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Platelets – From Function to Dysfunction in Essential Thrombocythaemia

Abnormal Functioning of Platelets It is clear that platelets play a major physiological role that can be either beneficial or deleterious depending on the circumstances. Platelet disorders lead to defects in primary haemostasis and have signs and symptoms different from coagulation factor deficiencies (disorders of secondary haemostasis). An abnormality or disease of platelets is called a thrombocytopathy and can take differing forms: e.g. low platelet number, increased platelet number or loss of function. Low platelet number (thrombocytopaenia), characterised by a platelet count of <100–150 x 109 per litre of blood, can cause excessive bleeding and may be drug induced, e.g. heparin-induced thrombocytopaenia,42


Platelets may be affected by a decrease or loss of function (thrombasthaenia) such as in Glanzmann’s thrombasthenia. Platelets in Glanzmann’s thrombasthenia lack GPIIb/IIIa due to either an inherited mutation or acquired immune disorder.45

ET is an example of

a disease in which there is an increased number of platelets that leads to an increased risk of blood clot formation.46,47

Platelets and Essential Thrombocythaemia ET is a myeloid proliferative disorder characterised by an increase in the peripheral blood platelet count that is associated with bone marrow megakaryocyte hyperplasia, without associated erythrocytosis or leukoerythroblastosis.47

ET manifests clinically as thrombocytosis46 and

is associated with a broad spectrum of microvascular disturbances48 and relatively frequent thrombohaemorrhagic complications.49


ET, platelets are larger, less mature and more responsive to activation compared with normal platelets. These abnormal platelets are present in a range of states including resting, activated and desensitised. Biochemically, the most frequently detected abnormality is impaired epinephrine-induced platelet aggregation,50 loss of α2-adrenergic receptors.51 acid metabolism,52

caused by In addition, defects in arachidonic

abnormalities of platelet receptors such as GPllb/llla53 aggregation in ET.

an acquired storage pool defect of dense granules or affect platelet

Second, in most patients with ET, erythromelalgia is particularly sensitive to aspirin. The contribution of platelet count as a risk factor is presumed from clinical data showing that cytoreductive therapy reduces the incidence of thrombosis.55

Essential Thrombocythaemia Clinical Expression The contribution of platelets to thrombotic risk is supported by several lines of evidence. First, histological studies of erythromelalgia demonstrate platelet-rich arteriolar microthrombi rich in vWF and minimal fibrin.54

Finally, a recently

published analysis of the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) data concluded that antiplatelet therapy was significantly associated with a lower risk of cardiovascular events, but that there was no clear relationship between such events and phlebotomy or cytoreductive therapy.56

Although these data

implicate the platelet in the pathogenesis of these events, any extrapolation of the role of cytoreductive therapy or phlebotomy should be interpreted with caution.

Published studies on ET pregnancies report live birth rates of 50–70% and spontaneous abortion rates of 25–50%.57,58

In a recent report of

103 pregnancies that occurred in 62 women with ET, about 50% of first pregnancies had complications, although no case of acute coronary syndrome or myocardial infarction was reported during


A higher platelet TF expression has been shown in ET patients when compared with controls not age- and sex-matched.63

In addition,

elevated plasma levels of vWF:antigen (Ag), a large glycoprotein mainly synthesised by the endothelial cells that plays an important role in platelet thrombus formation,64

have been observed in ET patients,

particularly those with previous thrombosis. Increased factor V levels are also associated with increased thrombotic risk in ET. Presumably, increased levels of these factors result in the acceleration of clotting, leading to enhanced risk of thrombus formation. The higher thrombin generation values observed in ET and polycythaemia vera patients with previous thrombosis are in agreement with these findings.65

It has been

shown that the presence of acquired activated protein C resistance (aAPCR) phenotype and elevated levels of coagulation factors are associated with increased risk of thrombosis.66

ET patients with

thrombosis have been shown to have significantly higher values than patients without thrombosis for a number of factors including: reticulated platelet (RP) percentage, aAPCR, levels of factors V and VIII, vWF:Ag, sP-selectin and sCD40L.67

In a multivariate analysis, RP

percentage, factor V levels and aAPCR were independently associated with an increased risk of thrombosis. The mechanisms causing aAPCR are not clear, although it has been suggested to be related to antiphospholipid antibodies, reduced P-selectin levels and high levels of factors V and VIII and vWF:Ag.68

Platelet Activation in Essential Thrombocythaemia Enhanced platelet activation in ET was initially documented over a decade ago. Activated platelets interact with other blood components (both cellular and circulating) and have the capacity to provoke endothelial activation/damage. Further features of platelet activation include the formation of platelet microparticles, which are associated with the expression of platelet procoagulant activity. These microparticles can be increased in ET and are correlated with


of immune origin, e.g. ITP. ITPs are acquired autoimmune disorders mediated by the production of antiplatelet antibodies, which are commonly directed against GPIIb/IIIa and GPIb/IX on the platelet surface.43,44

pregnancy or post-partum.59 Although a decrease in platelet count

during pregnancy is well documented, pregnancies in ET patients frequently end in early spontaneous abortions during the first trimester.60

Their occurrence cannot be predicted from the disease course, platelet count or a specific therapy.

Thrombosis and Haemorrhage in Essential Thrombocythaemia

Approximately 20% of ET patients will have had a major thrombotic event at the time of diagnosis and approximately another 20% will have an event subsequently. This makes venous and, more commonly, arterial thrombosis the leading causes of morbidity and mortality in ET. However, the precise incidence of thrombosis in ET is hard to ascertain. Confounding factors include the retrospective nature of the literature, comprising relatively small uncontrolled case series, variable event definition and patient selection and reporting bias. Established risk factors for thrombosis in ET are older age (over 60 years) and previous thrombotic events. Recently, leukocytosis has also been identified as an additional risk factor.61


mechanisms, including blood hyperviscosity and quantitative/ qualitative abnormalities of blood cells, have been postulated to be at the origin of the hypercoagulable state in these patients.62


increased thrombotic state in ET patients is still not completely understood but it is thought that increased platelet number, abnormal platelet function, platelet and leukocyte activation, platelet–leukocyte aggregation and endothelial activation may all be contributing factors.

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