Theodore E Warkentin

McMaster University, Hamilton, Ontario, Canada

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Publications (281)2001.89 Total impact

  • [Show abstract] [Hide abstract]
    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.
    Critical care medicine. 12/2014;
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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; · 9.78 Impact Factor
  • John W. Eikelboom, Theodore E. Warkentin
    Journal of the American College of Cardiology 11/2014; · 14.09 Impact Factor
  • Lori-Ann Linkins, Theodore E Warkentin
    Thrombosis Research 11/2014; · 3.13 Impact Factor
  • T E Warkentin, J-A I Sheppard, J C Manheim
    Thrombosis and haemostasis. 10/2014; 112(6).
  • Journal of cardiothoracic and vascular anesthesia. 08/2014;
  • Theodore E Warkentin
    Journal of clinical monitoring and computing. 07/2014;
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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; · 1.99 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; · 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; · 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; · 2.13 Impact Factor
  • Theodore E Warkentin, Jo-Ann I Sheppard
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    ABSTRACT: Heparin re-exposure despite a history of previous heparin-induced thrombocytopenia (HIT) can be appropriate if platelet-activating antibodies are no longer detectable. We determined the frequency, timing, and magnitude of the anti-PF4/heparin immune response (by serotonin-release assay [SRA] and enzyme-immunoassay [EIA]), and the frequency of recurrent HIT, in 20 patients with previous HIT re-exposed to heparin 4.4 years (mean) post-HIT; 17 patients were given heparin intraoperatively (without postoperative heparin) for cardiac/vascular surgery. One patient developed recurrent HIT beginning 7 days post-cardiac surgery, with newly-regenerated HIT antibodies exhibiting strong heparin-independent platelet-activating properties. Intraoperative heparin induced EIA seroconversion in 11/17 (65%) patients (IgG>IgA>IgM) and SRA seroconversion in 8/17 (47%), whereas none of 3 medical patients re-exposed to heparin developed seroconversion. Anti-PF4/heparin IgG became detectable at day 7 (median), i.e., no sooner than observed in typical-onset HIT. The high proportion of SRA-positivity among EIA-seroconverting patients (8/11 [73%]) suggests that patients with previous HIT may be especially predisposed to forming recurrent antibodies with platelet-activating properties. We conclude that among patients with a previous history of HIT who are re-exposed to intraoperative (but not postoperative) heparin the risk of recurrent HIT appears to be low, but is possible if antibodies with strong heparin-independent platelet-activating properties are formed.
    Blood 02/2014; · 9.78 Impact Factor
  • Theodore E Warkentin
    Thrombosis Research 01/2014; · 3.13 Impact Factor
  • Theodore E. Warkentin
    Thrombosis Research 01/2014; · 3.13 Impact Factor
  • Theodore E. Warkentin
    Thrombosis Research 01/2014; · 3.13 Impact Factor
  • Theodore E Warkentin
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Devastating thromboses can complicate heparin-induced thrombocytopenia (HIT) and disseminated intravascular coagulation (DIC). In these disorders, acquired abnormalities of the partial thromboplastin time (PTT) and international normalized ratio (INR) can confound monitoring of PTT- and INR-adjusted anticoagulant therapies, contributing to treatment failure. Areas covered: Illustrative patient cases of anticoagulant failure due to PTT and INR confounding are discussed. Four different scenarios of thrombosis progression associated with inappropriate anticoagulant interruption/underdosing, contributing to ischemic limb necrosis, are presented: i) PTT confounding of heparin therapy of warfarin-associated microthrombosis complicating cancer hypercoagulability; ii) PTT confounding of direct thrombin inhibitor (DTI) therapy complicating HIT-associated DIC; iii) INR confounding during argatroban-warfarin overlap of HIT-associated deep-vein thrombosis; and iv) PTT confounding of anticoagulant therapy during acute DIC/hepatic necrosis-ischemic limb necrosis syndrome. Expert opinion: Abnormal coagulation test results at pre-treatment baseline can provide an important clue regarding the risk of subsequent anticoagulant failure due to PTT or INR confounding. Greater awareness of the potential for anticoagulant failure due to PTT and INR confounding could assist clinicians in management of prothrombotic coagulopathies, for example, by choosing alternative anticoagulants (e.g., fondaparinux, danaparoid) that are not monitored by global coagulation assays, or by obtaining specific drug levels (anti-factor Xa levels, DTI levels).
    Expert Opinion on Drug Safety 08/2013; · 2.74 Impact Factor
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    ABSTRACT: Drug-induced immune thrombocytopenia (DITP) is a challenging clinical problem that is under-recognized, difficult to diagnose and associated with severe bleeding complications. DITP may be caused by classic drug-dependent platelet antibodies (eg, quinine); haptens (eg, penicillin); fiban-dependent antibodies (eg, tirofiban); monoclonal antibodies (eg, abciximab); autoantibody formation (eg, gold); and immune complex formation (eg, heparin). A thorough clinical history is essential in establishing the diagnosis of DITP and should include exposures to prescription medications, herbal preparations and even certain foods and beverages. Clinical and laboratory criteria have been established to determine the likelihood of a drug being the cause of thrombocytopenia, but these criteria can only be applied retrospectively. The most commonly implicated drugs include quinine, quinidine, trimethoprim/sulfamethoxazole and vancomycin. We propose a practical approach to the diagnosis of the patient with suspected DITP. Key features are: the presence of severe thrombocytopenia (platelet nadir <20×10(9)/L); bleeding complications; onset 5 to 10days after first drug exposure, or within hours of subsequent exposures or after first exposure to fibans or abciximab; and exposure to drugs that have been previously implicated in DITP reactions. Treatment involves stopping the drug(s), administering platelet transfusions or other therapies if bleeding is present and counselling on future drug avoidance. The diagnosis can be confirmed by a positive drug re-challenge, which is often impractical, or by demonstrating drug-dependent platelet reactive antibodies in vitro. Current test methods, which are mostly flow cytometry-based, must show drug-dependence, immunoglobulin binding, platelet specificity and ideally should be reproducible across laboratories. Improved standardization and accessibility of laboratory testing should be a focus of future research.
    Transfusion medicine reviews 07/2013; · 3.61 Impact Factor
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    ABSTRACT: Thrombocytopenia is the most common hemostatic disorder in critically ill patients. The objective of this study was to describe the incidence, risk factors, and outcomes of thrombocytopenia in patients admitted to medical-surgical intensive care units (ICUs). 3746 patients in 67 centers were enrolled in a randomized trial in which unfractionated heparin was compared to low-molecular-weight heparin (LMWH) for thromboprophylaxis. Patients who had baseline platelet counts <75x109/L or severe coagulopathy at screening were excluded. We analyzed the risk of developing mild (100-149x109/L), moderate (50-99x109/L) and severe (<50x109/L) thrombocytopenia during ICU stay. We also assessed independent and time-varying predictors of thrombocytopenia and the effect of thrombocytopenia on major bleeding, transfusions, and death. The incidence of mild, moderate, and severe thrombocytopenia was 15.3%, 5.1% and 1.6%, respectively. Predictors of each category of thrombocytopenia were: APACHE II score, use of inotropes or vasopressors, and renal replacement therapy. The risk of moderate thrombocytopenia was lower in patients who received LMWH thromboprophylaxis, but higher in surgical patients and in patients who had liver disease. Each category of thrombocytopenia was associated with subsequent bleeding and transfusions. Moderate and severe thrombocytopenia were associated with increased ICU and hospital mortality. A high severity of illness, prior surgery, use of inotropes or vasopressors, renal replacement therapy, and liver dysfunction are associated with a higher risk of thrombocytopenia developing in ICU, whereas LMWH thromboprophylaxis is associated with a lower risk. Patients who develop thrombocytopenia in the ICU are more likely to bleed, receive transfusions and die.
    Chest 06/2013; · 7.13 Impact Factor
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    ABSTRACT: ABSTRACT BACKGROUND: In a recent multicenter randomized trial comparing unfractionated heparin (UFH) with low-molecular-weight heparin (dalteparin) for thromboprophylaxis in 3746 critically-ill patients, 17 (0.5%) patients developed heparin-induced thrombocytopenia (HIT) based on serotonin-release assay-positive (SRA+) status. A trend to lower frequency of HIT with dalteparin vs UFH was observed in the intention-to-treat analysis (5 vs 12 patients; P=0.14), which was statistically significant (3 vs 12 patients; P=0.046) in a prespecified per-protocol analysis which excluded patients with deep-vein thrombosis (DVT) at study entry. We sought to characterize HIT outcomes and to determine how dalteparin thromboprophylaxis might reduce HIT frequency in ICU patients. METHODS: In 17 patients with HIT, we analyzed platelet counts and thrombotic events in relation to study drug and other open-label heparin, to determine whether study drug plausibly explained seroconversion to SRA+ status and/or breakthrough of thrombocytopenia/thrombosis. We also compared antibody frequencies (dalteparin vs UFH) in 409 patients serologically investigated for HIT. RESULTS: HIT-associated thrombosis occurred in 10/17 (58.8%) patients (8:1:1 venous:arterial:both). Dalteparin was associated with fewer study drug-attributable HIT-related events (P=0.020), including less seroconversion (P=0.058) and less breakthrough of thrombocytopenia/thrombosis (P=0.032). Anti-PF4/heparin IgG antibodies by ELISA were less frequent among patients receiving dalteparin vs UFH (13.5% vs 27.3%; P<0.001). One patient with HIT-associated DVT died post-UFH bolus, whereas platelet counts recovered in two others with HIT-associated VTE despite continuation of therapeutic-dose UFH. CONCLUSIONS: The lower risk of HIT in ICU patients receiving dalteparin appears related to both decreased antibody formation and decreased clinical breakthrough of HIT among patients forming antibodies.
    Chest 05/2013; · 7.13 Impact Factor
  • A B Zimrin, T E Warkentin
    Thrombosis and Haemostasis 05/2013; 109(5):971-3. · 5.76 Impact Factor

Publication Stats

11k Citations
2,001.89 Total Impact Points

Institutions

  • 1989–2014
    • McMaster University
      • • Department of Medicine
      • • Michael G. DeGroote School of Medicine
      • • Department of Pathology and Molecular 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
  • 2000–2012
    • Hamilton Health Sciences
      Hamilton, Ontario, Canada
  • 2011
    • Academia Nacional de Medicina, Buenos Aires
      Buenos Aires, Buenos Aires F.D., Argentina
    • Population Health Research Institute
      Hamilton, Ontario, Canada
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2010
    • Société canadienne du sang
      Ottawa, Ontario, Canada
  • 2009
    • Simon Fraser University
      • Department of Statistics and Actuarial Sciences
      Burnaby, British Columbia, Canada
  • 2008
    • Università degli Studi di Bari Aldo Moro
      • Dipartimento della Emergenza e Trapianti d´Organo (DETO)
      Bari, Apulia, Italy
    • University of Toronto
      Toronto, Ontario, Canada
    • University of Waterloo
      • Department of Statistics and Actuarial Science
      Waterloo, Quebec, Canada
  • 2007
    • Washington Hospital Center
      Washington, Washington, D.C., United States
  • 2003
    • The Chinese University of Hong Kong
      • Department of Anaesthesia and Intensive Care
      Hong Kong, Hong Kong
  • 1997
    • Universidade Federal de São Paulo
      San Paulo, São Paulo, Brazil