Thrombotic complications in essential thrombocythemia (ET): clinical facts and biochemical riddles

Hemostatic complications which can occur in the arterial or venous vasculature or in the microcirculation are the major causes of morbidity and mortality in patients with ET. In order to prevent these complications, often platelet reductive drugs are used. These agents are by themselves potentially toxic, i.e. may cause leukemia or cardiac side effects. In order to avoid these adverse effects, a better understanding of the mechanism of thrombus formation which is causative in ET is mandatory. Unfortunately, until now, no biomarkers have been identified which allow the estimation of the risk of thrombotic complications. Platelet number is not a good predictor per se since thrombotic complications can occur in some patients at low platelet numbers whereas others do not encounter a thrombosis even at very high platelet levels. On the other hand, lowering of the platelet count usually results in symptomatic improvement. In ET, morphological alterations of the megakaryocyte in the bone marrow and the circulating platelets are observed: megakaryocyte nuclei show a staghorn appearance, circulating platelets are characterized by anisocytosis and giant size. Functional studies indicate that these anatomically altered platelets function abnormally. When platelets are analyzed with a platelet function analyzer (PFA-100, which uses cartridges that measure how well a patient's platelets adhere and aggregate to form a platelet plug in the first phase of thrombus formation), in many patients with ET, closure time using collagen/ADP and collagen/epinephrine cartridges is prolonged. This seems paradoxical since these patients do not show an increased bleeding time. These results indicate that either receptors and/or consecutive signaling events are abnormal in ET platelets. Proteomic analysis of platelets of ET patients has revealed individual differences but not yet led to the identification of disease-specific proteins. Moreover, the search for alternative risk factors (factor V Leiden, prothrombin gene polymorphism, etc.) has not provided evidence for the contribution of these factors to the generation of the thrombotic risk in ET patients. In summary, despite intensive research over several decades, relatively little is known about the pathogenesis and risk factors for thrombosis in ET. I expect that this conference will contribute to the development of new strategies to identify patients at risk for hemostatic complications.