Phase I study of a novel recombinant human soluble thrombomodulin, ART-123.

BACKGROUND: Anticoagulants are often given for extended periods of time to patients at high risk for venous thromboembolism, such as after orthopedic surgery. Daily subcutaneous (sc) injections can be inconvenient to the patient. A long-acting anticoagulant requiring less frequent dosing could make treatment more acceptable. Thrombomodulin is a natural anticoagulant that activates protein C, which leads to inactivation of factor (F)Va and FVIIIa and decreased thrombin formation. Recombinant human thrombomodulin is a novel anticoagulant with a long half-life in animal models. METHODS AND RESULTS: This phase I study examined pharmacokinetics, pharmacodynamics, and safety of recombinant human soluble thrombomodulin (ART-123) after administration of doses between 0.02 and 0.06 mg kg(-1) body weight intravenously (iv), and between 0.02 and 0.45 mg kg(-1) sc in 55 healthy volunteers. The plasma half-life was 2-3 days after sc injection of various single doses. Plasma ART-123 levels estimated to be needed for prevention of thrombus formation in humans were maintained for at least 6 days after single sc injection of 0.30 and 0.45 mg kg(-1) ART-123. Antithrombotic activity with these doses was demonstrated by achieving prothrombinase inhibition of more than 80% for more than 6 days after administration. No major bleeding occurred. Pharmacodynamic modeling revealed that adequate antithrombotic ART-123 levels can be achieved for 6 days with one dose of 0.45 mg kg(-1) ART-123, and for 12 days with 2 doses of 0.30 mg kg(-1), given 5 days apart. CONCLUSIONS: Recombinant human soluble thrombomodulin (ART-123) has a long half-life after sc injection and is well tolerated, making it a suitable agent to be tested in clinical thromboprophylaxis trials.

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].