Thrombosis heparin-induced

Figure 24.4 The decision-analytic model shows the three strategies that were examined by Arnold and researchers [22] to evaluate the financial implications of the direct thrombin inhibitor argatroban for early treatment (<48 hours after thrombocytopenia onset), compared with delayed treatment, of heparin-induced thrombocytopenia (HIT) with or without thrombosis.

Arnold R, Kim R, Zhou Y, Tang B. Budgetary impact of heparin-induced thrombocytopenia with thrombosis and treatment with the direct thrombin inhibitor Argatroban (P401E). ASHP 39th Midyear Clinical Meeting. Orlando, FL, 2004. 

DVT, deep vein thrombosis HIT, heparin-induced thrombocytopenia PAI-I, plasminogen activator inhibitor PE, pulmonary embolism SERM, selective estrogen receptor modulator VTE, venous thromboembolism. 

Heparin-induced thrombocytopenia A clinical syndrome of IgG antibody production against the heparin-platelet factor 4 complex occurring in approximately 1% to 5% of patients exposed to either heparin or low-molecular-weight heparin. Heparin-induced thrombocytopenia results in excess production of thrombin, platelet aggregation, and thrombocytopenia (due to platelet clumping), often leading to venous and arterial thrombosis, amputation of extremities, and death. 

Franchini, M, Heparin-induced thrombocytopenia An update, Thrombosis, 3, 14, 2005. 

Heparin-induced thrombocytopenia Warfarin should be used with caution in patients with heparin-induced thrombocytopenia and deep venous thrombosis. 

Thrombosis, prophylaxis or treatment As an anticoagulant for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT). 

Initial dosage in HIT or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) Before administering argatroban, discontinue heparin therapy and obtain a baseline activated partial thromboplastin time (aPTT). The recommended initial dose of argatroban for adults without hepatic impairment is 2 mcg/kg/min administered as a continuous infusion (see table). 

A 23-year old pregnant woman who has been administered IV heparin for treatment of deep vein thrombosis has developed heparin-induced thrombocytopenia. Altering therapy by removing heparin and adding warfarin is not a viable option, because warfarin can cross the placenta and exert an anticoagulant effect in the fetus. Suggest a treatment approach. 

Latham P, et al. Use of recombinant hirudin in patients with heparin-induced thrombocytopenia with thrombosis requiring cardiopulmonary, bypass. Anesthesiology 2000 92 263-6. 

Heparin-induced thrombocytopenia (HIT) can likewise be asymptomatic and resolve spontaneously (type I HIT), or it can be severe (type II HIT). Type II HIT is mediated by an immune reaction, which can lead to serious complications including increased thrombosis in vascular tissues throughout the... 

Argatroban is a small molecule thrombin inhibitor that is FDA approved for use in patients with heparin-induced thrombocytopenia (HIT) with or without thrombosis and coronary angioplasty in patients with HIT. It, too, has a short half-life, is given by continuous intravenous infusion, and monitoring is done by aPTT. Its clearance is not affected by renal disease but is dependent on liver function. The drug requires dose reduction in patients with liver disease. Patients on argatroban will demonstrate elevated INRs because of test interference, rendering the transition to warfarin difficult. 

Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med 1995 332 1374-1376. 

Jang IK, Hursting MJ. When heparins promote thrombosis review of heparin-induced thrombocytopenia. Circulation 2005 I I 1 2671-2683. 

Lubenow N, Eichler R Lietz T, et al, Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia an analysis of three prospective studies, Blood 2004 104 3072-3077. 

Thrombotic thrombocytopenic purpura is a rare acute or subacute disease in adults, rather similar to the hemolytic uremic syndrome in children, in which there is systemic malaise, fever, skin purpura, renal failure, hematuria and proteinuria. Hemorrhagic infarcts caused by platelet microthrombi occur in many organs in the brain they may cause stroke-like episodes (Matijevic and Wu 2006) although more commonly there is global encephalopathy. The blood film shows thrombocytopenia, hemolytic anemia and fragmented red cells. The differential diagnosis includes infective endocarditis, idiopathic thrombocytopenia, heparin-induced thrombocytopenia with thrombosis, systemic lupus erythematosus, non-bacterial thrombotic endocarditis and disseminated intravascular coagulation. 

For the past few decades, heparin has been widely used for the prevention of postoperative thiomboemboUsm (6,7). However, there are several adverse side-effects associated with the use of heparin such as bleeding, heparin induced thrombocytopenia, heparin induced thrombosis (8,9) and osteoporosis (10). In addition, the regimen of pioph actic heparin used in the prevention of deep venous thrombosis (DVT) is tedious, requiring 2 to 3 daily injections because of the limited bioavailability and short half-life of heparin when administered subcutaneously. 

Argatroban has been approved in the USA and Canada for the prophylaxis and treatment of thrombosis in patients with heparin-induced thrombocytopenia, and in Japan and Korea for various thrombotic disorders. Its effects can be monitored using the activated partial thromboplastin time for low doses and the activated clotting time for high doses. Its pharmacology, clinical pharmacology, and uses have been reviewed (7-14). 

A third variety, so-called delayed-onset heparin-induced thrombocytopenia has also been described in several reports. In 12 patients, recruited from secondary and tertiary care hospitals, thrombocytopenia and associated thrombosis occurred at a mean of 9.2 (range 5-19) days after the withdrawal of heparin nine received additional heparin, with further falls in platelet counts (32). In a retrospective case series, 14 patients, seen over a 3-year period, developed thromboembolic complications a median of 14 days after treatment with heparin (33). The emboli were venous (n — 10), or arterial (n — 2), or both (n — 2) of the 12 patients with venous embolism, 7 had pulmonary embolism. Platelet counts were mildly reduced in all but two patients at the time of the second presentation. On readmission, 11 patients received therapeutic heparin, which worsened their clinical condition and further reduced the platelet count. 

Venous limb gangrene due to heparin-induced thrombocytopenia is characterized by distal tissue losses, with extensive venous thrombosis involving large veins and small venules (53). This reaction seems to be related to acquired deficiency of protein C induced by concomitant oral anticoagulants. 

From the therapeutic point of view, prophylaxis of thrombosis must be continued after withdrawal of heparin, since even when there is no evidence of thrombosis in association with heparin-induced thrombocytopenia, thrombosis can follow after some days (52). Because of cross-reactivity, low molecular weight heparin should not be used when heparin has been withdrawn because of heparin-induced thrombocytopenia nor should warfarin be used, because of the risk of venous gangrene, at least until the thrombocytopenia has resolved. Patients with life-threatening or limb-threatening thrombosis can be treated with thrombolytic drugs. Current views are that two antithrombotic drugs should be used, for example danaparoid plus lepirudin (58). 

Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001 135(7) 502-6. 

Warkentin TE, Bernstein RA. Delayed-onset heparin-induced thrombocytopenia and cerebral thrombosis after a single administration of unfractionated heparin. N Engl J Med 2003 348(ll) 1067-9. 

Boshkov LK, Warkentin TE, Hayward CP, Andrew M, Kelton JG. Heparin-induced thrombocytopenia and thrombosis clinical and laboratory studies. Br J Haematol 1993 84(2) 322-8. 

Two forms of heparin-induced thrombocytopenia (HIT) have been observed. The first (HIT I) is a transient, mild, and benign thrombocytopenia seen soon after initiation of heparin therapy (normally within 2 days) and is felt to be due to inherent plateletaggregating properties of heparin. A second, more severe form of HIT (HIT II) is typically seen later and is immune-mediated. The incidence of HIT II is estimated at 3-5%. The onset is generally 3-14 days after initiation of heparin therapy but may occur sooner with repeat exposure. HIT II may occur with any dose and type of heparin, but the frequency is highest with continuous intravenous infusions of unfractionated heparin. HIT with subsequent thrombosis is a feared complication. These thrombi can form in the venous or arterial circulation. Thrombotic complications include necrotic skin lesions, myocardial infarction, stroke, and gangrene. Hyperkalemia may be seen with heparin therapy due to aldosterone synthesis inhibition. 

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