Guido Finazzi

The Management of Essential Thrombocythaemia

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder with a relatively benign clinical course and long survival in most patients. The major cause of mortality and morbidity are thromboembolic complications, which occur more frequently in older subjects or in those with a previous thrombosis. The therapeutic options comprise cytoreductive agents (cytotoxic drugs, interferon, anagrelide) and anti-aggregating drugs. In clinical practice the choice of treatment primarily takes into account the patients age, history and symptoms. The use of platelet-lowering agents is indicated in patients above 60 years and in those with a history of thrombosis or major bleeding, or very high platelet count (e.g. >1,000 X 10(9)/1). Hydroxyurea has emerged as the treatment of choice after the recent demonstration of its efficacy in reducing not only the platelet count but also thromboembolic complications. Low-dose aspirin may be added in the presence of thrombosis or microvascular disturbances. In younger, asymptomatic patients, an initial policy of observation, without specific treatment, or with only low-dose antiaggregating agents seems reasonable. Doubt about the risk of leukaemia transformation associated with hydroxyurea suggests that the use of interferon or anagrelide should be explored.

Therapy of Polycythemia Vera and Essential Thrombocythemia

Major causes of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET) are represented by thrombosis and bleeding, progression to myelofibrosis, and transformation to acute leukemia. Myelosuppressive therapy, preferentially with hydroxyurea, can reduce the rate of vascular complications, but there is some concern about an increased rate of leukemic transformation with this agent. Therefore, management of these disorders poses a significant challenge, and a risk-oriented therapeutic approach should be followed to avoid inappropriate exposure to cytotoxic drugs on one side or suboptimal treatment on the other. Established risk factors for cardiovascular events are represented by older age and previous thrombosis, while impact of novel biological factors, including leukocytosis and JAK2V617F mutational status and/or mutational burden, is under investigation. Low-risk PV patients should be managed only with phlebotomy and aspirin, while high-risk patients should also receive cytotoxic therapy. Regarding the management of ET, there is no clear indication for intervention in low-risk patients, while high-risk patients should be managed with chemotherapy. Other therapeutic options, such as interferon alpha or anagrelide, may find place in selected patients including those who are resistant/intolerant to hydroxyurea.

Antithrombin III and Other Natural Inhibitors of Coagulation

The presence of naturally occurring inhibitory proteins appears to be one of the major systems for controlling the activation sequence in coagulation and for limiting thrombin formation. Plasma proteins which have been characterized as inhibitors of coagulation enzymes and cofactors are listed in Table 1.