Heparin-Induced Thrombocytopenia
2004; Lippincott Williams & Wilkins; Volume: 110; Issue: 18 Linguagem: Inglês
10.1161/01.cir.0000147537.72829.1b
ISSN1524-4539
Autores Tópico(s)Intramuscular injections and effects
ResumoHomeCirculationVol. 110, No. 18Heparin-Induced Thrombocytopenia Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBHeparin-Induced ThrombocytopeniaDiagnosis and Management Theodore E. Warkentin, MD Theodore E. WarkentinTheodore E. Warkentin From the Department of Pathology and Molecular Medicine and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Originally published2 Nov 2004https://doi.org/10.1161/01.CIR.0000147537.72829.1BCirculation. 2004;110:e454–e458Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis.1 It is caused by heparin-dependent, platelet-activating antibodies that recognize a "self" protein, platelet factor 4 (PF4), bound to heparin. The resulting platelet activation is associated with increased thrombin generation (Figure).2 Typically, the platelet count fall begins 5 to 10 days after starting heparin, although a rapid platelet count fall can occur in a patient who has antibodies from recent heparin use.3 Remarkably, transience of HIT antibodies permits safe heparin reexposure in selected patients (for example, heart surgery patients) despite a history of HIT.3,4Download figureDownload PowerPointPathogenesis of HIT. HIT antibodies of IgG class bind to multimolecular complexes of platelet factor 4 (PF4) and heparin on platelet surfaces, resulting in platelet activation when the IgG molecules interact with the platelet Fc receptors. Platelet-derived microparticles are generated, which enhance coagulation reactions. In addition, HIT antibodies can activate endothelium and monocytes, exacerbating the procoagulant response. Activation of platelets and increased production of thrombin could explain the high risk of arterial and venous thrombosis in HIT. Reprinted with permission from Greinacher and Warkentin.2Case SummaryA 61-year-old woman5 with Ray-naud's phenomenon underwent mechanical aortic valve replacement for aortic insufficiency. She developed persistent vasospasm of fingers and toes after surgery that responded to warming measures. Unfractionated heparin (UFH) prophylaxis was given until postoperative day 4, and warfarin (5, 5, and 2.5 mg) was given from days 2 to 4. On day 8, the patient developed ischemic necrosis of multiple fingers and toes. The platelet count had fallen by 44% from 221×109/L (day 4) to 124×109/L (day 8), and the international normalized ratio (INR) rose to 4.3. The diagnosis of delayed-onset HIT complicated by warfarin-induced digital necrosis was supported by strong positive tests for HIT antibodies, including a positive platelet serotonin release assay (100% serotonin release; normal <20%).When Should HIT Be Suspected?Thrombocytopenia is common in hospitalized patients receiving UFH, yet only a minority have HIT. A clinical scoring system may be useful for identifying those with HIT.Pretest Probability of HIT: The "4 T's"Table 1 summarizes a clinical scoring system ("4 T's") for estimating the pretest probability of HIT1 based on its characteristic features (Thrombocytopenia, Timing, Thrombosis) and the absence of oTher explanation(s). Preliminary evaluation suggests that HIT antibodies are unlikely ( 80%) with a high score (≥6). An intermediate score (4 or 5) indicates a clinical profile compatible with HIT but with another plausible explanation. Laboratory testing for HIT antibodies is especially useful in this last group of patients. TABLE 1. Estimating the Pretest Probability of HIT: The "Four T's"Points (0, 1, or 2 for Each of 4 Categories: Maximum Possible Score = 8)210Pretest probability score: 6–8 indicates high; 4–5, intermediate; and 0–3, low.*First day of immunizing heparin exposure considered day 0.Thrombocytopenia>50% Platelet fall to nadir ≥2030–50% Platelet fall, or nadir 10–19<30% Platelet fall, or nadir Day 10 or timing unclear; or <day 1 with recent heparin (past 31–100 days) 80% serotonin release), which yields good diagnostic specificity. Delays in obtaining test results mean that physicians must make appropriate decisions on the basis of their assessment of the pretest probability of HIT.Treatment of HITThe box summarizes key treatment principles.2 In patients strongly suspected of having HIT, the physician should replace heparin with an appropriate nonheparin anticoagulant. In the United States, two direct thrombin inhibitors (DTIs), lepirudin and argatroban, are approved for treating thrombosis complicating HIT. In some jurisdictions (but not the United States), danaparoid (a mixture of nonheparin anticoagulant glycosaminoglycans with predominant anti-factor Xa activity) is approved and available. Other marketed anticoagulants that have shown favorable results in HIT and may be appropriate "off-label" treatments include bivalirudin and fondaparinux, although experience with these drugs in HIT is limited.4Treatment Principles When HIT Is Strongly Suspected (or Confirmed)Discontinue and avoid all heparin.Give a nonheparin alternative anticoagulant.Postpone warfarin pending substantial platelet count recovery (give vitamin K if warfarin has already been started).Test for HIT antibodies.Investigate for lower-limb deep-vein thrombosis.Avoid prophylactic platelet transfusions.If HIT is strongly suspected, all heparin should be stopped and further heparin avoided. UFH is commonly used to "flush" intravascular catheters, and an order simply to "discontinue heparin" may not necessarily prevent such incidental heparin exposure.Warfarin predisposes to microvascular thrombosis in patients with acute HIT, for example, warfarin-induced venous limb gangrene11 and skin necrosis12 syndromes. Affected patients typically have a supratherapeutic INR (typically >4.0) that corresponds to severe protein C depletion. It is recommended that warfarin not be started until substantial resolution of thrombocytopenia has occurred (preferably, platelet count >150×109/L).4 Reversal of warfarin anticoagulation with vitamin K is advised when HIT is diagnosed only after warfarin has already been started4; besides reducing risk of coumarin necrosis, it minimizes risk of DTI underdosing (because warfarin prolongs the activated partial thromboplastin time [aPTT] used to monitor the DTI).LepirudinLepirudin is a recombinant hirudin (leech anticoagulant) that forms irreversible 1:1 complexes with thrombin. Its half-life (80 minutes) increases dramatically in renal insufficiency. Because no antidote exists, it must be used cautiously or avoided completely in patients with renal compromise. The approved dose is 0.4 mg/kg (IV bolus) followed by an initial infusion rate at 0.15 mg/kg per hour, adjusted for target aPTT 1.5× to 2.5× baseline. However, in the absence of severe thrombosis, and to reduce the risk of bleeding, some experts advise omitting the initial bolus, using a lower target aPTT range (1.5× to 2.0× baseline), and monitoring the aPTT every 4 hours until steady state is achieved.Compared with historical controls, lepirudin was associated with reduced thrombotic events (relative risk reduction, 0.63 to 0.78).4,13 Lepirudin also is effective for patients with isolated HIT when a lower-dose protocol is used (0.10 mg/kg per hour adjusted by aPTT without initial bolus).14Because lepirudin is a foreign protein, its use frequently triggers anti-hirudin antibodies that occasionally lead to drug accumulation, presumably from impaired renal clearance of lepirudin–immunoglobulin G (IgG) complexes. Fatal anaphylaxis after intravenous bolus administration has been reported in patients who received lepirudin within the previous few months.15ArgatrobanArgatroban is approved to treat both HIT complicated by thrombosis and isolated HIT. It is a small-molecule DTI that, unlike lepirudin, is not immunogenic. The usual dose is 2 μg/kg per minute adjusted by aPTT (usual target, 1.5× to 3× baseline aPTT). Compared with historical controls, argatroban was associated with reduced thrombotic events (relative risk reduction, 0.44 to 0.62).4,16 The starting dose should be reduced by 75% in a patient with significant liver dysfunction because argatroban undergoes hepatobiliary excretion. Prolongation of the INR by argatroban is considerably greater than that observed with lepirudin,17 which complicates argatroban–warfarin overlap; this underscores the importance of postponing warfarin pending substantial resolution of HIT (to avoid warfarin-induced microvascular thrombosis).18Future AnticoagulantsThe patient described at the beginning of this article was treated with danaparoid; no new thrombosis occurred (although severe digital ischemia evolved to acral necrosis). The withdrawal of danaparoid from the US market in April 2001 coincided with the introduction of fondaparinux, a synthetic antithrombin-binding pentasaccharide with exclusive anti-factor Xa activity. Given its lack of in vitro cross-reactivity for HIT antibodies and its favorable early anecdotal results in HIT,19 fondaparinux may well prove useful in managing HIT, especially in patients with venous thromboembolism—a situation in which its long half-life (17 hours) and lack of INR prolongation facilitate warfarin overlap. However, optimal dosing for the hypercoagulability state of HIT is not established. The oligopeptide hirudin analogue, bivalirudin, is another promising agent, with favorable initial results in HIT.20 Pharmacological advantages include predominant nonrenal metabolism and lack of immunogenicity (compare with lepirudin) and minor prolongation of the INR (compare with argatroban).TABLE 2. Comparison of Laboratory Assays to Detect HIT AntibodiesAssayAdvantagesDisadvantagesIn general, the greater the magnitude of a positive test result, the greater the likelihood that the patient has HIT, eg, most patients with HIT have serotonin release >80% and optical density >1.0 absorbance unit, ie, values well above the cutoffs defining a positive test.*Assay from GTI (Brookfield, Wis) uses PF4/polyvinyl sulfonate, whereas assay from Stago (Asnieres, France) uses PF4/heparin.†High sensitivity for clinical HIT (similar to EIAs) but with greater diagnostic specificity than the EIAs.Commercial PF4/polyanion-EIA*Widely available; high sensitivityDetects many nonpathogenic anti-PF4/polyanion IgA, IgM, and IgG antibodies (moderate specificity)PF4/heparin-EIA that only detects IgGDetecting only IgG improves specificityLimited availability (research labs)Platelet aggregation test (citrated platelet-rich plasma)Many labs have conventional platelet aggregometersPoor sensitivity and specificity; limited number of tests can be done; platelet donors requiredWashed platelet activation assay (eg, serotonin release assay)Highest sensitivity–specificity tradeoff†Technically demanding; limited availability (research labs); platelet donors requiredSome of the studies described in this report were funded by the Heart and Stroke Foundation of Ontario (No. T5207).DisclosureDr Warkentin has received grants or research support from Sanofi-Synthelabo and Organon, Inc; has served as a consultant to Medicines Co. and Aventis; and has served on the Speakers' Bureaus of Aventis, Berlex Laboratories, Calea, GlaxoSmithKline, and Pharmion.FootnotesCorrespondence to Dr Ted Warkentin, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, General Site, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. E-mail [email protected] References 1 Warkentin TE, Aird WC, Rand JH. Platelet–endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology (Am Soc Hematol Educ Program). 2003; 497–519.Google Scholar2 Greinacher A, Warkentin TE. Treatment of heparin-induced thrombocytopenia: an overview. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 3rd ed. New York: Marcel Dekker, Inc; 2004: 335–370.Google Scholar3 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001; 344: 1286–1292.CrossrefMedlineGoogle Scholar4 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126 (3 suppl): 311S–337S.CrossrefMedlineGoogle Scholar5 Warkentin TE, Whitlock RP, Teoh KHT. Warfarin-associated multiple digital necrosis complicating heparin-induced thrombocytopenia and Raynaud's phenomenon after aortic valve replacement for adenocarcinoma-associated thrombotic endocarditis. Am J Hematol. 2004; 75: 56–62.CrossrefMedlineGoogle Scholar6 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg. 2003; 76: 2121–2131.CrossrefMedlineGoogle Scholar7 Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med. 2001; 135: 502–506.CrossrefMedlineGoogle Scholar8 Abrams CS, Cines DB. Thrombocytopenia after treatment with platelet glycoprotein IIb/IIIa inhibitors. Curr Hematol Rep. 2004; 3: 143–147.MedlineGoogle Scholar9 Girolami B, Prandoni P, Stefani PM, Tanduo C, Sabbion P, Eichler P, Ramon R, Baggio G, Fabris F, Girolami A. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. 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