Thrombin Generation and Fibrinolysis in the Thrombotic Thrombocytopenic Purpura and the Hemolytic-Uremic Syndrome

Monteagudo, J M; Pereira, Arturo; Reverter, Joan Carles; Pijoan, Josefina; Tusell, J; Puig, L.; Ordinas, Antonio; Castillo, Ricardo

doi:10.1055/s-0038-1646451

Cited by 36 publications

(25 citation statements)

References 23 publications

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“…45 TM syndromes are associated with systemic lupus erythematosus and antiphospholipid antibodies, 46 and the inactivation of factor Va by activated protein C is inhibited by antiphospholipid antibodies, suggesting a pathogenic defect similar to factor V Leiden. 47,48 Abnormalities of fibrinolysis have been implicated in the pathogenesis of TM syndromes, 32,33,35,49 and activated protein C has been shown to enhance fibrinolysis indirectly by down-regulating production of thrombin and thrombin-activatable fibrinolysis inhibitor. 50 In vitro studies have shown that acceleration of fibrinolysis by activated protein C is markedly attenuated by factor V Leiden, 51 which might promote microvascular thrombosis.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Reported abnormalities of coagulation proteins in TM include increased PAI-1 activity and deficiencies of protein C, protein S, tissue plasminogen activator, and urokinase-type plasminogen activator. [32][33][34][35] Studies in kindreds with familial HUS indicate that genetic alterations of complement factor H, a plasma protein that down-regulates complement activity, are prevalent in this subset of TM patients. [36][37][38][39] Complement activation is known to induce expression of tissue factor and adhesion molecules on endothelial cells and procoagulant alterations on platelet surfaces.…”

Section: Discussionmentioning

confidence: 99%

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Factor V Leiden: a genetic risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor–cleaving protease activity

Raife

Lentz

Atkinson

et al. 2002

Blood

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Thrombotic microangiopathy (TM) is associated with abnormalities of von Willebrand factor-cleaving protease (VWCP) and other hemostatic factors. This study hypothesized that TM patients might have genetically determined thrombotic risk factors that predispose them to aberrant microvascular thrombosis. DNA samples from 30 white and 12 African American adult TM patients were analyzed for genetic alleles associated with vascular thrombosis, and plasma samples were analyzed for levels of VWCP activity. DNA was analyzed by using allele-specific polymerase chain reaction for factor V 1691A (Leiden), factor II 20 210A, methylenetetrahydrofolate reductase 667T, type 1 plasminogen activator inhibitor 4G/5G, and platelet GPIa 807T. Patients were segregated by race (white or African American) and plasma level of VWCP activity (normal or deficient). The prevalence of factor V Leiden was significantly increased among the white TM patients that had normal VWCP activity: 4 (36%) of 11 patients compared with 6 (3%) of 186 white control subjects possessed the factor V Leiden allele (P < .001; odds ratio, 17. IntroductionThrombotic microangiopathy (TM) disorders, including thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS), are characterized by widespread microvascular thrombosis leading to end-organ injury. The etiologies and pathogenic mechanisms of TM syndromes remain poorly understood. However, evidence implicates a deficiency of von Willebrand factor (VWF)-cleaving protease (VWCP) activity in the pathogenesis of TM in patients with the clinical diagnosis of TTP. 1,2 Deficiency of VWCP activity has been proposed to impair proteolytic processing of ultralarge endothelial cell-derived VWF multimers, resulting in a predisposition to platelet thrombosis. 2,3 Deficient VWCP activity provides support for a platelet-VWFdependent mechanism of microvascular thrombosis in a subset of TM patients. However, the mechanism of microvascular thrombosis in TM patients with normal levels of VWCP activity remains obscure. Patients who have TM associated with bone marrow transplantation 4 and enteropathic Escherichia coli infection, 5 as well as some patients with idiopathic TM, 6 have been reported to have normal VWCP activity. Microvascular thrombosis in these TM patients might involve a wide range of hemostatic abnormalities, and the syndromic nature of TM suggests the possibility of multiple pathogenic factors.An increasing number of genetic mutations and polymorphisms have been found to be associated with various manifestations of vascular thrombosis. The implicated mutant or polymorphic alleles affect hemostatic mechanisms by encoding variant proteins or altered regulatory sequences that have the potential to enhance thrombus formation or decrease fibrinolysis. We hypothesized that thrombosis-associated mutations or polymorphisms may contribute to the pathogenic mechanisms of TM disorders. Moreover, because certain hemostatic abnormalities, such as deficient VWCP activity, are found in some TM patients but n...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Factor V Leiden: a genetic risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor–cleaving protease activity

Raife

Lentz

Atkinson

et al. 2002

Blood

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“…Marburg, FRG). In our hands, F, + 2 refer ence range was 0.28-1.08 nmol/1, with intra-and inter assay variation coefficients of 4.3-13.7 and 5.9-17.2% [12], respectively, whereas no thrombin was further generated in vitro [12,13]. ATIII activity was mea sured according to Abildgaard et al [14].…”

mentioning

confidence: 99%

“…Forty patients undergoing 43 consecutive OLT, with ages ranging from 13 to 61 years (median 47), have been prospectively studied. Etiologies including liver cirrhosis were associated to previous hepatitis (13), alcoholism (5), and porphyria cutanea [1], whereas 8 were of unknown origin; other causes were primary biliary cirrhosis (6), hepatocarcinoma (1), and hemochromatosis (2). Acute, fulminant forms of liver failure required OLT in 4 patients.…”

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confidence: 99%

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Prothrombin Fragment 1+2 and Thrombin-Antithrombin Complex Measurements Indicate Continuous and Progressive Intraoperative Thrombin Generation in Liver Transplantation

Monteagudo¹,

Reverter²,

Pereira³

et al. 1993

Pathophysiol Haemos Thromb

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Prothrombin fragment 1 + 2 (F₁₊₂) and thrombin-antithrom-bin complex (TAT) have been measured in the different surgical phases in 40 patients undergoing 43 orthotopic liver transplantations (OLT), in order to study thrombin generation throughout the surgical procedure. F₁₊₂ and TAT progressively rose from preoperative values (1.47 ± 0.92 nmol/l and 22.41 ± 19.15 ng/ml, respectively) to the end of anhepatic phase (5.97 ± 2.20 nmol/l, 64.24 ± 11.30 ng/ml), whereas changes in circulating antithrombin III (ATIII) were negligible in this period. Thrombin generation continued to slightly but significantly increase immediately after liver graft reperfusion (F₁₊₂ 6.87 ± 1.65 nmol/l, TAT 89.32 ± 7.54 ng/ml), and ATIII levels decreased from 70.61 ± 12.28 to 57.16 ± 9.57%. Higher preoperative values of F₁₊₂ were associated with larger requirements of both packed red blood cells and fresh frozen plasma (FFP) in the host liver explantation phase, whereas the lowest basal levels of ATIII were related to a higher plasma expense in the whole OLT procedure. The activation of circulating prothrombin begins early in OLT, and adequate FFP infusion is capable of maintaining appropriate circulating thrombin-inhibitory activity.

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Hemostatic complications in renal disorders of the young

Andrew

Brooker

1996

Pediatr Nephrol

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This review focuses on the hemorrhagic and thrombotic complications sometimes associated with the most common renal disorders in children. A Medline search of the literature was conducted from 1966 to January 1995, using combinations of key words appropriate for each disorder. Additional references were located through the bibliographies of the publications and recent journals were searched independently. The most common renal disorders with hemostatic complications in children were: renal vein thrombosis (268 children in 80 publications), hemolytic uremic syndrome (473 children in 29 publications), nephrotic syndrome (4,158 children in 51 publications), renal transplantation (3,976 children in 14 publications), glomerulonephritis (20 publications), end-stage renal disease, and dialysis (22 publications). The age distribution, clinical presentation, etiology, diagnosis, treatment, and outcome of the affected children were analyzed for each disorder. Children with inherited pre-thrombotic disorders usually do not present during childhood unless there is a secondary risk factor. Similarly, most children with renal disease do not develop thromboembolic complications. Therefore, when a child with a renal disorder develops a thromboembolic event, evaluation for an inherited pre-thrombotic disorder should be seriously considered. Guidelines for the use of heparin and warfarin in these children (both therapeutically and prophylactically) are given. At this time, the risk/benefit of thrombolytic therapy in children is not known and a general recommendation for thrombolytic therapy cannot be made.

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Thrombin Generation and Fibrinolysis in the Thrombotic Thrombocytopenic Purpura and the Hemolytic-Uremic Syndrome

Cited by 36 publications

References 23 publications

Factor V Leiden: a genetic risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor–cleaving protease activity

Factor V Leiden: a genetic risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor–cleaving protease activity

Prothrombin Fragment 1+2 and Thrombin-Antithrombin Complex Measurements Indicate Continuous and Progressive Intraoperative Thrombin Generation in Liver Transplantation

Hemostatic complications in renal disorders of the young

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