Heparin‐induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests

Greinacher, Andreas; Ittermann, Till; Bagemühl, Jessica; Althaus, Karina; Fürll, Birgitt; Selleng, Sixten; Lübenow, Norbert; Schellong, Sebastian; Sheppard, Jo‐Ann I.; Warkentin, Theodore E.

doi:10.1111/j.1538-7836.2010.03974.x

Cited by 75 publications

(69 citation statements)

References 16 publications

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“…8 Although IgG-specific assays have greater diagnostic specificity than do polyspecific EIAs (detecting IgG, IgA, and IgM), a strong positive polyspecific EIA is far more predictive of HIT than is a weakly positive IgG-specific assay. 9 …”

Section: Consultative Hematology I: Common Questions In Thrombosis Comentioning

confidence: 99%

How I Diagnose and Manage HIT

2011

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Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4)/polyanion complexes. Platelet activation assays, such as the serotonin-release assay, are superior to PF4-dependent immunoassays in discerning which heparin-induced antibodies are clinically relevant. When HIT is strongly suspected, standard practice includes substituting heparin with an alternative anticoagulant; the 2 US-approved agents are the direct thrombin inhibitors (DTIs) lepirudin and argatroban, which are "niche" agents used only to manage HIT. However, only ϳ 10% of patients who undergo serological investigation for HIT actually have this diagnosis. Indeed, depending on the clinical setting, only 10%-50% of patients with positive PF4-dependent immunoassays have platelet-activating antibodies. Therefore, overdiagnosis of HIT can be minimized by insisting that a positive platelet activation assay be required for definitive diagnosis of HIT. For these reasons, a management strategy that considers the real possibility of non-HIT thrombocytopenia is warranted. One approach that I suggest is to administer an indirect, antithrombin (AT)-dependent factor Xa inhibitor (danaparoid or fondaparinux) based upon the following rationale: (1) effectiveness in treating and preventing HIT-associated thrombosis; (2) effectiveness in treating and preventing thrombosis in diverse non-HIT situations; (3) both prophylactic-and therapeutic-dose protocols exist, permitting dosing appropriate for the clinical situation; (4) body weight-adjusted dosing protocols and availability of specific anti-factor Xa monitoring reduce risk of under-or overdosing (as can occur with partial thromboplastin time [PTT]-adjusted DTI therapy); (5) their long half-lives reduce risk of rebound hypercoagulability; (6) easy coumarin overlap; and (7) relatively low cost.

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Section: Consultative Hematology I: Common Questions In Thrombosis Comentioning

confidence: 99%

How I Diagnose and Manage HIT

2011

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“…Only 1 of 24 sera that activated platelets in the presence of protamine-heparin also showed the typical pattern found in heparininduced thrombocytopenia, 18 that is, activation of platelets in the presence of 0.2 IU/mL of heparin within 30 minutes (indicated by the open circle in Figure 2). Of the 154 patients with anti-protamineheparin IgG antibodies, 97 (63.0%) also tested positive for anti-PF4-heparin IgG.…”

Section: Index Patientmentioning

confidence: 99%

Anti–protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis

Bakchoul¹,

H²,

Amiral³

et al. 2013

Blood

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Key Points• Immunization against protamine/heparin complexes was frequently observed in patients undergoing cardiac surgery.• Platelet-activating antiprotamine-heparin antibodies are a potential risk factor for early postoperative thrombosis and thrombocytopenia.Protamine, which is routinely used after cardiac surgery to reverse the anticoagulant effects of heparin, is known to be immunogenic. Observing patients with an otherwise unexplained rapid decrease in platelet count directly after protamine administration, we determined the incidence and clinical relevance of protamine-reactive antibodies in patients undergoing cardiac-surgery. In vitro, these antibodies activated washed platelets in a FcgRIIa-dependent fashion. Using a nonobese diabetic/severe combined immunodeficiency mouse model, those antibodies induced thrombocytopenia only when protamine and heparin were present but not with protamine alone. Of 591 patients undergoing cardiopulmonary bypass surgery, 57 (9.6%) tested positive for anti-protamine-heparin antibodies at baseline and 154 (26.6%) tested positive at day 10. Diabetes was identified as a risk factor for the development of anti-protamine-heparin antibodies. In the majority of the patients, these antibodies were transient and titers decreased substantially after 4 months (P < .001). Seven patients had platelet-activating, anti-protamine-heparin antibodies at baseline and showed a greater and more prolonged decline in platelet counts compared with antibody-negative patients (P 5 .003). In addition, 2 of those patients experienced early arterial thromboembolic complications vs 9 of 584 control patients (multivariate analysis: odds ratio, 21.58; 95% confidence interval, 2.90-160.89; P 5 .003). Platelet-activating antiprotamine-heparin antibodies show several similarities with anti-platelet factor 4-heparin antibodies and are a potential risk factor for early postoperative thrombosis. (Blood. 2013;121(15):2821-2827

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“…1,10 Functional assays, such as the serotonin release assay (SRA) or the heparin-induced platelet activation assay (HIPA) are accepted as gold standard, but are rarely available in a timely manner. 2,3,11 Clinical assessment tools such as the thrombocytopenia, thrombosis, timing of decrease in platelet count, and other causes for thrombocytopenia (4Ts) score can exclude HIT in many patients if conducted by experienced observers. 12 However, the positive predictive value is low, 12 they are subject to a relevant inter-observer variability, 13 and they are not adequately evaluated in all settings.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] HIT is a life-threatening complication of heparin therapy that affects a significant number of patients. 5 It is associated with a high morbidity and mortality because of a massive pro-coagulant state, with a high incidence of extensive venous and arterial thrombosis, limb loss, and even death.…”

Section: Introductionmentioning

confidence: 99%