From confusion to clarity: Direct thrombin inhibitors for patients with heparin-induced thrombocytopenia

2001 ◽  
Vol 52 (4) ◽  
pp. 473-475 ◽  
Author(s):  
John A. Bittl
Keyword(s):  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Heparin Induced Thrombocytopenia

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.

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.

Decreasing Adverse Drug Events Associated with Lepirudin and Argatroban for the Treatment of Heparin-Induced Thrombocytopenia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1787-1787 ◽  
Author(s):  
Molly McDaniel ◽  
Gerald A. Soff
Keyword(s):  
Case Reports ◽  
Significant Risk ◽  
Thrombin Inhibitors ◽  
Recommended Dose ◽  
Physician Education ◽  
Direct Thrombin Inhibitors ◽  
Poor Correlation ◽  
Close Monitoring ◽  
Heparin Induced Thrombocytopenia ◽  
The Mean

Abstract Purpose: Case reports, as well as our anecdotal experience, revealed frequently elevated activated partial thromboplastin time (aPTT) levels in some patients on the direct thrombin inhibitors (DTI) lepirudin and argatroban when dosed according to the FDA-approved guidelines in the Product Inserts. We analyzed our institution’s experience with these agents to determine if dosing guidelines need reconsideration. Methods: A retrospective chart review was conducted under the auspices of the pharmacy quality management team, with IRB approval. Cases were from the pharmacy database of all patients that received lepirudin or argatroban from September 2002 through March 2004. Sixty-six cases were identified and reviewed. Results: Patients were treated with the DTI for Heparin Induced Thrombocytopenia, with or without thrombosis (HIT, HITT), based on a decline of platelet count on heparin by 50% or to <100,000/uL (70%, n=46), and/or a positive HIPA ELISA (27%, n=18). 39 patients received lepirudin and 27 patients argatroban. The mean dose of the DTI which resulted in a therapeutic aPTT (55–80 sec) was calculated for each patient. The mean lepirudin dose resulting in therapeutic aPTT was 0.071 mg/kg/hr with 35 (90%) of patients requiring less than the recommended dose of 0.15mg/kg/hr. Only 4 (10%) patients had a mean dose at or above the recommended dose. 19 (49%) patients required 0.05 mg/kg/hr or lower. The mean argatroban dose resulting in therapeutic aPTT was 1.52 mcg/kg/min. 18 (67%) of patients required less than the recommended dose, 4 (15%) patients had a dose equal to the recommended, and only 5 (18%) had a mean dose above the recommended dose. aPTT levels were therapeutic or supratherapeutic a majority of the time in both groups, even though the dosing of the two DTI was overall lower than the recommended dosing. Furthermore, for many of the patients with both agents, there was a poor correlation between the dose of the DTI and the resulting aPTT, making it difficult to predict the resulting aPTT for a given dose adjustment of the DTI. Lastly, twenty occurrences of written prescription errors in five patients receiving argatroban were identified. These errors were due to the confusion between the dosing of argatroban as mcg/kg/min and not mg/kg/hr. The incorrect dose of argatroban was not dispensed to any patient. Conclusion: The DTI, Lepirudin and argatroban, used for HIT/HITT lack specific dosing titration guidelines, yet they require careful dosing and close monitoring for safe use. As with any acute anticoagulant, they carry a significant risk of life-threatening hemorrhage. Results of this study suggest that current dosing recommendations for both agents are too high, and that for safer use with lower risk of hemorrhage, the dosing guidelines need to be lowered. And while it is not likely that the prescribing errors for argatroban will be administered by pharmacy departments and nurses, the appropriateness of dosing the agent as mcg/kg/min as opposed to the more typical mg/kg/hr should be addressed, at least by greater physician education and possibly by altering the product insert. This study also supports that both lepirudin and argatroban should be considered high-alert medications requiring special attention by experienced clinicians.

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 Direct Thrombin Inhibitor Resistance and Possible Mechanisms

2016 ◽  
Vol 51 (11) ◽  
pp. 922-927 ◽  
Author(s):  
Maria Cardinale ◽  
Michael Ha ◽  
Michael H. Liu ◽  
David P. Reardon
Keyword(s):  
International Normalized Ratio ◽  
Resistance Mechanisms ◽  
Direct Thrombin Inhibitor ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Heparin Induced Thrombocytopenia ◽  
Vein Thrombosis ◽  
Inhibitor Resistance ◽  
Deep Vein

Objective To report 3 cases in which doses of bivalirudin higher than commonly used in clinical practice were required in order to achieve therapeutic anticoagulation as monitored by the activated partial thromboplastin time (aPTT). Case Summary The medical records of 3 patients who required large doses of bivalirudin to remain therapeutic were thoroughly reviewed. In all 3 patients, bivalirudin was initiated at a rate appropriate for the patients' renal function and titrated using a nurse-driven protocol with recommended dose adjustments based on aPTT. Indications for bivalirudin were anticoagulation in intra-aortic balloon pump, treatment of deep vein thrombosis, and heparin-induced thrombocytopenia with thrombosis. Target aPTT was achieved between 25.5 and 134 hours after initiation despite appropriate titration intervals per protocol. Discussion Bivalirudin is a direct thrombin inhibitor frequently used off-label for the medical management of heparin-induced thrombocytopenia. It typically exhibits predictable, dose-dependent anticoagulation. Heparin-induced thrombocytopenia was suspected in 2 of the 3 cases and confirmed in 1. In all 3 patients, target aPTT was initially achieved with doses between 0.456 and 1.0 mg/kg/h after a median of 30.7 hours; up to 1.8 mg/kg/h was required to maintain therapeutic aPTT. In 2 of the cases, the international normalized ratio also increased unexpectedly upon achievement of therapeutic aPTT values. Conclusion Direct thrombin inhibitors may be subject to resistance mechanisms similar to those previously described in patients receiving heparin. The anticoagulation status of these patients remains unknown.

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