Heparin-induced Thrombocytopenia: Pathophysiology, Diagnosis, and Review of Pharmacotherapy

2009 ◽  
Vol 22 (2) ◽  
pp. 149-157 ◽  
Author(s):  
Abir O. Kanaan ◽  
A. Samer Al-Homsi
Keyword(s):  
Myocardial Infarction ◽  
Adverse Drug Reaction ◽  
Randomized Trials ◽  
Clinical Presentation ◽  
Case Reports ◽  
Heparin Therapy ◽  
Thrombin Inhibitors ◽  
Limb Amputation ◽  
Direct Thrombin Inhibitors ◽  
Heparin Induced Thrombocytopenia

Heparin-induced thrombocytopenia is an adverse drug reaction to heparin therapy leading to devastating clinical outcomes including venous thromboembolism, myocardial infarction, stroke, and limb amputation. Heparin cessation alone is not sufficient for the management of heparin-induced thrombocytopenia. Direct thrombin inhibitors, such as argatroban and lepirudin, are considered the mainstay for the management of heparin-induced thrombocytopenia. Case reports support the use of fondaparinux in the management of heparin-induced thrombocytopenia; however, randomized trials are still lacking. This article will review the pathophysiology, clinical presentation, complications, diagnosis, and pharmacotherapy management of heparin-induced thrombocytopenia.

scholarly journals Heparin-Induced Thrombocytopenia in the Pediatric Population: A Review of Current Literature

2012 ◽  
Vol 17 (1) ◽  
pp. 12-30
Author(s):  
Niyati H Vakil ◽  
Abir O Kanaan ◽  
Jennifer L Donovan
Keyword(s):  
Case Reports ◽  
Pediatric Population ◽  
Subsequent Treatment ◽  
Thrombin Inhibitors ◽  
Limb Amputation ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Heparin Induced Thrombocytopenia ◽  
Disease States ◽  
Key Terms

Heparin-induced thrombocytopenia is a rare and serious reaction to unfractionated heparin and low-molecular-weight heparins in children. Quick recognition, discontinuation of heparin, and subsequent treatment with an alternative anticoagulant are essential steps to prevent serious complications such as thrombus and limb amputation. The purpose of this review is to describe the clinical features of heparin-induced thrombocytopenia in children and to summarize the data available for its management. This paper summarizes data and relates the use of direct thrombin inhibitors with clinical outcomes. A literature search was conducted with Ovid, using the key terms argatroban, bivalirudin, hirulog, danaparoid, lepirudin, direct thrombin inhibitor, heparin-induced thrombocytopenia, thrombosis, warfarin, and fondaparinux. Articles were excluded if they were classified as editorials, review articles, or conference abstracts or if they involved patients 18 years of age or older or described disease states not related to thrombosis. Nineteen articles containing 33 case reports were identified and evaluated for this review. Of the 33 cases, 14, 10, 4, and 2 cases described the use of lepirudin, danaparoid, argatroban, and bivalirudin, respectively. Two cases did not report the type of anticoagulant used, and 1 case used aspirin. The most commonly reported complication was bleeding.

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.

Heparin-Induced Thrombocytopenia in Neonates

2005 ◽  
Vol 24 (5) ◽  
pp. 33-37 ◽  
Author(s):  
Julie Martchenke ◽  
Lynn Boshkov
Keyword(s):  
Heart Surgery ◽  
Heparin Therapy ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Type I ◽  
Type Ii ◽  
Heparin Induced Thrombocytopenia ◽  
Heparin Administration ◽  
Immune Mediated ◽  
Limiting Condition

Heparin-induced thrombocytopenia (HIT), an immune-mediated response to heparin administration, has been recognized in adults for some time, but only recently recognized in neonates and children. HIT Type I is a mild, self-limiting condition. HIT type II is a severe immune reaction to heparin that leads to thrombocytopenia and often thromboembolic complications. The incidence of HIT Type II is 2–5 percent in adults on heparin products and may be as high in neonates and children. The mortality rate from HIT in adults is 7–30 percent and is unknown but potentially high in newborns as well. The cardinal sign of HIT is a drop in platelet count by 50 percent or platelet counts below 70,000–100,000/mm3. This drop usually occurs five to ten days after the first exposure to heparin. Treatment is immediate cessation of all heparin therapy and initiation of alternative anticoagulants, especially the direct thrombin inhibitors lepirudin and argatroban. This article reviews the literature on HIT and presents a case of neonatal HIT following heart surgery.

The uncalibrated prothrombinase-induced clotting time test

2010 ◽  
Vol 30 (04) ◽  
pp. 212-216 ◽  
Author(s):  
R. Jovic ◽  
M. Hollenstein ◽  
P. Degiacomi ◽  
M. Gautschi ◽  
A. Ferrández ◽  
...  
Keyword(s):  
Factor Xa ◽  
Heparin Therapy ◽  
Thrombin Inhibitors ◽  
Coagulation Cascade ◽  
Diagnostic Tools ◽  
Direct Thrombin Inhibitors ◽  
Functional Assay ◽  
Clotting Time ◽  
Coagulation Time ◽  
Time Test

SummaryThe activated partial thromboplastin time test (aPTT) represents one of the most commonly used diagnostic tools in order to monitor patients undergoing heparin therapy. Expression of aPTT coagulation time in seconds represents common practice in order to evaluate the integrity of the coagulation cascade. The prolongation of the aPTT thus can indicate whether or not the heparin level is likely to be within therapeutic range. Unfortunately aPTT results are highly variable depending on patient properties, manufacturer, different reagents and instruments among others but most importantly aPTT’s dose response curve to heparin often lacks linearity. Furthermore, aPTT assays are insensitive to drugs such as, for example, low molecular weight heparin (LMWH) and direct factor Xa (FXa) inhibitors among others. On the other hand, the protrombinase-induced clotting time assay (PiCT®) has been show to be a reliable functional assay sensitive to all heparinoids as well as direct thrombin inhibitors (DTIs). So far, the commercially available PiCT assay (Pefakit®-PiCT®, DSM Nutritional Products Ltd. Branch Pentapharm, Basel, Switzerland) is designed to express results in terms of units with the help of specific calibrators, while aPTT results are most commonly expressed as coagulation time in seconds. In this report, we describe the results of a pilot study indicating that the Pefakit PiCT UC assay is superior to the aPTT for the efficient monitoring of patients undergoing UFH therapy; it is also suitable to determine and quantitate the effect of LMWH therapy. This indicates a distinct benefit when using this new approach over the use of aPPT for heparin monitoring.

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.

scholarly journals Use of Edoxaban for the Treatment of Heparin-Induced Thrombocytopenia

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Ryo Kanamoto ◽  
Shinichi Hiromatsu ◽  
Tomoyuki Anegawa ◽  
Kanako Sakurai ◽  
Shohei Yoshida ◽  
...  
Keyword(s):  
Adverse Drug Reaction ◽  
Esophageal Cancer ◽  
Oral Treatment ◽  
Length Of Hospital Stay ◽  
Heparin Therapy ◽  
Vitamin K Antagonist ◽  
Bleeding Complications ◽  
Heparin Induced Thrombocytopenia ◽  
Life Threatening

Heparin-induced thrombocytopenia (HIT) is a life-threatening adverse drug reaction of heparin therapy, which increases a patient’s risk of developing venous and/or arterial thromboembolism. HIT should be treated through discontinuation of heparin and administration of nonheparin anticoagulants such as argatroban. For long-term anticoagulation, parenteral nonheparin anticoagulants are generally converted to oral treatment with a vitamin K antagonist such as warfarin. Although administration of warfarin is recommended to overlap with a nonheparin anticoagulant for a minimum of 5 days, overlapping with argatroban and warfarin presents high risks of bleeding. We describe a case of HIT treated with edoxaban. A 78-year-old man underwent surgery for esophageal cancer and was administered heparin perioperatively. After surgery, he was diagnosed with HIT and venous thromboembolism. We immediately stopped heparin and initiated parenteral argatroban. The patient was subsequently started on edoxaban without any overlap between the two drugs. The treatment was successful. The treatment of edoxaban following argatroban for HIT could reduce bleeding complications and shorten the length of hospital stay. To the best of our knowledge, this is the first report of the use of edoxaban for HIT treatment.

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