Clinical management of protein C deficiency.

Protein C (PC) is a vitamin K-dependent plasma protein that is structurally similar to other coagulation factors such as prothrombin and Factor X. PC is converted to its active anticoagulant form by a thrombin-thrombomodulin complex on the surface of capillary endothelial cells. Activated PC (APC) prevents the formation of blood clots by specifically inactivating factors Va and VIIIa in the clotting cascade. Both acquired and hereditary forms of PC deficiency exist, with hereditary further categorised as heterozygous, homozygous as well as doubly heterozygous. Patients suffering from symptomatic heterozygous PC deficiency present with purpura fulminans, venous thrombosis and/or pulmonary embolism. Homozygous PC deficiency is usually associated with the development of severe and often fatal, purpura fulminans and disseminated intravascular coagulation (DIC) during the neonatal period. Various therapeutic options have been described for long-term management of severe heterozygous and homozygous PC deficiencies. For the treatment of heterozygous PC deficiency, oral anticoagulation with a coumarin derivative or heparin therapy remains standard therapy. Homozygous patients may be treated with fresh frozen plasma (FFP) and iv. PC concentrate or coumarin derivatives. Other therapeutic options for the treatment of hereditary PC deficiency include the use of low-molecular weight heparin (LMWH), steroids and liver transplantation. Maintenance of a symptom-free life depends on response to therapy. Patients responding well to treatment can expect normalisation of haemostasis as well as improvement of microcirculation and resolution of purpura fulminans.

Anagrelide: a novel agent for the treatment of myeloproliferative disorders.

Anagrelide hydrochloride (Agrylin, Roberts Pharmaceutical Corp.) is an oral imidazoquinazoline agent that has been shown to reduce elevated platelet counts and the risk of thrombosis in patients with thrombocythaemia in various myeloproliferative disorders (MPD). It is currently approved by the FDA as oral treatment for essential thrombocythaemia (ET) and thrombocythaemia associated with polycythaemia vera (PV). Anagrelide selectively suppresses bone marrow megakaryocytes by interfering with the maturation process and decreasing platelet production without affecting the erythroid and myeloid progenitor cells. Other medications indicated for the treatment of thrombocythaemia, including interferon alpha (IFN-alpha), alkylating agents and hydroxyurea, suppress all cell lines. Anagrelide is known to inhibit platelet cyclic adenosine monophosphate (cAMP) phosphodiesterase at concentrations that exceed those achieved at doses used to treat ET. Anagrelide is extensively metabolised in the liver and its metabolites are primarily excreted in the urine. Adverse effects associated with the use of anagrelide are primarily caused by the drugs' direct vasodilating and positive inotropic effects. These include headache, hypotension and diarrhoea. It has also been known to cause fluid retention, tachycardia, nausea, abdominal pain and arrhythmias. The starting dose of anagrelide ranges from 0.5 mg q.i.d. to 1 mg b.i.d. with a maximum dose of 2.5 mg q.i.d. Adequate responses have been maintained with a median dose of 2-2.5 mg/day. Platelet counts begin to decrease in 7-10 days, however, they return to pre-treatment levels within 4-8 days if therapy is stopped. Anagrelide 2 mg/day for one year costs approximately US$6439, and treatment must continue indefinitely [1].