Theodore E Warkentin

McMaster University, Hamilton, Ontario, Canada

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Publications (295)2144.44 Total impact

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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies against complexes of platelet factor 4 (PF4) and heparin. The diagnosis of HIT is contingent on accurate and timely laboratory testing. Recently, alternative anticoagulants for the treatment of HIT have been introduced along with algorithms for better HIT diagnosis. However, the increased reliance on immunoassays for the diagnosis of HIT may have harmful consequences due to the high rate of false positive results. To compare trends and implications of current HIT testing approaches, we analyzed results over a six-year period from the McMaster University Platelet Immunology Reference Laboratory. From 2008 to 2013, 8546 samples were investigated for HIT using both an in-house IgG-specific anti-PF4/heparin enzyme immunoassay (EIA) and the serotonin-release assay (SRA). Of 8546 samples tested, 13.4% were true-positives (positive in both assays); 65.6% were true-negatives (negative in both assays); 20.9% were presumed false positive for HIT (EIA-positive/SRA-negative); and 0.2% were EIA-negative/SRA-positive. The frequency of EIA-positive/SRA-negative results increased over time (from 12.9% in 2008 to 22.9% in 2013). We found that the number of SRA-negative samples was reduced from referring centers that used an immunoassay as an initial screen; however, 41% of those samples tested negative in the immunoassay and in the SRA at the reference laboratory. The suspicion of HIT continues at a high rate and the agreement between the EIA and SRA test results remains problematic. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    American Journal of Hematology 03/2015; DOI:10.1002/ajh.24025 · 3.48 Impact Factor
  • Theodore E Warkentin, Donald M Arnold, Ishac Nazi, John G Kelton
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    ABSTRACT: Few laboratory assays are as clinically useful as the platelet serotonin-release assay (SRA): a positive SRA in the appropriate clinical context is virtually diagnostic of heparin-induced thrombocytopenia (HIT), a life- and limb-threatening prothrombotic disorder caused by anti-platelet factor 4 (PF4)/heparin antibodies that activate platelets, thereby triggering serotonin-release. The SRA's performance characteristics include high sensitivity and specificity, although caveats include indeterminate reaction profiles (observed in ∼4% of test sera) and potential for false-positive reactions. As only a subset of anti-PF4/heparin antibodies detectable by enzyme-immunoassay (EIA) are additionally platelet-activating, the SRA has far greater diagnostic specificity than the EIA. However, requiring a positive EIA, either as an initial screening test or as an SRA adjunct, will reduce risk of a false-positive SRA (since a negative EIA in a patient with a "positive" SRA should prompt critical evaluation of the SRA reaction profile). The SRA also provides useful information on whether a HIT serum produces strong platelet activation even in the absence of heparin: such heparin-"independent" platelet activation is a marker of unusually severe HIT, including delayed-onset HIT and severe HIT complicated by consumptive coagulopathy with risk for microvascular thrombosis. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    American Journal of Hematology 03/2015; DOI:10.1002/ajh.24006 · 3.48 Impact Factor
  • Theodore E. Warkentin, Andreas Greinacher, Jürgen Bux
    Transfusion 02/2015; DOI:10.1111/trf.12994 · 3.57 Impact Factor
  • Theodore E Warkentin, Eric L Safyan, Lori-Ann Linkins
    New England Journal of Medicine 01/2015; 372(5):492-4. DOI:10.1056/NEJMc1414161 · 54.42 Impact Factor
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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin utilization. An enzyme-linked immunosorbent assay (ELISA) is usually performed to assist in the diagnosis of HIT. ELISAs tend to be sensitive but lack specificity. We sought to utilize a new cut-off to define a positive HIT ELISA. We conducted a prospective observational study of hospitalized patients undergoing ELISA testing. All patients who underwent ELISA testing were eligible for inclusion (n=496). Irrespective of the results, all subjects had confirmatory testing with a serotonin release assay (SRA). We compared a threshold optical density (OD)>1.00 to the current definition of a positive ELISA (OD>0.40) as a screening test for a positive SRA. We used sensitivity, specificity, and area under the receiver operating curve to determine whether an OD>1.00 would improve diagnostic accuracy for HIT. The SRA was positive in 10 patients (prevalence: 2.0%). Adjusting the definition of a positive HIT ELISA to >1.00 maintained the sensitivity and negative predictive value at 100% in our cohort. The positive predictive value (PPV) of the higher cutoff OD was more than triple the PPV of an OD>0.40 (41.7% vs 13.3%). No patient with a positive SRA had an OD measurement <1.00. Increasing the OD threshold enhances specificity without noticeably compromising sensitivity. Altering the definition of the HIT ELISA could prevent unnecessary testing and/or treatment with non-heparin based anticoagulants in patients with possible HIT. (NCT 00946400).
    Chest 01/2015; DOI:10.1378/chest.14-1417 · 7.13 Impact Factor
  • T E Warkentin
    Thrombosis and Haemostasis 01/2015; 113(3). DOI:10.1160/TH14-11-0974 · 5.76 Impact Factor
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    ABSTRACT: To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU. Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial. Sixty-seven medical-surgical ICUs in six countries. Three thousand seven hundred forty-six medical-surgical critically ill patients. All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses. Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004). Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.
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    ABSTRACT: Repeated therapeutic plasma exchange (TPE) has been advocated to remove heparin-induced thrombocytopenia (HIT) IgG antibodies prior to cardiac/vascular surgery in patients who have serologically-confirmed acute or subacute HIT; for this situation, a negative platelet activation assay (e.g., platelet serotonin-release assay [SRA]) has been recommended as the target serological endpoint to permit safe surgery. We compared reactivities in the SRA and an anti-PF4/heparin IgG-specific enzyme-immunoassay (EIA), testing serial serum samples in a patient with recent (subacute) HIT who underwent serial TPE pre-cardiac surgery, as well as for 15 other serially-diluted HIT sera. We observed that post-TPE/diluted HIT sera-when first testing SRA-negative-continue to test strongly positive by EIA-IgG. This dissociation between the platelet activation assay and a PF4-dependent immunoassay for HIT antibodies indicates that patients with subacute HIT undergoing repeated TPE prior to heparin re-exposure should be tested by serial platelet activation assays even when their EIAs remain strongly positive. Copyright © 2014 American Society of Hematology.
    Blood 11/2014; DOI:10.1182/blood-2014-07-590844 · 9.78 Impact Factor
  • John W. Eikelboom, Theodore E. Warkentin
    Journal of the American College of Cardiology 11/2014; 64(20). DOI:10.1016/j.jacc.2014.09.014 · 15.34 Impact Factor
  • Lori-Ann Linkins, Theodore E Warkentin
    Thrombosis Research 11/2014; DOI:10.1016/j.thromres.2014.10.019 · 2.43 Impact Factor
  • T E Warkentin, J-A I Sheppard, J C Manheim
    Thrombosis and Haemostasis 10/2014; 112(6). DOI:10.1160/TH14-08-0711 · 5.76 Impact Factor
  • Theodore E Warkentin
    Journal of Clinical Monitoring and Computing 07/2014; DOI:10.1007/s10877-014-9594-2 · 1.45 Impact Factor
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    ABSTRACT: Data on the frequency of anti-platelet factor 4/heparin (PF4/H) antibodies and their association with outcomes in intensive care unit (ICU) patients are sparse. In this prospective, observational study we screened 320 consecutive surgical/medical ICU patients for anti-PF4/H antibodies by enzyme-immunoassay (EIA) for immunoglobulin (Ig)G/A/M separately and heparin-induced platelet activation assay (HIPA) at ICU admission (=baseline), day 6, and day 10. HIPA-positive patients were additionally tested by serotonin-release assay (SRA). Patients tested positive by day 10: for anti-PF4/H-IgG = 17.2 % and for anti-PF4/H-IgM = 42.1 %. Within the first 10 ICU days, platelet counts decreased to <100 Gpt/L in 27.8 % patients. However, only seven patients (2.2 %) experienced a drop in the platelet count ≥50 % beginning after the fourth ICU day. These included the only two patients (0.6 %; 95 % confidence interval 0.08-2.2 %) with heparin-induced thrombocytopenia (HIT). Only strong reactions in the HIPA were reproducible by SRA. This study confirms that testing for anti-PF4/H IgG antibodies should be restricted to ICU-patients who develop a platelet count decrease of >50 % that begins after day four of heparin treatment (which may have started before ICU admission). Among patients testing positive by IgG-specific EIA a functional platelet activation assay should be performed (regarding only strong reactions as positive).
    Journal of Thrombosis and Thrombolysis 07/2014; DOI:10.1007/s11239-014-1105-2 · 1.99 Impact Factor
  • Theodore E. Warkentin
    Thrombosis Research 07/2014; 134(1). DOI:10.1016/j.thromres.2014.03.045 · 2.43 Impact Factor
  • Theodore E. Warkentin
    Thrombosis Research 06/2014; 133(6). DOI:10.1016/j.thromres.2014.01.028 · 2.43 Impact Factor
  • Ilana Kopolovic, Theodore E Warkentin
    Canadian Medical Association Journal 04/2014; 186(12). DOI:10.1503/cmaj.131449 · 5.81 Impact Factor
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    ABSTRACT: The existence of "spontaneous" heparin-induced thrombocytopenia (HIT) syndrome (or "autoimmune HIT"), defined as a transient prothrombotic thrombocytopenic disorder without proximate heparin exposure serologically indistinguishable from HIT, is controversial. We describe two new cases presenting with thrombotic stroke/thrombocytopenia, one following shoulder hemi-arthroplasty (performed without heparin), and the other presenting to the emergency room without prior hospitalization, heparin exposure or preceding infection. Both patients tested strongly positive for anti-PF4/heparin IgG in two different immunoassays, and in the platelet serotonin-release assay. Crucially, both patients' sera also caused strong (>80%) serotonin-release in the absence of heparin, a serologic feature characteristic of "delayed-onset" HIT (i.e., where heparin use precedes HIT but is not required for subsequent development of thrombocytopenia). We propose that a rigorous definition of spontaneous HIT syndrome should include otherwise unexplained thrombocytopenia/thrombosis without proximate heparin exposure, and with anti-PF4/heparin IgG antibodies that cause strong in-vitro platelet activation even in the absence of heparin.
    Blood 03/2014; 123(23). DOI:10.1182/blood-2014-01-549741 · 9.78 Impact Factor
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    ABSTRACT: Rivaroxaban is an ideal potential candidate for treatment of heparin-induced thrombocytopenia (HIT) because it is administered orally by fixed dosing, requires no laboratory monitoring and is effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study evaluating the incidence of new symptomatic venous and arterial thromboembolism in patients with suspected or confirmed HIT who are treated with rivaroxaban. Methodological challenges faced in the design of this study include heterogeneity of the patient population, differences in the baseline risk of thrombosis and bleeding dependent on whether HIT is confirmed or just suspected, and heterogeneity in laboratory confirmation of HIT. The rationale for how these challenges were addressed and the final design of the Rivaroxaban for HIT study is reviewed.
    Journal of Thrombosis and Thrombolysis 02/2014; 38(4). DOI:10.1007/s11239-014-1064-7 · 1.99 Impact Factor
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    ABSTRACT: Thrombocytopenia occurs in 20% to 45% of critically ill medical-surgical patients. The 4Ts heparin-induced thrombocytopenia (HIT) score (with 4 domains: Thrombocytopenia, Timing of thrombocytopenia, Thrombosis and oTher reason[s] for thrombocytopenia) might reliably identify patients at low risk for HIT. Interobserver agreement on 4Ts scoring is uncertain in this setting. To evaluate whether a published clinical prediction rule (the "4Ts score") reliably rules out HIT in "low-risk" intensive care unit (ICU) patients as assessed by research coordinators (who prospectively scored) and 2 adjudicators (who scored retrospectively) during an international heparin thromboprophylaxis trial (PROTECT, NCT00182143). Of 3746 medical-surgical ICU patients in PROTECT, 794 met the enrollment criteria for this HIT substudy. Enrollment was predicated on one of the following occurring in ICU: platelets less than 50 × 10(9)/L, platelets decreased to 50% of ICU admission value (if admission value <100 × 10(9)/L), any venous thrombosis, or if HIT was otherwise clinically suspected. Independently, 4Ts scores were completed in real time by research coordinators blinded to study drug and laboratory HIT results, and retrospectively by 2 adjudicators blinded to study drug, laboratory HIT results, and research coordinators' scores; the adjudicators arrived at consensus in all cases. Of the 763 patients, 474 had a central or local laboratory HIT test performed and had 4Ts scoring by adjudicators; 432 were scored by trained research coordinators. Heparin-induced thrombocytopenia was defined by a centrally performed positive serotonin release assay (SRA). Of the 474 patients with central adjudication, 407 (85.9%) had a 4Ts score of 3 or lower, conferring a low pretest probability (PTP) of HIT; of these, 6 (1.5% [95% confidence interval, 0.7%-3.2%) had a positive SRA. Fifty-nine (12.4%) had a moderate PTP (4Ts score of 4-5); of these, 4 (6.8%) had a positive SRA. Eight patients had a high PTP (4Ts score of ≥6); of these, 1 (12.5%) had a positive SRA. Raw agreement between research coordinators and central adjudication on each domain of the 4Ts score and low, intermediate, and high PTP was good. However, chance-corrected agreement was variable between adjudicators (weighted κ values of 0.31-0.93) and between the adjudicator consensus and research coordinators (weighted κ values of 0.13 and 0.78). Post hoc review of the 6 SRA-positive cases with an adjudicated low PTP demonstrated that their scores would have been increased if the adjudicators had had additional information on heparin exposure prior to ICU admission. In general, the fourth domain of 4Ts (oTher causes of thrombocytopenia) generated the most disagreement. Real-time 4Ts scoring by research coordinators at the time of testing for HIT was not consistent with 4Ts scores obtained by central adjudicators. The results of this comprehensive HIT testing highlight the need for further research to improve the assessment of PTP scoring of HIT for critically ill patients.
    Journal of critical care 02/2014; DOI:10.1016/j.jcrc.2014.02.004 · 2.13 Impact Factor

Publication Stats

15k Citations
2,144.44 Total Impact Points


  • 1989–2015
    • McMaster University
      • • Department of Pathology and Molecular Medicine
      • • Department of Medicine
      Hamilton, Ontario, Canada
  • 2005–2013
    • University of Greifswald
      • Institute of Immunology and Transfusion Medicine
      Greifswald, Mecklenburg-Vorpommern, Germany
  • 2012
    • University of Pennsylvania
      • Perelman School of Medicine
      Philadelphia, PA, United States
  • 2010
    • Société canadienne du sang
      Ottawa, Ontario, Canada
  • 2007
    • Drexel University
      • Division of Pulmonary, Critical Care and Sleep Medicine
      Filadelfia, Pennsylvania, United States
  • 2000–2006
    • Hamilton Health Sciences
      Hamilton, Ontario, Canada
  • 2003
    • The Chinese University of Hong Kong
      • Department of Anaesthesia and Intensive Care
      Hong Kong, Hong Kong
  • 1996
    • St. Joseph's Healthcare Hamilton
      Hamilton, Ontario, Canada