scholarly journals Resistance to activated protein C - a genetic risk factor for neonatal necrotizing enterocolitis?

1997 ◽  
Vol 42 (3) ◽  
pp. 407-407
Author(s):  
W Göpel ◽  
B Christiansen ◽  
I Reiss ◽  
J Möller ◽  
L Gortner
Keyword(s):  
Risk Factor ◽  
Necrotizing Enterocolitis ◽  
Genetic Risk ◽  
Protein C ◽  
Activated Protein C ◽  
Genetic Risk Factor ◽  
Neonatal Necrotizing Enterocolitis

scholarly journals Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3518-3523 ◽  
Author(s):  
B Zoller ◽  
A Berntsdotter ◽  
P Garcia de Frutos ◽  
B Dahlback
Keyword(s):  
Risk Factor ◽  
Genetic Risk ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Genetic Risk Factor ◽  
Factor V ◽  
Protein S Deficiency ◽  
Apc Resistance ◽  
S Deficiency

Inherited resistance to activated protein C (APC), which is caused by a single point mutation in the gene for factor V, is a common risk factor for thrombosis. In this study, the prevalence of APC resistance in 18 unrelated thrombosis-prone families with inherited protein S deficiency was investigated to determine its role as additional genetic risk factor for thrombosis. In addition, a detailed evaluation of the clinical manifestations in these families was performed. Venous thrombotic events had occurred in 47% of the protein S-deficient patients (64/136) and in 7% of relatives without protein S deficiency (14/191). As estimated from Kaplan-Meier analysis, 50% of protein S-deficient family members and 12% of those without protein S deficiency had had manifestation of venous thromboembolism at the age of 45 years. The age at the first thrombotic event ranged from 10 to 81 years (mean, 32.5 years) and a large intrafamilial and interfamilial variability in expression of thrombotic symptoms was seen. The factor V gene mutation related to APC resistance was present in 6 (38%) of 16 probands available for testing; in total, the mutation was found in 7 (39%) of the 18 families. In family members with combined defects, 72% (13/18) had had thrombosis as compared with 19% (4/21) of those with only protein S deficiency and 19% (4/21) of those with only the factor V mutation. In conclusion, APC resistance was found to be highly prevalent in thrombosis-prone families with protein S deficiency and was an additional genetic risk factor for thrombosis in these families. The results suggest thrombosis-prone families with protein S deficiency often to be affected by yet another genetic defect.

scholarly journals Prothrombin Arg541Trp Mutation Leads to Defective PC (Protein C) Pathway Activation and Constitutes a Novel Genetic Risk Factor for Venous Thrombosis

2020 ◽  
Vol 40 (2) ◽  
pp. 483-494 ◽  
Author(s):  
Xi Wu ◽  
Jing Dai ◽  
Xiaoqian Xu ◽  
Fang Li ◽  
Lei Li ◽  
...  
Keyword(s):  
Risk Factor ◽  
Family History ◽  
Venous Thrombosis ◽  
Genetic Risk ◽  
Protein C ◽  
Positive Family History ◽  
Genetic Risk Factor ◽  
Procoagulant Activity ◽  
Factor V Leiden Mutation ◽  
History Of

Objective: Defective PC (protein C) pathway predisposes patients to venous thromboembolism (VTE) and is mostly, but not exclusively, attributed to hereditary PC or PS (protein S) deficiencies and activated PC resistance caused by factor V Leiden mutation. Approach and Results: In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the 3 pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. Conclusions: In summary, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin’s procoagulant activity over anticoagulant function.

Factor V Leiden (Arg506Gln), a Confounding Genetic Risk Factor but not Mandatory for the Occurrence of Venous Thromboembolism in Homozygotes and Obligate Heterozygotes for Cystathionine β-synthase Deficiency

1999 ◽  
Vol 81 (04) ◽  
pp. 502-505 ◽  
Author(s):  
S. Yap ◽  
K. A. O’Donnell ◽  
C. O’Neill ◽  
P. D. Mayne ◽  
P. Thornton ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thrombosis ◽  
Genetic Risk ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Allelic Frequency ◽  
Genetic Risk Factor ◽  
Factor V ◽  
Contributing Factors ◽  
Thrombotic Risk

SummaryThrombosis is the major cause of morbidity and mortality in individuals with untreated classical homocystinuria (HCU) due to cystathionine β-synthase deficiency and characterised by severe hyperhomocysteinaemia. In addition, mild and moderate hyperhomocysteinaemia and Factor V Leiden (FVL; Arg506Gln) have recently been identified as thrombotic risk factors. FVL, which renders resistance to activated Protein C, is the most common inherited genetic risk factor for thrombosis with a high allelic frequency amongst Caucasians. As thrombophilia is a multigenic disorder, 26 individuals with HCU (median age 17.6 years, range 3.5-32.8 years) and 36 obligate heterozygotes (median age 51.5 years, range 34-74 years) were screened for FVL. All the HCU individuals received treatment, except one, within 6 weeks of birth for those who were diagnosed at birth through the national newborn screening programme (n = 20) and at the time of diagnosis for those late detected (n = 5, mean age of starting treatment 4.9 years, range 1.4-11 years). All had been free from venous thrombosis, except one HCU individual and one HCU obligate heterozygote. Neither of the two individuals with venous thrombosis carried FVL. Two independent individuals with HCU (male 14.8 years; female 18.2 years) were heterozygous for FVL (allelic frequency 3.8%) and three independent HCU obligate heterozygotes (males 40 and 45.8 years; female 45.6 years) were also heterozygous for FVL (allelic frequency 4.16%). The findings in this small group suggest that FVL is not a mandatory but a significant confounding risk factor for the occurrence of thrombosis in HCU individuals and additional contributing factors may be required for thrombosis to occur in HCU obligate heterozygotes with FVL heterozygosity. Our data also suggest that treatment of HCU not only reduces the thrombotic risk in patients with isolated HCU but also in those with the additional FVL heterozygosity.

scholarly journals Advances in Understanding Mechanisms of Thrombophilic Disorders

2020 ◽  
Vol 40 (01) ◽  
pp. 012-021
Author(s):  
Björn Dahlbäck
Keyword(s):  
Risk Factor ◽  
Genetic Risk ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Medical Problem ◽  
Factor V ◽  
Apc Resistance ◽  
Thrombosis Risk ◽  
Increased Risk

AbstractVenous thromboembolism constitutes a major medical problem afflicting millions of individuals worldwide each year. Its pathogenesis is multifactorial, involving both environmental and genetic risk factors. The most common genetic risk factor known to date is a mutation in the factor V (FV) gene (R506Q or FV Leiden), which impairs the normal regulation of FV by activated protein C (APC). APC is an important regulator of blood coagulation, cleaving and inactivating not only FV/FVa but also activated factor VIII (FVIIIa). In FVa, APC cleaves several sites, Arg506 (R506) being one of them. The R506Q mutation results in the APC resistance phenotype and a lifelong hypercoagulable state. A prothrombin gene mutation is another relatively frequent thrombosis risk factor, whereas deficiencies of the anticoagulant proteins antithrombin, protein C, or protein S are less common. As a result of the high prevalence of FV and prothrombin mutations in the general population, combinations of genetic defects are relatively common. Such individuals have highly increased risk of thrombosis.

A Mutation in Plasma Platelet-activating Factor Acetylhydrolase (Val279Phe) Is a Genetic Risk Factor for Cerebral Hemorrhage but not for Hypertension

1998 ◽  
Vol 80 (09) ◽  
pp. 372-375 ◽  
Author(s):  
Hidemi Yoshida ◽  
Tadaatsu Imaizumi ◽  
Koji Fujimoto ◽  
Hiroyuki Itaya ◽  
Makoto Hiramoto ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genetic Risk ◽  
Platelet Activating Factor ◽  
Vascular Diseases ◽  
Genetic Risk Factor ◽  
Brain Hemorrhage ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Paf Acetylhydrolase ◽  
Polymerase Chain ◽  
The Difference

SummaryPlatelet-activating factor (PAF) acetylhydrolase is an enzyme that inactivates PAF. Deficiency of this enzyme is caused by a missense mutation in the gene. We previously found a higher prevalence of this mutation in patients with ischemic stroke. This fact suggests that the mutation might enhance the risk for stroke through its association with hypertension. We have addressed this hypothesis by analyzing the prevalence of the mutation in hypertension. We studied 138 patients with essential hypertension, 99 patients with brain hemorrhage, and 270 healthy controls. Genomic DNA was analyzed for the mutant allele by the polymerase-chain reaction. The prevalence of the mutation was 29.3% (27.4% heterozygotes and 1.9% homozygotes) in controls and 36.2% in hypertensives and the difference was not significant. The prevalence in patients with brain hemorrhage was significantly higher than the control: 32.6% heterozygotes and 6.1% homozygotes (p <0.05). PAF acetylhydrolase deficiency may be a genetic risk factor for vascular diseases.

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