Fondaparinux in the Treatment of Heparin-Induced Thrombocytopenia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1775-1775 ◽  
Author(s):  
James Bradner ◽  
Robert K. Hallisey ◽  
David J. Kuter
Keyword(s):  
Massachusetts General Hospital ◽  
Prospective Trial ◽  
Cross Reactivity ◽  
High Risk Group ◽  
Thrombin Inhibitor ◽  
Type Ii ◽  
Platelet Factor ◽  
Platelet Recovery ◽  
Heparin Induced Thrombocytopenia

Abstract The development of new non-heparin anticoagulant therapies has increased interest in the treatment of type II heparin-induced thrombocytopenia (HIT). Standard therapy involves administration of an intravenous direct thrombin inhibitor (DTI), either argatroban or lepirudin. Due to a lack of cross-reactivity to HIT antibodies in vitro, the synthetic pentasaccharide fondaparinux sodium is an appealing alternative, but its use in this disorder has not been comprehensively examined. Here, we report our experience with fondaparinux in HIT and an analysis of safety and efficacy in this setting. We reviewed all in-patient cases of HIT at the Massachusetts General Hospital that were confirmed by the heparin-platelet factor 4 antibody test and were treated with fondaparinux. Twenty patients satisfied diagnostic criteria for HIT. Each patient studied lacked another competing, compelling etiology for thrombocytopenia and was treated with fondaparinux for more than five days within one month of diagnosis. The average duration of therapy was 17 days and 16 patients (80%) were treated within two weeks of diagnosis. Patients were grouped according to whether they received fondaparinux after initial therapy with a DTI (n=10) or as initial treatment following the diagnosis of HIT (n=10). The initial dose of fondaparinux administered was 2.5 mg in 18 patients. Neither absolute nor relative thrombocytopenia was identified in either group following treatment. Patients with HIT treated with fondaparinux while thrombocytopenic experienced platelet recovery on average in 3.7 days, as represented in Figure 1. In addition, there were no observed thrombotic complications among patients treated with fondaparinux. In this analysis of a high-risk group of inpatients with type-II HIT, fondaparinux was tolerated without the continuation or recurrence of thrombocytopenia. This suggests that cross-reactivity between the heparin-PF4 antibody and fondaparinux is not likely to be clinically significant. Additionally, the absence of thrombotic sequelae among fondaparinux-treated patients argues that fondaparinux may be a well-tolerated, effective treatment for this morbid, prothrombotic disorder. A prospective trial of fondaparinux in the treatment of type-II HIT is planned. Figure Figure

scholarly journals Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3791-3796 ◽  
Author(s):  
Theodore E. Warkentin ◽  
Richard J. Cook ◽  
Victor J. Marder ◽  
Jo-Ann I. Sheppard ◽  
Jane C. Moore ◽  
...  
Keyword(s):  
Cross Reactivity ◽  
Platelet Factor 4 ◽  
Low Molecular Weight ◽  
Igg Antibodies ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Antithrombotic Prophylaxis ◽  
High Concentrations ◽  
To Receive

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.

Successful Use of Bivalirudin in the Treatment of Patients Suspected, or at Risk of, Heparin-Induced Thrombocytopenia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4077-4077 ◽  
Author(s):  
John L. Francis ◽  
Alane Drexler ◽  
Gage Gwyn ◽  
Rebecca Moroose
Keyword(s):  
Severe Renal Impairment ◽  
Retrospective Chart Review ◽  
Heparin Therapy ◽  
Thrombin Inhibitor ◽  
Published Data ◽  
Minor Effect ◽  
Platelet Factor ◽  
Platelet Recovery ◽  
Heparin Induced Thrombocytopenia ◽  
Increased Risk

Abstract Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy. As thrombosis occurs in 50% of untreated patients, prompt treatment with a direct thrombin inhibitor (DTI) is recommended. Lepirudin and argatroban are currently approved for the treatment of HIT. However, their use is complicated by antibody formation with potential for anaphylactic shock (lepirudin), effects on the PT/INR that complicate transition to coumadin (argatroban), and significant dose adjustments in patients with renal (lepirudin) or liver (argatroban) impairment. The effectiveness of bivalirudin, another DTI, as a replacement for heparin has been well documented in percutaneous coronary intervention, but there are little published data on its use in treating HIT. We now report our experience with bivalirudin in 52 patients with clinical suspicion of HIT, or at increased risk of this complication. HIT was suspected on the basis of a falling platelet count and/or thrombosis in the setting of current or recent heparin therapy (n=49). Patients were considered at increased risk of HIT if they required ongoing intravenous anticoagulation in a setting associated with a high incidence of heparin-platelet factor 4 (HPF4) antibodies (n=3). Data were collected by retrospective chart review, and patients classified according to whether HIT was very likely (n=13), likely (n=17), unlikely (n=11) or very unlikely (n=11). Bivalirudin was given by intravenous infusion, typically at an initial dose of 0.15 - 0.20 mg/kg/h and adjusted to achieve an APTT of approximately 1.5–2.5 x baseline. Twenty-one patients had moderate or severe renal impairment. The infusion rate was significantly lower for patients with severe renal insufficiency, but was not different in those with mild renal dysfunction. ELISA-detectable HPF4 antibodies were present in 43/52 cases. Twenty-seven patients were significantly thrombocytopenic (<100,000 x 109/L) and 22 had thrombosis before therapy. Transition to warfarin was achieved in 44/52 patients with a median overlap of therapy of 4 (0.5–14) days. Bivalirudin therapy was continued for an average of 8.0 (3–47) days, and had a relatively minor impact on the PT/INR. The mean INR on monotherapy was 1.50 (1.23–2.18) with a mean change in INR due to bivalirudin therapy of 0.33 ± 0.22. Therapeutic APTTs were achieved in all patients, with approximately 92.5% of tests in the desired range. The average time to platelet recovery was 3.0 (1–10) days. There were no cases of major bleeding, no deaths attributable to HIT, and no patient required amputation. We conclude that bivalirudin provides safe and effective anticoagulation for patients with suspected HIT, as well as for those with an increased risk of HIT that require intravenous anticoagulation. Potential advantages of bivalirudin include the relatively minor effect on the PT, which facilitates transition to warfarin therapy, and its short half-life in patients at high risk of bleeding or who require invasive procedures at short notice.

In vitro cross-reactivity of danaparoid sodium in patients with heparin-induced thrombocytopenia type II undergoing cardiovascular surgery

2000 ◽  
Vol 12 (4) ◽  
pp. 324-327 ◽  
Author(s):  
Andreas Koster ◽  
Oliver Meyer ◽  
Harald Hausmann ◽  
Herrmann Kuppe ◽  
Roland Hetzer ◽  
...  
Keyword(s):  
Cardiovascular Surgery ◽  
Cross Reactivity ◽  
Type Ii ◽  
Danaparoid Sodium ◽  
Heparin Induced Thrombocytopenia

Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia

2016 ◽  
Vol 116 (11) ◽  
pp. 813-822 ◽  
Author(s):  
Theodore E. Warkentin
Keyword(s):  
Correct Diagnosis ◽  
Cross Reactivity ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Delayed Onset ◽  
Timing Of Onset ◽  
Fatal Haemorrhage ◽  
Heparin Exposure

SummaryHIT is an acquired antibody-mediated disorder strongly associated with thrombosis, including microthrombosis secondary to disseminated intravascular dissemination (DIC). The clinical features of HIT are reviewed from the perspective of the 4Ts scoring system for HIT, which emphasises its characteristic timing of onset of thrombocytopenia. HIT antibodies recognize multimolecular complexes of platelet factor 4 (PF4)/heparin. However, a subset of HIT sera recognise PF4 bound to platelet chondroitin sulfate; these antibodies activate platelets in vitro and in vivo even in the absence of heparin, thus explaining: delayed-onset HIT (where HIT begins or worsens after stopping heparin); persisting HIT (where HIT takes several weeks to recover); spontaneous HIT syndrome (a disorder clinically and serologically resembling HIT but without proximate heparin exposure); and fondaparinux-associated HIT (four distinct syndromes featuring thrombocytopenia that begins or worsens during treatment with fondaparinux), with a new patient case presented with ongoing thrombocytopenia (and fatal haemorrhage) during treatment of HIT with fondaparinux, with fondaparinux-dependent platelet activation induced by patient serum (“fondaparinux cross-reactivity”). Ironically, despite existence of fondaparinux-associated HIT, this pentasaccharide anticoagulant is a frequent treatment for HIT (including one used by the author). HIT can be confused with other disorders, including those with a) timing similar to HIT (e. g. abciximab-associated thrombocytopenia of delayed-onset); b) combined thrombocytopenia/thrombosis (e. g. symmetrical peripheral gangrene secondary to acute DIC and shock liver); and c) both timing of onset and thrombosis (e. g. warfarin-associated venous limb gangrene complicating cancer-associated DIC). By understanding clinical and pathophysiological similarities and differences between HIT and non-HIT mimicking disorders, the clinician is better able to make the correct diagnosis.

Combined Thrombin and Platelet Inhibition Treatment for HIT Patients

1999 ◽  
Vol 19 (03) ◽  
pp. 128-133 ◽  
Author(s):  
B.E. Lewis ◽  
W. P. Jeske ◽  
F. Leya ◽  
Diane Wallis ◽  
M. Bakhos ◽  
...  
Keyword(s):  
Standard Dose ◽  
Combined Therapy ◽  
Platelet Inhibition ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Heparin Induced Thrombocytopenia ◽  
Acute Thrombosis ◽  
Anti Platelet Drug ◽  
Receptor Inhibitor

SummaryDespite the use of potent anticoagulants such as r-hirudin and argatroban, the morbidity and mortality in heparin-induced thrombocytopenia (HIT) patients remains unacceptable. Data from our in vitro investigations show that thrombin inhibitors do not block platelet activation induced by heparin antibodies and heparin but that GPIIb/IIIa receptor inhibitors do block this process. We have treated four HIT positive patients with a combined therapy of thrombin inhibitor and GPIIb/IIIa receptor inhibitor when treatment with thrombin inhibitor alone failed to alleviate acute thrombosis. Combination therapies included r-hirudin (Refludan®) with tirofiban (Aggrastat®) and argatroban (Novastan®) with abciximab (ReoPro®). A reduced dose of the thrombin inhibitor was used with the standard dose of the anti-platelet drug. In all cases, there was no overt bleeding which required intervention, and all patients exhibited clinical improvement or full recovery. These case studies suggest that treatment of active thrombosis in HIT patients with adjunct GPIIb/IIIa receptor inhibitor therapy may be more effective than thrombin inhibitor treatment alone.

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.

Diagnosis and treatment of heparin-induced thrombocytopenia

Perfusion ◽  
2003 ◽  
Vol 18 (1) ◽  
pp. 47-53 ◽  
Author(s):  
William J DeBois ◽  
Junli Liu ◽  
Leonard Y Lee ◽  
Leonard N Girardi ◽  
Charles Mack ◽  
...  
Keyword(s):  
New York ◽  
Platelet Inhibition ◽  
Heparin Therapy ◽  
Serotonin Release ◽  
Antibody Detection ◽  
Thrombin Inhibitor ◽  
Heparin Infusion ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Life Threatening

Heparin-induced thrombocytopenia (HIT) is a major side effect secondary to the administration of heparin. This syndrome is serious and potentially life threatening. This response is the result of antibodies formed against the platelet factor 4 (PF4)/heparin complex. The incidence of this immune-mediated syndrome has been estimated to be 1-3% of all patients receiving heparin therapy. The occurrence of HIT in patients requiring full anticoagulation for cardiopulmonary bypass (CPB), therefore, presents a serious challenge to the cardiac surgery team. The diagnosis of HIT should be based on both clinical and laboratory evidence. While functional assays, platelet aggregation tests, and the serotonin release assay can be used to support the diagnosis, the negative predictive value of these tests is generally less than 50%. In contrast, although non-functional antibody detection assays are more sensitive, they have a low specificity. HIT can be treated in several ways, including cessation of all heparin and giving an alternative thrombin inhibitor, platelet inhibition followed by heparin infusion, and the use of low molecular weight heparins. In this presentation, the pathology and current diagnostic tests, as well as the successful management of patients with HIT undergoing CPB at New York Presbyterian Hospital, are reviewed.

Serologic Results in >1000 Patients With Suspected Heparin-Induced Thrombocytopenia

2007 ◽  
Vol 14 (4) ◽  
pp. 410-414 ◽  
Author(s):  
Suresh G. Shelat ◽  
Anne Tomaski ◽  
Eleanor S. Pollak
Keyword(s):  
Laboratory Diagnosis ◽  
Serotonin Release ◽  
Enzyme Linked Immunosorbent Assay ◽  
Functional Assay ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Life Threatening ◽  
Release Assay ◽  
Pathogenic Antibodies

Heparin-induced thrombocytopenia (HIT) can lead to life-threatening and limb-threatening thrombosis. HIT is thought to be initiated by the interaction of pathogenic antibodies toward a complex platelet factor 4 (PF4) and heparin (PF4:H), which can activate platelets and predispose to thrombosis. As such, the laboratory diagnosis of HIT includes antigenic and functional assays to detect antibodies directed at PF4:H complexes. We performed a retrospective analysis of 1017 consecutive samples tested by serotonin-release assay and by enzyme-linked immunosorbent assay (ELISA). Most samples showed no serologic evidence of HIT, whereas 4% to 5% of samples demonstrated both antigenic and functional serological evidence for HIT. Approximately 12% to 18% of samples showed immunologic evidence of anti-PF4:H antibodies but without functional evidence of serotonin release in vitro. Interestingly, a small minority of samples (0.7%) caused serotonin release but were negative in the ELISA. The results are presented using cutoff values established at our hospital and for the ELISA manufacturer. This study provides a pretest probability of the serologic results from an antigenic assay (ELISA) and a functional assay (serotonin-release assay) in patients clinically suspected of having HIT.

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

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