelet counts in the normal range,5Greinacher A Janssens U Berg G et al.Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia: Heparin-Associated Thrombocytopenia Study (HAT) investigators.Circulation. 1999; 100: 587-593Crossref PubMed Scopus (343) Google Scholar yet all such HIT patients had a significant fall in platelet count. The occurrence of thromboembolism in HIT reflects platelet activation, formation of cross-linked platelet aggregates via platelet Fc receptors, platelet microparticle generation, and thrombin activation9Aster RH Heparin-induced thrombocytopenia and thrombosis.N Engl J Med. 1995; 332: 1374-1376Crossref PubMed Scopus (185) Google Scholar that occur after specific IgG (or IgM) antibodies bind to a complex of platelet factor 4 and heparin on platelet and endothelial surfaces.10Newman PM Chong BH Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation.Blood. 2000; 96: 182-187Crossref PubMed Google Scholar After heparin therapy is stopped, these antibodies remain and trigger thromboembolic complications in many HIT cases. Thus, therapy of HIT is not just stopping heparin treatment. Anticoagulation may not only be needed for the original indication, but for the high risk of thromboembolism due to HIT antibodies. Clinical benefits and platelet recovery were demonstrated in prospective trials5Greinacher A Janssens U Berg G et al.Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia: Heparin-Associated Thrombocytopenia Study (HAT) investigators.Circulation. 1999; 100: 587-593Crossref PubMed Scopus (343) Google Scholar11Hirsh J New anticoagulants.Am Heart J. 2001; 142: S3-S8Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar of alternative anticoagulants in HIT. Based on these studies, consensus guidelines recommend immediate therapy of HIT to limit thrombin generation, either with one of the direct thrombin inhibitors lepirudin5Greinacher A Janssens U Berg G et al.Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia: Heparin-Associated Thrombocytopenia Study (HAT) investigators.Circulation. 1999; 100: 587-593Crossref PubMed Scopus (343) Google Scholar and argatroban, or the factor Xa inhibitor danaparoid, a desulfated heparinoid.11Hirsh J New anticoagulants.Am Heart J. 2001; 142: S3-S8Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Only danaparoid is approved for thromboembolism prevention in patients with previous HIT. LMWH crossreacts with HIT antibodies and should never be used in HIT. All three alternative agents are not reversible, cause bleeding, and have contraindications and pharmacodynamic quirks that mandate involvement of a clinician familiar with their use. The use of warfarin alone during the acute phase of HIT is discouraged, due to reports of thrombosis from warfarin-mediated protein S depletion in the face of ongoing antibody-mediated thrombin generation. Interestingly, HIT antibodies are transient and HIT antibody generation does not involve an anamnestic response. The platelet factor IV heparin enzyme-linked immunosorbent assay remains positive for an average of 3 months, while the heparin-induced platelet activation assay (serotonin release) remains positive after an average of 50 days.8Warkentin TE Kelton JG Temporal aspects of heparin-induced thrombocytopenia.N Engl J Med. 2001; 344: 1286-1292Crossref PubMed Scopus (788) Google Scholar Reflecting this, Lubenow and colleagues found that subjects with prior HIT who were inadvertently reexposed to heparin after 3 months rarely had early HIT develop; their circulating antibodies had cleared. Nonetheless, all HIT patients should have heparin listed as an allergy, and any future heparin therapy can be done only for compelling indications, only when HIT antibodies disappear, and for as briefly as possible. Substitution of alternative anticoagulants may be safer, though their use for cardiac bypass and in renal failure is problematic. Recurrent HIT due to inadvertent readministration of heparin within 3 months of the first HIT event is well documented and preventable. How do we lessen the punch of HIT? Early diagnosis and immediate cessation of heparin therapy are necessary. Urgent administration of an alternative anticoagulant is recommended. We should rarely stop heparin therapy before day 5 in heparin-na i˙˙ve patients, as we have learned that HIT is unlikely in that group. Avoiding heparin use in routine catheter flushes should prevent some HIT. Future prevention may involve more widespread use of LMWH or alternative anticoagulants in place of UFH. The higher cost of these agents and the low incidence of HIT from UFH therapy limits the appeal of such a strategy. For now, HIT is here to stay.