To cite this article: Greinacher A, Juhl D, Strobel U, Wessel A, Lubenow N, Selleng K, Eichler P, Warkentin TE. Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost 2007; 5: 1666-73.Summary. Introduction: Platelet-activating antiplatelet factor 4/heparin (anti-PF4/heparin) antibodies are the major cause of heparin-induced thrombocytopenia (HIT). However, the relative utility of functional (platelet activation) vs. antigen [enzymeimmunoassay (EIA)] assays, and the significance of assay discrepancies remain unresolved. Methods: Consecutive patient sera (n = 1650) referred for diagnostic HIT testing were screened prospectively by both the heparin-induced platelet activation (HIPA) test and anti-PF4/heparin EIA -including individual classes (IgG, IgA, IgM) -with clinical correlations studied. Platelet microparticle and annexin-V-binding properties of the sera were also investigated. Results: Only 205 (12.4%) sera tested positive in either the HIPA and/or EIA: 95 (46.3%) were positive in both, 109 (53.1%) were only EIApositive, and, notably, only one serum was HIPA-positive/EIAnegative. Of 185 EIA-positive sera, only 17.6% had detectable IgM and/or IgA without detectable IgG. Among sera positive for EIA IgG, optical density values were higher when the sera were HIPA-positive (1.117 vs. 0.768; P < 0.0001), with widely overlapping values. Two HIPA-positive but EIA-IgG-negative sera became HIPA-negative following IgG depletion, suggesting platelet-activating antibodies against non-PF4-dependent antigens. Clinical correlations showed that HIPA-negative/ EIA-positive patients did not develop thrombosis and had reasons other than HIT to explain thrombocytopenia. IgM/A antibodies did not increase microparticle penetration, but increased annexin-V binding. Conclusions: The anti-PF4/ heparin EIA has high (99%) sensitivity for HIT. However, only about half of EIA-positive patients are likely to have HIT. Anti-PF4/heparin antibodies of IgM/A class and non-PF4-dependent antigens have only a minor role in HIT.

thrombocytopenia in post-cardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive. See also Gruel Y, Pouplard C. Post-operative platelet count profile: the most reliable tool for identifying patients with true heparin-induced thrombocypenia after cardiac surgery. This issue, pp 27-9.Summary. Background: The high frequency of thrombocytopenia in post-cardiac surgery patients makes it challenging to diagnose heparin-induced thrombocytopenia (HIT). Two platelet count profiles are reported as indicating possible HIT in these patients: profile 1 describes a platelet count fall that begins between postoperative days 5 and 10, whereas profile 2 denotes early-onset thrombocytopenia that persists beyond day 5. Objectives: Toexaminehowthese platelet count profiles correlate withantibodystatusandHITpost-cardiacsurgery.Methods:We prospectively screened 581 cardiac surgery patients for heparindependent antibodies by platelet factor 4 (PF4)-heparin immunoassay and platelet-activation test, and performed daily platelet counts (until day 10) with 30-day follow-up. Results: All three patients with platelet count profile 1 tested positive for platelet-activating anti-PF4-heparin IgG antibodies [odds ratio (OR) 521.7, 95% confidence interval (CI) 3.9-34 000, P = 0.002], and were judged to have HIT. In contrast, none of 25 patients with early-onset and persisting thrombocytopenia (profile 2) was judged to have HIT, including five patients testing positivefor platelet-activating anti-PF4-heparin IgG antibodies. In these patients, the frequency of heparin-dependent antibodies didnot differfromthat in non-thrombocytopeniccontrols, either for anti-PF4-heparin IgG (OR 1.7, 95% CI 0.7-4.1, P = 0.31) or for platelet-activating antibodies (OR 1.9, 95% CI 0.6-5.7, P = 0.20). Multivariate analysis revealed that type of cardiac surgery, but not HIT antibody status, predicted early-onset and persisting thrombocytopenia. Together, these findings show that HIT was uncommon in this study population [overall frequency, 3/581 (0.5%), 95% CI 0.1-1.5%]. Conclusions: Thrombocytopenia that begins between 5 and 10 days post-cardiac surgery is highly predictive for HIT. In contrast, early-onset and persisting thrombocytopenia is usually caused by non-HIT factors with coinciding heparin-dependent antibody seroconversion.

Detection of IgG, IgM and IgA class antibodies by PF4/heparin ELISA yields a positive test result about twice as often as does a platelet activation assay, with only a minority of the additional patients detected likely having HIT. Thus, there is a potential for considerable over-diagnosis of HIT by laboratories that utilize only an ELISA for diagnostic testing.

The risk of TT-CMV is low in high-risk CMV(neg/neg) HSCT patients transfused with leukoreduced blood products not tested for anti-CMV. The cause of anti-CMV IgG seroconversion is most likely passive antibody transmission by blood products.