Hypercoagulability and Hypofibrinolysis and Risk of Deep Vein Thrombosis and Splanchnic Vein Thrombosis

Smalberg, Jasper H.; Kruip, Marieke J.H.A.; Janssen, Harry L.A.; Rijken, D.C.; Leebeek, Frank W.G.; Maat, Moniek P.M. de

doi:10.1161/atvbaha.110.213371

Cited by 52 publications

(45 citation statements)

References 115 publications

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“…In addition, we have compared BCS and PVT for each of these variables, as it is increasingly recognized that, despite several similarities, risk profiles are different between these patients. 67 To achieve this goal, we have assessed all the publications regarding MPNs in SVT since 1980.…”

Section: Discussionmentioning

confidence: 99%

Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis

Smalberg

Arends

Valla

et al. 2012

Blood

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306

246

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Section: Discussionmentioning

confidence: 99%

Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis

Smalberg

Arends

Valla

et al. 2012

Blood

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306

246

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“…The clinical manifestations are usually confined to a mild to moderate bleeding tendency, but some forms of the disorders present with progressive nephritis, cataracts, and sensorineural hearing loss. The gene for these disorders was first reported to be located on the long arm of chromosome 22, and mutations of the MYH9 gene, the gene encoding non-muscle myosin heavy chain IIA (NMMHC-IIA), were then identified [1][2][3]. The diagnosis of MYH9 disorders has conventionally been made by peripheral blood smear staining with…”

Section: Addendummentioning

confidence: 99%

“…severe sepsis and atherosclerosis [1][2][3][4]. In cases of occlusive thrombi, the only approved pharmacologic treatment to obtain acute revascularization consists of intravenous infusion of plasminogen activators, which is limited by low efficiency (low recanalization and high reocclusion rates) and a high bleeding risk [5].…”

mentioning

confidence: 99%

Evaluation of the profibrinolytic properties of a bispecific antibody‐based inhibitor against human and mouse thrombin‐activatable fibrinolysis inhibitor and plasminogen activator inhibitor‐1

Wyseure

Gils

Declerck

2013

Journal of Thrombosis and Haemostasis

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To cite this article: Wyseure T, Gils A, Declerck PJ. Evaluation of the profibrinolytic properties of a bispecific antibody-based inhibitor against human and mouse thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1. J Thromb Haemost 2013; 11: 2069-71.To date, no profibrinolytic agent has reached the market, although such an agent would be particularly useful in certain disease states associated with impaired endogenous fibrinolysis, e.g. severe sepsis and atherosclerosis [1][2][3][4]. In cases of occlusive thrombi, the only approved pharmacologic treatment to obtain acute revascularization consists of intravenous infusion of plasminogen activators, which is limited by low efficiency (low recanalization and high reocclusion rates) and a high bleeding risk [5]. Elevated levels of antifibrinolytic proteins, such as thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1), lead to an increased risk of thrombosis, and are therefore interesting drug targets [1]. TAFI and PAI-1 are intimately linked proteins, as activated TAFI only suppresses fibrinolysis when its level is above a certain threshold that is proportional to the tissue-type plasminogen activator (t-PA) concentration [6,7]. Consequently, this threshold value increases in the presence of an inhibitor of PAI-1. In this study, we developed a dual targeting strategy towards TAFI and PAI-1 to robustly enhance fibrinolysis. This would allow a lower dosage of t-PA, which would constitute a safer treatment without compromising thrombolytic efficiency.In a previous study, Develter et al.[8] created a bispecific antibody fragment, a diabody, which enables simultaneous targeting of TAFI and PAI-1. Although this diabody stimulates fibrinolysis of model thrombi to a higher extent than the combination of the two parental mAbs, a clear limitation was the lack of cross-reactivity to the respective antigens from other species, thereby ruling out in vivo studies.In the present study, a new diabody was designed after the selection of two parental mAbs, MA-TCK26D6, directed towards human TAFI [9], and MA-33H1F7, directed towards human PAI-1 [10], which are both cross-reactive with their murine counterparts. The inhibitory properties of this novel diabody, Db-TCK26D6x33H1F7, were extensively characterized. Briefly, maximal inhibition of TAFI by MA-TCK26D6 was 97% AE 2% and 86% AE 6% for human and mouse TAFI, respectively. Similar maximal inhibitory values were observed for Db-TCK26D6x33H1F7 (100% AE 2% and 86% AE 3% for human and mouse TAFI, respectively). For both human and mouse TAFI, IC 50 values were approximately two-fold higher than the respective IC 50 value of the parental mAb (0.2 AE 0.1 vs. 0.4 AE 0.1 for human TAFI, P < 0.02; and 0.5 AE 0.2 vs. 0.8 AE 0.3 for mouse TAFI, P < 0.05; expressed as molar ratio over TAFI, mean AE standard deviation [SD], n = 3-6). This two-fold increase corresponds with the two-fold lower valency of the diabody compared to that of the parental mAb. Maximal inhibition o...

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“…Many studies highlight the role of elevated PAI-1 level as a risk factor for thrombosis [19][20][21]. On the contrary, there are few studies in the available literature that concern increased concentration of PAI-1 in patients with MPNs.…”

Section: Discussionmentioning

confidence: 99%

Selected parameters of hemostasis in patients with myeloproliferative neoplasms

Gadomska

Rość²,

Stankowska³

et al. 2014

Blood Coagulation &Amp; Fibrinolysis

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Hemostatic disorders are a major clinical problem in patients with myeloproliferative neoplasms (MPNs) and they are the second most common cause of death in MPN patients, after infections. The aim of this study was to assess the fibrinolytic potential of the blood of patients with MPNs. The study involved 112 patients with MPNs diagnosed at the Hematology Clinic Dr J. Biziel University Hospital No. 2 in Bydgoszcz, Poland. The study group included 63 patients with essential thrombocythemia, 29 with polycythemia vera, 11 with chronic myelogenous leukemia (CML) and nine with primary myelofibrosis. The control group consisted of 25 healthy volunteers who were age and sex-matched. The following parameters were determined: concentration of tissue plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor type 1 antigen concentration (PAI-1:Ag), D-dimer, thrombin-antithrombin complexes, fibrinogen, activated partial thromboplastin time and international normalized ratio. The study showed significantly increased t-PA:Ag, PAI-1:Ag and D-dimer levels in patients with MPNs. Moreover, we found increased concentrations of thrombin-antithrombin complexes and fibrinogen, as well as elevated platelet counts. Detailed analysis revealed that t-PA:Ag concentration was elevated in patients with essential thrombocythemia, CML and polycythemia vera. Concentration of PAI-1:Ag was increased in patients with essential thrombocythemia and polycythemia vera; D-dimer was significantly higher in essential thrombocythemia, polycythemia vera, CML and primary myelofibrosis patients. Increased concentrations of t-PA:Ag and D-dimer indicate secondary activation of the fibrinolytic system in patients with MPNs. Elevated levels of PAI-1 in MPN patients may result from its increased production by elevated number of activated platelets and vascular endothelial damage. PAI-1 by having an inhibitory effect on fibrinolysis manifests its procoagulant activity.

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Hypercoagulability and Hypofibrinolysis and Risk of Deep Vein Thrombosis and Splanchnic Vein Thrombosis

Abstract: Abstract-In this review, we provide an overview of the risk factors for venous thromboembolism, focusing on hypercoagulability and hypofibrinolysis. In the first part of this review, we discuss the risk factors

Cited by 52 publications

References 115 publications

Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis

Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis

Evaluation of the profibrinolytic properties of a bispecific antibody‐based inhibitor against human and mouse thrombin‐activatable fibrinolysis inhibitor and plasminogen activator inhibitor‐1

Selected parameters of hemostasis in patients with myeloproliferative neoplasms

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