Genetic Heterogeneity in Hereditary Thrombophilia

Abstract

Venous thromboembolism is a multifactorial disease that depends on variable combinations of acquired and genetic risk factors. The genetic risk factors include loss-of-function mutations in the genes that encode proteins with clot-restraining function, and gain-of-function mutations in procoagulant factors. The loss-of-function mutations are heterogeneous and comprise any mutation that impairs gene function. On the whole, these mutations are rare, with fewer than 1/200–500 individuals affected. This low prevalence in the population is probably caused by the loss of mutant alleles from the gene pool through critically ill homozygous subjects. The gain-of-function mutations in procoagulant proteins differ from the loss-of-function mutations in at least three important respects: these are more homogeneous (factor V Leiden and PT 20210), homozygous individuals are relatively mildly affected, and these are relatively prevalent (3–15%) in Caucasian populations.

Primary thrombophilia in Mexico. V. A comprehensive prospective study indicates that most cases are multifactorial

“…In an effort to further clarify the causes of thrombophilia in Mexican mestizos, we have prospectively assessed several thrombophilic conditions in a group of 46 consecutive Mexican mestizos. In 42 (91%), abnormal results were found, which in most cases (37/42, 88%) were several thrombosis-prone conditions at the same time, thus supporting the concept of a multifactorial thrombophilia [4][5][6][7][8][9]. The phenotype and genotype studies of thrombophilia accomplished to date seem to indicate that, as with most diseases, hereditary thrombophilia is genetically complex: current tests for thrombophilia provide useful diagnostic tools, but, as with most laboratory tests, results must be interpreted in the context of other clinical and laboratory findings.…”

Clinical and genetic risk factors for venous thromboembolism in Chinese population

“…The thrombophiliac risk factors include loss-of-function mutations in the genes that encode proteins with clot-restraining function, and gain-of-function mutations in pro-coagulant factors. The loss-offunction mutations are heterogeneous and comprise mutations that impair gene function [25,26]. Loss-offunction disorders include deficiencies of the endogenous anticoagulants, antithrombin, protein C (PC) and protein S (PS).…”

Stellungnahme des Zürcher Gesprächskreises zum Gentest

“…Mutationen im Gen des Protein C können zum Verlust der Funktion dieses Gerinnungsinhibitors führen. Während homozygote Träger bereits in jungem Alter eine Thrombose erleiden, ist von 'late-onset'-Ereignissen nur eine Minderheit der heterozygoten Träger betroffen [28].…”

“…Die Leiden-Mutation des Faktor-V-Gens bedeutet eine Resistenz gegenüber dem APC und zählt damit zu den wichtigsten Thrombophilien [28]. Sie spielt auch bei Schwangerschaftskomplikationen und habituellen Aborten eine Rolle.…”