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Resolution of Platelet-Rich Thrombi in Essential Thrombocythemia: Mechanisms, Risks, and Benefits of Antiplatelet Therapy
Mayo Clin Proc, April 2001, Vol 76
Editorial
356
Editorial
Resolution of Platelet-Rich Thrombi in Essential Thrombocythemia: Mechanisms, Risks, and Benefits of Antiplatelet Therapy The authors claim that the resolution of the aortic thrombus was a direct consequence of the therapy administered to the patient. This hypothesis is provocative and warrants careful consideration. Hydroxyurea suppresses clonal expansion and decreases the platelet count, thereby reducing the rate of accretion of platelets to the thrombus both by decreasing the derivation of hyperaggregable platelets from the clone and by a cellular “mass action” effect. In addition, aspirin suppresses platelet activation and granule secretion,4 which limits recruitment of platelets to the thrombus. However, to attribute the dissolution of the thrombus to the effects of these agents alone is not supported by known mechanisms of thrombus clearance.
E
ssential thrombocythemia (ET) is a myeloproliferative disorder characterized by megakaryocyte proliferation that is often, but not invariably, clonal.1,2 Platelet formation is unregulated, leading often to dramatic increases in the circulating platelet count. While the resulting platelets can be hemostatically competent, they are often dysfunctional, leading either to spontaneous hemorrhage or to in situ thrombosis. Elevated platelet counts in ET in high-risk patients are typically treated with hydroxyurea or anagrelide in younger patients or in those who cannot tolerate hydroxyurea. A thrombotic tendency, should it exist, is commonly treated with aspirin. In this issue of Proceedings, Fang and colleagues3 describe the case of a middle-aged woman with ET who presented with abdominal and lower extremity pain, gastrointestinal cramping and diarrhea, and transient mottling of the toes. By abdominal computed tomography, the patient was found to have visceral infarctions and a large aortic thrombus. Treatment with hydroxyurea and aspirin was accompanied by complete resolution of the thrombus after 3 weeks, with no apparent clinical sequelae. The authors state that, to their knowledge, this is the first demonstration of the resolution of an aortic thrombus in a patient with ET treated with medical therapy alone. Platelet function in patients with ET can be either normal or abnormal; dysfunctional platelets are frequently hemostatically incompetent, leading to hemorrhage, or hyperaggregable, leading to thrombosis. Thrombotic events are typically arterial or microvascular and commonly develop in situ. The renal and splenic infarctions reported in this patient without documented atherosclerotic vascular disease may have been a consequence of in situ thrombosis; however, owing to the size of the aortic thrombus and its location, we cannot exclude peripheral embolization as an underlying pathophysiological mechanism for these visceral infarctions. In support of this mechanism are the transient mottling of the patient’s left foot on presentation and the irregular nature of the aortic thrombus, both clues to the embolic propensity of the thrombus.
See also page 427. Antithrombotic agents, including both antiplatelet agents and anticoagulants, principally prevent thrombus growth by inhibiting platelet activation and fibrin formation. Thrombus is cleared from the circulation by endogenous thrombolytic mechanisms, including plasmin-mediated fibrinolysis and macrophage-mediated clearance through the action of lysozomal enzymes such as cathepsin D.5 One may argue that the platelet-rich nature of the ET thrombus limits its ability to be cleared by these endogenous mechanisms, and available data do, indeed, support the platelet-rich predominance of these “white” thrombi, at least in the microvasculature.6 However, no thrombus, least of all an extensive, large aortic thrombus, is likely to be a “pure” platelet thrombus. In addition, even pure platelet thrombi are held together by fibrinogen and von Willebrand factor polymers that bridge platelets by binding to glycoprotein IIb/IIIa or glycoprotein Ib/IX. Plasmin, generated by the action of endogenous plasminogen activators on plasminogen, can degrade fibrinogen to facilitate platelet disaggregation,7 cleave glycoprotein Ib from the platelet surface to impair von Willebrand factor–dependent adhesion,8 and proteolyze glycoprotein IIIa to weaken the affinity of glycoprotein IIb/IIIa for fibrinogen,9 all leading to impaired platelet function. Other endogenous platelet inhibitors can act synergistically with plasmin to facilitate platelet disaggregation, including endothelial nitric oxide and prostacyclin,10 and these endothelial products are likely important for limiting thrombus growth as well as facilitating its endogenous dissolution. Aspirin can, as well, promote thrombus dissolution by facilitating platelet disaggregation,11 suggesting
Address reprint requests and correspondence to Joseph Loscalzo, MD, PhD, Evans Department of Medicine, Boston University School of Medicine, 88 E Newton St, Boston, MA 02118-2394 (e-mail: [email protected]). Mayo Clin Proc. 2001;76:356-357
356
© 2001 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, April 2001, Vol 76
another mechanism by which the aspirin used to treat this patient may have contributed to the ultimate dissolution of the thrombus. It is then reasonable to conclude that, as a combined result of lowering the platelet count, inhibiting platelet activation and aggregation, and facilitating platelet disaggregation, thrombus growth was inhibited and its endogenous dissolution facilitated. One must, however, also consider the possibility that these agents led to lysis of the thrombus in a process that involved fragmentation and peripheral embolization. These events, had they occurred, were clinically silent. Nevertheless, that they occurred cannot be excluded since clinically silent arterial embolic events have been documented to occur in both autopsy and imaging studies—even in the central nervous system.12,13 The use of thrombolytic therapy for peripheral arterial embolism has been reported to produce distal embolization in up to 12% of patients.14 In the case described by Fang et al,3 the abdominal aortic location of the thrombus limited its embolic potential to the visceral, renal, and peripheral circulatory beds. The authors do not report the results of examination of the peripheral pulses, the ankle-brachial index, peripheral pulse volume recordings, or a urinalysis that might have been used to exclude small or clinically subtle peripheral emboli arising from treatment. Antiplatelet therapy appears to be a potentially useful approach to the treatment of a presumed platelet-rich arterial thrombus in patients with ET. However, treatment with medical therapy alone should be individualized on the basis of the location of the thrombus, its potential for embolism, and the suitability of the patient for thrombectomy.15,16 Antiplatelet therapy can readily facilitate thrombus resolution but may also facilitate embolization, emphasizing the therapeutic challenge that confronts the clinician in these uncommon but difficult cases.
Editorial
1. 2. 3. 4. 5.
6.
7.
8.
9.
10.
11.
12.
13.
14. 15.
16.
Joseph Loscalzo, MD, PhD Boston University School of Medicine Boston, Mass
357
Fialkow PJ, Faguet GB, Jacobson RJ, Vaidya K, Murphy S. Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood. 1981;58:916-919. Pearson TC, Messinezy M. The diagnostic criteria of polycythaemia rubra vera. Leuk Lymphoma. 1996;22(suppl 1):87-93. Fang M, Agha S, Lockridge L, et al. Medical management of a large aortic thrombus in a young woman with essential thrombocythemia. Mayo Clin Proc. 2001;76:427-431. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101:12061218. Simon DI, Ezratty AM, Francis SA, Rennke H, Loscalzo J. Fibrin(ogen) is internalized and degraded by activated human monocytoid cells via Mac-1 (CD11b/CD18): a nonplasmin fibrinolytic pathway. Blood. 1993;82:2414-2422. van Genderen PJ, Lucas IS, van Strik R, et al. Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation. Thromb Haemost. 1996;76:333-338. Loscalzo J, Vaughan DE. Tissue plasminogen activator promotes platelet disaggregation in plasma. J Clin Invest. 1987;79:17491755. Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood. 1985;65:32-40. Pasche B, Ouimet H, Francis S, Loscalzo J. Structural changes in platelet glycoprotein IIb/IIIa by plasmin: determinants and functional consequences. Blood. 1994;83:404-414. Stamler JS, Vaughan DE, Loscalzo J. Synergistic disaggregation of platelets by tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin. Circ Res. 1989;65:796-804. Ambrus JL, Ambrus CM, Stadler S, Toumbis C, Markus G. Potentiation of thrombolytic therapy by enzyme combinations and with aspirin or pentoxifylline. J Med. 1994;25:145-161. Kempster PA, Gerraty RP, Gates PC. Asymptomatic cerebral infarction in patients with chronic atrial fibrillation. Stroke. 1988;19: 955-957. Boon A, Lodder J, Heuts-van Raak L, Kessels F. Silent brain infarcts in 755 consecutive patients with a first-ever supratentorial ischemic stroke: relationship with index-stroke subtype, vascular risk factors, and mortality. Stroke. 1994;25:2384-2390. Galland RB, Earnshaw JJ, Baird RN, et al. Acute limb deterioration during intra-arterial thrombolysis. Br J Surg. 1993;80:1118-1120. Johnson M, Gernsheimer T, Johansen K. Essential thrombocytosis: underemphasized cause of large-vessel thrombosis. J Vasc Surg. 1995;22:443-447. Laperche T, Laurian C, Roudaut R, Steg PG, Filiale Echocardiographie de la Société Française de Cardiologie. Mobile thromboses of the aortic arch without aortic debris: a transesophageal echocardiographic finding associated with unexplained arterial embolism. Circulation. 1997;96:288-294.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Editorial
356
Editorial
Resolution of Platelet-Rich Thrombi in Essential Thrombocythemia: Mechanisms, Risks, and Benefits of Antiplatelet Therapy The authors claim that the resolution of the aortic thrombus was a direct consequence of the therapy administered to the patient. This hypothesis is provocative and warrants careful consideration. Hydroxyurea suppresses clonal expansion and decreases the platelet count, thereby reducing the rate of accretion of platelets to the thrombus both by decreasing the derivation of hyperaggregable platelets from the clone and by a cellular “mass action” effect. In addition, aspirin suppresses platelet activation and granule secretion,4 which limits recruitment of platelets to the thrombus. However, to attribute the dissolution of the thrombus to the effects of these agents alone is not supported by known mechanisms of thrombus clearance.
E
ssential thrombocythemia (ET) is a myeloproliferative disorder characterized by megakaryocyte proliferation that is often, but not invariably, clonal.1,2 Platelet formation is unregulated, leading often to dramatic increases in the circulating platelet count. While the resulting platelets can be hemostatically competent, they are often dysfunctional, leading either to spontaneous hemorrhage or to in situ thrombosis. Elevated platelet counts in ET in high-risk patients are typically treated with hydroxyurea or anagrelide in younger patients or in those who cannot tolerate hydroxyurea. A thrombotic tendency, should it exist, is commonly treated with aspirin. In this issue of Proceedings, Fang and colleagues3 describe the case of a middle-aged woman with ET who presented with abdominal and lower extremity pain, gastrointestinal cramping and diarrhea, and transient mottling of the toes. By abdominal computed tomography, the patient was found to have visceral infarctions and a large aortic thrombus. Treatment with hydroxyurea and aspirin was accompanied by complete resolution of the thrombus after 3 weeks, with no apparent clinical sequelae. The authors state that, to their knowledge, this is the first demonstration of the resolution of an aortic thrombus in a patient with ET treated with medical therapy alone. Platelet function in patients with ET can be either normal or abnormal; dysfunctional platelets are frequently hemostatically incompetent, leading to hemorrhage, or hyperaggregable, leading to thrombosis. Thrombotic events are typically arterial or microvascular and commonly develop in situ. The renal and splenic infarctions reported in this patient without documented atherosclerotic vascular disease may have been a consequence of in situ thrombosis; however, owing to the size of the aortic thrombus and its location, we cannot exclude peripheral embolization as an underlying pathophysiological mechanism for these visceral infarctions. In support of this mechanism are the transient mottling of the patient’s left foot on presentation and the irregular nature of the aortic thrombus, both clues to the embolic propensity of the thrombus.
See also page 427. Antithrombotic agents, including both antiplatelet agents and anticoagulants, principally prevent thrombus growth by inhibiting platelet activation and fibrin formation. Thrombus is cleared from the circulation by endogenous thrombolytic mechanisms, including plasmin-mediated fibrinolysis and macrophage-mediated clearance through the action of lysozomal enzymes such as cathepsin D.5 One may argue that the platelet-rich nature of the ET thrombus limits its ability to be cleared by these endogenous mechanisms, and available data do, indeed, support the platelet-rich predominance of these “white” thrombi, at least in the microvasculature.6 However, no thrombus, least of all an extensive, large aortic thrombus, is likely to be a “pure” platelet thrombus. In addition, even pure platelet thrombi are held together by fibrinogen and von Willebrand factor polymers that bridge platelets by binding to glycoprotein IIb/IIIa or glycoprotein Ib/IX. Plasmin, generated by the action of endogenous plasminogen activators on plasminogen, can degrade fibrinogen to facilitate platelet disaggregation,7 cleave glycoprotein Ib from the platelet surface to impair von Willebrand factor–dependent adhesion,8 and proteolyze glycoprotein IIIa to weaken the affinity of glycoprotein IIb/IIIa for fibrinogen,9 all leading to impaired platelet function. Other endogenous platelet inhibitors can act synergistically with plasmin to facilitate platelet disaggregation, including endothelial nitric oxide and prostacyclin,10 and these endothelial products are likely important for limiting thrombus growth as well as facilitating its endogenous dissolution. Aspirin can, as well, promote thrombus dissolution by facilitating platelet disaggregation,11 suggesting
Address reprint requests and correspondence to Joseph Loscalzo, MD, PhD, Evans Department of Medicine, Boston University School of Medicine, 88 E Newton St, Boston, MA 02118-2394 (e-mail: [email protected]). Mayo Clin Proc. 2001;76:356-357
356
© 2001 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, April 2001, Vol 76
another mechanism by which the aspirin used to treat this patient may have contributed to the ultimate dissolution of the thrombus. It is then reasonable to conclude that, as a combined result of lowering the platelet count, inhibiting platelet activation and aggregation, and facilitating platelet disaggregation, thrombus growth was inhibited and its endogenous dissolution facilitated. One must, however, also consider the possibility that these agents led to lysis of the thrombus in a process that involved fragmentation and peripheral embolization. These events, had they occurred, were clinically silent. Nevertheless, that they occurred cannot be excluded since clinically silent arterial embolic events have been documented to occur in both autopsy and imaging studies—even in the central nervous system.12,13 The use of thrombolytic therapy for peripheral arterial embolism has been reported to produce distal embolization in up to 12% of patients.14 In the case described by Fang et al,3 the abdominal aortic location of the thrombus limited its embolic potential to the visceral, renal, and peripheral circulatory beds. The authors do not report the results of examination of the peripheral pulses, the ankle-brachial index, peripheral pulse volume recordings, or a urinalysis that might have been used to exclude small or clinically subtle peripheral emboli arising from treatment. Antiplatelet therapy appears to be a potentially useful approach to the treatment of a presumed platelet-rich arterial thrombus in patients with ET. However, treatment with medical therapy alone should be individualized on the basis of the location of the thrombus, its potential for embolism, and the suitability of the patient for thrombectomy.15,16 Antiplatelet therapy can readily facilitate thrombus resolution but may also facilitate embolization, emphasizing the therapeutic challenge that confronts the clinician in these uncommon but difficult cases.
Editorial
1. 2. 3. 4. 5.
6.
7.
8.
9.
10.
11.
12.
13.
14. 15.
16.
Joseph Loscalzo, MD, PhD Boston University School of Medicine Boston, Mass
357
Fialkow PJ, Faguet GB, Jacobson RJ, Vaidya K, Murphy S. Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood. 1981;58:916-919. Pearson TC, Messinezy M. The diagnostic criteria of polycythaemia rubra vera. Leuk Lymphoma. 1996;22(suppl 1):87-93. Fang M, Agha S, Lockridge L, et al. Medical management of a large aortic thrombus in a young woman with essential thrombocythemia. Mayo Clin Proc. 2001;76:427-431. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101:12061218. Simon DI, Ezratty AM, Francis SA, Rennke H, Loscalzo J. Fibrin(ogen) is internalized and degraded by activated human monocytoid cells via Mac-1 (CD11b/CD18): a nonplasmin fibrinolytic pathway. Blood. 1993;82:2414-2422. van Genderen PJ, Lucas IS, van Strik R, et al. Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation. Thromb Haemost. 1996;76:333-338. Loscalzo J, Vaughan DE. Tissue plasminogen activator promotes platelet disaggregation in plasma. J Clin Invest. 1987;79:17491755. Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood. 1985;65:32-40. Pasche B, Ouimet H, Francis S, Loscalzo J. Structural changes in platelet glycoprotein IIb/IIIa by plasmin: determinants and functional consequences. Blood. 1994;83:404-414. Stamler JS, Vaughan DE, Loscalzo J. Synergistic disaggregation of platelets by tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin. Circ Res. 1989;65:796-804. Ambrus JL, Ambrus CM, Stadler S, Toumbis C, Markus G. Potentiation of thrombolytic therapy by enzyme combinations and with aspirin or pentoxifylline. J Med. 1994;25:145-161. Kempster PA, Gerraty RP, Gates PC. Asymptomatic cerebral infarction in patients with chronic atrial fibrillation. Stroke. 1988;19: 955-957. Boon A, Lodder J, Heuts-van Raak L, Kessels F. Silent brain infarcts in 755 consecutive patients with a first-ever supratentorial ischemic stroke: relationship with index-stroke subtype, vascular risk factors, and mortality. Stroke. 1994;25:2384-2390. Galland RB, Earnshaw JJ, Baird RN, et al. Acute limb deterioration during intra-arterial thrombolysis. Br J Surg. 1993;80:1118-1120. Johnson M, Gernsheimer T, Johansen K. Essential thrombocytosis: underemphasized cause of large-vessel thrombosis. J Vasc Surg. 1995;22:443-447. Laperche T, Laurian C, Roudaut R, Steg PG, Filiale Echocardiographie de la Société Française de Cardiologie. Mobile thromboses of the aortic arch without aortic debris: a transesophageal echocardiographic finding associated with unexplained arterial embolism. Circulation. 1997;96:288-294.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.