T E Warkentin

Publications (94)656.15 Total impact

• Article: FcγRIIa proteolysis as a diagnostic biomarker for heparin-induced thrombocytopenia.

  I Nazi, D M Arnold, J W Smith, P Horsewood, J C Moore, T E Warkentin, M A Crowther, J G Kelton
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  ABSTRACT: BACKGROUND: A significant challenge in the management of heparin-induced thrombocytopenia (HIT) patients is making a timely and accurate diagnosis. The readily available enzyme immunoassays (EIAs) have low specificities. In contrast, platelet activation assays have higher specificities, but they are technically demanding and not widely available. In addition, about 10% of samples referred for HIT testing are initially classified as indeterminate by the serotonin release assay (SRA), which further delays an accurate diagnosis. HIT is characterized by platelet activation, which leads to FcγRIIa proteolysis. This raises the possibility that identification of the proteolytic fragment of FcγRIIa could serve as a surrogate marker for HIT. OBJECTIVES: To determine the specificity of platelet FcγRIIa proteolysis induced by sera from patients with HIT and to correlate results with the SRA. METHODS/PATIENTS: Sera from HIT patients and control patients with other thrombocytopenic/prothrombotic disorders were tested for their ability to proteolyse FcγRIIa. The results were correlated to anti-PF4/heparin antibodies (EIA), and heparin-dependent platelet activation (SRA). RESULTS: Only HIT patient samples (20/20) caused heparin-dependent FcγRIIa proteolysis, similar to the SRA. None of the samples from the other patient groups or hospital controls caused FcγRIIa proteolysis. Of 9 additional samples that tested indeterminate in the SRA, FcγRIIa proteolysis resolved five samples that had a positive anti-PF4/heparin EIA; three had no FcγRIIa proteolysis and two were shown to have heparin-dependent FcγRIIa proteolysis CONCLUSIONS: This study suggests that heparin-dependent FcγRIIa proteolysis is at least as specific as the SRA for the diagnosis of HIT. © 2013 International Society on Thrombosis and Haemostasis.
  Journal of Thrombosis and Haemostasis 04/2013; · 5.73 Impact Factor
• Article: Anti-PF4/heparin antibodies and venous graft occlusion in post-coronary artery bypass surgery patients randomized to postoperative unfractionated heparin or fondaparinux thromboprophylaxis.

  T E Warkentin, J I Sheppard, J C J Sun, H Jung, J W Eikelboom
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  ABSTRACT: BACKGROUND: Anti-PF4/heparin antibodies are frequently generated following coronary artery bypass grafting (CABG) surgery, with platelet-activating IgG implicated in heparin-induced thrombocytopenia. It is controversial whether non-platelet-activating antibodies are associated with thrombosis. OBJECTIVES: To determine in post-CABG patients whether thromboprophylaxis using fondaparinux vs unfractionated heparin (UFH) reduces frequency of anti-PF4/heparin antibodies, and whether anti-PF4/heparin antibodies are associated with early graft occlusion. METHODS/PATIENTS: In a pre-planned secondary analysis of an RCT comparing fondaparinux vs UFH thromboprophylaxis post-CABG, we determined the frequency of anti-PF4/heparin antibody formation by solid-phase enzyme-immunoassay (EIA) and of platelet-activating antibodies by serotonin-release assay (SRA); the SRA and fluid-phase EIA were used to assess fondaparinux cross-reactivity. We also examined whether anti-PF4/heparin antibodies were associated with early arterial or venous graft occlusion (6-week CT angiography). RESULTS: We found no significant difference in frequency of antibody formation between patients who received fondaparinux vs UFH (65.3% vs 46.0%; P = 0.069), and no significant fondaparinux cross-reactivity. Venous graft occlusion(s) occurred in 6/26 patients who formed 'strong' IgG antibodies (≥1.0 OD units and ≥2× baseline) vs 3/66 who did not (P=0.0139). In both unadjusted and adjusted analyses, strong postoperative (but not preoperative) anti-PF4/heparin IgG responses were associated with markedly increased risk of early venous (but not arterial) graft occlusion (adjusted OR, 9.25 [95% CI, 1.73, 49.43]; P=0.0093); notably, none of 3 SRA-positive patients developed venous graft occlusion. CONCLUSIONS: Fondaparinux vs UFH thromboprophylaxis post-CABG does not reduce anti-PF4/heparin antibody formation. Non-platelet-activating anti-PF4/heparin IgG antibodies generated postoperatively are associated with early venous graft occlusion. © 2012 International Society on Thrombosis and Haemostasis.
  Journal of Thrombosis and Haemostasis 12/2012; · 5.73 Impact Factor
• Article: The serological profile of fondaparinux-associated heparin-induced thrombocytopenia syndrome.

  Theodore E Warkentin, Anup K Chakraborty, Jo-Ann I Sheppard, Danielle K Griffin
  Thrombosis and Haemostasis 05/2012; 108(2):394-6. · 5.04 Impact Factor
• Article: A prospective study measuring the development of antibodies against platelet factor 4-heparin in healthy males after exposure to heparins.

  J G Kelton, T E Warkentin, J C Moore, D M Arnold, I Nazi, G M Arepally, J M Roach, I Fier
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  ABSTRACT: To cite this article: Kelton JG, Warkentin TE, Moore JC, Arnold DM, Nazi I, Arepally GM, Roach JM, Fier I. A prospective study measuring the development of antibodies against platelet factor 4-heparin in healthy males after exposure to heparins. J Thromb Haemost 2012; 10: 1446-9.
  Journal of Thrombosis and Haemostasis 04/2012; 10(7):1446-9. · 5.73 Impact Factor
• Article: The serological profile of early-onset and persisting post-cardiac surgery thrombocytopenia complicated by "true" heparin-induced thrombocytopenia.

  Theodore E Warkentin, Jane C Moore, Susan Vogel, Jo-Ann I Sheppard, Nathan I Warkentin, John W Eikelboom
  Thrombosis and Haemostasis 02/2012; 107(5):998-1000. · 5.04 Impact Factor
• Article: Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis.

  T E Warkentin, A Greinacher, Y Gruel, R H Aster, B H Chong
  Journal of Thrombosis and Haemostasis 12/2011; 9(12):2498-2500. · 5.73 Impact Factor
• Article: Prognostic importance of preoperative anti-PF4/heparin antibodies in patients undergoing cardiac surgery. A systematic review.

  Arif M Yusuf, Theodore E Warkentin, Kyle A Arsenault, Richard Whitlock, John W Eikelboom
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  ABSTRACT: It was the objective of this study to obtain best estimates of the prevalence of anti-PF4/heparin antibodies in patients not suspected to have clinical heparin-induced thrombocytopenia (HIT) prior to undergoing cardiac surgery and to determine whether preoperative antibody status and antibody class is predictive of postoperative thromboembolic outcomes, non-thromboembolic outcomes, length of stay, and mortality. PubMed and EMBASE online databases were searched up to July 2011, and we included studies involving adults undergoing cardiac surgery examining the relationship between preoperative anti-PF4/heparin antibodies (ELISA) and postoperative clinical outcomes. Five studies involving a combined total of 2,332 patients met our inclusion criteria. Preoperative anti-PF4/heparin antibodies were detected in 5-22% of patients. No study demonstrated an association between preoperative anti-PF4/heparin antibodies and postoperative thromboembolic outcomes or mortality. Three studies demonstrated a statistically significant association between preoperative anti-PF4/heparin antibodies and length of stay while two showed an association with non-thromboembolic complications. In the one study that examined outcomes by anti-PF4/heparin antibody class, IgM antibodies predicted non-thromboembolic complications and length-of-stay. None of the studies reported prior heparin exposure, and most studies did not examine the relationship of the absolute value of antibody titres (ELISA OD) and risk, nor the incidence of true/clinical HIT in preoperative positive or negative patients. In conclusion, pre-formed anti-PF4/heparin antibodies are common in patients undergoing cardiac surgery, but the available literature does not support that they predict postoperative thromboembolic complications or death. There does appear to be an association between anti-PF4/heparin antibodies and non-thromboembolic adverse events, but a causal relationship is unlikely.
  Thrombosis and Haemostasis 11/2011; 107(1):8-14. · 5.04 Impact Factor
• Article: Intraoperative anticoagulation and limb amputations in patients with immune heparin-induced thrombocytopenia who require vascular surgery.

  Theodore E Warkentin, M Pai, R J Cook
  Journal of Thrombosis and Haemostasis 10/2011; 10(1):148-50. · 5.73 Impact Factor
• Article: Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series.

  T E Warkentin, M Pai, J I Sheppard, S Schulman, A C Spyropoulos, J W Eikelboom
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  ABSTRACT: Fondaparinux is theoretically an attractive agent for the treatment of immune heparin-induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet-activating anti-platelet factor 4/heparin antibodies. Although reports of the use of fondaparinux for this indication have thus far been favorable, the diagnosis of HIT in most cases was not based on definitive laboratory confirmation of heparin-dependent, platelet-activating antibodies. To report thrombotic and major bleeding outcomes with fondaparinux in patients with a high likelihood of having acute HIT based on clinical features and a positive result in the confirmatory platelet serotonin-release assay (SRA), a sensitive and specific test for platelet-activating HIT antibodies. We reviewed consecutive eligible patients with SRA-positive HIT (mean peak serotonin release, 91% [normal, < 20%]; mean IgG-specific PF4/heparin enzyme immunoassay result, 2.53 optical density units [normal, < 0.45 units]) in one medical center over a 30-month period who received fondaparinux for anticoagulation during acute HIT (platelet count, < 150 × 10(9) L(-1)). Where available, plasma samples were used to measure thrombin-antithrombin (TAT) complex levels. Results: Sixteen patients with SRA-positive HIT received fondaparinux: 14 surgical (11 after cardiac surgery; three after vascular surgery) and two medical (acute stroke). Fifty-six per cent of patients had HIT-associated thrombosis at the time of diagnosis. No patient developed new, recurrent or progressive thrombosis; one patient developed a major bleed (calf hematoma). One patient judged to have irreversible tissue necrosis before receiving fondaparinux therapy ultimately required limb amputation. TAT complex levels were reduced within 24 h of starting fondaparinux, and 13 of 13 patients were successfully switched to warfarin. Fondaparinux shows promise for the treatment of patients with SRA-positive acute HIT.
  Journal of Thrombosis and Haemostasis 08/2011; 9(12):2389-96. · 5.73 Impact Factor
• Article: The association between platelet activation and FcγRIIa proteolysis.

  I Nazi, J W Smith, D M Arnold, P Horsewood, J C Moore, T E Warkentin, J G Kelton
  Journal of Thrombosis and Haemostasis 02/2011; 9(4):885-7. · 5.73 Impact Factor
• Article: Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests.

  A Greinacher, T Ittermann, J Bagemühl, K Althaus, B Fürll, S Selleng, N Lubenow, S Schellong, J I Sheppard, T E Warkentin
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  ABSTRACT: Laboratory confirmation of heparin-induced thrombocytopenia (HIT) is based on detection of heparin-dependent platelet-activating antibodies. Platelet factor 4 (PF4)/heparin enzyme-immunoassays (EIA) are a widely available surrogate for platelet-activating antibodies. Defining the optical density (OD) reactivity profiles of a PF4/heparin EIA in reference subject and patient populations and the correlation of the EIA results (expressed in OD units) with the prevalence of platelet-activating antibodies. Using quantile regression we determined the 97.5th percentile of PF4/heparin-immunoglobulin G (IgG) EIA reactivities in non-heparin-treated individuals [blood donors (n = 935)] and patients before heparin therapy (n = 1207). In patients with suspected HIT, we compared the correlation of EIA-IgG reactivities (Greifswald laboratory; n = 2821) and the heparin-induced platelet activation assay (HIPA) with the correlation of reactivities of another EIA-IgG (McMaster laboratory; n = 1956) with the serotonin-release assay (SRA). PF4/heparin-IgG EIA OD reactivities had a lower OD 97.5th percentile in blood donors compared with patient groups before heparin treatment (P < 0.001). The percentage of sera testing positive in the functional assays strongly correlated with PF4/heparin-IgG EIA OD reactivities in both laboratories with very similar results (correlation coefficient > 0.9) when normalized OD ranges (maximum OD divided by 10) were used instead of absolute OD values. Results of PF4/heparin-IgG EIA should not be reported as only positive or negative as there is no single acceptable cut-off value. Instead, reporting PF4/heparin-IgG EIA OD results in ranges allows for risk-stratified prediction for presence of platelet-activating antibodies. Use of normalized OD ranges permits a standardized approach for inter-laboratory comparisons.
  Journal of Thrombosis and Haemostasis 09/2010; 8(9):2025-31. · 5.73 Impact Factor
• Article: Non-necrotizing heparin-induced skin lesions and the 4T's score.

  T E Warkentin, L-A Linkins
  Journal of Thrombosis and Haemostasis 07/2010; 8(7):1483-5. · 5.73 Impact Factor
• Article: Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization.

  T E Warkentin, R J Cook, V J Marder, A Greinacher
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  ABSTRACT: Heparin-induced thrombocytopenia is an antibody-mediated disorder exhibiting variable frequency in different clinical settings. Antibodies recognize PF4/heparin complexes formed at optimal stoichiometric molar ratios. To identify clinical factors influencing risk of anti-PF4/heparin immunization. We performed observational studies and exploratory analyses of the frequency of anti-PF4/heparin antibody formation in 6324 patients who received enoxaparin or fondaparinux in four randomized controlled trials of postorthopedic surgery thromboprophylaxis. Variables included surgery type (knee vs. hip), timing of first anticoagulant dose (pre- vs. postsurgery), circumstances of surgery (elective vs. hip fracture), anticoagulant (enoxaparin vs. fondaparinux) and body-mass index (BMI). We applied a stoichiometry-based model that predicts immunization risk based on expected differences in PF4/anticoagulant ratios in different settings, and specifically used this model to predict the effect of increasing BMI quartiles upon relative risk (RR) of immunization for fondaparinux vs. enoxaparin. Anti-PF4/heparin immunization was more frequent after knee vs. hip surgery (particularly for enoxaparin), and when enoxaparin was given post- rather than pre-elective surgery; however, the opposite occurred with hip fracture surgery, that is, antibody formation was more frequent when enoxaparin or fondaparinux was given presurgery. The RR of immunization for fondaparinux vs. enoxaparin decreased significantly for increasing BMI quartiles, an effect predominantly because of increasing immunization with enoxaparin at increasing BMI quartiles. Several non-drug factors--including type and circumstances of surgery, timing of first anticoagulant dose and BMI--influence risk of anti-PF4/heparin antibody formation, consistent with a stoichiometry-based immunization model of PF4 and anticoagulant ratios occurring during the early peri-operative period.
  Journal of Thrombosis and Haemostasis 03/2010; 8(3):504-12. · 5.73 Impact Factor
• Article: Heyde's syndrome: From controversy to mainstream.

  T E Warkentin, J C Moore
  Thrombosis and Haemostasis 12/2009; 103(2):251-3. · 5.04 Impact Factor
• Article: The use of well-characterized sera for the assessment of new diagnostic enzyme-immunoassays for the diagnosis of heparin-induced thrombocytopenia.

  T E Warkentin, J I Sheppard, J C Moore, J G Kelton
  Journal of Thrombosis and Haemostasis 10/2009; 8(1):216-8. · 5.73 Impact Factor
• Article: Early-onset and persisting thrombocytopenia in post-cardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive.

  S Selleng, B Malowsky, U Strobel, A Wessel, T Ittermann, H-G Wollert, T E Warkentin, A Greinacher
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  ABSTRACT: 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. To examine how these platelet count profiles correlate with antibody status and HIT post-cardiac surgery. We prospectively screened 581 cardiac surgery patients for heparin-dependent 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. 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 positive for platelet-activating anti-PF4-heparin IgG antibodies. In these patients, the frequency of heparin-dependent antibodies did not differ from that in non-thrombocytopenic controls, 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%]. 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.
  Journal of Thrombosis and Haemostasis 09/2009; 8(1):30-6. · 5.73 Impact Factor
• Article: Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents.

  M A Crowther, T E Warkentin
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  ABSTRACT: Heparin, low molecular weight heparin (LMWH) and coumarins are familiar to most clinicians, inexpensive, highly effective when correctly used and widely available. However, coumarin has a delayed onset of action, interacts with many medications, has a narrow therapeutic window, and can cause thrombosis in some settings (e.g. hereditary protein C deficiency, heparin induced thrombocytopenia, warfarin loading). Additionally, warfarin and heparin require monitoring of their therapeutic effect. These real and perceived limitations have led to the development of 'novel' anticoagulants. However, these new agents have one general limitation--a lack of a widely available antidote. We focus on the management of bleeding in anticoagulated patients, with particular regard to novel anticoagulants.
  Journal of Thrombosis and Haemostasis 08/2009; 7 Suppl 1:107-10. · 5.73 Impact Factor
• Article: The paradox of heparin-induced thrombocytopenia.

  T E Warkentin
  Journal of Thrombosis and Haemostasis 07/2009; 7(9):1472-3. · 5.73 Impact Factor
• Article: Immunoassays are not created equal.

  T E Warkentin, L-A Linkins
  Journal of Thrombosis and Haemostasis 07/2009; 7(8):1256-9. · 5.73 Impact Factor
• Article: Antiphospholipid and anti-PF4 antibodies: an association affecting anti-PF4/heparin assay analysis.

  T E Warkentin
  Journal of Thrombosis and Haemostasis 05/2009; 7(7):1067-9. · 5.73 Impact Factor