Thrombosis inhibitors

Since plasmin in free form (not bound to fibrin) is extremely and rapidly inactivated by the inhibitor system (Fig. 4), plasminogen activators are used for treatment of thrombosis. Under such a condition, if plasmin is formed by the activators (especially by tPA) at the site of fibrin, the bound form can degrade fibrin because it is protected against the inhibitor system. In the medical practice, mainly two endogenous plasminogen activators, tPA and uPA, and one exogenous, the streptokinase (SK) are used [1,4]. 

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. 

An important namral inhibitor of coagulation is antithrombin III genetic deficiency of this protein can result in thrombosis. 

Junghans U, Seitz RJ, Wittsack HJ, Aulich A, Siebler M. Treatment of acute basilar artery thrombosis with a combination of systemic alteplase and tirofiban, a nonpeptide platelet glycoprotein Ilb/HIa inhibitor report of four cases. Radiology 2001 221 795-801. 

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

The advent of COX-2-selective inhibitors has led to unexpected results. By selectively inhibiting the COX-2 isoform, COX-2-selective NSAIDs increase the risk of cardiovascular events in certain patientsP COX-2 is responsible for the production of prostacyclin, a vasodilatory and antiplatelet substance. On the other hand, COX-1 controls the production of thromboxane A2, a vasoconstrictor and platelet aggregator. Selective inhibition of COX-2 results in decreased prostacyclin levels in the face of stable thromboxane A2 levels. An imbalance in the thromboxane A2 prostacyclin ratio ensues, which creates an environment that favors thrombosis. 

Direct thrombin inhibitors such as hirudin, Hirulog, the peptide aldehyde efegatran, and peptidomimetic compound argatroban have undergone clinical trials. Their application in the prevention and treatment of deep vein thrombosis contin-... 

Alternatives to estrogen for hot flushes are shown in Table 31-6. Progesterone alone may be an option in women with a history of breast cancer or venous thrombosis, but side effects limit their use. For women with contraindications to hormone therapy, selective serotonin reuptake inhibitors and venlafaxine are considered by some to be first-line therapy, but efficacy of venlafaxine beyond 12 weeks has not been shown. 

Penicillins Proton pump inhibitors Chronic interstitial nephritis Cyclosporine Lithium Aristolochic acid Renal vasculitis, thrombosis, and cholesterol emboli ... 

Yamamoto, K. et al., Plasminogen activator inhibitor-1 is a major stress-regulated gene Implications for stress-induced thrombosis in aged individuals, Proc. Nat. Acad. Sci., 99, 890, 2002. 

A number of P3 position modified thrombin inhibitors exhibited oral bioavailability in rats and dogs, and were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compoimds like 151 and the corresponding... 

Non-peptide inhibitors of thrombin (obtained by random screening procedures) include compounds based around benzothiophene (e.g. 155) and other ring systems and cyclic and linear oligocarbamate derivatives (e.g. 156). The benzothiophene derivative 155 showed antithrombotic efficacy in a rat model of thrombosis after infusion (ED50 2.3 mg/kg/h). The cyclic oligocarbamate tetramer 156 inhibited thrombin with an apparent K[ of 31 nM. 

Answer Treatment of thrombosis can be initiated during pregnancy with infusion of argatroban, a direct inhibitor of thrombin. This drug does not cross the placenta and has not been reported to produce effects in the fetus. Argatroban is discontinued at the time of delivery, and thrombosis is then managed postpartum for 2 months with warfarin. 

Wang, X., Smith, P. L., Hsu, M. -Y, Ogletree, M. L., Schumacher, W. A. (2006). Murine model of ferric chloride-induced vena cava thrombosis evidence for effect of potato carboxypeptidase inhibitor. J. Thromb. Haemost., 4, 403 10. 

Morbidity and mortality in HIT are related to thrombotic events. Venous thrombosis occurs most commonly, but occlusion of peripheral or central arteries is not infrequent. If an indwelling catheter is present, the risk of thrombosis is increased in that extremity. Skin necrosis has been described, particularly in individuals treated with warfarin in the absence of a direct thrombin inhibitor, presumably due to acute depletion of the vitamin -dependent anticoagulant protein C occurring in the presence of high levels of procoagulant proteins and an active hypercoagulable state. 

A major focus of drug development has been to develop orally active anticoagulants that do not require monitoring. Rivaroxiban is the first oral factor Xa inhibitor to reach phase III clinical trials. The safety and efficacy of rivaroxiban appears to be at least equivalent, and possibly superior, to LMW heparins for prevention of deep vein thrombosis no routine monitoring is required. This drug is also in clinical trials for treatment of deep vein thrombosis and prevention of stroke in atrial fibrillation. 

Argatroban is a small molecule thrombin inhibitor that is FDA-approved for use in patients with 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 is monitored by aPTT. Its clearance is not affected by renal disease but is dependent on liver function dose reduction is required in patients with liver disease. Patients on argatroban will demonstrate elevated INRs, rendering the transition to warfarin difficult (ie, the INR will reflect contributions from both warfarin and argatroban). (INR is discussed in detail in the discussion of warfarin administration.) A nomogram is supplied by the manufacturer to assist in this transition. 

Vorinostat (Zolinza) is a histone deacetylase inhibitor that is approved for the treatment of cutaneous T-cell lymphoma in patients with progressive, persistent, or recurrent disease on or after two systemic therapies. The recommended dosing is 400 mg orally once daily. Adverse effects include pulmonary embolus, deep vein thrombosis, thrombocytopenia, anemia, and gastrointestinal disturbances. 

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