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Biomedical subjects

Theodore E Warkentin

Publications and source records attributed to Theodore E Warkentin.

At least 19 recordsLinked to original sources
PubMed2007

Very severe thrombocytopenia and fragmentation hemolysis mimicking thrombotic thrombocytopenic purpura associated with a giant intracardiac vegetation infected with Staphylococcus epidermidis: role of monocyte procoagulant activity induced by bacterial supernatant.

The pathogenesis of very severe thrombocytopenia in bacterial endocarditis is uncertain. We report a 50-year-old male with platelet counts < 10 x 10(9)/l and fragmentation hemolysis complicating Staphylococcus epidermidis pacemaker endocarditis with a giant vegetation. Antibiotics, corticosteroids, high-dose intravenous gammaglobulin, and plasmapheresis (for initially-suspected thrombotic thrombocytopenic purpura) failed to produce significant platelet count increase. However, therapeutic-dose heparin anticoagulation was associated with a platelet count increase from <10 to approximately 40 x 10(9)/l, with parallel reduction in thrombin-antithrombin complexes (from 8.9 to 3.5 microg/l), facilitating surgical intervention. The thrombocytopenia promptly resolved following surgical removal of the vegetation. Culture supernatant from S. epidermidis isolated from the patient's blood induced monocytes to express procoagulant activity (assessed by factor Xa generation) equivalent to lipopolysaccharide (1 microg/ml), with half-maximal activation seen with culture supernatant diluted to 1:12,800. These data are consistent with previous animal models of endocarditis demonstrating staphylococci-induced procoagulant changes in monocytes. This case demonstrates that heparin anticoagulation can be therapeutic in infective endocarditis-associated severe thrombocytopenia in a non-bleeding patient, and that such therapy may ameliorate the platelet count enough to permit surgical intervention.

Blood Coagulation↗
PubMed2006

Minimizing costs for treating deep vein thrombosis: the role for fondaparinux.

BACKGROUND: Deep vein thrombosis (DVT) remains a major burden and fondaparinux represents a new option for DVT therapy. We sought to determine if fondaparinux offered financial advantages over low-molecular weight heparin since it is given as a fixed dose over a wide range of patient weights rather then dosed directly on weight and because fondaparinux is not associated with heparin-induced thrombocytopenia (HIT). METHODS: We conducted a cost-minimization analysis comparing fondaparinux to enoxaparin for acute anticoagulation in DVT. We modeled a cohort of 1,000 hypothetical subjects and drew estimates for model inputs from the published literature. We completed multiple sensitivity analyses to asses the significance of our assumptions and used Monte Carlo simulation to estimate the 95% confidence intervals (CIs) around our estimation of the cost differential for the two agents. RESULTS: In the base case, total disease management costs per patient with fondaparinux are US 472 dollars compared to 769 dollars with enoxaparin. The 95% CI around this difference ranges from US 48 dollars to US 401 dollars. The model was mildly sensitive to the pharmacy acquisition costs of fondaparinux and enoxaparin which was the major driver of overall costs. Neither the rates of nor costs associated with DVT recurrence, major bleeding, nor HIT substantially affected our observations. Breakeven analysis indicated our findings to be robust over a wide range of likely clinical scenarios. CONCLUSIONS: From the perspective of a healthcare system, fondaparinux use offers an attractive economic alternative to other agents for initial DVT therapy. Expanded reliance on fondaparinux could potentially result in savings.

Body Weight↗
PubMed2006

Close approximation of two platelet factor 4 tetramers by charge neutralization forms the antigens recognized by HIT antibodies.

OBJECTIVE: Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by antibodies that recognize positively charged platelet factor 4 (PF4), bound to the polyanion, heparin. The resulting immune complexes activate platelets. Unfractionated heparin (UFH) causes HIT more frequently than low-molecular-weight heparin (LMWH), whereas the smallest heparin-like molecule (the pentasaccharide, fondaparinux), induces anti-PF4/heparin antibodies as frequently as LMWH, but without exhibiting cross-reactivity with these antibodies. To better understand these findings, we analyzed the molecular structure of the complexes formed between PF4 and UFH, LMWH, or fondaparinux. METHODS AND RESULTS: By atomic force microscopy and photon correlation spectroscopy, we show that with any of the 3 polyanions, but in the order, UFH>LMWH>>fondaparinux--PF4 forms clusters in which PF4 tetramers become closely apposed, and to which anti-PF4/heparin antibodies bind. By immunoassay, HIT antibodies bind strongly to PF4/H/PF4 complexes, but only weakly to single PF4/heparin molecules. CONCLUSIONS: HIT antigens are formed when charge neutralization by polyanion allows positively charged PF4 tetramers to undergo close approximation. Whereas such a model could explain why all 3 polyanions form antibodies with similar specificities, the striking differences in the relative size and amount of complexes formed likely correspond to the observed differences in immunogenicity (UFH>LMWH approximately fondaparinux) and clinically relevant cross-reactivity (UFH>LMWH>>fondaparinux).

Adsorption↗
PubMed2006

Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is caused by antibodies against a "self" protein-platelet factor 4-bound to heparin. We observed an overrepresentation of the female gender in 290 patients who developed HIT after cardiac or orthopedic surgery compared with the representation found in national databases (study 1). Therefore, we investigated gender imbalance in HIT by logistic regression analysis of a randomized controlled trial of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) (study 2), and we analyzed individual patient data from 7 prospective studies comparing HIT frequency between UFH and LMWH, evaluating effects of gender, heparin (UFH vs LMWH), and patient type (surgical vs medical) (study 3). All 3 studies showed female overrepresentation, which for study 3 was a common odds ratio (OR) of 2.37 (95% confidence interval [95% CI], 1.37-4.09; P = .0015). Study 3 also showed an interaction between gender, heparin, and patient type. Although UFH was more likely than LMWH to cause HIT (P < .0001), this effect was predominantly seen in women compared with men (common OR, 9.22 vs 1.83; P = .020) and in surgical patients compared with medical patients (common OR, 13.93 vs 1.75; P = .005). We conclude that females are at greater risk for HIT and that using LMWH to prevent HIT may have greatest absolute benefit in females undergoing surgical thromboprophylaxis.

Databases, Factual↗
PubMed2006

Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s.

INTRODUCTION: Randomized controlled trials evaluating treatment of acute, transient, but uncommon diseases are difficult to perform. The prothrombotic adverse drug reaction, heparin-induced thrombocytopenia (HIT), is such an example. During the mid-1980s, the defibrinogenating snake venom, ancrod (+/-warfarin, Canada), or coumarin (warfarin, Canada; phenprocoumon, Germany) alone, were often used to treat HIT. During the 1990s, danaparoid+/-coumarin began to replace ancrod (+/-coumarin), or coumarin alone, for treating HIT, despite danaparoid not being approved for treatment of HIT. METHODS: We performed a retrospective evaluation of treatment outcomes from 1986 to 1999, comparing danaparoid+/-coumarin (n=62) versus ancrod+/-coumarin or coumarin alone (controls, n=56). RESULTS: The predefined composite endpoint of adjudicated new, progressive, or recurrent thrombosis (including thrombotic death), or limb amputation, at day 7 (maximum, one event per patient) was significantly lower in danaparoid-treated patients, compared with controls: 8/62=12.9% (95% CI, 4.3-21.5) vs. 22/56=39.3% (95% CI, 26.1-52.5); p=0.0014. We also found a lower frequency of the composite endpoint at end of study (day 35) in danaparoid-treated patients: 12/62=19.4% vs. 24/56=42.9% (p=0.0088). Major bleeding (by day 7) occurred in 7/62 (11.3%) and 16/56 (28.6%) of danaparoid-treated and control patients, respectively (p=0.0211). CONCLUSIONS: The replacement of ancrod+/-coumarin, or coumarin alone, by danaparoid (+/-coumarin) in the mid-1990s for the treatment of HIT was justified by improved efficacy and safety.

Aged↗
PubMed2006

Testing for heparin-induced thrombocytopenia antibodies.

Heparin-induced thrombocytopenia (HIT) has a distinct clinical profile and unique pathogenesis. It is caused by platelet-activating IgG antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) bound to heparin or certain other polyanions. Although an immune response to PF4/heparin associated with heparin treatment is very common, clinical HIT occurs only among the minority of patients whose antibodies are capable of strongly activating platelets. This explains why certain platelet activation assays and anti-PF4/polyanion immunoassays have high sensitivity for HIT and why diagnostic specificity is highest for those assays that preferentially detect pathogenic antibodies, such as the washed platelet activation assays or immunoassays that detect only IgG antibodies. Negative results obtained in a solid-phase PF4/polyanion immunoassay generally exclude HIT (high negative predictive value), especially in a setting of a low pretest probability. In addition, because the magnitude of a positive test result correlates with greater likelihood of HIT, a Bayesian diagnostic approach that combines pretest probability and the magnitude of a positive test result is recommended. Recent studies suggest that presence of anti-PF4/polyanion antibodies in certain clinical settings confers an adverse prognosis, even without clinically evident HIT. Whether such antibodies impart "forme fruste" HIT or are simply a surrogate marker for a non-HIT adverse risk factor such as inflammation is unresolved.

Anticoagulants↗
PubMed2006

Heparin-induced thrombocytopenia in the critical care setting: diagnosis and management.

BACKGROUND: Thrombocytopenia is a common occurrence in critical illness, reported in up to 41% of patients. Systematic evaluation of thrombocytopenia in critical care is essential to accurate identification and management of the cause. Although sepsis and hemodilution are more common etiologies of thrombocytopenia in critical illness, heparin-induced thrombocytopenia (HIT) is one potential etiology that warrants consideration. OBJECTIVE: This review will summarize the pathogenesis and clinical consequences of HIT, describe the diagnostic process, and review currently available treatment options. DATA SOURCE: MEDLINE/PubMed search of all relevant primary and review articles. DATA SYNTHESIS AND CONCLUSIONS: HIT is a clinicopathologic syndrome characterized by thrombocytopenia (>/=50% from baseline) that typically occurs between days 5 and 14 after initiation of heparin. This temporal profile suggests a possible diagnosis of HIT, which can be supported (or refuted) with a strong positive (or negative) laboratory test for HIT antibodies. When considering the diagnosis of HIT, critical care professionals should monitor platelet counts in patients who are at risk for HIT and carefully evaluate for, a) temporal features of the thrombocytopenia in relation to heparin exposure; b) severity of thrombocytopenia; c) clinical evidence for thrombosis; and d) alternative etiologies of thrombocytopenia. Due to its prothrombotic nature, early recognition of HIT and prompt substitution of heparin with a direct thrombin inhibitor (e.g., argatroban or lepirudin) or the heparinoid danaparoid (where available) reduces the risk of thromboembolic events, some of which may be life-threatening.

Anticoagulants↗
PubMed2006

HIT: lessons learned.

The peculiar pathogenesis of heparin-induced thrombocytopenia (HIT), involving a "self" antigen-platelet factor 4 (PF4) bound to heparin-and resulting antibody-mediated platelet activation, is a model for thrombosis triggered by drug-induced autoimmunity. The high probability of forming an immune response to heparin, and the highly-variable clinical significance of a positive laboratory test-depending on the type of assay and the magnitude of a given positive test result-provides lessons regarding appropriate interpretation of diagnostic laboratory testing in the context of pretest probability. The relatively high risk of inducing microvascular thrombosis due to coumarin-induced vitamin K antagonism attests to the dangers of a compromised protein C natural anticoagulant system in the setting of a hypercoagulability state such as HIT. Unusual immunologic features of HIT, such as the dissociation between immunogenicity (induction of immune response) and cross-reactivity (capacity to form the antigens recognized by HIT antibodies)of the implicated polysaccharide anticoagulants, and the generally rapid formation and disappearance of anti-PF4/heparin antibodies, suggest that further lessons regarding HIT immunopathogenesis remain to be learned.

Antibodies↗
PubMed2006

Think of HIT.

Heparin-induced thrombocytopenia, or HIT, can present in many ways, ranging from common-isolated thrombocytopenia, venous thromboembolism, acute limb ischemia-to less common but specific presentations-necrotizing skin lesions at heparin injection sites, post-bolus acute systemic reactions, and adrenal hemorrhagic necrosis (secondary to adrenal vein thrombosis). Many patients with HIT have mild or moderate thrombocytopenia: the median platelet count nadir is 60 x 10(9)/L, and ranges from 15 to 150 x 10(9)/L in 90% of patients, most of whom evince a 50% or greater fall in the platelet count. HIT that begins after stopping heparin ("delayed-onset HIT") is increasingly recognized. Factors influencing risk of HIT include type of heparin (unfractionated heparin > low-molecular-weight heparin), type of patient (surgical > medical), and gender (female > male). Since timely diagnosis and treatment of HIT may reduce the risk of adverse outcomes, this review focuses on those clinical circumstances that should prompt the clinician to "think of HIT." Coumarin anticoagulants such as warfarin are ineffective in acute HIT and can even be deleterious by predisposing to micro-thrombosis via protein C depletion (venous limb gangrene and skin necrosis syndromes). Thus, it is important to avoid or postpone coumarin while managing HIT hypercoagulability, focusing on agents that inhibit thrombin directly (lepirudin, argatroban) or that inhibit its generation (danaparoid, fondaparinux). Post-marketing experience suggests that standard dosing of lepirudin is too high; current recommendations are to avoid the initial lepirudin bolus and to begin with lower infusion rates, even in patients without overt renal dysfunction.

Contraindications↗
PubMed2005

Recognition, treatment, and prevention of heparin-induced thrombocytopenia: review and update.

Heparin-induced thrombocytopenia (HIT) is one of the most important life- and limb-threatening adverse drug events encountered by physicians. Serious sequelae associated with HIT can be avoided with early recognition and appropriate treatment. This review examines the recommendations published in 2004 by the American College of Chest Physicians on the recognition, treatment, and prevention of HIT together with more recent data, especially regarding treatment with direct thrombin inhibitors.

Anticoagulants↗
PubMed2005

Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin.

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti-PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti-PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.

Anticoagulants↗