Comparison of Clinical Outcomes in Patients with Heparin-Induced Thrombocytopenia Treated with Direct Thrombin Inhibitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3942-3942 ◽  
Author(s):  
John L. Francis ◽  
Ranjeev Sandhu ◽  
Alane Drexler ◽  
John Dougherty
Keyword(s):  
Length Of Stay ◽  
Clinical Outcomes ◽  
Clinical Syndrome ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Efficacy And Safety ◽  
Platelet Factor ◽  
Platelet Recovery ◽  
Heparin Induced Thrombocytopenia ◽  
All Cause Mortality

Abstract Heparin-induced thrombocytopenia (HIT) is a clinical syndrome that has been reported to occur in 3–5% of patients treated with unfractionated heparin. If untreated, 36–50% of patients diagnosed with HIT develop life or limb-threatening thromboses. The occurrence of thrombosis, the most common serious complication of HIT, results in rates of amputation and death of 10–20% and 20–30% respectively. Thus, the desired clinical outcomes in patients with HIT are the prevention of thromboembolic complications, limb amputation, and death. The three direct thrombin inhibitors available in the U.S. are lepirudin, argatroban and bivalirudin. Lepirudin and argatroban have both been shown in clinical trials to significantly decrease the incidence of these complications in patients with HIT. Our institution also has experience with bivalirudin as treatment for HIT. We therefore sought to confirm whether all-cause mortality, length of stay, bleeding rate, time to platelet recovery, absolute change in platelet count following therapy, and percentage of therapeutic APTTs differed among patients treated with these agents at our institution. Data were collected by retrospective chart reviews, and from the Florida Hospital pharmacy computer system. Length of stay was calculated as the time to hospital discharge following the finding of a positive heparin-platelet factor 4 antibody test. For the purposes of comparison, the therapeutic range for APTT was taken as 50–90 seconds. As shown in the table, there were no statistically significant differences in any of the endpoints, when the efficacy and safety of the three direct thrombin inhibitors were compared. It therefore appears that within our institution, each of the direct thrombin inhibitors are equally efficacious and safe in treating the clinical syndrome of HIT, with similar outcomes with respect to length of stay, recovery of platelet counts, incidence of bleeding, and overall mortality. We conclude that selection of a direct thrombin inhibitor can be guided by the patient’s clinical status and organ function instead of efficacy and safety considerations. Drug n All-cause mortality (%) Length of stay (days) Bleeding (%) Time to platelet recovery (days) Therapeutic APTT (%) Lepirudin 7 28.5 11.0 28.5 5.3 70 Argatroban 20 30.0 15.1 20.0 5.2 65 Bivalirudin 24 25.0 18.7 25.0 5.4 74 P-value NS NS NS NS NS

scholarly journals Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies

Blood ◽  
2012 ◽  
Vol 119 (5) ◽  
pp. 1248-1255 ◽  
Author(s):  
Krystin Krauel ◽  
Christine Hackbarth ◽  
Birgitt Fürll ◽  
Andreas Greinacher
Keyword(s):  
Factor Xa ◽  
Platelet Factor 4 ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Alternative Anticoagulation ◽  
Heparin Complexes ◽  
History Of

Abstract Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). HIT requires treatment with alternative anticoagulants. Approved for HIT are 2 direct thrombin inhibitors (DTI; lepirudin, argatroban) and danaparoid. They are niche products with limitations. We assessed the effects of the DTI dabigatran, the direct factor Xa-inhibitor rivaroxaban, and of 2-O, 3-O desulfated heparin (ODSH; a partially desulfated heparin with minimal anticoagulant effects) on PF4/heparin complexes and the interaction of anti-PF4/heparin Abs with platelets. Neither dabigatran nor rivaroxaban had any effect on the interaction of PF4 or anti-PF4/heparin Abs with platelets. In contrast, ODSH inhibited PF4 binding to gel-filtered platelets, displaced PF4 from a PF4-transfected cell line, displaced PF4/heparin complexes from platelet surfaces, and inhibited anti-PF4/heparin Ab binding to PF4/heparin complexes and subsequent platelet activation. Dabigatran and rivaroxaban seem to be options for alternative anticoagulation in patients with a history of HIT. ODSH prevents formation of immunogenic PF4/heparin complexes, and, when given together with heparin, may have the potential to reduce the risk for HIT during treatment with heparin.

Incidence of Isolated Heparin-Induced Thrombocytopenia and the Risk of Developing Subsequent Thrombosis Using the New IgG Specific Anti-PF4/Heparin ELISA

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1448-1448
Author(s):  
Sofyan M. Radaideh ◽  
Eugene P. Frenkel ◽  
Ravindra Sarode ◽  
Yu-Min Shen
Keyword(s):  
Conflicts Of Interest ◽  
Clinical Findings ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
High Dose ◽  
Elisa Assay ◽  
Initial Manifestation ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Number Of Patients

Abstract Abstract 1448 BACKGROUND: The new IgG specific ELISA for anti-platelet factor 4 (PF4)/heparin antibody is recently introduced for the diagnosis of heparin-induced thrombocytopenia (HIT). It is as sensitive but more specific than the poly-specific IgG, M, A ELISA. About 50% of patients testing positive for the anti-PF4/heparin antibody have thrombocytopenia alone as initial manifestation of HIT without thrombosis (isolated HIT). These patients are thought to be at high risk (≂f30%) for developing thrombosis within next 28 days. The incidence of isolated HIT using IgG-specific ELISA is unknown. OBJECTIVES: Evaluate the incidence of isolated HIT using the IgG specific anti-PF4/heparin ELISA and the risk of developing subsequent thrombosis in these patients. PATIENTS AND METHODS: We performed a retrospective observational study of patients being tested for the anti-PF4/heparin antibody at our institution from December 2008 to May 2010 using the IgG-specific anti-PF4/heparin ELISA with a two-step assay using high dose heparin in the second step to demonstrate heparin specificity. A positive test was defined as optical density (OD) >0.4 with >50% inhibition. RESULTS: 319 patients were tested during the study period. 23 (7.2%) patients were diagnosed with HIT based on clinical findings (4T score) and ELISA. 16/23 (70%) had thrombosis at diagnosis whereas 7/ 23 (30%) had isolated HIT. All 7 patients with isolated HIT had follow up data for at least 3 months after diagnosis. Only 2/7 were treated with direct thrombin inhibitors (DTI) and 4/7 were treated with warfarin for at least 1 month. While only 3 of the 7 isolated HIT patients had compression ultrasonography to rule out occult lower extremity thrombus, none of these 7 patients (including 4 with an OD of >1.0) developed symptoms or signs of thrombosis in the subsequent 3 months after the diagnosis of isolated HIT. CONCLUSION: The incidence of isolate HIT in this study (7.2%) is significantly lower than previously reported by others and our own historical patients (57.4%, Altuntus et al, Euro J of Haematology 2008) using the IgG, M, A poly -specific anti-PF4/heparin ELISA (z value 2.092, p=0.036). It is possible that many patients previously thought to have HIT by the poly-specific anti-PF4/heparin ELISA assay were false positive. Using the IgG-specific anti-PF4/heparin ELISA not only improved the specificity of the ELISA assay, it also reduced the number of patients with isolated HIT significantly who also seem to have lower risk of developing subsequent thrombosis. Disclosures: No relevant conflicts of interest to declare.

Heparin-induced thrombocytopenia in cardiac surgery and critically ill patients

2016 ◽  
Vol 116 (11) ◽  
pp. 843-851 ◽  
Author(s):  
Sixten Selleng ◽  
Kathleen Selleng
Keyword(s):  
Cardiac Surgery ◽  
Clinical Symptoms ◽  
Therapeutic Option ◽  
Thrombin Inhibitors ◽  
Ventricular Assist Devices ◽  
Direct Thrombin Inhibitors ◽  
Impaired Liver Function ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Off Pump

SummaryThrombocytopenia as well as anti-platelet factor 4/heparin (PF4/H) antibodies are common in cardiac surgery patients and those treated in the intensive care unit. In contrast, heparin-induced thrombocytopenia (HIT) is uncommon in these populations (∼1 % and ∼0.5 %, respectively). A stepwise approach where testing for anti-PF4/H antibodies is performed only in patients with typical clinical symptoms of HIT improves diagnostic specificity of the laboratory assays without losing sensitivity, thereby helping to avoid overdiagnosis and resulting HIT overtreatment. Short-term re-exposure to heparin, especially given intraoperatively for cardiovascular surgery, is a reasonable therapeutic option in patients with a history of HIT who subsequently test negative for HIT antibodies. Organ failure(s), enhanced bleeding risks, and other characteristics require special considerations regarding non-heparin anticoagulation: Argatroban is the alternative anticoagulant with pharmacokinetics independent of renal function, but it has a prolonged half-life in case of impaired liver function. For bivalirudin, protocols during cardiopulmonary bypass surgery are established, and it is suitable for patients with liver insufficiency. A major issue of direct thrombin inhibitors are false high activated partial thromboplastin time values in patients with comorbidities affecting prothrombin, which can result in systematic underdosing of the drugs. This is not the case for danaparoid and fondaparinux, which can be monitored by anti-factor Xa assays, but have long half-lives and no suitable antidote. This review includes also information on management of on- and off-pump cardiac surgery, ventricular assist devices, percutaneous interventions, continuous renal replacement therapy, and extracorporeal membrane oxygenation in patients with HIT.

Heparin-Induced Thrombocytopenia in Liver Transplant Recepients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4668-4668
Author(s):  
Basem M. William ◽  
Sandeep K. Rajan
Keyword(s):  
Clinical Characteristics ◽  
Clinical Course ◽  
Direct Consequence ◽  
Bleeding Risk ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Bleeding Events ◽  
Platelet Recovery ◽  
Heparin Induced Thrombocytopenia ◽  
Heparin Administration

Abstract Abstract 4668 Background: Heparin-induced thrombocytopenia (HIT) is an adverse immune-mediated drug reaction, resulting in a platelet count decrease of 50% within 5 to 10 days after heparin administration. HIT is often associated with venous and/or arterial thrombosis (HITT). The clinical course of HIT developing after liver transplantation (LT) had not been reported. Direct thrombin inhibitors (DTI) were reported to be safe and efficacious in patients who developed HIT yet their safety and efficacy had not been determined in patients who had LT. Also, the optimal management of HIT developing after LT has not been defined. Objectives: To evaluate the incidence and the clinical course of patients who developed HIT after LT and the safety of use of DTI in this population. Methods: We performed a retrospective analysis of all patients who had a LT and had clinical HIT confirmed by the anti-PF4/heparin (HIT) antibody by ELISA at our institution between January 2006 and July 2011. A positive test is defined as optical density of > 0.4 with > 50% inhibition. Bleeding was defined per GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) scale. Alternate causes of thrombocytopenia were excluded by relevant hematologic testing. Results: During the study period, 438 patients received LT and163 patients were diagnosed with clinical HIT in our 689 bed hospital. Clinical HIT was confirmed in 11 LT patients (2.5%) based on a positive HIT antibody. LT cases constitute 11/163 (6.75%) of all HIT diagnosed in our center. Clinical characteristics of these are described in attached table. Previous thrombosis was reported in 7/11 (63%) patients, of these 5/11 (46%) received prior therapeutic anticoagulation. Baseline thrombocytopenia below 150K was present in 10/11 (90%) cases and 7/11 (63%) had INR prolongation ≥ 1.5. HIT was documented in 2 patients before LT, in 3 patients within 14 days of surgery and in 6 patients more than 14 days post LT. Six (54%) developed HITT and 7/11 (63%) were treated with a DTI (bivalirudin in 6 cases and argatroban in 1 case). On discharge 2/11 (18%) received fondaparinux and 5/11 (45%) received warfarin. Median dose of IV bivalirudin was 0.3 (0.09-0.89) mg/kg/hr. Platelet recovery was noted in all patients at mean of 9.8 (3-30) days. Progressive thrombosis was noted in 2/11 (18%). Moderate bleeding events within 40 days of LT included 2 gastrointestinal bleeds and one episode of epistaxis. Two traumatic bleeds occurred with prolonged anticoagulation for HITT. No deaths or amputations were documented as a direct consequence of HIT. Only one patient with HIT and LT died as a complication of sepsis. Clinical characteristics of HIT in LT patients: n=11 Conclusion: HIT is common (2.5%) in LT recipients despite low rates of deep venous thromboprophylaxis with heparin due to underlying coagulopathy. Basal thrombocytopenia is frequent in these patients and widely accepted 4T probability score has low predictive value. The risk of HITT and progressive thrombosis is high. Despite baseline coagulopathy, in our experience the use of DTI, especially bivalirudin, seems to be well tolerated and efficacious in this population. Future studies are needed to optimize dosing to reduce bleeding risk. Disclosures: Off Label Use: Use of bivalirudin and fondaparinaux in the treatment of heparin-induced thrombocytopenia.

Platelet Factor 4 (PF4) Antigenic Complexes on the Macrophage Surface: Implications for the Pathogenesis of Heparin Induced Thrombocytopenia (HIT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 94-94
Author(s):  
Lubica Rauova ◽  
Douglas B. Cines ◽  
Mortimer Poncz
Keyword(s):  
Host Protein ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Igg Antibody ◽  
Drug Induced ◽  
Platelet Factor ◽  
Platelet Surface ◽  
Heparin Induced Thrombocytopenia ◽  
Heparan Sulfates ◽  
Bell Shaped Curve

Abstract HIT is the most frequent antibody-mediated drug-induced thrombocytopenia and is unique in the associated prevalence of thrombosis. HIT is caused by antibodies to a normal host protein, PF4, complexed to heparin or cellular glycosaminoglycans (GAGs). We have shown that binding of HIT antibodies and a monoclonal HIT-like antibody KKO to platelet surface chondroitin sulfate (CS) follows a bell-shaped curve with respect to PF4 concentration. At external PF4 concentrations below the peak value of <50 μg/mL, heparin dissociates PF4 and thereby decreases surface antigenicity, whereas at PF4 concentrations >50 μg/mL, heparin initially increases antigenicity. Surface GAGs on macrophages differ from those on platelets in several ways, including having a higher affinity for PF4. In addition, the binding of HIT-IgG elicits the elaboration of tissue factor. Therefore, we characterized the binding of HIT IgG antibody to macrophages exposed to different concentrations of PF4. Binding of PF4 to the surface of human/murine macrophages also followed a bell-shaped curve with peak antigenicity at the same PF4 concentration as seen on platelets. However, HIT antigenticity persisted at lower PF4 concentrations. For example at a PF4 concentration of 6 μg/mL, six times as much KKO bound to macrophages as to platelets. PF4-coated monocytes were also more resistant to the abrogation of KKO binding by heparin. At therapeutic concentrations of heparin, HIT antigenicity actually increased on macrophages exposed to optimal concentrations of PF4, while platelet surface antigenicity was nearly eliminated. Enzymatic removal of surface GAGs showed that unlike platelet surfaces, where CS is the major GAG involved in HIT antigenicity, a more complex pattern was seen on macrophages that included heparan sulfates, CS and likely dermatan sulfates. Thus, these studies show that expression of surface HIT antigenic complexes on macrophages develop at much lower concentrations of PF4 than platelets and that these complexes are more resistant to removal by heparin. The enhanced avidity of macrophages for PF4/GAG complexes may also contribute to the persistent risk of thrombosis for at least several days after heparin exposure has been stopped. Whether measurement of antigenic complexes on macrophages would identity patients at higher risk of thrombosis and whether reduction in the risk of thrombosis requires measures directed at the integrity of these complexes in addition to use of direct thrombin inhibitors are under investigation.

Pathophysiology of Heparin-Induced Thrombocytopenia

2000 ◽  
Vol 124 (11) ◽  
pp. 1657-1666 ◽  
Author(s):  
Fabrizio Fabris ◽  
Sarfraz Ahmad ◽  
Giuseppe Cella ◽  
Walter P. Jeske ◽  
Jeanine M. Walenga ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Serotonin Release ◽  
Platelet Factor 4 ◽  
Thrombin Inhibitors ◽  
Platelet Factor ◽  
Cellular Activation ◽  
Heparin Induced Thrombocytopenia ◽  
New Information ◽  
Study Selection ◽  
Release Assay

Abstract Objective.—This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome. Data Sources and Study Selection.—Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin–platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a “superactive” heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT. Conclusions.—The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.

Direct Thrombin Inhibitors

2006 ◽  
Author(s):  
Richard C. Becker ◽  
Frederick A. Spencer
Keyword(s):  
Half Life ◽  
Cell Activation ◽  
Cellular Proliferation ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Endothelial Cell Activation ◽  
Heparin Induced Thrombocytopenia ◽  
Fibrinogen Binding ◽  
Inflammatory Processes ◽  
Repeated Dosing

The pivotal role of thrombin in all phases of coagulation, cellular proliferation, and cellular interactions involved centrally in inflammatory processes provides an attractive target for pharmacologic inhibition. The development of direct thrombin inhibitors has evolved rapidly to include both intravenous and oral preparations. Hirudin is extracted from the parapharyngeal gland of the medicinal leech Hirudo medicinalis. Several derivatives and recombinant preparations have been developed, including the most widely used agent lepirudin (Refludan). Hirudin binds to both the catalytic and fibrinogen-binding sites of thrombin and thus is considered a bivalent inhibitor. The plasma half-life of hirudin is 50 to 65 minutes, with a biologic half-life of 2 hours (Verstraete et al., 1993). The properties of heparin, hirudin, and bivalirudin are highlighted in Table 16.1. The predominant renal clearance of hirudin must be emphasized for safe clinical use. Hirudin forms a tight complex with thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet aggregation (Verstraete, 1997). These actions are independent of the presence of antithrombin, and also affect thrombin bound to fibrin. On the downside, the ability of thrombin to complex with thrombomodulin, activating protein C, is also inhibited. Hirudin does not bind to platelet factor , nor does it elicit antibodies that induce platelet and endothelial cell activation; thus, it can be safely administered to patients with heparin induced thrombocytopenia (HIT). Hirudin does have weak immunogenicity, so diminished (or rarely increased) responsiveness after repeated dosing is possible. The use of hirudin in the management of heparin-induced thrombocytopenia is discussed in Chapter 29.

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