Thrombocytopenia inhibitors

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. 

Milrinone and inamrinone work by inhibiting phosphodiesterase III, the enzyme responsible for the breakdown of cAMP. The increase in cAMP levels leads to increased intracellular calcium concentrations and enhanced contractile force generation. Milrinone has replaced inamrinone as the phosphodiesterase inhibitor of choice due to the higher frequency of thrombocytopenia seen with inamrinone. 

Doses and contraindications to glycoprotein Ilb/IIIa receptor blockers are described in Table 5-2. Major bleeding and rates of transfusion are increased with administration of a glycoprotein Ilb/IIIa receptor inhibitor in combination with aspirin and an anticoagulant,30 but there is no increased risk of intracranial hemorrhage in the absence of concomitant fibrinolytic treatment. The risk of thrombocytopenia with tirofiban and eptifibatide appears lower than that with abciximab. Bleeding risks appear similar between agents. 

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

Anagrelide -inhibitor of platelet aggregation which causes thrombocytopenia -cardiovascular effects (CHF, edema, palpitations) -anemia -nausea and vomiting -headache... 

GP Ilb/IIIa inhibitors may increase the risk of bleeding, especially if given in the setting of recent (<4 hours) administration of fibrinolytic therapy. An immune-mediated thrombocytopenia occurs in about 5% of patients. 

The results of these studies showed a remarkable similarity in the effects produced by the selective DPP-8 inhibitor and a//o-isoleucyl thiazolidide [21]. Both compounds produced mortality and alopecia at the highest doses tested, and both also produced thrombocytopenia of similar magnitude at doses >30mpk, and enlarged spleens and lymph nodes at all doses tested. The QPP selective inhibitor produced significant reductions in reticulocyte counts at the 100 mpk dose. No other changes were noted. In contrast to the above compounds,... 

The antagonistic properties of FR 900452 have also been examined in a model of endotoxin shock, the haemodynamic and haematological manifestations of this condition closely resembling the changes induced by PAF. FR 900452 (10 mg/kg, i.v.) almost completely prevents PAF (1 /ig/kg, i.v.)-induced thrombocytopenia and leukocytopenia in rabbits [295]. It also significantly inhibits endotoxin (E. coli LPS, 30 /ig/kg, i.v.)-induced thrombocytopenia but not leukocytopenia. The same dose of FR 900452 also causes the decreased arterial blood pressure to return to normal in the endotoxin-induced rat hypotension model, an effect also reported for other PAF inhibitors [121, 274], Finally, FR 900452 has been tested for its therapeutic effect on rat nephrosis induced by aminonucleoside (puromycin, 100 mg/kg, i.p.). At 100 mg/kg twice a day orally for 6 days, the agent significantly reduces urinary protein loss in nephrotic rats [298]. 

An intravenous infusion of PAF causes rapid (within 60 s) intravascular platelet aggregation, thrombocytopenia and platelet factor 4 release, as well as a profound and reversible neutropenia, due to enhanced aggregation and adherence of these cells. In vitro, PAF effects on neutrophils are dependent upon extracellular Ca2+ and Mg2+ and occur within 60 s of addition. The addition of inhibitors of 5-lipoxygenase activity (e.g. ETYA, 5,8,11,14-eicosatetraenoic acid and NDGA, nordihydroguaiaretic acid) - but not those... 

Alprostadil JProstaglandin E ] (Prostin VR) [Vasodilator/ Prostaglandin] WARNING Apnea in up to 12% of neonates esp <2 kg at birth Uses Conditions ductus arteriosus blood flow must be maintained sustain puhn/systemic circulation until OR (eg, pulm atresia/stenosis and transposition) Action Vasodilator (ductus arteriosus very sensitive), pit inhibitor Dose 0.05 mcg/kg/min IV to lowest that maintains response Caution [X, -] Contra Neonatal resp distress synd Disp Inj meg SE Cutaneous vasodilation, Sz like activity, jitteriness, T temp, thrombocytopenia, BP may cause apnea Interactions T Effects OF anticoagulants antihypertensives, effects OF cyclosporine EMS Given to newborns in hospital OD May cause apnea, bradycardia, hypotension, and flushing symptomatic and supportive... 

WARNING Renal impair is the major tox foUow administration instructions Uses CMV retinitis w/ HIV Action Selective inhibition of viral DNA synth Dose Rx 5 mg/kg IV over 1 h once/wk for 2 wk w/ probenecid Maint 5 mg/kg IV once/2 wk w/ probenecid (2 g PO 3 h prior to cidofovir, then 1 g PO at 2 h 8 h after cidofovir) X in renal impair Caution [C, -] Contra Probenecid or sulfa allergy Disp Inj SE Renal tox, chills, fever, HA, NA /D, thrombocytopenia, neutropenia Interactions t Nephrotox W/ aminoglycosides, amphot icin B, foscar-net, IV pentamidine, NSAIDs, vancomycin t effects W/zidovudine EMS Monitor ECG for hypocalcemia (t QT int val) and hypokalemia (flattened T waves) OD May cause renal failure hydration may be effective in reducing drug levels/effects Cilostazol (Pletal) TAntiplatelet, Arterial Vasodilator/ Phosphodiesterase Inhibitor] Uses Reduce Sxs of intermittent claudication Action Phosphodiesterase in inhibitor t s cAMP in pits blood vessels, vasodilation inhibit pit aggregation Dose 100 mg PO bid, 1/2 h before or 2 h after breakfast dinner Caution [C, +/-] Contra CHE, hemostatic disorders. 

Vorinostat (Zolinza) [Histone Deacetylase Inhibitor] Uses Rx cutaneous manifestations in cutaneous T-cell lymphoma Action Histone deacetylase inhibitor Dose 400 mg PO daily w/ food if intolerant X 300 mg PO d for X 5 d each wk Caution [D /-] w/ warfarin (t INR) Disp Caps SE NA /D, dehydration, fatigue, anorexia, dysgeusia, DVT, PE, Xplt, anemia, hypoglycemia, QT prolongation Interactions t Risk of thrombocytopenia GI bleed W/HDAC inhibitors (valproic acid) EMS May t QT interval, monitor ECG may t glucose T risk of DVT has been r orted OD Sxs unknown... 

Il.b.l.1. Adverse effects of anti-secretory treatment. Histamine H2 antagonists and proton pump inhibitors are very safe as well as effective treatments. Cimetidine has small effects on hepatic drug metabolism which are only of clinical signiflcance with drugs used in doses close to toxic levels, notably phenytoin, aminophylline and warfarin. Other adverse effects such as headache, rash and thrombocytopenia are rare. 

Lepirudin is a recombinant derivative of hirudin (direct thrombin inhibitor secreted by salivary glands of leech). It inhibits thrombin directly and is mainly used in heparin induced thrombocytopenia. 

F. Role in therapy Lepirudin is a thrombin-inhibitor indicated for use in the treatment of adults with heparin-induced thrombocytopenia (HIT) type II diagnosis... 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

The following points should be considered in all patients receiving heparin Platelet counts should be performed frequently thrombocytopenia appearing in a time frame consistent with an immune response to heparin should be considered suspicious for HIT and any new thrombus occurring in a patient receiving heparin therapy should raise suspicion of HIT. Patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor or fondaparinux (see below). 

Toxicities of the PSIs can include profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache. Because nephrotoxicity is of major concern when administering calcineurin inhibitors, there is interest in increased early use of PSIs since renal toxicity is less common with these agents. However, increased use in stem cell transplantation regimens as graft-versus-host disease prophylaxis, particularly when combined with tacrolimus, has revealed an increased incidence of hemolytic-uremic syndrome. 

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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