The Double Hazard of Thrombophilia and Bleeding in Acute Promyelocytic Leukemia

Tallman, Martin S.; Abutalib, Syed Ali; Altman, Jessica K.

doi:10.1055/s-2007-976168

Cited by 56 publications

(39 citation statements)

References 74 publications

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“…APL is well known for its coagulopathy and high susceptibility to all-trans retinoic acid (ATRA) [1,2]. Our previous study revealed that 77.6% of patients had overt disseminated intravascular coagulation (DIC) upon diagnosis.…”

Section: Introductionmentioning

confidence: 99%

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Acute Promyelocytic Leukemia-Associated Thrombosis

Chang

Kuo²,

Shih³

et al. 2013

Acta Haematol

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Patients with acute promyelocytic leukemia (APL) are prone to both bleeding and thrombosis. The bleeding complications are well known. In contrast, APL-associated thrombosis is relatively underappreciated. We aimed to explore the issue of APL-associated thrombosis events. In the past 20 years, 127 cases with APL were found in our hospital database. We collected their coagulation laboratory profiles, including leukemia burdens, white blood cell and platelet counts, prothrombin time, activated partial thromboplastin time, fibrinogen levels, and disseminated intravascular coagulation scores. Data were compared between patients with or without thrombosis. Clinical outcomes and potential risk factors were obtained for analysis. Ten cases with APL-associated thrombosis were found. The incidence of thrombosis was 7.9% in our cohort. Five patients had cerebral infarction, 5 had catheter-related thrombosis and 1 had acute myocardial infarction. No laboratory data were associated with clinical thrombosis. Three patients died during the induction phase but thrombosis was not the direct cause of death for any of them. We conclude that patients with APL are susceptible to thrombosis in addition to bleeding. Laboratory coagulation parameters did not predict thrombosis in our series. Ischemic stroke and catheter-related thrombosis were the most common events in our Taiwanese cohort. Such a thrombosis pattern is unique and worth further investigation.

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Section: Introductionmentioning

confidence: 99%

“…Clinically significant bleeding occurred in 22.4% and fatal bleeding in 11.2% of patients [3]. Although the major threat of APL is severe bleeding complications in the early phase [3,4,5,6], patients with APL are also prone to thrombosis [1,2,7,8]. Both arterial and venous thrombosis may occur in APL.…”

Section: Introductionmentioning

confidence: 99%

Acute Promyelocytic Leukemia-Associated Thrombosis

Chang

Kuo²,

Shih³

et al. 2013

Acta Haematol

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“…40 APL is a special subtype of acute myeloid leukemia whose biologic and clinical features include the presence of the specific t(15;17) chromosomal translocation in leukemic blasts and the frequent existence of severe hemorrhagic diathesis at the time of diagnosis. [106][107][108] The mechanism for the hemorrhagic deaths partially involves hyperfibrinolysis, which occurs because of the excessive production of plasmin at the surface of the promyelocytic leukemic cells. 109 We observed that depletion of S100A10 from the APL cell line, NB4, which constitutively expresses the PML-RAR-␣ oncoprotein, resulted in a 70% loss in plasminogen binding and a 64% loss in plasmin generation by the NB4 cells.…”

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confidence: 99%

The role of the annexin A2 heterotetramer in vascular fibrinolysis

Madureira¹,

Surette²,

Phipps³

et al. 2011

Blood

110

129

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The vascular endothelial cells line the inner surface of blood vessels and function to maintain blood fluidity by producing the protease plasmin that removes blood clots from the vasculature, a process called fibrinolysis. Plasminogen receptors play a central role in the regulation of plasmin activity. The protein complex annexin A2 heterotetramer (AIIt) is an important plasminogen receptor at the surface of the endothelial cell. AIIt is composed of 2 molecules of annexin A2 (ANXA2) bound together by a dimer of the protein S100A10. Recent work performed by our laboratory allowed us to clarify the specific roles played by ANXA2 and S100A10 subunits within the AIIt complex, which has been the subject of debate for many years. The ANXA2 subunit of AIIt functions to stabilize and anchor S100A10 to the plasma membrane, whereas the S100A10 subunit initiates the fibrinolytic cascade by colocalizing with the urokinase type plasminogen activator and receptor complex and also providing a common binding site for both tissue-type plasminogen activator and plasminogen via its C-terminal lysine residue. The AIIt mediated colocalization of the plasminogen activators with plasminogen results in the rapid and localized generation of plasmin to the endothelial cell surface, thereby regulating fibrinolysis. (Blood. 2011;118(18):4789-4797) IntroductionThe vascular endothelium consists of a single cell layer lining all vessels that separates the blood from the tissues. It is estimated to be composed of ϳ 10 13 cells, representing a weight of 1.5 kg and an area of 4000 to 7000 m 2 . 1 Endothelial cells play a role in primary hemostasis, coagulation, fibrinolysis, and regulation of vasomotor tone. In addition to regulating the flow of nutrients, the vascular endothelium regulates many diverse biologically active molecules. These functions of the endothelium are achieved through the presence of membrane-bound receptors for various proteins, lipidtransporting complexes, hormones, and metabolites, as well as through specific extracellular proteins and receptors that regulate cell-cell and cell-matrix interactions. 2 Whereas exposure to inflammatory and/or septic stimuli rapidly leads to procoagulant behavior, unperturbed endothelial cells provide an anticoagulant environment. After vascular insult, endothelial cells express tissue factor and initiate the coagulation cascade that results in thrombin activation and fibrin clot deposition. At the same time, anticoagulant pathways and fibrinolysis are activated to avoid disseminated coagulation and to also limit fibrin accumulation. [3][4][5] Fibrinogen is a large glycoprotein that constitutes the main component of a fibrin clot. Each fibrinogen molecule is composed of 2 sets of A␣-, B␤-, and ␥-polypeptide chains that form a protein containing 2 distal D regions connected to a central E region by a coiled-coil segment. 6 Fibrin is produced on cleavage of the fibrinopeptides by thrombin, which results in the formation of double-stranded half-staggered oligomers that lengthen into protofibrils...

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“…The pathogenesis of coagulopathy is complex and is a manifestation of disseminated intravascular coagulation, primary fibrinolysis and direct proteolysis. 43 ATRA should be initiated at the earliest suspicion of the disease without waiting for cytogenetic or molecular confirmation. Aggressive blood product support to maintain the platelet count ≥ 30,000 to 50,000/μL and the fibrinogen level at ≥ 150 mg/ dL has been recommended.…”

Section: Reducing Early Death In Aplmentioning

confidence: 99%

Curative Strategies in Acute Promyelocytic Leukemia

Tallman

Altman

2008

Hematology

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Acute promyelocytic leukemia (APL) was initially described as a distinct clinical entity in 1957, one year before the first meeting of the American Society of Hematology. With routine administration of all-trans retinoic acid (ATRA) combined with chemotherapy in the early 1990s and arsenic trioxide (ATO) in the late 1990s, cure can now be expected in the majority of both newly diagnosed and relapsed patients. ATRA with anthracycline-based chemotherapy for induction and consolidation followed by ATRA plus low-dose chemotherapy maintenance is currently the standard of care for newly diagnosed patients. Early institution of ATRA before the diagnosis is confirmed by genetics and aggressive blood product support are important to reduce induction mortality, which remains approximately 10% among patients entered on clinical trials, but is certainly higher when all patients are considered. The relapse rate among high-risk patients is approximately 20%, and new strategies include administration of intensified anthracyclines, intermediate-or high-dose ara-C in either induction or consolidation, or ATO as early consolidation. Central nervous system (CNS) prophylaxis for such patients and those with relapsed disease may be important to prevent the development of extramedullary disease. New therapeutic strategies have focused on minimizing chemotherapy and administering ATRA plus ATO as initial therapy. Recent studies suggest that patients who are molecularly negative after intensive consolidation may not benefit from maintenance therapy. Most exciting is the combination of ATRA and ATO, given with minimal chemotherapy only for leukocytosis, which is a very effective new strategy for patients who are unable to tolerate anthracyclines or older adults and soon may replace conventional therapy for many patients. Patients with relapsed disease do well with ATO followed by autologous hematopoietic stem cell transplantation

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The Double Hazard of Thrombophilia and Bleeding in Acute Promyelocytic Leukemia

Cited by 56 publications

References 74 publications

Acute Promyelocytic Leukemia-Associated Thrombosis

Acute Promyelocytic Leukemia-Associated Thrombosis

The role of the annexin A2 heterotetramer in vascular fibrinolysis

Curative Strategies in Acute Promyelocytic Leukemia

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