Acquired Thrombophilic Syndromes: Daniela Matei, Benjamin Brenner, Victor J. Marder

Acquired thrombophilic syndromes

Daniela Matei,1 Benjamin Brenner,2 Victor J. Marder1
1
Vascular Medicine Program, Los Angeles Orthopaedic Hospital/University of Department of Hematology, Rambam Medical Center, Haifa, Israel
California at Los Angeles, Los Angeles, CA, USA

2
Abstract As the biochemical mechanisms of hypercoagulable states are revealed, the syndromes of venous thromboembolism have been increasingly associated with specific aberrations. Most of these changes involve an increase in procoagulant potential, for example, by activation of the coagulation cascade, or by a defect or decrease in natural inhibitors of clotting. Similar abnormalities of the fibrinolytic pathways may contribute, as can loss of inhibitory mechanisms of endothelial cells, as well as changes in vascular anatomy and rheologic patterns of blood flow.All of these factors can directly influence thrombus formation and/or the physiologic response to the thrombus.1 2001 Harcourt Publishers Ltd
INTRODUCTION s with the hereditary thrombophilias, acquired disorders vary widely in their propensity to cause venous and arterial thrombotic disease. Certain conditions such as the mucin-secreting adenocarcinomas have very high potential for thrombogenesis and can cause excessive thrombotic manifestations (arterial, venous, microcirculatory, endocardial) in a given patient.The antiphospholipid syndrome may manifest solely as a coincidental laboratory derangement or cause venothromboembolic disease (VTED), stroke or obstetric complications. Patients with myeloproliferative syndromes or paroxysmal nocturnal hemoglobinuria may have significant clinical thrombotic complications and can especially present with thrombosis in unusual sites; while in patients with acute promyelocytic leukemia the coagulation cascade can be triggered further during cytolytic therapy.The hypercoagulable tendency manifested in association with some medications leads mostly to VTED, and can be enhanced by other prothrombotic environmental factors such as smoking, obesity or by the presence of on occult inherited thrombophilic trait. ANTIPHOSPHOLIPID SYNDROME (APLS) Antiphospholipid syndrome (APLS) has many clinical facets and multiple manifestations, and is one of the more common causes of acquired thrombophilia.2 The presence of acquired circulating anticoagulants was first reported in patients with systemic lupus erythematosus (SLE) in 1948.3 Fifteen years later, Bowie et al. noted the occurrence of thrombosis in patients with SLE who also had a circulating anticoagulant.4 This phenomenon was called the lupus anticoagulant (LA), although it is now clear that the presence of LA is not restricted to patients with SLE.
Several laboratory tests have been developed to detect LAs including the partial thromboplastin time, the kaolin clotting time, the dilute phospholipid test, platelet neutralization tests, tissue thromboplastin inhibition tests, and anticardiolipin antibody.5,6 The concept supporting the detection of the LA antibodies relies on the use of low concentrations of phospholipid in phospholipid-based clotting assays to maximize the inhibitory effect of the antibody. In the confirmatory phase, large amounts of phospholipid are added to the liquid phase assay, overcoming the effect of the antibody. While no single test can stand alone in the diagnosis of APLS, multiple and persistently positive results anticipate more thrombotic events.7,8 The Subcommittee on Lupus Anticoagulants/Antiphospholipid Antibodies of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis has published criteria for LAs that include prolongation of at least one phospholipiddependent assay, evidence of inhibitory activity on normal plasma, and confirmation that the inhibitory activity is dependent upon the presence of phospholipid.9 Perhaps the most instructive of the new assays that have been developed for APLS is the one which detects antibodies against 2glycoprotein-I,10 especially in association with clinical thrombotic events.11 An association between the degree of elevation of the titer of a given test and the risk for thrombosis has been proposed, but the titer may change spontaneously or may fall to undetectable levels at a time of thrombosis.12,13 Recent studies reinforce the concept that the diagnosis of APLS is not increased by simply expanding the menu of assays,14 but more than one positive assay results, for example, anticardiolipin and LA, may have greater prognostic value for VTED and especially for arterial thrombotic disease.7 Mechanisms of thrombogenesis Various mechanisms have been proposed to explain the increased risk of thrombosis in patients with LA, including inhibition of endothelial activation of protein C and inhibition of endothelial cell release or production of prostacyclin,15,16 while alterations in fibrinolytic mechanisms have been discounted.17 Recent conceptual proposals on mechanisms of lupus inhibitors include interference with the action of 2-glycoprotein-I, which blocks free protein S binding to C4b-BP,18 expression of tissue factor on circulating monocytes,19 acquired activated protein C resistance20 and endothelial cell activation.21 Of special note is the evidence presented by Rand et al. on the LA antibody-induced reduction of annexin V levels in cultured endothelial cells and trophoblasts.22 If this mechanism is indeed operating,23 it may well explain the placental changes that underlie the fetal wastage of APLS. Clinical manifestations Population studies indicate that 515% of patients presenting with VTED have LA,2426 in comparison with 02% of the general population.2527 While it is reasonable to assume that co-existence of a hereditary thrombophilic marker could contribute to thrombotic events in patients with APLS,28,29 epidemiological analyses to date indicate that the mutations for factor V Leiden30 or prothrombin G20210A31,32 do not
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Table 1 Mechanisms of thrombogenesis in the acquired thrombophilic syndromes Mechanism Antiphospholipid syndrome Paroxysmal nocturnal hemoglobinuria Increased erythrocyte prothrombinase activity 74,76 Myeloproliferative disorders Acute promyelocytic leukemia Solid tumors Drugs
Coagulation, Natural inhibitors
Reduced protein S 18 Acquired APCR 20
Promyelocyte procoagulant activity 175, 176
Reduced protein C or ATIII activity 214, 215 Acquired APCR 217, 218
Increased coagulation factors248250 Acquired APCR 259 HIT-T 294
Blood cells
Loss of annexin V 22
Increased erythrocyte and whole blood viscosity 99101 Increased platelet count 108 and platelet activity 112, 113
Vessel wall
Endothelial cell activation 21 Loss of annexin V 22
HIT-T 297
Fibrinolysis
Impaired fibrinolysis 77
Impaired fibrinolysis 128
Antifibrinolytic treatment of fibrinolysis 184186 Promyelocyte procoagulant activity 175, 176
Other
Release of microparticles 210213
APCR: activated protein C resistance. HIT-T: heparin-induced thrombocytopenia with thrombosis.
explain the thrombotic events in patients who have antiphospholipid directed antibodies. The primary APLS, also called Hughes syndrome, comprises a cluster of clinical and laboratory features in patients with SLE or independent of SLE, including VTED with recurrence, arterial occlusions, fetal wastage and thrombocytopenia3335 accompanied by a positive assay for antibody against one or another of the phospholipid components.3638 The thrombotic manifestations of APLS are varied.The age of distribution is wide and children can be affected.35,39 In a series of 70 patients with APLS reported by Asherson et al.33, 38 had experienced deep venous thrombosis, 18 pulmonary embolism, one the Budd-Chiari syndrome, one portal vein thrombosis, and one thrombosis of the inferior vena cava; 31 had arterial thromboses, including 15 patients with transient ischemic attacks, four with multi-infarct dementia, and five with myocardial infarction. APLS has been associated with thrombosis of the cerebral veins, cerebral sagittal sinus vein, splenic vein, superior mesenteric vein, portal vein, hepatic vein, renal vein, kidney and liver allograft thrombosis, subclavian vein, retinal vein and other ocular vessels, inferior vena cava, intracardiac thrombi, cutaneous necrosis and adrenal gland hemorrhage and infarction.33,3952 Arterial events as part of the APLS include both thrombotic strokes33,52,53 and cerebral microembolic phenomena,54 which may be related to very elevated titers of anticardiolipin antibody.55 A malignant form of APLS, catastrophic APLS,5658 presents with sudden aggressive and fatal vascular occlusive 32
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disease and can be marked by some or most of the following events, including renal failure, retinopathy, thrombotic stroke, osteonecrosis, skin necrosis, acute MI, ischemic limb syndrome, DIC and immune cytopenias. Women with APLS are at increased risks for infertility, chorea gravidarum, preeclampsia, placenta previa, fetal growth restriction, and fetal wastage59 which can be recurrent in 1540% of patients.60 The antibodies probably act by interfering with the natural anticoagulant mechanisms of endometrial and vascular annexin V22 and may lead to extensive placental infarctions, the ultimate cause of fetal wastage.60,61 Therapeutic considerations Therapy for women with recurrent abortions due to APLS has improved. Of 14 women who had experienced a total of 28 miscarriages due to placental infarctions, full-dose heparin begun an average of 10 weeks into pregnancy and continued through delivery was associated with a good outcome in 14 of 15 pregnancies, with less evidence of placental infarction.62 The combination of subcutaneous heparin (5000 U sub-cutaneous twice daily) or low molecular weight heparin (20 mg enoxaparin/day) plus aspirin (75 mg/day) has been advocated by Backos et al.63 based on a study of 150 such patients. However, higher doses of enoxaparin, 40 mg/d and 40 mg b.i.d. have been suggested by others.64 Two pilot trials of intravenous immunoglobulin (IVIG) in 31 patients used IVIG in addition to heparin plus aspirin,65,66 with
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Table 2 Clinical manifestations in acquired thrombophilic syndromes Mechanism Antiphospholipid syndrome Paroxysmal nocturnal hemoglobinuria Myeloproliferative disorders Acute promyelocytic leukemia Solid tumors Drugs
VENOUS THROMBOEMBOLIC DISEASE (VTED) DVT/PE Unusual sites ARTERIAL THROMBOSIS Peripheral Endocardial MICROCIRCULATORY OCCLUSION Local Placental Erythromelalgia Systemic DIC TTP
+ + + +
+ +
+ + + +
+ +/ +
+ + + +
+ +
+ + +
+ + + +
+ +
inconclusive evidence of further benefit, but with a suggestion of quantitative advantages to the fetus, for example, less growth restriction and less use of the pediatric intensive care unit. Prednisone is not of value in the management of these patients.67 Therapeutic recommendations for non-pregnant patients should be individualized appropriately.38 Active thrombotic disease should be managed with anticoagulant and antiplatelet agents as indicated, and long-term management should be initiated if clinical judgment suggests that spontaneous recurrence is likely and that the risk of a bleeding complication is sufficiently remote and non-life-threatening. Thrombolytic therapy for serious VTED can be used as for patients without APLS.68 While plasma exchange therapy is not of proven use for long-term management of APLS, presentation of the catastrophicform warrants such an approach,as reported in the successful management of two cases.69 Longterm anticoagulation with vitamin K antagonists can be considered in balance with the increased risk of bleeding. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) PNH is an acquired clonal hematopoietic stem cell disorder characterized by hemolysis due to complement activation, associated predisposition to bone marrow failure and a predilection for thrombosis.70 The molecular basis of complement-sensitive hemolysis is a mutation of an Xchromosome gene that controls biosynthesis of glycosyl phosphatidylinositol (GPI) molecules, membrane proteins that serve as receptors and/or anchors for many proteins.71,72 The red cell vulnerability to lysis stems from absent complement-regulatory membrane proteins CD59 (or membrane inhibitor of reactive lysis, MIRL) and CD 55, the so-called decay accelerating factor (DAF).73 Early reports of PNH emphasized the presence of hemolytic anemia and hemoglobinuria,74 but also noted thrombosis in the cerebral and visceral vessels more often than in peripheral veins.70 Of
interest, the initial complete description of PNH reported by Strubing in 1882 included painful splenomegaly, which may have been caused by visceral venous occlusion.75 Mechanisms of thrombogenesis Although there is no association between hemolytic and thrombotic crises,76 in vitro studies of red cells suggest that membrane vesicles77 possessing prothrombinase-promoting activity76,78 presumably produced by complement-induced lysis of the cells, circulate and induce thrombotic events at various vascular sites of vulnerability.Additionally, it has been proposed that monocytes have defective receptors for urokinase (u-PAR), resulting in a reduced fibrinolytic capacity in the face of incipient pathologic thrombi.79 That these or other mechanisms are, in fact, due to a defect related to hemolysis is supported by observations that knock-out mice deficient in red cell spectrin are susceptible to thrombosis, tendency that is perhaps related to red blood cell membrane vesiculation.80 Thrombotic events could potentially be secondary to inheritance of a second thrombophilic tendency but, as with APLS noted above, there is no increased frequency of the factor V Leiden gene mutation in PNH patients that could explain the VTED.81 Clinical manifestations For reasons that are not well understood, patients with PNH have venous thrombotic events in unusual locations routinely, including cerebral or mesenteric veins, splenic, portal, hepatic or renal veins and the inferior vena cava.74,8288 Purpura fulminans may occur, but arterial events such as thrombotic stroke and myocardial infarction are only rarely reported.89 Venous thrombosis is a prominent, enduring and lifethreatening part of the illness, as borne out by two long-term follow-up studies of 80 patients at Hammersmith Hospital (London)90 and 220 patients at Hpital St Louis (Paris).91 The 33
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frequency of significant thrombotic disease was 39% and 28%, respectively, and thrombosis contributed significantly to mortality, causing death in 58% of known cases in London and increasing the relative risk of death to 10.2 in the Paris study. Therapeutic considerations Prophylactic anticoagulant treatment is to be seriously considered in all patients with PNH. Occasionally the thrombotic episode requires thrombolytic treatment, which can be administered as for any patient with equivalent thrombotic disease.92,93 PNH is particularly dangerous during pregnancy. In a review of 20 women (31 pregnancies), there was a 43% incidence of fetal wastage and a 74% incidence of maternal complications, with a 10% incidence of maternal death, nearly all of which were due to thrombotic events.94 One series of eight pregnancies reported favorable results using subcutaneous heparin prophylactically throughout the pregnancy, with fulldose heparin following delivery,95 but a similar approach did not prevent cerebral venous thrombosis in another case.96 MYELOPROLIFERATIVE DISORDERS (MPD) The myeloproliferative disorders (MPD) encompass a group of diseases characterized by clonal proliferation of bone marrow progenitors, with variable predisposition to thrombotic and hemorrhagic complications.97 These are generally divided into three clinical groups, which nevertheless may merge or evolve one into another. Idiopathic myelofibrosis (IMF) (agnogenic myeloid metaplasia) progresses to marrow failure or may convert into leukemia and can manifest venous thrombosis, especially of the portal system related to the thrombocythemia that follows splenectomy.98 Essential thrombocythemia (ET) and polycythemia vera (PV) are characterized by a more striking association with thrombotic disease, and excess morbidity and mortality is often due to arterial and venous thrombotic complications.99103 These disorders can also evolve into acute myelogenous leukemia, transformation that may be attributable in part to the use of cytoreductive therapy.104107 Mechanisms of thrombogenesis The mechanisms implicated in the prothrombotic state associated with these disorders are complex, with the exception of the earliest and most clear association of vascular occlusive episodes with high hematocrit (packed red blood cell volume) and hyperviscosity.101103,108,109 The relation between the platelet count and thrombosis is less precise, with a longheld general feeling that patients with counts above 400 109/L are 1.5-fold more likely to have venous thrombotic complications than those with lower counts. Further evidence that links a higher platelet count to thrombosis is provided by the study of cytoreductive therapy with hydroxyurea in patients with ET. Patients with platelet counts of about 500 109/L had fewer thrombotic events than patients with persistent counts between 800 and 1000 109/L.110 However, severe thrombotic complications at platelet counts below 500 10 9/L have been reported by Regev et al. in 15% of patients.111 Furthermore, extremely 34
high platelet counts (>1500 109/L) are mostly associated with hemorrhagic complications,112,113 especially when aspirin therapy has been initiated.114 The underlying cause of the increased platelet count is important, inasmuch as patients with ET are significantly more likely to have thrombotic events than are patients with thrombocytosis due to non-clonal (reactive) disorders.115 Of interest, reactive polycythemia (smokers polycythemia) also has a significantly lower, though still significant, risk of a thromboembolic problem (41% versus 60%; p <0.05).116 Landolfi et al.117 summarized the different cellular (platelet) and rheologic mechanisms that underlie thrombosis and bleeding in patients with MPD. Platelet activation in vivo, as reflected by an increased thromboxane A2 synthesis in both PV and ET, occurs independently of the platelet count and blood viscosity.118,119 In addition, thrombopoietin enhances platelet aggregation induced by ADP,collagen and epinephrine in patients with MPD as well as in healthy controls.120 A separate issue concerns the erythromelalgia and certain neurological manifestations that are not clearly explained by large vessel thrombotic phenomena and which seem to be more clearly associated with higher platelets count.121123 An increase in urinary excretion of thromboxane A2 byproducts has been observed in patients with PV and ET who developed such symptoms compared to patients who remained asymptomatic and treatment with aspirin was inhibitory on thromboxane-dependent platelet activation, thus preventing microvascular events.124 The predictive value of platelet function tests for venous and arterial thrombotic disease is not clear-cut, with evidence both in favor of and against their use in clinical situations. The report by Barbui et al. in 101 patients with MPD tested by platelet-rich plasma aggregometry showed no predictive value,125 but other studies suggest that hyperaggregation predisposes to or is related to thrombotic events, while hypoaggregation is related to hemorrhagic phenomena.126128 In the report by Kueh et al., 21 of 30 patients had decreased aggregation, and of these, six developed hemorrhagic complications. Another four patients had increased aggregation, of which three had thrombotic complications.127 Using whole blood aggregometry, Manoharan et al. found a larger population of patients with increased activity (53 of 75), 20 of whom had a history of venous or arterial thrombosis and nine of whom (17%) developed new thrombotic events within 33 months. In contrast, of the 22 patients with decreased or normal aggregation, only one had a history of thrombosis and only one (5%) developed a new thrombotic event.129 The group with decreased or normal aggregation had a slight tendency (12%) for hemorrhagic complications. Another mechanism that may play a role in thrombogenesis is impairment of fibrinolytic activity (increased PAI-1, slow clot lysis).130 A reduction in the level of natural anticoagulants (protein S, protein C and ATIII) was noted in 40% of patients with ET and PV who developed thrombosis, but these changes may have been the result rather than the cause of thrombosis.131 Homocysteine levels are similar in patients with ET or PV whether or not they are manifesting arterial or venous thrombosis.132

Clinical manifestations Identification of the susceptible patient who will develop a thrombotic event is a challenge for the clinician.Age greater than 60, history of a previous thrombotic event and prolonged duration of uncontrolled thrombocythemia have been associated with increased risk for subsequent thrombosis.133135 The Gruppo Italiano Studio Policitemia (GISP)133 followed 1213 patients with PV prospectively for 20 years, and found an overall thrombosis rate of 3.4%/year, less for patients who were younger than 40 and more for those over age 70 (1.8% and 5.1%, respectively).The GISP reports subsequent thrombosis in 17.3% of patients without a history of prior thrombosis, as compared to 24.6% for those with a positive history.A history of smoking or other risk factors for atherosclerosis such as dyslipidemia, diabetes, and hypertension were not predictive for thrombosis in some reports,104,133 but Watson and Key found an association of atherosclerotic risk factors with arterial thrombotic complications in patients with ET.136 Other studies document a direct relation between thrombocythemia and thrombosis.137,138 These observations raise the question as to whether treatment is warranted in all patients with MPD. Indeed, in a low risk cohort of 65 patients with ET, younger than 60 years of age and without a history of thrombosis, the incidence of thrombosis after 4 years without treatment was the same as in an age-and sex-matched control group (1.9% versus 1.5%).139 Most thrombotic episodes occur at presentation or within 2 years preceding the diagnosis, suggesting that the preclinical phase in MPD is associated with a latent prothrombotic potential.133,140,141 Arterial events are common and involve the cerebral, coronary and peripheral vessels, whereas venous events often occur in the large mesenteric veins, the portal vein, the inferior vena cava and cerebral veins.85,100,102,121,141153 Inherited thrombophilia, in particular factor V Leiden, is often found in MPD patients manifesting splanchnic vein thrombosis.154 Erythromelalgia is a typical manifestation of thrombocythemia, first described by Mitchel in 1878,155 and is characterized by red and painful extremities and progression in some instances to ischemic acrocyanosis and gangrene. Arteriolar intimal thickening and microthrombosis have been demonstrated, and clinical response to aspirin is usually dramatic.113 A transient neurologic syndrome manifesting by sudden onset of symptoms, which include headache, dysarthria, scotomata and hemiparesis, and lasting seconds to minutes, has also been ascribed to small vessel, platelet-mediated microocclusions responsive to either aspirin or to cytoreductive treatment.123 Finally, non-bacterial thrombotic endocarditis (NBTE) has been detected by echocardiography in over one third of patients with MPD.52 Therapeutic considerations The treatment of PV and ET is geared towards prevention of thrombotic phenomena, and must be balanced against the risks associated with cytoreductive therapy, especially malignant transformation. Mortality is mostly due to serious arterial and thrombotic events and malignancies.The incidence of malignancy is four times higher in patients who have received myelosuppressive therapy than in those treated with phlebotomy or with antithrombotic agents only.133,156 The classic study by the Polycythemia Vera Study Group156,157 compared phlebotomy with alkylating myelosuppressive therapy and found that thrombosis was lower in the group treated with chemotherapy despite a comparable reduction in the hematocrit with both treatments. Because of the risk of malignant transformation with alkylating agents, hydroxyurea is the preferred cytoreductive agent at present, and alkylating agents and radiophosphorus treatment use is discouraged. Direct comparison of results between hydroxyurea and phlebotomy has not been reported. Similarly, patients with ET have lower rates of thrombosis with hydroxyurea treatment and malignant transformation was not noted during a limited follow-up of 27 months.110 New agents such as interferon and anagrelide are being used increasingly, especially in young patients with thrombocythemia,158161 with positive results to date for controlling the platelet count and preventing thrombotic complications without an added risk of leukemogenesis. The role of aspirin in reducing thrombotic events has been overshadowed by reports of increased rates of hemorrhagic complications.97,162 However, these reports and other studies have been criticized because the dose of aspirin was higher than needed (approximately 1 gm/day). For example, dosages of aspirin as low as 100 mg/day reduce thromboxane A2 production and alleviate erythromelalgic, neurologic and vasomotor symptoms.113,124 Low-dose aspirin has been shown to be tolerated and effective in preventing recurrence of thrombotic complications in patients with ET.163165 A large prospective trial (European Collaboration on Low-dose Aspirin in Polycythaemia vera-ECLAP) that will evaluate safety and efficacy of low-dose aspirin is in progress.164 Until results are available, it is reasonable to use aspirin in patients considered at high risk for thrombosis, in addition to cytoreductive therapy. ACUTE PROMYELOCYTIC LEUKEMIA (APL) The high early mortality noted in patients with acute promyelocytic leukemia (APL) is related to a coagulopathy that can lead to hemorrhagic death.166 Since the introduction of the differentiating agent all-trans-retinoic acid (ATRA) which promotes maturation of promyelocytes, the remission rate has reached 8090%.167169 With aggressive hematological support plus/minus the use of heparin, the rate of fatal hemorrhage has been reduced to approximately 10% in specialized centers.170 The microgranular variant of the disease, characterized by a paucity of myeloid granules and a lobulated monocytoid nucleus,171,172 is associated with thrombosis, presumably due to the release of a procoagulant factor from the leukemic cells that is capable of inducing intravascular coagulation173 or massive fatal venous thrombosis, for example, Budd-Chiari syndrome.174
Mechanisms of thrombogenesis The coagulopathy related to APL is profound and reflects a dual disturbance of increased coagulation and increased fibrinolysis, both of which could be caused by the microgranular contents. Enhanced procoagulant activity could be
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mediated through the release of tissue factor175 or of a factor X-activating cysteine protease.176 Either way, thrombin would be generated, fibrinogen would be converted to fibrin and diffuse or localized thrombosis could follow. Evidence of such activation (prothrombin fragment F1+2, thrombinantithrombin complexes and fibrinopeptide A) was noted in five patients with a new diagnosis of APL. The levels are increased during induction chemotherapy, as the procoagulant material from promyelocytes is released into the circulation.177 If so, DIC could be induced and accompanied by consumption of clotting factors and platelets leading to severe hemorrhagic complications. On the other hand, patients with APL also have evidence of accelerated fibrinolysis. Gralnick and Abrell were the first to demonstrate fibrinolytic activity associated with these cells in 1973.178 Release of urokinase and tissue plasminogenlike activators179 could result in consumption of plasminogen and antiplasmin.180182 The resultant systemic lytic state could explain a severe bleeding diathesis without accompanying thrombotic events. More recently, Menell et al.183 demonstrated overexpression of a receptor for fibrinolytic proteins (annexin II) on the surface of APL cells, which is corrected when differentiation is induced with ATRA.Treatment of the systemic lytic state could be affected by the use of antifibrinolytic agents such as tranexamic acid or epsilon aminocaproic acid (EACA) given along with traditional chemotherapy.184,185 In one small, randomized study of 12 patients, a reduction in the hemorrhagic score and transfusion requirements in patients treated with EACA during induction chemotherapy was accomplished without an increase in thrombotic complications.184 However, these results have not been validated in larger studies. Clinical manifestations The spectrum of clinical manifestations in APL is stunningly variable.While some patients present with excessive hemorrhagic complications due to fibrinolysis and/or DIC, others have clear venous or arterial thrombotic episodes.166,171,172 The two opposite manifestations of this process (thrombosis and fibrinolysis) may coexist in the same patient, making the choice of therapy exceedingly difficult.The initiation of treatment for APL further complicates the matters.While cytolytic therapy (including leukapheresis) leads to rapid destruction of promyelocytes with the release of fibrinolytic and/or procoagulant material in the systemic circulation, fueling the thrombo-hemorrhagic process,ATRA, on the other hand, can increase the risk of thrombosis.186 Therapeutic considerations With the adoption of ATRA as a routine measure in the treatment of APL, the thrombo-hemorrhagic pattern of complications may well have changed.186 In place of the consumption-fibrinolysis-hemorrhage picture that historically dominated the clinical picture during induction therapy, patients may now be more at risk of major vessel occlusion. The rate of venous thrombosis is low but definite upon presentation,187 so a backdrop of VTED potential exists, perhaps mediated by platelet-leukocyte interactions at sites of vascular stasis or injury.188 With induction of promyelocyte maturation and with clinical or subclinical retinoic acid syn36
drome,189 the possibility exists that local concentrations of promyelocytes could induce large vessel thrombosis.186,190192 The genetic thrombophilic states such as factor V Leiden or hyperhomocysteinemia do not play a role in thrombogenesis in APL patients treated with ATRA, therefore these assays are not needed prior to initiation of treatment.193 The role of heparin in preventing either DIC or large vessel thrombosis in this setting is difficult to assess, since most of the studies analyzing the use of anticoagulation in the management of the complex coagulopathy associated with APL precede the ATRA era. Small case series or retrospective studies from the early 1980s report a benefit from the use of heparin along with induction chemotherapy.194,195 A larger Italian retrospective analysis showed no difference in the rate of hemorrhagic deaths and overall survival in a group of 282 patients who were treated with supportive care alone, anticoagulation with heparin or antifibrinolytic therapy during standard induction treatment.196 Because of the changing spectrum of complications since the adoption of ATRA as a differentiating agent for promyelocytes, translating in a more rapid correction of the fibrinolytic parameters197 and a concomitant increase in thrombotic risk, the role of heparin should be reconsidered. MALIGNANCY (INCLUDING TROUSSEAU SYNDROME) The association between thrombosis and malignancy dates to 1865, when Trousseau recognized the occurrence of DVT in patients with gastric malignancy.198 In 1938, Sproull noted that thrombosis is frequent in patients with pancreatic tumors and noted intracardiac and arterial thrombi in cancer patients.199 The migratory nature of venous thrombosis associated with malignancy was recognized by Edwards in 1949 in a series of 23 patients with pancreatic, gastric, bronchogenic, gallbladder or undetermined malignancy.200 Rohner et al. emphasized the association between mucinproducing tumors and thrombosis, and noted the noninflammatory nature of left heart vegetations in cancer patients, postulating that the thrombotic event occurred in non-damaged heart valves after collagen degeneration.201 Thromboembolic disease affects approximately 1015% of cancer patients and is the second commonest cause for death.202204 The mucin-producing adenocarcinomas are more often associated with thrombosis. In one series of 147 patients with cancer,VTED was the first sign of malignancy in patients with pancreatic and prostatic malignancy.205 Another series of 130 patients with pancreatic carcinoma showed a 7% incidence of Trousseau syndrome, all related to tumor in the body and tail but not in the head of the pancreas.206 A large population-based analysis of 61,998 patients in Sweden reported a standardized incidence ratio for cancer of 3.2 in patients admitted to the hospital with VTED, stronger for patients younger than 65 years, in the first year following the presentation with thrombosis and for cancers of the pancreas, ovary, brain, Hodgkins lymphoma and MPD.207 Mechanisms of thrombogenesis The causes of thrombosis in cancer patients are complex, including circumstantial risk factors such as the presence of indwelling catheters and prolonged immobilization,

chemotherapy or hormonal therapy, alteration of the vascular bed caused by tumor growth, direct extension of tumor into a vein and disturbances of the coagulation pathway and platelet number and/or function. Reactive thrombocytosis is common in untreated cancer patients and abnormal platelet aggregation in vitro, thought to be induced by material released from tumor cells,208,209 may contribute to the metastatic spread of the malignancy.210212 Tumor cells can activate the coagulation cascade by tissue factor expression that activates factor VII172,213215 or through cysteine-containing proteases that are capable of directly activating factor X.216 Natural anticoagulants (ATIII and protein C) are reduced in some malignancies217,218 attributed by one group to a decrease in hepatic synthesis rather than consumption.219 Resistance to activated protein C that is unrelated to a mutant factor V Leiden, perhaps due to elevated levels of factor VIII or fibrinogen, may contribute to thrombosis.220,221 None of these abnormalities is predictive of thrombosis in an individual cancer patient.222 Activation of fibrinolysis by secretion of plasminogen activators may contribute to fibrin degradation around the tumor bed and to metastatic spread.223 Chemotherapy may augment the risk for thrombosis, for example, breast cancer treatment with or without tamoxifen, especially in post-menopausal women.224,225 Lasparaginase use, perhaps depleting asparagine that is essential for the synthesis of inhibitors of coagulation, is also associated with thrombosis.226 Clinical manifestations The clinical spectrum of thrombotic events associated with malignancy includes VTED, non-bacterial thrombotic (marrantic) endocarditis, especially of valves on the left side of the heart, and primary arterial thrombosis or embolic occlusions.227,228 Trousseau syndrome encompasses migratory thrombophlebitis, unusual sites of thrombosis, intracardiac thrombi, arterial thrombosis, DIC and markers of microangiopathic hemolytic anemia, elevated fibrin degradation products and hypofibrinogenemia.229231 Characteristically, the thrombotic events are resistant to warfarin therapy and may be devastating in the absence of heparin.231 Reports describe patients with Trousseau syndrome treated successfully with low molecular weight heparin (LMWH), with lasting protection against recurrent thrombosis.232,233 cations or failure of anticoagulation. Serious complications related to filter placement occurred in 17% of the patients.237 Given the high risk for thrombosis in cancer patients, prophylactic therapy with LMWH is often initiated perioperatively and in high-risk medical situations.237,238 Anticoagulant therapy may have an antimetastatic potential and could potentially prolong survival when added to conventional chemotherapy.237 The mechanism involved in this process is uncertain, but perhaps it is related to the prevention of thrombus formation in distal capillaries where migrant metastatic cells nest.239 The Veterans Administration Study (#75) showed an improvement in survival (50 weeks versus 24 weeks) in patients with small cell lung carcinoma when warfarin was added to a combination chemoradiation regimen240 and similar results were reported for heparin added to standard chemotherapy for small cell cancer.241 However, these results were not replicated for patients with other types of malignancy (colon, head and neck, prostate)242 and a randomized CALGB trial did not find a beneficial role for anticoagulation in lung cancer patients.243
MEDICATIONS The fine hemostatic balance can be affected by a number of medications, most notably by hormonal preparations that incorporate estrogens and by chemotherapeutic agents. Theoretical considerations link the hematopoietic growth factors to thrombosis, but to date these concerns have not been translated into clinical proof of excess thrombosis.
Therapeutic considerations As with other patients with VTED in the absence of contraindications, standard anticoagulation with heparin or LMWH should be started immediately and continued as long as the tumor presents a threat of recurrence, often resulting in lifelong therapy.234 Greenfield filter placement should be reserved for the minority of patients who have serious contraindications to anticoagulation or who fail anticoagulation outright,235 especially considering that such patients have a high rate of DVT extension, inferior vena caval thrombosis and even pulmonary embolism after filter placement.236 In a retrospective study, 64% of patients with cancer could be managed with anticoagulation alone, 17% had filter placement for standard indications and an additional 19% underwent filter placement because of hemorrhagic compli-
Oral contraceptives and hormonal replacement therapy The oral contraceptives (OC) have been linked to a thrombophilic state in direct relation with the estrogen content.244250 Invoked mechanisms include an increase in the blood concentration of factors VII, VIII and XII, von Willebrand factor and fibrinogen,251253 as well as complex alterations of the platelet adhesiveness and aggregability.254257 The synthetic estrogens affect the levels of the clotting factors more than do the natural estrogen compounds like estriol succinate.258,259 On the other hand, decreased levels of PAI-1 have been noted in estrogen users, perhaps underlying an augmented fibrinolytic activity and cardioprotective effect.260,261 An acquired resistance to activated protein C was documented in current OC users.262 The increased risk of VTED with OC use is dependent on the dose of estrogen and the type of progestagen included in the hormonal combination, with higher risk associated with third generation progestagens than with first or second generation products (norethindrone and norgestrel respectively).244247 The coexistence of an inherited thrombophilic trait increases the susceptibility for thrombosis, a connection that is particularly important for factor V Leiden, which is present in up to 6% of the Caucasian population.Women that carry the factor V R506Q mutation have a 35-fold increase in VTED risk when using OC, compared to the control group.263 This observation raises the issue of screening for thrombophilic
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states, particularly for factor V Leiden, prior to initiating oral contraception.264266 Given the prevalence of OC use, cost considerations suggest that screening should be reserved for women with a personal or family history of thrombosis or with other recognized prothrombotic risk factors.A propensity for thrombosis has also been noted for hormonal replacement therapy users.250 In the Heart and Estrogen/ progestin Replacement Study (HERS), in which a hormonal combination was used in women with known coronary disease, the risk of VTED was 2.7-fold higher in the treatment versus the control group.249 Tamoxifen Tamoxifen is used as an antiestrogen in the adjuvant setting or as therapy in metastatic breast cancer, and is associated with an increased risk of VTED, with significant contributions by the body mass index, age and smoking status of the patient. A retrospective case control study of more than 10,000 women with breast cancer in the UK estimated a relative risk for VTED of 7.0 in current users of tamoxifen compared with controls.267 Higher risk for venous and arterial thromboembolism was also noted in women taking tamoxifen for breast cancer prevention in the National Adjuvant Breast and Bowel Project P1 study.268,269 A randomized trial in Canada observed a higher incidence and severity of VTED in women with breast cancer undergoing concomitant adjuvant therapy with tamoxifen and chemotherapy than among those receiving tamoxifen alone (13.6% vs 2.6%).225 Whether decreases in the concentration of natural coagulation inhibitors such as antithrombin III (AT III) and protein C270,271 simply correlate with a thrombophilic predisposition or reflect activation of coagulation is unresolved, with some studies reporting no concomitant increase in markers of thrombin generation (prothrombin fragments 1+2, thrombin-antithrombin complex or fibrin degradation products) in association with decreases in AT III and protein C levels.272274 Chemotherapy The prothrombotic potential of chemotherapeutic agents can be difficult to ascertain, as patients with malignancy already have an underlying thrombophilic state, and indwelling long-term catheters for delivery of the chemotherapy probably represent foci for thrombi genesis as well. However, some cytotoxic medications are associated with a probably intrinsic prothrombotic tendency, such as L Asparaginase, which causes AT III depletion,275 and estramustine, which can lead to arterial, and VTED through an estrogen-like effect.276 VTED may occur in 511% of children with all treated L-asparaginase, and inherited thrombophilia may substantially increase the risk.277 A pilot study suggests that low-molecular-weight heparin can prevent VTED in such patients during L-asparaginase therapy.278 Hematopoietic growth factors In vitro studies and occasional case reports have linked recombinant hematopoietic growth factors to a thrombophilic state. For instance, erythropoietin causes an increase in markers of endothelial cell injury (von Willebrand factor, thrombomodulin and tissue factor pathway 38
inhibitor,279, 280 a decrease in free protein S concentration281 and possibly enhances platelet aggregability.279,282,283 In addition, a rise in hematocrit secondary to erythropoietin could predispose to thrombosis.284 However, short-and long-term use of erythropoietin has not been associated with a significant increase in thromboembolic complications.285289 There are similar concerns regarding the use of thrombopoietin and granulocyte stimulating colony factor (G-CSF).290 Platelet aggregation can be augmented by thrombopoietin120 and platelets possess functional receptors for G-CSF.291,292 Rare episodes of thrombosis have been reported in patients receiving G-CSF.293 Clearly, definitive studies are needed to prove a causal relationship. Heparin and coumarins Patients who develop thrombocytopenia secondary to antibody against platelet factor 4: heparin complexes (HIT) are prone to both arterial and venous thrombosis (HIT-T).294 By a similarly curious thrombotic complication of an anticoagulant agent, coumarins can induce microvascular occlusions leading to skin necrosis and venous limb gangrene in patients with pre-existing protein C deficiency.295,296 These clinical situations in which patients with evident thrombotic disease or in need of prophylaxis against such events experience new and/or extended thrombotic complications may be difficult to manage and present unusual therapeutic dilemmas.Warkentin has reviewed the pathophysiology and treatment of the conditions in detail.297 OTHERS Acquired deficiencies of the natural inhibitors of the coagulation pathway can be associated with a variety of disorders, sometimes related to a true hypercoagulable state. For instance, low levels of AT III, protein C and protein S can be encountered in hepatic failure because of decreased synthesis; however the hemostatic balance will reflect a concomitant decrease in synthesis of the coagulation factors leading to a bleeding tendency. Loss of ATIII is encountered in nephrotic syndrome298 which is associated also with decreased levels of free protein S to about 75% of normal. In fact, the total level of protein S may actually be increased in this circumstance, but the level of the C4b-BP, to which protein S is bound in plasma, is also increased to nearly twice normal,accounting for a decreased level of free protein S.299,300 Low levels of protein S have been reported in multiple myeloma301 orthotopic liver transplantation302 inflammatory bowel disease303 and second trimester of the pregnancy, when the low protein S level may be related to an increased C4b-BP or an increased affinity for C4b-BP in plasma.304, 305 Extensive thrombosis leads to rapid consumption of these inhibitors, with subsequent reduced levels of AT III, protein C and S. Protein S can be decreased in SLE, in association or not with APL antibodies.306,307 In one series, protein S was reduced in nine of 36 patients with SLE and all patients deficient in protein S had APL antibodies suggesting that the thrombotic tendency was mediated through an acquired deficiency in protein S.308 A related case describes antibodies against protein S in association with a thrombotic event.309 Low levels of protein S have been reported in acute bacterial

or viral illnesses that predispose to purpura fulminans, with return of levels to normal after recovery.310312 HIV infection is associated with a prothrombotic state as reflected by increased markers of thrombin activation (prothrombin 1+2, FDP) and PAI 1 reported in a small series of 22 patients.313 Protein S is frequently decreased, sometimes in association with a thrombophilic state.314317 The mechanism of these changes may be related to abnormal endothelial cell function during HIV infection, and as yet there is no correlation with clinical manifestations or duration of HIV infection or with the CD4 count. Behcet disease is a systemic disorder that occurs most typically in males from the Mediterranean basin, and is characterized by oral and genital ulceration and ocular inflammation. Vascular manifestations are primarily VTED of large vessels, often in unusual sites including the inferior and superior vena cava, hepatic veins (Budd-Chiari syndrome), and cerebral sinuses as well as intracardiac thrombosis and pulmonary embolism.318321 Confounding and potentiating influences have been noted, for example, anti-endothelial antibodies, hyperhomocysteinemia and homozygosity for MTHFR and the prothrombin 20210 and factor V Leiden mutations,322324 although the latter observation has been disputed as a contributing cause.325 Circumstantial risk factors which would otherwise represent an insufficient cause for a thrombotic episode may unmask a prothrombotic predisposition as, for example, with stasis, pregnancy or advanced age. There are well-documented reports that strongly relate VTED to prolonged travel. Of interest, while air travel is increasingly but not universally recognized as a potential cause, automobile travel of similar duration is less associated with VTED,326,327 perhaps reflecting non-standardized evaluations of patients but possibly related to environmental or physical factors present during air travel. Bedridden patients are clearly at increased risk for VTED, and a trial has demonstrated that such patients with significant illness or with difficulty in ambulation have objectively documented high rates of VTED, on the order of 15%, and that such events can be reduced significantly (to 6%) by treatment with low molecular weight heparin.328 The risk of VTED is increased four-fold during pregnancy, being particularly high during the postpartum period. Due to anatomical considerations of the pelvic vessels, DVT is predominantly present in the left leg (80% of affected women).329 Proximal DVT is common, often resulting in the post-phlebitic syndrome, and the risk of VTED is increased in patients with prior disease, positive family history, age over 35 years, Cesarean section, and gestational vascular complications such as preeclampsia, placental abruption and intrauterine growth restriction.330 The coagulation cascade is activated during pregnancy as manifested by increased factor levels and activated peptides such as prothrombin fragment 1.2 and fibrinopeptide A, as well as by soluble fibrin and D-dimer.331 The natural anticoagulant systems may be affected, for example, reduced activity of protein S and increased APC-resistance332 and a reduced fibrinolytic response may further exaggerate the situation.333 Thus, these influences combine to produce a net effect that is prothrombotic. While inherited thrombophilia can be found in the majority of women who experience gestational VTED,334 these acquired mechanisms contribute to its expression and VTED may be manifest in women without inherited thrombophilia.
Acknowledgements
Supported by the Los Angeles Orthopaedic Hospital Foundation, Los Angeles, California, USA.
Correspondence to:Victor J. Marder MD,Vascular Medicine, Los Angeles Orthopaedic Hospital/UCLA, 2400 South Flower Street, Los Angeles, CA 90007, USA.Tel: + (213) 742 1519; Fax: + (213) 742 6568; E-mail: vmarder@laoh.ucla.edu
References 1.Virchow R. Phlogose und Thrombose in Gefilssystem. In: Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt: Staatsdruckerei, 1856. 2.Triplett DA, Brandt JT. Lupus anticoagulants: misnomer, paradox, riddle, epiphenomenon. Hematol Pathol 1988; 2: 121. 3.Conley CL, Rathburn HK, Morse WI II, Robinson JE Jr. Circulating anticoagulant as a cause of hemorrhagic diathesis in man. Bull Johns Hopkins Hosp 1948; 83: 288. 4.Bowie EJW,Thompson JH, Pascuzzi CA, Owen CA Jr.Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin Med 1963; 62: 416. 5.Derksen RH, Hasselaar P, Blokzijl L et al. Coagulation screen is more specific than the anticardiolipin antibody ELISA in defining a thrombotic subset of lupus patients.Ann Rheum Dis 1988; 47: 364. 6. Harris EN, Gharavi AE, Boey ML et al.Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2: 1211. 7. Nojima J, Suehisa E,Akita N et al. Risk of arterial thrombosis in patients with anticardiolipin antibodies and lupus anticoagulant. Br J Haematol 1997; 96: 447. 8. Feinstein DI. Lupus anticoagulant, anticardiolipin antibodies, fetal loss and systemic lupus erythematosus. Blood 1992; 80: 859. 9. Brandt JT,Triplett DA,Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update on behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardization Committee of the ISTH.Thromb Haemost 1995; 74: 1185. 10. Guerin J, Feighery C, Sim RB, Jackson J:Antibodies to 2glycoprotein I, a specific marker for the antiphospholipid syndrome. Clin Exp Immunol 1997; 109: 304. 11. Gomez-Pacheco L,Villa AR, Drenkard C et al: Serum anti-2glycoprotein-I and anticardiolipin antibodies during thrombosis in systemic lupus erythematosus patients.Am J Med 1999; 106: 417. 12. Kalunian KC, Peter JB, Middlekauff HR et al: Clinical significance of a single test for anticardiolipin antibodies in patients with systemic lupus erythematosus.Am J Med 1988; 85: 602. 13. Drenkard C, Sanchez-Guerrero J,Alarcon-Segovia D: Fall in antiphospholipid antibody at time of thrombo-occlusive episodes in systemic lupus erythematosus. J Rheumatol 1989; 16: 614. 14. Bertolaccini ML, Roch B,Amengual O et al: Multiple antiphospholipid tests do not increase the diagnostic
39
Matei et al.
yield in antiphospholipid syndrome. Br J Rheumatol 1998; 37: 1229. Cariou R,Tobelem G, Soria C, Caen J: Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 1986; 314: 1193. Marciniak E, Romond EH: Impaired catalytic function of activated protein C:A new in vitro manifestation of lupus anticoagulant. Blood 1989; 74: 2426. Francis RB Jr, Neely S: Effect of the lupus anticoagulant on endothelial fibrinolytic activity in vitro.Thromb Haemost 1989; 61: 314. Forastierro RR, Kordich L, Basilotta E, Carreras LO. Differences in protein S and C4b binding protein in different patients with antiphospholipid antibodies. Blood Coagul Fibrinolysis 1994; 5: 609. Amengual O,Atsumi T, Khamashta MA, Hughes GR:The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome.Thromb Haemost 1998; 79: 276. Griffin JH, Heeb MJ, Kojima Y et al:Activated protein C resistance: molecular mechanisms.Thromb Haemost 1995; 74: 444. Pierangeli SS, Colden-Stanfield M, Liu X et al:Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 1997, 1999; 99. Rand JH,Wu XX,Andree HA et al: Pregnancy loss in the antiphospholipid-antibody syndrome-a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154. Bevers EM, Janssen MP,Willems GM, Zwaal FA. No evidence for enhanced thrombin formation through displacement of annexin V by antiphospholipid antibodies.Thromb. Haemost. 2000; 83: 792. Ginsberg JS,Wells PS, Brill-Edwards P et al:Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685. Simioni P, Prandoni P, Zanon E et al: Deep venous thrombosis and lupus anticoagulant.Thromb Haemost 1996; 76: 187. Mateo J, Oliver A, Borell M, et al: Laboratory evaluation and clinical characteristics of 2, 132 consecutive unselected patients with venous thromboembolism results of the Spanish multicentric study on thrombophilia (EMET-study).Thromb Haemost 1997; 77: 444. Bick RL,Arun B, Frenkel EP:Antiphospholipid-thrombosis syndromes. Haemostasis 1999; 29 (23): 100. Brenner B.Vulfsons SL, Lanir N, Nahir M: Coexistence of familial antiphospholipid syndrome and factor V Leiden: impact on thrombotic diathesis: Br J Haematol 1996; 94: 166. Dori D, Beiran I, Gelfand Y, et al: Multiple retinal arteriolar occlusions associated with coexisting primary antiphospholipid syndrome and factor V Leiden mutation.Am J Ophthalmol 2000; 129: 106. Dizon-Townson D, Hutchison C, Silver R et al:The factor V Leiden mutation which predisposes to thrombosis is not common in patients with antiphospholipid syndrome.Thromb Haemost 1995; 74: 1029. Bentolila S, Ripoll L, Drouet L et al: Lack of association between thrombosis in primary antiphospholipid syndrome and the recently described thrombophilic 3-untranslated prothrombin gene polymorphism.Thromb Hemost 1997; 78: 1415. Bertolaccini ML,Atsumi T, Hunt BJ et al: Prothrombin mutation is not associated with thrombosis in patients with antiphospholipid syndrome.Thromb Haemost 1998; 80: 202. Asherson RA, Khamashta MA, Ordi-Ros J et al:The primary antiphospholipid syndrome: Major clinical and serological features. Medicine 1989; 68: 366. 34. Greaves M:Antiphospholipid antibodies and thrombosis. Lancet 1999; 353: 1348. 35. Manco-Johnson MJ, Nuss R: Lupus anticoagulant in children with thrombosis.Am J Hematol 1995; 48: 240. 36. Alarcon-Segovia D, Deleze M, Oria CV et al:Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus:A prospective analysis of 500 consecutive patients. dicine 1989; 68: 353. 37. Love PE, Santoro SA:Antiphospholipid antibodies:Anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders.Ann Intern Med 1990; 112: 682. 38. Lockshin MD:Antiphospholipid antibody syndrome. JAMA 1992; 268: 1451. 39. Bernstein ML, Salusinsky-Sternbach M, Bellefleur M, Esseltine DW: Thrombotic and hemorrhagic complications in children with the lupus anticoagulant.Am J Dis Child 1984; 138: 1132. 40. Levine SR, Kieran S, Puzio K et al: Cerebral venous thrombosis with lupus anticoagulants. Report of two cases. Stroke 1987; 18: 801. 41. Pertuiset E,Tribout B,Wechsler et al: Systemic lupus erythematosus presenting with portal venous thrombosis.Am J Med 1989; 86: 501. 42. Hershfield NB, Morrow I: Gastric bleeding due to splenic vein thrombosis. Can Med Assoc J 1968; 98: 649. 43. Nakamura H, Uehara H, Okada T et al: Occlusion of small hepatic veins associated with systemic lupus erythematosus with the lupus anticoagulant and anti-cardiolipin antibody. Hepatogastroenterology 1989; 36: 393. 44. Van Steenbergen W, Beyls J,Vermylen J et al:Lupus anticoagulant and thrombosis of the hepatic veins (Budd-Chiari syndrome): Report of three patients and review of the literature. J Hepatol 1986; 3: 87. 45. Mintz G,Acevedo-Vazauez E, Gutierrez-Espinosa G,Avelar-Garnica F: Renal vein thrombosis and inferior vena cava thrombosis in systemic lupus erythematosus: Frequency and risk factors.Arthritis Rheum 1984; 27: 539. 46. Yap AS, Powell EE,Yelland CE et al: Lupus anticoagulant.Ann Intern Med 1989; 111: 262. 47. Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJ: Lupus anticoagulant:An analysis of the clinical and laboratory features of 219 cases.Am J Hematol 1985; 19: 265. 48. Asherson RA, Merry P,Acheson JF et al:Antiphospholipid antibodies:A risk factor for occlusive ocular vascular disease in systemic lupus erythematosus and the primary antiphospholipid syndrome.Ann Rheum Dis 1989; 48: 358. 49. Rao RH,Vagnucci AH,Amico JA: Bilateral massive adrenal hemorrhage: Early recognition and treatment.Ann Intern Med 1989; 110: 227. 50. Granel B, Garcia E, Serratrice J et al:Asymptomatic intracardiac thrombi and primary antiphospholipid syndrome. Cardiology 1999; 92: 65. 51. Paira S, Roverano S, Zunino A, et al: Extensive cutaneous necrosis associated with anticardiolipin antibodies. J Rheumatol 1999; 26: 1197. 52. Reisner SA, Brenner B, Haim N, Edoute Y, Markiewicz W. Echocardiography in nonbacterial thrombotic endocarditis: from autopsy to clinical entity. J Am Soc Echocardiogr 2000; 13: 876. 53. Levine SR, Brey RI, Sawaya KL et al: Recurrent stroke and thrombo-occlussive events in the antiphospholipid syndrome.Ann Neurol 1995; 38: 119.
15.
16.
17.
18.
19.
20. 21.
22.
23.
24. 25. 26.
27. 28.
29.
30.
31.
32.
33.
40

54. Rademacher J, Sohngen D, Specker C et al: Cerebral microembolism, a disease marker for ischemic cerebrovascular events in the antiphospholipid syndrome of systemic lupus erythematosus? Acta Neurol Scand 1999; 99: 356. 55. Verro P, Levine SR,Tietjen GE: Cerebrovascular ischemic events with high positive anticardiolipin antibodies. Stroke 1998; 29: 2245. 56. Schaar CG, Ronday KH, Boets EP et al: Catastrophic manifestations of the antiphospholipid syndrome. J Rheumatol 1999; 26: 2261. 57. Voisin L, Derumeaux G, Borg JY et al: Catastrophic antiphospholipid syndrome with fatal acute course in rheumatoid arthritis. J Rheumatol 1995; 22: 1586. 58. Egan RM, Munn RK: Catastrophic antiphospholipid antibody syndrome presenting with multiple thromboses and sites of avascular necrosis. J Rheumatol 1994; 21: 2376. 59. Triplett DA. Obstetrical implications of antiphospholipid antibodies. Baillieres Clin Obstet Gynaecol 1992; 6: 507. 60. De Wolf F, Carreras LO, Moerman P et al. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant.Am J Obstet Gynecol 1982; 142: 829. 61. Hanly JG, Gladman DD, Rose TH et al. Lupus pregnancy.A prospective study of placental changes.Arthritis Rheum 1988; 31: 358. 62. Rosove MH,Tabsh K,Wasserstrum N et al. Heparin therapy for pregnant women with lupus anticoagulant of anticardiolipin antibodies. Obstet Gynecol 1990; 75: 630. 63. Backos M, Rai R, Baxter N, et al. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin. Br J Obstet Gynaecol 1999; 106: 102. 64. Brenner B, Hoffman R, Blumenfeld Z,Weiner Z,Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost 2000; 83: 693. 65. Clark AL, Branch DW, Silver RM et al. Pregnancy complicated by the antiphospholipid syndrome: outcomes with intravenous immunoglobulin therapy. Obstet Gynecol 1999; 93: 437. 66. Branch DW, Peaceman AM, Druzin M et al.A multicenter, placebocontrolled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy.The Pregnancy Loss Stdy Group.Am J Obstet Gynecol 2000; 182: 122. 67. Cowchock FS, Reece EA, Balaban D et al. Repeated fetal losses associated with antiphospholipid antibodies a collaborative randomized trial comparing prednisone with low-dose heparin treatment.Am J Obstet Gynecol 1992; 166: 1318. 68. Khoo KB, Long FL,Tuck RR et al. Cerebral venous sinus thrombosis associated with the primary antiphospholipid syndrome. Resolution with local thrombolytic therapy. Med J Aust 1995; 162: 30. 69. Flamholz R,Tran T, Grad GI et al.Therapeutic plasma exchange for the acute management of the catastrophic antiphospholipid syndrome: (2)-glycoprotein I antibodies as a marker of response to therapy. J Clin Apheresis 1999; 14: 171. 70. Rosse WF, Parker CJ. Paroxysmal nocturnal haemoglobinuria. Clin Haematol 1985; 14: 105. 71. Bessler M, Hillmen P. Somatic mutation and clonal selection in the pathogenesis and in the control paroxysmal nocturnal hemoglobinuria. Semin Hematol 1998; 35: 149. 72. Rosti V.The molecular basis of paroxysmal nocturnal hemoglobinuria. Haematologica 2000; 85: 82. 73. Nicholson-Weller A, Spicer DB,Austen KF. Deficiency of the complement regulatory protein,decay-accelerating factor, on membranes of granulocytes, monocytes and platelets in paroxysmal nocturnal hemoglobinuria. N Engl J Med 1985; 312: 1091. 74. Forman K, Sokol RJ, Hewitt S et al. Paroxysmal nocturnal haemoglobinuria.A clinicopathological study of 26 cases.Acta Haematol 1984; 71: 217. 75. Wilmanns JC. Paroxysmal nocturnal hemoglobinuria first described in 1882 by Paul Strubing.An example of cooperation between clinical and basic research. Blut 1982; 45: 367. 76. McKellar M, Dacie JV.Thromboplastic activity of the plasma in paroxysmal nocturnal haemoglobinuria. Br J Haematol 1958; 4: 404. 77. Hugel B, Socie G,Vu T et al. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia. Blood 1999; 93: 3451. 78. Wiedmer T, Hall SE, Ortel TL et al. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood 1993; 82: 1447. 79. Ploug M, Plesner T, Ronne E et al.The receptor for urokinase-type plasminogen activator is deficient on peripheral blood leukocytes in patients with paroxysmal nocturnal hemoglobinuria. Blood 1992; 79: 1447. 80. Wandersee NJ, Lee JC, Kaysser TM et al. Hematopoietic cells from spectrin-deficient mice are sufficient to induce thrombotic events in hematopoietically ablated recipients. Blood 1998; 92: 4856. 81. Nafa K, Bessler M, Mason P et al. Factor V Leiden mutation investigated by amplification created restriction enzyme site (ACRES) in PNH patients with and without thrombosis. Haematologica 1996; 81: 540. 82. Peytremann R, Rhodes RS, Hartmann RC.Thrombosis in paroxysmal nocturnal hemoglobinuria with particular reference to progressive diffuse hepatic venous thrombosis. Ser Haematol 1972; 3: 115. 83. Van Vleymen B, Dehaene I,Van Hoof A et al. Cerebral venous thrombosis in paroxysmal nocturnal haemoglobinuria.Acta Neurol Belg 1987; 87: 80. 84. Valla D, Dhumeaux D, Babany G et al. Hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria:A spectrum from asymptomatic occlusion of hepatic venules to fatal Budd-Chiari syndrome. Gastroenterology 1987; 93: 569. 85. Mitchell MC, Boitnott JK, Kaufman S et al. Budd-Chiari syndrome: Etiology, diagnosis and management. Medicine 1982; 61: 199. 86. Hartmann RC, Luther AB, Jenkins DE Jr et al. Fulminant hepatic venous thrombosis (Budd-Chiari syndrome) in paroxysmal nocturnal hemoglobinuria: Definition of a medical emergency. Johns Hopkins Med J 1980; 146: 247. 87. Draelos ZK, Hansen RC. Hemorrhagic bullae in an anemic woman. Paroxysmal nocturnal hemoglobinuria.Arch Dermatol 1986; 122: 1325. 88. Rietschel RL, Lewis CW, Simmons RA, Phyliky RL. Skin lesions in paroxysmal nocturnal hemoglobinuria.Arch Dermatol 1978; 114: 560. 89. Klein KL, Hartmann RC.Acute coronary artery thrombosis in paroxysmal nocturnal hemoglobinuria. South Med J 1989; 82: 1169. 90. Hillmen P, Lewis SM, Bressler M et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333: 1253.
41
Matei et al.
91. Socie G, Mary JY, de Gramont A et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet 1996; 348: 573. 92. Sholar PW, Bell WR.Thrombolytic therapy in inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria.Ann Intern Med 1985; 103: 539. 93. Mcmullin MF, Hillmen P, Jackson J et al.Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria. J Int Med, 1994; 235(1): 85. 94. Greene MF, Frigoletto FD Jr, Claster S, Rosenthal D. Pregnancy and paroxysmal nocturnal hemoglobinuria: Report of a case and review of the literature. Obstet Gynecol Surv 1983; 38: 591. 95. Solal-Celigny P,Tertian G, Fernandez H et al. Pregnancy and paroxysmal nocturnal hemoglobinuria.Arch Intern Med 1988; 148: 593. 96. Wozniak AJ, Kitchens CS. Prospective hemostatic studies in a patient having paroxysmal nocturnal hemoglobinuria, pregnancy, and cerebral venous thrombosis.Am J Obstet Gynecol 1982; 142: 591. 97. Murphy S.Therapeutic dilemmas: balancing the risks of bleeding, thrombosis and leukemic transformation in myeloproliferative disorders (MPD).Thromb Haemost 1997; 78: 622. 98. Tefferi A, Mesa RA, Nagorney DM et al. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 2000; 95: 2226. 99. Anger BR, Seifried E, Scheppach J, Heimpel H. Budd-Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases. Klin Wochenschr 1989; 67: 818. 100. Wasserman LR, Gilbert HS. Complications of polycythemia vera. Semin Hematol 1966; 3: 199. 101. Hoffman R,Wasserman LR. Natural history and management of polycythemia vera.Adv Intern Med 1979; 24: 255. 102. Schafer AI. Bleeding and thrombosis in the myeloproliferative disorders. Blood 1984; 64: 1. 103. Conley CL. Polycythemia vera. JAMA 1990; 263: 2481. 104. Bazzan M,Tamponi G, Schinco P et al.Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia.Ann Hematol 1999; 78: 539. 105. Barbui T, Finazzi G.Treatment of polycythemia vera. Haematologica 1998; 83: 143. 106. Tefferi A, Silverstein MN.Treatment of polycythaemia vera and essential thrombocythaemia. Baillieres Clin Haematol 1998; 11: 769. 107. Murphy S. Polycythemia vera. Dis Mon 1992; 38: 153. 108. Pearson TC,Wetherley-Mein G.Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2: 1219. 109. Schafer AI. Essential thrombocythemia. Prog Hemost Thromb 1991; 11: 69. 110. Cortelazzo S, Finazzi G. Ruggeri M et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 332: 1132. 111. Regev A, Stark P, Blickstein D, Lahav M.Thrombotic complications in essential thrombocythemia with relatively low platelet counts. Am J Hematol 1997; 56: 168. 112. Van Genderen P, Michiels J. Erythromelalgic, thrombotic and haemorrhagic manifestations of thrombocythaemia. Press Med 1994; 23: 73. 113. Michiels JJ, van Genderen PJ, Lindemans J, van Vliet HH. Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia. Leuk Lymphoma 1996; 22 (Suppl 1): 47. Willoughby S, Pearson TC.The use of aspirin in polycythaemia vera and primary thrombocythaemia. Blood Rev 1998; 12: 12. Harrison CN, Gale RE, Machin SJ, Linch DC.A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood 1999; 93: 417. Schwarcz TH, Hogan LA, Endean ED et al.Thromboembolic complications of polycythemia: polycythemmia vera versus smokers polycythemia. J Vasc Surg 1993; 17: 518. Landolfi R, Marchioli R, Patrono C. Mechanisms of bleeding and thrombosis in myeloproliferative disorders.Thromb Haemost 1997; 78: 617. Landolfi R, Ciabattoni G, Patrignani P et al. Increased thromboxane A2 biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo. Blood 1992; 80: 1965. Rocca B, Ciabattoni G,Tartaglione R et al. Increased thromboxane biosynthesis in essential thrombocythemia.Thromb Haemost 1995; 74:1225. Usuki K, Iki S, Endo M et al. Influence of thrombopoietin on platelet activation in myeloproliferative disorders. Br J Haematol 1997; 97:530. Jabaily J, Iland HJ, Laszlo J et al. Neurologic manifestations of essential thrombocythemia.Ann Intern Med 1983; 99:513. Singh AK,Wetherley-Mein G. Microvascular occlusive lesions in primary thrombocythaemia. Br J Hematol 1977; 36:553. Michiels JJ, Koudstaal PJ, Mulder AH, van Vliet HH:Transient neurologic and ocular manifestations in primary thrombocythemia. Neurology 1993; 43:1107. Van Genderen PJ, Prins FJ, Michiels JJ, Schror K.Thromboxanedependent platelet activation in vivo precedes arterial thrombosis in thrombocythaemia: a rationale for the use of low-dose aspirin as an antithrombotic agent. Br J Haematol 1999; 104:438. Barbui T, Cortelazzo S,Viero P et al.Thrombohaemmorrhagic complications in 101 cases of myeloproliferative disorders: relationship to platelet number and function. Eur J Cancer Clin Oncol 1983; 19:1593. Fabris F, Randi M, Sbrojavacca R et al.The possible value of platelet aggregation studies in patients with increased platelet number. Blut 1981; 43:279. Kueh YK, Chan L, Lim BC et al.The clinical relevance of platelet aggregation study in myeloproliferative disorders.Ann Acad Med Singapore 1983; 12:466. Wehmeier A, Scharf RE, Fricke S, Schneider W. Bleeding and thrombosis in chronic myeloproliferative disorders: relation of platelet disorders to clinical aspects of the disease. Haemostasis 1989; 19:251. Manoharan A, Gemmell R, Brighton T et al.Thrombosis and bleeding in myeloproliferative disorders: Identification of at-risk patient with whole blood platelet aggregation studies. Br J Haematol 1999; 105:618. Posan E, Ujj G, Kiss A et al. Reduced in vitro clot lysis and release of more active platelet PAI-1 in polycythemia vera and essential thrombocythemia.Thromb Res 1998; 90:51. Bucalossi A, Marotta G, Bigazzi C et al. Reduction of antithrobin III, protein C, and protein S levels and activated protein C resistance in polycythemia vera and essential thrombocythemia patients with thrombosis.Am J Hematol 1996; 52:14.
114. 115.
116.
117.
118.
119.
120.
121. 122. 123.
124.
125.
126.
127.
128.
129.
130.
131.
42

132. Gisslinger H, Rodeghiero F, Ruggeri M et al. Homocysteine levels in polycythaemia vera and essential thrombocythaemia. Br J Haematol 1999; 105:551. 133. Gruppo Italiano Studio Policitemia: Polycythemia vera:The natural history of 1213 patients followed for 20 years.Ann Intern Med 1995; 123:656. 134. Cortelazzo S,Viero P, Finazzi G et al. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990; 8:556. 135. Orlandi E, Castelli G, Brusamolino E et al. Hemorrhagic and thrombotic complications in polycythemia vera.A clinical study. Haematologica 1989; 74:45. 136. Watson KV, Key N.Vascular complications of essential thrombocythaemia: a link to cardiovascular risk factors. Br J Haematol 1993; 83:198. 137. Fenaux P, Simon M, Caulier MT et al. Clinical course of essential thrombocythemia in 147 cases. Cancer 1990; 66:549. 138. Bellucci S, Janvier M,Tobelem G et al. Essential thrombocythemias. Clinical evolutionary and biological data. Cancer 1986; 58:2440. 139. Ruggeri M, Finazzi G,Tosetto A et al. No treatment for low-risk thrombocythaemia: results from a prospective study. Br J Haematol 1998; 103:772. 140. Pagliuca A, Mufti GJ, Janossa-Tahernia M et al. In vitro colony culture and chromosomal studies in hepatic portal vein thrombosis possible evidence of an occult myeloproliferative state. Q J Med 1990; 76:981. 141. Valla D, Casadevall N, Huisse MG et al. Etiology of portal vein thrombosis in adults. A prospective evaluation of primary myeloproliferative disorders. Gastroenterology 1988; 94:1063. 142. Cobo F, Cervantes F, Garcia-Pagan JC et al. Budd- Chiari syndrome associated with chronic myeloproliferative syndromes: analysis of 6 cases. Med Clin (Barc) 1996; 107:660. 143. Lee JJ, Kim HJ, Chung IJ et al. Portal, mesenteric, and splenic vein thromboses after splenectomy in a patient with chronic myeloid leukemia variant with thrombocythemic onset.Am J Hematol 1999; 61:212. 144. Willoughby SJ, Fairhead S,Woodcock BE, Pearson TC: Postpartum thrombosis in primary thrombocythaemia. Eur J Haematol 1997; 59:121. 145. Usui T, Kitano K, Midorikawa T et al. Budd-Chiari syndrome caused by hepatic vein thrombosis in a patient with myeloproliferative disorder. Intern Med 1996; 35:871. 146. Mossier C, Kerbl R,Wagner T et al. Portal vein thrombosis in a 17-year-old female adolescent with essential thrombocytosis. Ped Hematol Oncol 1997; 14:457. 147. Haan J, Caekebeke JF, van der Meer FJM et al. Cerebral venous thrombosis as presenting sign of myeloproliferative disorders. J Neurol Neurosurg Psychiatry 1988; 51:1219. 148. Ostermiller W Jr, Carter R. Mesenteric venous thrombosis secondary to polycythemia vera.Am Surgeon 1969; 35:407. 149. Kneeland JB,Auh YH, Zirinsky K et al. MR, CT, and ultrasonographic demonstration of splenic vein thrombosis. J Comput Assist Tomogr 1984; 8:1199. 150. Shaldon S, Sherlock: Portal hypertension in the myeloproliferative syndrome and the reticuloses.Am J Med 1962; 32:758. 151. Conlan MG, Haire WD. Low protein S in essential thrombocythemia with thrombosis.Am J Hematol 1989; 32:88. 152. Teofili L, De Stefano V, Leone G et al. Hematologic causes of venous thrombosis in young people: High incidence of myeloproliferative disorder as underlying disease in patients with splenic venous thrombosis.Thromb Haemost 1992; 67:297. 153. McCarthy PM, van Heerden JA,Adson MA et al.The Budd-Chiari syndrome: Medical and surgical management of 30 patients.Arch Surg 1985; 120:657. 154. Janssen HL, Meinardi JR,Vleggaar FP, van Uum SH, Haagsma EB, van Der Meer FJ, van Hattum J, Chamuleau RA,Adang RP, Vandebroucke JP, van Hoek B, Rosendaal FR. Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with budd-chiari syndrome and portal vein thrombosis: results of a case-control study. Blood 2000; 96:2364. 155. Mitchell SW. On a rare vaso-motor neurosis of the extremities and on the maladies with which it may be confounded.Am J Med Sci 1878; 76:2. 156. Berk PD, Goldberg JD, Donovan PB et al.Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986; 23:132. 157. Najean Y, Dresch C, Rain JD.The very long-term course of polycythaemia: a complement to the previously published data of the Polycythemia Vera Study Group. Br J Haematol 1994; 86:233. 158. Sacchi S.The role of -interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): a concise update. Leuk Lymphoma 1995; 19:13. 159. Lengfelder E, Griesshammer M, Hehlmann R. Interferon- in the treatment of essential thrombocythemia. Leuk Lymphoma 1996; 22:135. 160. Silver RT. Interferon-: effects of long-term treatment for polycythemia vera. Sem Hematol 1997; 34:40. 161. Anagrelide Study Group:Anagrelide, a therapy for thrombocythemic states: Experience in 577 patients.Am J Med 1992; 92:69. 162. Tartaglia AP, Goldberg JD, Berk PD,Wasserman LR.Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera. Sem Hematol 1986; 23:172. 163. Van Genderen PJ, Mulder PG,Waleboer M et al. Prevention and treatment of thrombotic complicatons in essential thrombocythaemia: efficacy and safety of aspirin. Br J Haematol 1997; 97:179. 164. Gruppo Italiano Studio Policitemia (GISP): Low-dose aspirin in polycythaemia vera: a pilot study. Br J Haematol 1997; 97:453. 165. Randi ML, Rossi C, Fabris F et al.Aspirin seems as effective as myelosuppressive agents in the prevention of rethrombosis in essential thrombocythemia. Clin Appl Thromb Hemost 1999; 5:131. 166. Warrell RP, de ThH,Wang ZY, Degos L.Acute promyelocytic leukemia. N Engl J Med 1993; 329:177. 167. Warrell R, Frankel S, Miller W et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 1991; 324:1385. 168. Fenaux P, Le Deley MC, Castaigne S et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 1993; 82: 3241. 169. Degos L, Dombret H, Chomienne C et al.All-transretinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood 1995; 85: 2643.
43
Matei et al.
170. Rodeghiero F,Avvisati G, Castaman G et al. Early deaths and antihemorrhagic treatments in acute promyelocytic leukemia.A GIMEMA retrospective study in 286 consecutive patients. Blood 1990; 75: 2112. 171. Golomb HM, Rowley JD,Vardiman JW et al.Microgranular acute promyelocytic leukemia: a distinct clinical, ultrastructural and cytogenetic entity. Blood 1980; 55: 253. 172. Gralnick HR, Bennett JM, Catovoski D et al.A variant form of hypergranular promyelocytic leukemia (M3).Ann Intern Med 1980; 92: 261. 173. Sakuragawa N,Takahaski K, Hoshiyama M et al. Pathologic cells as procoagulant substance of disseminated intravascular coagulation syndrome in acute promyelocytic leukemia.Thromb Res 1976; 8: 263. 174. Riccio JA, Colley T, Cera PJ. Hepatic vein thrombosis (Budd-Chiari Syndrome) in the microgranular variant of acute promyelocytic leukemia.Am J Clin Pathol 1989; 92: 366. 175. Gouault-Heilmann M, Chardon E, Sultan C, Josso F:The procoagulant factor of leukaemic cells: demonstration of immunologic cross-reactivity with human brain tissue factor. Br J Haematol 1975; 30: 151. 176. Gordon SG, Cross BA:A factor X activating cysteine protease from malignant tissue. J Clin Invest 1981; 67: 1655. 177. Bauer K, Rosenberg R:Thrombin generation in acute promyelocytic leukemia. Blood 1984; 64: 791. 178. Gralnick HR,Abrell E: Studies of the procoagulant and fibrinolytic activity of promyelocytes in acute promyelocytic leukemia. Br J Haematol 1973; 24: 89. 179. Wilson EL, Jacobs P, Dowdle EB:The secretion of plasminogen activators by human myeloid leukemic cells in vitro. Blood 1983; 61: 568. 180. Avvisati G, ten Cate JW, Sturk A et al.Acquired -2-antiplasmin deficiency in acute promyelocytic leukemia. Br J Haematol 1988; 70: 43. 181. Chan TK, Chan GTC, Chan V: Hypofibrinogenemia due to increased fibrinolysis in two patients with acute promyelocytic leukemia.Aust NZ J Med 1984; 14: 245. 182. Bennett B, Booth NA, Croll A, Dawson AA:The bleeding disoder in acute promyelocytic leukaemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol 1989; 71: 511. 183. Menell JS, Cesarman GM, Jacovina AT et al.Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med 1999; 340: 994. 184. Avvisati G, ten Cate JW, Bller HR, Mandelli F:Tranexamic acid for control of haemorrhage in acute promyelocytic leukemia. Lancet 1989; 2: 122. 185. Keane T, Gorman M, OConnell L, Fennelly JJ: Epsilon-aminocaproic acid in the management of acute promyelocytic leukemia. Acta Haematol 1976; 56: 202. 186. Escudier SM, Kantarjian HM, Estey EH:Thrombosis in patients with acute promyelocytic leukemia treated with and without alltrans retinoic acid. Leuk Lymphoma 1996; 20: 435. 187. Groopman J, Ellman L:Acute promyelocytic leukemia.Am J Hematol 1979; 7: 395. 188. Palabrica T, Lobb R, Furie BC et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selection on adherent platelets. Nature 1992; 59: 848. 189. Frankel SR, Eardley A, Lauwers G et al.The retinoic acid syndrome in acute promyelocytic leukemia.Ann Int Med 1992; 117: 292. 190. Fass R, Haddad M, Zaizov R et al. Recurrent peripheral arterial occlusion by leukemic cells sedimentation in acute promyelocytic leukemia. J Pediatr Surg 1992; 27: 665. 191. Runde V,Aul C, Heyll A, Schneider W:All-trans retinoic acid: not only a differentiating agent, but also an inducer of thromboembolic events in patients with M3 leukemia. Blood 1992; 79: 534. 192. Pogliani EM, Rossini F, Casaroli I et al.Thrombotic complications in acute promyelocytic leukemia during all-transretinoic acid therapy.Acta Haematol 1997; 97: 228. 193. Rees D, Grimwade D, Langabeer S, et al. Influence of genetic predisposition to thrombosis on natural history of acute promyelocytic leukaemia. MRC Adult Leukaemic Working Party. Br J Haematol 1997; 96: 490. 194. Hoyle CF, Swirsky DM, Freedman L et al. Beneficial effect of heparin in the management of patients with APL. Br J Haematol 1988; 68: 283. 195. Drapkin RL, Gee TS, Dowling MD et al. Prophylactic heparin therapy in acute promyelocytiv leukemia. Cancer, 1978; 41: 2484. 196. Rodeghiero F,Avvisati G, Castaman G et al. Early deaths and antihemorrhagic treatments an acute promyelocytic leukemia.A GIMEMA retrospective study in 268 consecutive patients. Blood 1990; 75: 2112. 197. Dombret H, Scrobohaci ML, Daniel MT et al. In vivo thrombin and plasmin activities in patients with acute promyelocytic leukemia (APL): Effect of all-trans retinoic acid (ATRA) therapy. Leukemia 1995; 9: 19. 198. Trousseau A: Phlegmasia alba dolens. Clinique medicale de lHotel-Dieu de Paris. London,The New Sydenham Society, 1865. 199. Sproull EE: Carcinoma and venous thrombosis:The frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis.Am J Cancer 1938; 34: 566. 200. Edwards EA: Migratory nature of venous thrombi seen in 23 cases of carcinoma. N Engl J Med 1949; 240: 1031. 201. Rohner RF, Prior JT, Sipple JH: Mucinous malignancies, venous thrombosis and terminal endocarditis with emboli.A syndrome. Cancer 1966; 19: 1805. 202. Green KB, Slverstein RL: Hypercoaglability in cancer. Hematol Oncol Clin North Am 1996; 10: 499. 203. Donati MB: Cancer and thrombosis. Haemostasis 1994; 24: 128. 204. Harrington KJ, Bateman AR, Syrigos KN et al. Cancer-related thromboembolic disease in patients with solid tumors: a retrospective analysis.Ann Oncol 1997; 8: 669. 205. Monreal M, Fernandez-Llamazares J, Perandreu J et al. Occult cancer in patients with venous thromboembolism: which patients, which cancers.Thromb Haemost 1997; 78: 1316. 206. Pinzon R, Drewinko B,Trujillo JM et al. Pancreatic carcinoma and Trousseaus syndrome: Experience at a large cancer center. J Clin Oncol 1986; 4: 509. 207. Baron JA, Gridley G,Weiderpass E et al.Venous thromboembolism and cancer. Lancet 1998; 351: 1077. 208. Honn KV, Steinert BW, Moin K et al.The role of platelet oxygenase and lipoxygenase pathways in tumor cell induced platelet aggregation. Biochem Biophys Res Commun 1987; 145: 384. 209. Hara Y, Steiner M, Baldini MG: Characterization of platelet aggregative activity of tumor cells. Cancer Res 1980; 40: 1217. 210. Gasic GJ, Gasic TB, Galanti N et al. Platelet tumor interactions in mice.The role of platelets in spread of malignant disease. Int J Cancer 1973; 11: 704.
44

211. Karpatkin S, Pearlstein E: Role of platelets in human tumor cell metastases.An Intern Med 1981; 95: 636. 212. Pearlstein E, Salk PL,Yogeswaran G, Karpatkin S: Correlation between spontaneous metastatic potential, platelet- aggregating activity of cell surface extracts and cell surface sialylation in 10 metastatic variant derivatives of a rat renal sarcoma cell line. Proc Natl Acad Sci USA 1980; 77: 4336. 213. Garg SK, Niemetz J:Tissue factor activity of normal and leukemic cells. Blood 1973; 42: 729. 214. Hudig D, Rapaport SI, Bajaj SP.Tissue factor like activity of the human monocyte tumor cell line U-937.Thromb Res 1982; 27: 321. 215. Callander NS,Varki N, Rao LV: Immunohistochemical identification of tissue factor in solid tumors. Cancer 1992; 70: 1194. 216. Gordon SG, Cross BA:A factor X activating cysteine protease from malignant tissue. J Clin Invest 1981; 67: 1665. 217. Nand S, Fisher SG, Salgia R, Fisher RI: Hemostatic abnormalities in untreated cancer. Incidence and correlation with thrombotic and hemorrhagic complications. J Clin Oncol 1987; 5: 1998. 218. Honegger H,Anderson N, Hewitt LA et al.Antithrombin III profiles in malignancy. Relationship to primary tumor and metastatic sites.Thromb Haemost 1981; 46: 500. 219. Rodeghiero F, Mannucci PM,Vigano PM et al. Liver dysfunction rather than intravascular coagulation is the main cause of low protein C and antithrombin III in acute leukemia. Blood 1984; 63: 965. 220. Green D, Maliekel K. Sushko E et al.Activated protein C resistance in cancer patients. Haemostasis 1997; 27: 112. 221. Haim N, Lanir N and Hoffman R, et al.Acquired activated protein C resistance is common in cancer patients with venous thromboembolism.Am J Med, in press. 222. Gouin-Thibault I, Samama MM: Laboratory diagnosis of the thrombophilic state in cancer patients. Sem Thromb Hemost 1999; 25: 167. 223. Wilson EL, Becker ML, Hoal EG et al. Molecular species of plasminogen activators secreted by normal and neoplastic cells. Cancer Res 1980; 40: 933. 224. Levine MN, Gent M, Hirsh J et al.The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988; 318: 404. 225. Pritchard KI, Paterson AHG, Paul NA et al. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol 1996; 14: 2731. 226. Lee AYY, Levine MN.The thrombophilic state induced by therapeutic agents in the cancer patient. Sem Thromb Haemost 1999; 25: 137. 227. Monreal M, Prandoni P.Venous thromboembolism as first manifestation of cancer. Sem Thromb Hemost 1999; 25: 131. 228. Edoute Y, Haim N, Rinkevich D et al. Cardiac valvular vegetations in cancer patients:A prospective echocardiographic study of 200 patients.Am J Med 1997; 102: 252. 229. Sack GH Jr, Levin J, Bell WR.Trousseaus syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: Clinical, pathophysiologic and therapeutic features. Medicine 1977; 56: 1. 230. Rickles FR, Edwards RL.Activation of blood coagulation in cancer: Trousseaus syndrome revisited. Blood 1983; 62: 14. 231. Bell WR, Starksen NF,Tong S et al.Trousseaus syndrome: Devastating coagulopathy in the absence of heparin.Am J Med 1985; 79: 423. 232. Walsh-McMonagle D, Green D. Low-molecular-weight heparin in the management of Trousseaus syndrome. Cancer 1997; 80: 649. 233. Zuger M, Demarmels Biasiutti F,Wuillemin WA et al. Subcutaneous low-molecular-weight heparin for treatment of Trousseaus syndrome.Ann Hematol 1997; 75: 165. 234. Levine M, Rickles FR.Treatment of venous thromboembolism in cancer patients. Haemostasis 1998; 28(Suppl 3): 66. 235. Greenfield LJ, Proctor MC, Saluja A. Clinical results of Greenfield filter use in patients with cancer. Cardiovasc Surg 1997; 5: 145. 236. Ihnat DM, Mills JL, Hughes JD et al.Treatment of patients with venous thromboembolism and malignant disease: should vena cava filter placement be routine? J Vasc Surg 1998; 28: 800. 237. Kakkar AK,Williamson RC: Prevention of venous thromboembolism in cancer using low-molecular-weight heparins. Haemostasis 1997; 27 (Suppl 1): 32. 238. ENOXACAN Study Group: Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicenter trial with venographic assessment. Br J Surg 1997; 84: 1099. 239. Hejna M, Raderer M, Zielinski CC. Inhibition of metastasis by anticoagulants. J Natl Cancer Inst 1999; 91: 22. 240. Zacharski LR, Henderson WG, Rickles FR et al. Effect of warfarin on survival in small cell carcinoma of the lung.Veterans Administration Study (#75). JAMA 1981; 24: 831. 241. Lebeau B, Chastang C, Brechot JM et al. Subcutaneous heparin treatment increases survival in small cell lung cancer.Petites Cellules Group. Cancer 1994; 74: 38. 242. Zacharski LR, Henderson WG, Rickles FR et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final Report of VA Cooperative Study #75. Cancer 1984; 53: 2046. 243. Maurer LH, Herndon JE 2nd, Hollis DR et al. Randomized trial of chemotherapy and radiation therapy with and without warfarin for limited stage small cell lung cancer.A Cancer and Leukemic Group B Study. J Clin Oncol 1997; 15: 3378. 244. Vessey M, Mant D, Smith A et al. Oral contraceptives and venous thromboembolism: findings in a large prospective study. Br Med J 1986; 292: 526. 245. Gerstman BB, Piper JM,Tomita DK, Ferguson WJ, Stadel BV, Lundin FE: Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease.Am J Epidemiol 1991; 133: 32. 246. Venous thromboembolic disease and combined oral contraceptives: results of an international multicentre case control study.World Health Organization Collaborative Study of Cardiovascular Disease and Steroid hormone Contraception. Lancet 1995; 346; 1575. 247. Middeldorp S, Meijers JCM, van den Ende AE et al. Effects on coagulation of levonorgestrel and desogestrel containing low dose oral contraceptives: a cross-over study.Thromb Haemost 2000; 84: 4. 248. Kluft C. Renewed interest in haemostasis changes induced by oral contraceptives (Ocs).Thromb Haemost 2000; 84: 1. 249. Grady D,Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D,Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease.The Heart and Estrogen/progestin Replacement Study.Ann Intern Med 2000; 132: 689.
45
Matei et al.
250. Daly E,Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977. 251. Bremme K,Wramsby H,Andersson O,Wallin M, Blomback M. Do lowered factor VII levels at extremely high endogenous oestradiol levels protect against thrombin formation? Blood Coagul Fibrinolysis 1994; 5: 205. 252. Citarella F, Misiti S, Felici A, Farsetti A, Pontecorvi A, Fantoni A. Estrogen induction and contact phase activation of human factor XII. Steroids 1996; 61: 270. 253. Davies T, Fieldhouse G, McNicol GP.The effects of therapy with oestriol succinate and ethinyl oestradiol on the haemostatic mechanism in post-menopausal women.Thromb Haemost 1976; 35: 403. 254. Miller ME, Dores GM,Thorpe SL,Akerley WL. Paradoxical influence of estrogenic hormones on platelet-endothelial cell interactions.Thromb Res 1994; 74: 577. 255. Dores GM, Miller ME,Thorpe SL. Platelet adhesion at low shear rate: study of a normal population.Thromb Res 1993; 69: 173. 256. Huch KM, Elam MB, Chesney CM: Oral contraceptive steroid induced platelet coagulant hyperactivity: dissociation of in vivo and in vitro effects.Thromb Res 1987; 48: 41. 257. Nakano Y, Oshima T, Matsuura H, Kajiyama G, Kambe M: Effect of 17 -estradiol on inhibition of platelet aggregation in vitro is mediated by an increase in NO synthesis. Arterioscler Thromb Vasc Biol 1998; 18: 961. 258. Toy JL, Davies JA, McNicol GP.The effects of long-term therapy with oestriol succinate on the haemostatic mechanism in postmenopausal women. Br J Obstet Gynaecol 1978; 85: 363. 259. Toy JL, Davies JA, Hancock KW, McNicol GP.The comparative effects of a synthetic and a natural oestrogen on the haemostatic mechanism in patients with primary amenorrhoea. Br J Obstet Gynaecol 1978; 85: 359. 260. Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS,Tracy RP. Hormone replacement therapy, inflammation, and hemostasis in elderly women.Arterioscler Thromb Vasc Biol 1999; 19: 893. 261. Gebara OC, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P,Welty FK,Wilson PW, Levy D, Muller JE, et al.Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952. 262. Tans G, Curvers J, Middeldrop S et al.A randomized cross-over study on the effects of levonorgestrel and desogestrel-containing oral contraceptives on the anticoagulant pathways.Thromb Haemost 2000; 84: 15. 263. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR: Increased risk of venous thrombosis in oralcontraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453. 264. Vandenbroucke JP, van der Meer FJ, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? Br Med J 1996; 313: 1127. 265. Andersen BS, Olsen J. Oral contraception and factor V Leiden mutation in relation to localization of deep vein thrombosis. Thromb Res 1998; 90: 191. 266. Ward T. Should oral contraceptive users be screened for factor V Leiden? Oral contraceptives are not the only effective contraceptives. Br Med J 1997; 315: 60. 267. Meier CR, Jick H.Tamoxifen and risk of idiopathic venous thromboembolism. Br J Clin Pharmacol 1998; 45: 608. 268. Fisher B, Costantino JP,Wickerham DL, et al.Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371. 269. Sasco AJ,Ah-Song R, Saez S, Kuttenn F: Medical adverse effects of chemoprevention: the example of tamoxifen. Bull Cancer 1995; 82 Suppl 3: 186s. 270. Japan Advanced Breast Cancer Study Group and Japan Clinical Oncology Group. Effects of chemoendocrine therapy on the coagulation-fibrinolytic systems in patients with advanced breast cancer. Jpn J Cancer Res 1993; 84: 455. 271. Pemberton KD, Melissari E, Kakkar VV.The influence of tamoxifen in vivo on the main natural anticoagulants and fibrinolysis. Blood Coagul Fibrinolysis 1993; 4: 935. 272. Auger MJ, Mackie MJ. Effects of tamoxifen on blood coagulation. Cancer 1988; 61: 1316. 273. Mannucci PM, Bettega D, Chantarangkul V,Tripodi A, Sacchini V, Veronesi U. Effect of tamoxifen on measurements of hemostasis in healthy women.Arch Intern Med 1996; 156: 1806. 274. Oberhoff C, Szymeczek J, Hoffmann O,Winkler UH, Kaiser S, Schindler AE:Adjuvant antiestrogen treatment with tamoxifen in postmenopausal women with breast cancer: a longitudinal study of blood coagulation and fibrinolysis. Breast Cancer Res Treat 1998; 50: 73. 275. Mitchell L, Hoogendoom H, Giles AR et al. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: Risk of thrombotic complications in 1 Asparaginase induced antithrombin III deficiency. Blood 1994; 83: 386. 276. Andersson L, Edsmyr F, Jonsson G, Konyves I. Estramustine phosphate therapy in carcinoma of the prostate. Recent Results Cancer Res 1977; 60: 73. 277. Nowak-Gottl U,Wermes C, Junker R, Koch HG, Schobess R, Fleischhack G, Schwabe D, Ehrenforth S. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood 1999; 93: 1595. 278. Elhasid R, Lanir N, Rivka S,Wevl Ben-Arush M, Levin C, Postovsky S, Barak AB, Brenner B. Prophylactic therapy with enoxaparin during L-asparginase treatment in children with acute lymphoblastic leukemia (ALL). Blood 2000; 96: ?. 279. Malyszko JS, Malyszko J, Pawlak D et al. Importance of serotoninergic mechanisms in the thrombotic complications in hemodyalized patients treated with erythropoietin. Nephron, 2000; 84(4): 305. 280. Sowade O, Ziemer S, Sowade B et al. the effect of preoperative recombinant human erythropoietin therapy on platelets and hemostasis in patients undergoing cardiac surgery. J Lab Clin med 1997; 129(3): 376. 281. Jaar B, Denis A,Viron B et al. Effects of long term treatment with recombinant human erythropoietin on physiologic inhibitors of coagulation.Am J Nephrol 1997; 17: 399. 282. Borawski J, Rydzewski A, Pawlak K,Azzadin A, Buczko W, Mysliwiec M. Long-term effects of erythropoietin on platelet serotonin storage and platelet aggregation in hemodialysis patients with reference to ketanserin treatment.Thromb Res 1998; 90: 171. 283. Taylor JE, Henderson IS, Stewart WK, Belch JJ. Erythropoietin and spontaneous platelet aggregation in hemodialysis patients. Lancet 1991; 338(8779): 1361.
46

284. Finelli PF, Carley MD. Cerebral venous thrombosis associated with epoietin alfa therapy.Arch Neurol: 2000; 57(2): 260. 285. de Andrade JR, Frei D, Guilfoyle M. Integrated analysis of thrombotic/vascular event occurrence in epoetin alfa-treated patients undergoing major, elective orthopedic surgery. Orthopedics 1999; 22: 113. 286. Canadian Orthopedic Perioperative Erythropoietin Study Group. Effectiveness of perioperative recombinant erythropoietin in elective hip replacement. Lancet, 1993; 341: 1227. 287. Martino MA,Vogel KM, O Brien SP, Kerstein MD. Erythropoietin therapy improves graft patency with no increased incidence of thrombosis or thrombophlebitis. J Am Coll Surg: 1998; 187(60): 616. 288. Standage BA, Schuman ES,Ackerman D, Gross GF et al. Does the use of erythropoietin in hemodialysis patients increase dialysis graft thrombosis rates? Am J Surg: 1993; 165(5): 650. 289. Singbartl G.Adverse events of erythropoietin in long term and in acute/short term treatment. Clin Investig: 1994; 72(6): S36. 290. Altun B, Usalan C, Haznedaroglu IC et al.Thrombopoietin and thrombospondin in renal allograft recipients. Blood Coagul Fibrinolysis 1999; 10: 233. 291. Shimoda K, Okamura S, Harada N et al. Identification of a functional receptor for granulocyte colony stimulating factor on platelets. J Clin Invest: 1993; 91(4): 1310. 292. Avenarius HJ, Freund M, Deinhardt J, Poliwoda H. Effect of recombinant human granulocyte colony stimulating factor (rhG-CSF) on circulating platelets.Ann Hematol, 1992; 65(10): 6. 293. Kawaki Y,Watanabe A, Uchida T et al.Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor. Br J Haematol: 1996; 94(2): 413. 294. Warkentin TE, Levine MN, Hirsh J et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330. 295. Nalbandian RM, Mader IJ, Barret JL, Pearce JP, Rupp EC. Petechiae, ecchymoses, and necrosis of skin induced by coumarin congeners. JAMA 1965; 192: 603. 296. Comp PC. Coumarin-induced skin necrosis. Incidence, mechanisms, management and avoidance. Drug Saf 1993; 8: 128. 297. Warkentin TE.Thrombotic complications of anticoagulant therapy. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and thrombosis, basic principles and clinical practice, 4th Edition. 2001, pp 13711382. 298. Muller G:Acquired antithrombin III deficiency. Z Gesamte Inn Med 1992; 47: 74. 299. Vigano-DAngelo S, DAngelo A, Kaufman DE Jr et al. Protein S deficiency occurs in the nephrotic syndrome.Ann Intern Med 1987; 107: 42. 300. Gouault-Heilmann M, Gadelha-Parente T, Levent M et al.Total and free protein S in nephrotic syndrome.Thromb Res 1988; 49: 37. 301. Deitcher SR, Erban JK, Limentani SA:Acquired free protein S deficiency associated with multiple myeloma: a case report.Am J Hematol 1996; 51: 319. 302. Schuetze SM, Linenberger M.Acquired protein S deficiency with multiple thrombotic complications after orthotopic liver transplant.Transplantation 1999; 67: 1366. 303. Kemkes-Matthes B.Acquired protein S deficiency. Clin Invest 1992; 70: 529. 304. Faught W, Garner P, Jones G, Ivey B. Changes in protein C and protein S levels in normal pregnancy.Am J Obstet Gynecol 1995; 172: 147. 305. Gilabert J, Fernandez JA, Espana F et al. Physiological coagulation inhibitors (protein S, protein C and antithrombin III) in severe pre-eclamptic states and in users of oral contraceptives.Thromb Res 1988; 49: 319. 306. Comp PC,Vigano S, DAngelo A et al:Acquired protein S deficiency occurs in pregnancy, the nephrotic syndrome and acute systemic lupus erythematosus (abstract). Blood 1985; 66 (Suppl 1): 348. 307. Friedman KD, Marlar RA, Gill JC et al: Protein S deficiency in patients with the lupus anticoagulant (abstract). Blood 1988; 68 (Suppl 1): 333. 308. Ginsberg JS, Demers C, Brill-Edwards P et al:Acquired free protein S deficiency is associated with antiphospholipid antibodies and increased thrombin generation in patients with systemic lupus erythematosus.Am J Med 1995; 98: 379. 309. Morange PE,Alessi MC, Barthet MC et al:Acquired protein S deficiency, likely due to anti-PS autoantibodies, following a thrombotic event in a patient with a systemic lupus erythematosus.Thromb Haemost 1997; 78: 1416. 310. Madden RM, Gill JC, Marlar RA. Protein C and protein S levels in two patients with acquired purpura fulminans. Br J Haematol 1990; 75: 112. 311. Dominey AK, Kettler A,Yiannias J,Tschen JA. Purpura fulminans and transient protein C and S deficiency.Arch Dermatol 1988; 124: 1442. 312. Bergmann F, Hoyer PF, DAngelo SV et al. Severe autoimmune protein S deficiency in a boy with idiopathic purpura fulminans. Br J Haematol 1995; 89: 610. 313. Trotti R, Rondanelli M,Anesi A.Thrombophilic condition in HIV infected patients. Haematol 1997; 82(6): 733. 314. Sugerman RW, Church JA, Goldsmith JC, Ens GE.Acquired protein S deficiency in children infected with human immunodeficiency virus. Pediatr Infect Dis J 1996; 15: 106. 315. Lafeuillade A,Alessi MC, Poizot-Martin I et al. Protein S deficiency and HIV infection. N Engl J Med 1991; 324: 1220. 316. Wong E, Berry E, Ellis-Pelger RB:Thrombosis and protein S deficiency in HIV infection. N Z Med J 1996; 109: 451. 317. Stahl CP,Wideman CS, Spira TJ et al. Protein deficiency in men with long-term human immunodeficiency virus infection. Blood 1993; 81: 1801. 318. Orloff LA, Orloff MJ. Budd-Chiari syndrome caused by Behcets disease: treatment by side-to-side portacaval shunt. J Am Coll Surg 1999; 188: 396. 319. Kroger K,Ansasy M, Rudofsky G. Postoperative thrombosis of the superior caval vein in a patient with primary asymptomatic Behcets disease.A case report.Angiology 1997; 48: 649. 320. Wechsler B, Genereau T, Biousse V,Vauthier-Brouzes D, Seebacher J, Domont D, Godeau P. Pregnancy complicated by cerebral venous thrombosis in Behcets disease.Am J Obstet Gynecol 1995; 173: 1627. 321. Mogulkoc N, Burgess MI, Bishop PW. Intracardiac thrombus in Behcets disease: a systematic review. Chest 2000; 118: 479. 322. Hoffman R, Gavish I,Azam A, Bergman R, Lanir N, Brenner B. Thrombophilic state in Behcets disease. Haemostasis 2000; 30 (Suppl 1): 2. 323. Salvarani C, Calamia K, Silingardi M, Ghirarduzzi A, Olivieri I. Thrombosis associated with the prothrombin GA20210 mutation in Behcets disease. J Rheumatol 2000; 27: 515.
47
Matei et al.
324. Oner AF, Gurgey A, Gurler A, Mesci L. Factor V Leiden mutation in patients with Behcets disease. J Rhuematol 1998; 25: 496. 325. Lesprit P,Wechsler B, Piette JC, Du-Boutin LT, Godeau P,AlhencGelas M,Aiach M.Activated protein C resistance caused by factor V Arg 506Gln mutation has no role in thrombotic manifestations of Behcets disease.Ann Rheum Dis 1995; 54: 860. 326. Ferrari E, Chevallier T, Chapelier A, Baudouy M.Travel as a risk factor for venous thromboembolic disease; a case-control study. Chest 1999; 115: 440. 327. Kraaijenhagen RA, Haverkamp D, Loopman MM, Prandoni P, Piovella F, Buller HR.Travel and risk of venous thrombosis. Lancet 2000; 356: 1492. 328. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, et al.A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341: 793. 329. McColl M, Ramsay JE,Tait RC, et al. Risk factors for pregnancy associated venous thromboembolism.Thromb Haemost 1997; 78: 1183. 330. Greer IA.Thrombosis in pregnancy: material and fetal issues. Lancet 1999; 353: 1258. 331. Kjelberg U,Andersson NE, Rosen S, et al.APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb Haemost 1999; 81: 527. 332. Clark P, Brennand J, Conkie JA, et al.Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy.Thromb Haemost 1998; 79: 1166. 333. Kruithof EKO,Tran-Thang C, Gudinchet A et al. Fibrinolysis in pregnancy:A study of plasminogen activator inhibitors. Blood 1987; 69: 460. 334. Gerhardt A, Scharf RE, Beckmann NW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342: 374.
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Acquired Thrombophilic Syndromes: Daniela Matei, Benjamin Brenner, Victor J. Marder

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