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Michiels JJ, Berneman Z, Gadisseur A, Lam KH, De Raeve H , et al.
Acta haematologica •
Migraine-like cerebral transient ischemic attacks (MIAs) and ocular ischemic manifestations were the main presenting features in 10 JAK2(V617F)-positive patients studied, with essential thrombocythemia (ET) in 6 and polycythemia vera (PV) in 4. Symptoms varied and included cerebral ischemic attacks, mental concentration disturbances followed by throbbing headaches, nausea, vomiting, syncope or even seizures. MIAs were frequently preceded or followed by ocular ischemic events of blurred vision, scotomas, transient flashing of the eyes, and sudden transient partial blindness preceded or followed erythromelalgia in the toes or fingers. The time lapse between the first symptoms of aspirin-responsive MIAs and the diagnosis of ET in 5 patients ranged from 4 to 12 years. At the time of erythromelalgia and MIAs, shortened platelet survival, an increase in the levels of the platelet activation markers β-thromboglobulin and platelet factor 4 and also in urinary thromboxane B2 were clearly indicative of the spontaneous in vivo platelet activation of constitutively JAK2(V617F)-activated thrombocythemic platelets. Aspirin relieves the peripheral, cerebral and ocular ischemic disturbances by irreversible inhibition of platelet cyclo-oxygenase (COX-1) activity and aggregation ex vivo. Vitamin K antagonist, dipyridamole, ticlopidine, sulfinpyrazone and sodium salicylate have no effect on platelet COX-1 activity and are ineffective in the treatment of thrombocythemia-specific manifestations of erythromelalgia and atypical MIAs. If not treated with aspirin, ET and PV patients are at a high risk of major arterial thrombosis including stroke, myocardial infarction and digital gangrene.
Microvascular circulation disturbances including erythromelalgia, its microvascular ischemic complications, and migraine-like atypical or typical transient ischemic cerebral, ocular, and coronary ischemic attacks are specific clinical manifestations in patients with essential thrombocythemia (ET), and polycythemia vera (PV) associated with thrombocythemia. Thrombocythemia (ET and PV) patients with microvascular disturbances have shortened platelet survival, increased beta-thromboglobulin (beta-tg), platelet factor 4 (PF4), and thrombomoduline (TM) levels, and increased urinary thromboxane B2 (TxB2) excretion indicating platelet-mediated processes in vivo. Inhibition of platelet cyclooxygenase (COX 1) by aspirin is followed by relief of microvascular disturbances, correction of shortened platelet survival, and return of plasma levels of beta-tg, PF4, TM levels and TxB2 excretion to normal. The transient ischemic attacks and thrombotic complications in thrombocythemia are very likely caused by hypersensitive platelets produced by spontaneously proliferating enlarged megakaryocytes in the bone marrow of ET and PV patients. In contrast to normal platelets in healthy individuals the circulating hypersensitive thrombocythemic platelets spontaneously activate and secrete their products, thus forming aggregates that transiently plug the microcirculation, or result in occlusive platelet thrombi in arterioles or small arteries. Clear evidence is presented that the microvascular transient ischemic and occlusive thrombotic complications in thrombocythemia patients are relieved by treatment with aspirin and by reduction of platelet counts to normal (<400 x 109/l), but not by coumadin. In patients with thrombocythemia associated with PV, increased hematocrit and whole blood viscosity aggravate the platelet-mediated microvascular ischemic and thrombotic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Correction of hematocrit and blood viscosity by phlebotomy significantly reduces the major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated microvascular circulation disturbances in PV patients because thrombocythemia persists. Complete relief and prevention of microvascular and major thrombosis in PV patients are obtained by treatment with low-dose aspirin on top of phlebotomy or by treatment with the platelet lowering agents, anagrelide, interferon or hydroxyurea.
Michiels JJ, Berneman Z, Van Bockstaele D, van der Planken M, De Raeve H , et al.
Seminars in thrombosis and hemostasis •
Microvascular disturbances in essential thrombocythemia (ET) and polycythemia vera (PV), including erythromelalgia, and atypical and typical transient cerebral, ocular, and coronary ischemic attacks, are caused by platelet-mediated transient and occlusive thrombosis in the end-arterial circulation. ET patients with microvascular disturbances have shortened platelet survival, increased beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), and thrombomodulin (TM) levels, and increased urinary thromboxane B2 (TXB2) excretion, indicating platelet-mediated thrombotic processes. Inhibition of platelet cyclooxygenase-1 by aspirin is followed by relief of microvascular disturbances; correction of shortened platelet survival; correction of increased plasma beta-TG, PF4, and TM levels; and correction of increased TXB2 excretion to normal. In PV associated with thrombocythemia, increased hematocrit and whole blood viscosity aggravate the platelet-mediated microvascular syndrome of thrombocythemia to produce major arterial and venous thrombotic complications. Correction of hematocrit to normal by phlebotomy will reduce the major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated microvascular circulation disturbances in PV patients because thrombocythemia persists. Complete relief and prevention of microvascular and major thrombosis in ET and PV patients, in addition to phlebotomy, are obtained by treatment with aspirin and not with coumarin. The discovery of JAK2 V617F gain of function mutation in patients with myeloproliferative disorders (MPDs) expands our insights into the molecular etiology and biological features of ET, PV, and chronic idiopathic myelofibrosis (CIMF). The current concept is that heterozygous JAK2 V617F mutation with increased kinase activity is enough for megakaryocyte proliferation and increased hypersensitive platelets with no or slightly increased erythropoiesis in ET and in early PV mimicking ET. Homozygous JAK2 mutation with pronounced kinase activity is associated with trilinear megakaryocyte, erythroid, and granulocytic myeloproliferation, myeloid metaplasia, and secondary myelofibrosis (MF), with the most frequent clinical picture of classical PV complicated by major thrombosis in addition to the platelet-mediated microvascular thrombotic syndrome of thrombocythemia. The positive predictive value of a JAK2 V617F polymerase chain reaction test for the diagnosis of MPDs is high (near to 100%), but only half of ET and MF (sensitivity 50%) and the majority of PV (sensitivity 85 to 97%) are JAK2 V617F positive. Bone marrow histopathology, when used in combination with specific markers such as serum erythropoietin, PRV-1, endogenous erythroid colony formation, peripheral blood parameters and red cell mass, has a high sensitivity and specificity (near 100%) to detect the early and overt stages of the MPDs and to differentiate between ET, PV, and CIMF in both JAK2 V617F-positive and -negative MPDs.
The broad spectrum of aspirin-sensitive erythromelalgia, its microvascular ischemic complications, migraine-like atypical or typical transient ischemic attacks (cerebral and ocular) as well as acute coronary syndromes in thrombocythemia vera (essential thrombocythemia and thrombocythemia associated with polycythemia vera in maintained remission by phlebotomy) is caused by platelet cyclo-oxygenase-mediated arteriolar inflammation, fibromuscular intimal proliferation without and with occlusive thrombosis by platelet-rich thrombi in the end-arterial microvasculature of the peripheral, cerebral, ocular and coronary circulation. These microvascular ischemic and thrombotic complications does not respond to Coumadin, but are immediately relieved by a loading dose of 500 mg aspirin, and does not recur when the patient is maintained on low dose aspirin (50 mg per day) or after reduction of platelet counts to normal (<400.000/microl).
Michiels JJ, Berneman ZN, Schroyens W, Van Vliet HH
Platelets •
Essential thrombocythaemia (ET) is associated with a broad spectrum of microvascular circulation disturbances including erythromelalgia and its ischaemic complications, episodic neurological symptoms of atypical and typical transient ischaemic attacks (TIAs), transient ocular ischaemic attacks, acute coronary syndromes, and superficial 'thrombophlebitis'. The microvascular circulation disturbances are caused by spontaneous activation and aggregation of hypersensitive thrombocythaemic platelets at high shear stress in the endarterial microcirculation involving the peripheral, cerebral and coronary circulation. As this microvascular syndrome is a pathognomonic feature of essential thrombocythaemia and of thrombocythaemia associated with polycythaemia vera (PV) in complete remission with normal haematocrit, we have labelled these two variants of thrombocythaemia as thrombocythaemia vera. The arterial thrombophilia of microvascular circulation disturbances in thrombocythaemia vera already occur at platelet counts in excess of 400 x 10(9)/l. Complete relief of microvascular circulation disturbances in thrombocythaemia vera is obtained with the platelet cyclooxygenase inhibitor aspirin 50-100 mg/day, but not with dipyridamole, ticlopidine, coumarin or heparin. Haemorrhagic thrombocythaemia (HT) is a clinical syndrome of recurrent spontaneous mucocutaneous and secondary haemorrhages associated with extremely high platelet counts far in excess of 1000 x 10(9)/l. The paradoxical occurrence of microvascular circulation disturbances and mucocutaneous bleeding is usually seen at platelet counts between 1000 and 2000 x 10(9)/l. At increasing platelet counts from below 1000 to in excess of 2000 x 10(9)/l, the arterial thrombophilia of thrombocythaemia vera changes into a spontaneous bleeding tendency of HT as a consequence of platelet-mediated increased proteolysis of the large von Willebrand factor multimers leading to a type 2 acquired von Willebrand syndrome. As PV is usually associated with thrombocythaemia, the vascular complications in PV patients are microvascular circulation disturbances typical of thrombocythaemia. On top of this, major arterial and venous thrombotic events and haemorrhages are related to increased haematocrit, red cell mass and its concomitant increased blood viscosity. Correction of increased blood viscosity and haematocrit to normal values (0.40-0.44) by bloodletting alone will significantly reduce the risk of major thrombotic complications, but does not prevent the microvascular circulation disturbances because thrombocythaemia persists. The microvascular syndrome associated with thrombocythaemia in PV patients in remission after bloodletting is best controlled by low-dose aspirin (50-100 mg/day) or by reduction of platelet count to normal (< 350 x 10(9)/l).
Five patients with red, purple blue, or black toes or fingers due to thrombocythemia associated with polycythemia vera (polycythemia and thrombocythemia vera) in four and essential thrombocythemia (thrombocythemia vera) in one are described. The microvascular erythromelalgic syndrome of thrombocythemia was overlooked and progressed to cold blue swollen and painful fingers or black toes in three patients with polycythemia and thrombocythemia vera due to arteriographically documented occlusions of digital or large peripheral arteries with no evidence of preexistent atherosclerotic vascular disease. Concomitant erythromelalgia of the hand palm could be confirmed by the histopathological findings of arteriolar thrombotic lesions in the reticular dermis in two patients with polycythemia and thrombocythemia vera. The increased hematocrit in the presented patients with polycythemia and thrombocythemia vera contributed to the progression of the microvascular syndrome of thrombocythemia to major occlusive ischemic events of the extremities. Standard therapy with oral anticoagulants and reduction of the hematocrit to normal by bloodletting did not affect the platelet-mediated microvascular erythromelalgic, ischemic symptoms in the patients with polycythemia vera because thrombocythemia vera persisted. Complete relief of pain and restoration of the ischemic acral circulation disturbances in patients with thrombocythemia vera or thrombocythemia associated with polycythemia vera in maintained remission by bloodletting could be obtained by long-term treatment with low-dose aspirin.