Association of genotypes of thrombin-activatable fibrinolysis inhibitors with thrombotic microangiopathies--a pilot study

Sucker, Christoph; Hetzel, Gerd R.; Farokhzad, Firuseh; Dahhan, Fieras; Schmitz, Michael; Kurschat, Christine; Grabensee, B; Maruhn-Debowski, Beate; Zotz, Rainer B.; Scharf, R

doi:10.1093/ndt/gfl753

Cited by 4 publications

(6 citation statements)

References 20 publications

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“…36 We tested the effect of the thrombomodulin variants on thrombin-mediated generation of TAFIa, as assessed by the appearance of a 36-kD fragment 37 (Fig. 5C).…”

Section: Resultsmentioning

confidence: 99%

“…The additional impairment in TAFIa generation probably aggravates the disease. 36 Thrombomodulin has a binding site for C3b and CFH, thereby accelerating CFI-mediated inactivation of C3b. Beyond these activities, which negatively regulate the alternative pathway, thrombomodulin plays a wider role in suppressing complement-mediated cell injury.…”

Section: Discussionmentioning

confidence: 99%

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Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome

et al. 2009

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BACKGROUND The hemolytic–uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin–producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic–uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic–uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic–uremic syndrome. METHODS We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic–uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic–uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells. RESULTS Of 152 patients with atypical hemolytic–uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I–mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic–uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement. CONCLUSIONS Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic–uremic syndrome.

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“…36 We tested the effect of the thrombomodulin variants on thrombin-mediated generation of TAFIa, as assessed by the appearance of a 36-kD fragment 37 (Fig. 5C).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome

et al. 2009

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“…While one study found that the 147Thr allele of the Ala147Thr polymorphism protected against MI [27], in another study, the 147Thr allele was associated with a higher risk of angina [28]. TAFI polymorphisms C+1542G and Thr325Ile were also found to be related to the type of ACS [29] and thrombotic microangiopathies [30]. Regarding cerebrovascular diseases, Akatsu et al did not find any association between the Ala147Thr and Thr325Ile polymorphisms of TAFI and cerebral infarction [18].…”

Section: Discussionmentioning

confidence: 99%

Association between polymorphisms in the flanking region of the TAFI gene and atherosclerotic cerebral infarction in a Chinese population

et al. 2014

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BackgroundAtherosclerosis is the leading etiologic factor of Atherosclerotic Cerebral Infarction (ACI). Previous studies have shown that thrombin activatable fibrinolysis inhibitor (TAFI) may play an important role in the occurrence of acute cerebral infarction, and the levels of TAFI are affected by several single nucleotide polymorphisms (SNPs) located in the regulatory and coding regions of the gene encoding TAFI. The present study aimed to determine whether polymorphisms (TAFI –2345 2G/1G, –1690 A/G, –438 A/G, +1583 A/T) of the TAFI gene were associated with ACI in a Han Chinese population.MethodsThe variant genotypes were identified by restriction fragment length polymorphism (RFLP) and allele-specific polymerase chain reactions (AS-PCR) in 225 patients with ACI and 184 age-matched healthy individuals.ResultsThere was a significant difference in the genotype and allele frequencies of TAFI –2345 2G/1G and −1690 A/G polymorphisms between the ACI and control subjects. Further stratification analysis by gender revealed that the presence of the –438 AA genotype and the A allele conferred a higher risk of developing ACI in male patients (p < 0.05). Haplotype analysis demonstrated that four haplotypes of TAFI are significantly associated with ACI.ConclusionsOur study provides preliminary evidence that the TAFI –2345 2G/1G and –1690 A/G polymorphisms are associated with ACI susceptibility in a Han Chinese population.

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“…4,5 Recently, we identified the GG genotype of the G1642A polymorphism of the thrombin-activatable fibrinolysis inhibitor (TAFI), an important regulator at the interface of fibrinolysis and inflammation, and the homozygous Leu variant of the factor XIII Val34Leu polymorphism as another factor predisposing to the onset of thrombotic microangiopathies. 6 In the presented study, we focused on the potential role of prothrombotic variants of platelet receptor polymorphisms in the pathogenesis of thrombotic microangiopathies. Respective polymorphisms of platelet receptors involved in platelet adhesion and aggregation were shown to modulate platelet thrombogenicity in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Are Prothrombotic Variants of Platelet Glycoprotein Receptor Polymorphisms Involved in the Pathogenesis of Thrombotic Microangiopathies?

Sucker

Schmitz

Hetzel

et al. 2008

Clin Appl Thromb Hemost

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anemia, low platelet count and signs of organ dysfunction. Depending on the pattern of organ involvement, hemolytic-uremic syndrome (HUS) with predominant renal dysfunction, thrombotic-thrombocytopenic purpura (TTP) with predominant neurological deficiency, and intermediate forms (TTP-HUS) are distinguished. 1,2 Although a subgroup of affected patients, particularly among those suffering from TTP, were shown to have a defect in the von Willebrand factor cleaving protease ADAMTS 13 ("a desintegrin like and metalloprotease with thrombospondin-1 motif") and others, particularly among those with HUS, had a deficiency of complement regulatory factors such as

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Association of genotypes of thrombin-activatable fibrinolysis inhibitors with thrombotic microangiopathies--a pilot study

Cited by 4 publications

References 20 publications

Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome

Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome

Association between polymorphisms in the flanking region of the TAFI gene and atherosclerotic cerebral infarction in a Chinese population

Are Prothrombotic Variants of Platelet Glycoprotein Receptor Polymorphisms Involved in the Pathogenesis of Thrombotic Microangiopathies?

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