Theodore E Warkentin

McMaster University, Hamilton, Ontario, Canada

Are you Theodore E Warkentin?

Claim your profile

Publications (323)2415.28 Total impact

  • T. E. Warkentin · M. Pai
    [Show abstract] [Hide abstract]
    ABSTRACT: For unknown reasons, a small minority of critically ill patients with septic or cardiogenic shock, multi-organ failure, and disseminated intravascular coagulation (DIC) develop symmetrical acral (distal extremity) limb loss due to microvascular thrombosis ('limb gangrene with pulses'). Case reports have described preceding 'shock liver' in some critically ill patients who developed such a picture of ischemic limb necrosis. This suggests that profoundly disturbed procoagulant-anticoagulant balance featuring uncontrolled generation of thrombin-resulting from failure of the protein C and antithrombin natural anticoagulant systems due to insufficient hepatic synthesis of these crucial proteins-could explain the microvascular thrombosis and associated limb loss. We hypothesize that shock liver is the key predisposing risk factor underlying ischemic limb necrosis in the majority of patients who develop this complication in the setting of acute DIC complicating septic or cardiogenic shock. As shock liver precedes onset of limb ischemia by several days, therapeutic intervention may be possible. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Journal of Thrombosis and Haemostasis
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although red blood cell transfusion is a potentially lifesaving intervention in severely anemic and acutely bleeding patients, some observational studies have suggested that prolonged red cell storage before transfusion is associated with harm. INFORM is a large, pragmatic, randomized controlled trial comparing the effect of the shorter storage with longer storage red blood cell transfusions on inhospital mortality in hospitalized patients who require a blood transfusion. The trial is being conducted in centers in Australia, Canada, Israel, and the United States and is expected to enroll 31497 patients. If the results of INFORM indicate that shorter storage red blood cell transfusion is associated with superior outcomes compared with standard issue red blood cell transfusion, consideration may be given to shortening blood storage times. If, in contrast, the INFORM trial provides no evidence of harm from longer storage red blood cells, clinicians and patients may be reassured that current blood inventory management strategies are appropriate.
    No preview · Article · Nov 2015 · Transfusion medicine reviews
  • Theodore E Warkentin

    No preview · Article · Aug 2015 · New England Journal of Medicine
  • I. Nazi · D. M. Arnold · T. E. Warkentin · J. W. Smith · P. Staibano · J. G. Kelton
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Many patients exposed to heparin develop antibodies against platelet factor 4 (PF4) and heparin, yet only those antibodies that activate platelets cause heparin-induced thrombocytopenia (HIT). Patients who produce anti-PF4/heparin antibodies without developing HIT either have antibodies that do not cause platelet activation or produce pathogenic antibodies at levels that are insufficient to cause HIT. Understanding the differences between anti-PF4/heparin antibodies with and without HIT will improve test methods and reduce overdiagnosis.Objectives To investigate the presence of low levels of platelet-activating antibodies in patients investigated for HIT who had anti-PF4/heparin antibodies but failed to cause platelet activation in the 14C-serotonin release assay (SRA).Methods We developed a platelet activation assay similar to the SRA using exogenous PF4 without added heparin (PF4-SRA). This assay was able to detect low levels of platelet-activating antibodies. We used this PF4-SRA to test for platelet-activating antibodies in patients investigated for HIT.ResultsThe PF4-SRA detected platelet-activating antibodies in 7/7 (100%) SRA-positive sera even after the samples were diluted until they were no longer positive in the standard SRA. Platelet-activating antibodies were detected in 14/39 (36%) patients who had anti-PF4/heparin antibodies but tested negative in the SRA and did not have clinical HIT. The clinical diagnosis of HIT was confirmed by chart review and concordant with the SRA results.ConclusionsA subset of heparin-treated patients produce subthreshold levels of platelet-activating anti-PF4/heparin antibodies that do not cause HIT. An increase in the titre of these pathogenic antibodies, along with permissive clinical conditions could lead to HIT.This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2015 · Journal of Thrombosis and Haemostasis
  • [Show abstract] [Hide abstract]
    ABSTRACT: Methylene blue pathogen inactivation and storage of thawed plasma both lead to changes in the activity of several clotting factors. We investigated how this translates into a global loss of thrombin generation potential and alterations in the protein C pathway. Fifty apheresis plasma samples were thawed and each divided into three subunits. One subunit was stored for 7 days at 4 °C, one was stored for 7 days at 22 °C and one was stored at 4 °C after methylene blue/light treatment. Thrombin generation parameters, ProC(®)Global-NR, prothrombin time and activated partial thromboplastin time were assessed on days 0 and 7. The velocity of thrombin generation increased significantly after methylene blue treatment (increased thrombin generation rate; time to peak decreased) and decreased after storage (decreased thrombin generation rate and peak thrombin; increased lag time and time to peak). The endogenous thrombin generation potential remained stable after methylene blue treatment and storage at 4 °C. Methylene blue treatment and 7 days of storage at 4 °C activated the protein C pathway, whereas storage at room temperature and storage after methylene blue treatment decreased the functional capacity of the protein C pathway. Prothrombin time and activated partial thromboplastin time showed only modest alterations. The global clotting capacity of thawed plasma is maintained at 4 °C for 7 days and directly after methylene blue treatment of thawed plasma. Thrombin generation and ProC(®)Global are useful tools for investigating the impact of pathogen inactivation and storage on the clotting capacity of therapeutic plasma preparations.
    No preview · Article · Jul 2015 · Blood transfusion = Trasfusione del sangue
  • Theodore E Warkentin · Richard J Cook · Ravi Sarode · Debi A Sloane · Mark A Crowther
    [Show abstract] [Hide abstract]
    ABSTRACT: Venous limb gangrene can occur in cancer patients, but the clinical picture and pathogenesis remain uncertain. We identified 10 patients with metastatic cancer (7 pathologically-proven) who developed severe venous limb ischemia (phlegmasia/venous limb gangrene) after initiating treatment for DVT; in 8 patients, cancer was not known or suspected at presentation. The patients exhibited a novel, clinically-distinct syndrome: warfarin-associated supratherapeutic INR (median, 6.5) at onset of limb ischemia; rising platelet count during heparin anticoagulation; and platelet fall after stopping heparin. Despite supratherapeutic INRs, patient plasma contained markedly elevated thrombin-antithrombin (TAT) complex levels (indicating uncontrolled thrombin generation) and protein C (PC) depletion; this profile resembles the greatly elevated TAT/PC activity ratios reported in patients with warfarin-associated venous limb gangrene complicating HIT. Analyses of vitamin K-dependent factors in 6 cancer patients with available serial plasma samples showed that variations in the INR corresponded most closely with changes in factor VII, with a highly collinear relationship between VII and PC. We conclude that venous limb ischemia/gangrene is explained in some cancer patients by profoundly disturbed procoagulant-anticoagulant balance, whereby warfarin fails to block cancer-associated hypercoagulability while nonetheless contributing to severe PC depletion, manifest as a characteristic supratherapeutic INR caused by parallel severe factor VII depletion. Copyright © 2015 American Society of Hematology.
    No preview · Article · May 2015 · Blood
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rapid exclusion of heparin-induced thrombocytopenia (HIT) is needed to determine which patients can continue to receive heparin. In this prospective management study, 526 participants had a 4Ts score, rapid immunoassay (PF4/H-PaGIA) and serotonin-release assay (SRA) performed. While awaiting SRA results, participants with low 4Ts score (irrespective of PF4/H-PaGIA result) or intermediate 4Ts score plus a negative PF4/H-PaGIA result received prophylactic doses of danaparoid or fondaparinux; all others received therapeutic doses of nonheparin anticoagulants. The primary outcome was the frequency of management failures defined as HIT positive participants with a low 4Ts score (irrespective of PF4/H-PaGIA result) or intermediate 4Ts score plus negative PF4/H-PaGIA result. Six participants (1.1%; 95%CI,0.2-2.1%) were management failures. A negative PF4/H-PaGIA result reduced the pretest probability of HIT from 1.9% to 0% (95%CI, 0-1.3%), 6.7% to 0% (95%CI, 0-2.7%) and 36.6% to 0% (95%CI, 0-14.3%) in the low, intermediate and high score groups, respectively. A positive PF4/H-PaGIA increased the probability of HIT in the low score group to 15.4% (95%CI, 5.9-30.5). Thus, a low or intermediate 4Ts score plus negative PaGIA excluded HIT, whereas any other combination of results justified use of alternative anticoagulants until HIT could be excluded. This trial was registered at #NCT00489437. Copyright © 2015 American Society of Hematology.
    Preview · Article · Apr 2015 · Blood
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Mar 2015 · American Journal of Hematology
  • Twylla Tassava · Theodore E Warkentin

    No preview · Article · Mar 2015 · American Journal of Hematology
  • Theodore E Warkentin · Donald M Arnold · Ishac Nazi · John G Kelton
    [Show abstract] [Hide abstract]
    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.
    No preview · Article · Mar 2015 · American Journal of Hematology
  • Theodore E Warkentin
    [Show abstract] [Hide abstract]
    ABSTRACT: Many critically ill patients receive heparin, either before intensive care unit (ICU) admission (e.g., postcardiac surgery), for prophylaxis/treatment of thrombosis, for hemodialysis/filtration, or even incidentally (e.g., flushing of intravascular catheters), and are therefore at risk for developing immune heparin-induced thrombocytopenia (HIT), a prothrombotic drug reaction caused by platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies. However, HIT explains at most 1 in 100 thrombocytopenic ICU patients (HIT frequency 0.3-0.5% vs. 30-50% background frequency of ICU-associated thrombocytopenia), and most patients who form anti-PF4/heparin antibodies do not develop HIT; hence, HIT overdiagnosis often occurs. This review discusses HIT-related issues relevant to ICU patients, including how to (1) distinguish HIT both clinically and serologically from non-HIT-related thrombocytopenia; (2) recognize HIT-mimicking disorders, such as the acute disseminated intravascular coagulation (DIC)/liver necrosis-limb necrosis syndrome; (3) prevent HIT in the ICU through use of low-molecular-weight heparin; and (4) treat HIT, including awareness of PTT confounding when anticoagulating patients with DIC. Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York.
    No preview · Article · Feb 2015 · Seminars in Thrombosis and Hemostasis
  • Theodore E. Warkentin · Andreas Greinacher · Jürgen Bux

    No preview · Article · Feb 2015 · Transfusion
  • Source
    Theodore E Warkentin · Eric L Safyan · Lori-Ann Linkins

    Preview · Article · Jan 2015 · New England Journal of Medicine
  • [Show abstract] [Hide abstract]
    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).
    No preview · Article · Jan 2015 · Chest
  • Theodore E. Warkentin

    No preview · Article · Jan 2015 · Thrombosis and Haemostasis
  • Source
    [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.
    Full-text · Article · Dec 2014 · Critical Care Medicine
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Nov 2014 · Blood
  • John W. Eikelboom · Theodore E. Warkentin

    No preview · Article · Nov 2014 · Journal of the American College of Cardiology
  • Lori-Ann Linkins · Theodore E Warkentin

    No preview · Article · Nov 2014 · Thrombosis Research
  • Theodore E. Warkentin · J-A I Sheppard · Jonathan C. Manheim

    No preview · Article · Oct 2014 · Thrombosis and Haemostasis

Publication Stats

19k Citations
2,415.28 Total Impact Points


  • 1989-2015
    • McMaster University
      • • Department of Medicine
      • • Department of Pathology and Molecular Medicine
      Hamilton, Ontario, Canada
  • 2005-2011
    • University of Greifswald
      • • Institute of Immunology and Transfusion Medicine
      • • Department of Transfusion Medicine
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 2000-2006
    • Hamilton Health Sciences
      Hamilton, Ontario, Canada
  • 1996
    • St. Joseph's Healthcare Hamilton
      Hamilton, Ontario, Canada