A deep-vein blood clot in the leg is painful and disabling. When such athrombus breaks loose and travels to a lung, it can be fatal.What causes these thromboembolisms of limb and lung is a matter ofmedical debate. Infection, malignancy or mechanical trauma areblamed. So is prolonged bed rest; even the inovulatory contraceptivepill. Diagnosis too is tricky. Often the first hint of a saphenous veinthrombus in the leg is its metastasis as a pulmonary embolism.About one in 1,000 Americans a year experience venous thrombosis ofunknown origin.The latest etiologic theory, that thrombosis runs in families, gainsfurther credence from a paper in today's Nature, titled: "Mutation inblood coagulation factor V associated with resistance to activatedprotein C." This finding of a hereditary factor in thrombophilia is, in asense, the flip side of hemophilia, which is the absence of clottingowing to a different inherited gene defect in the same blood-coagulation cascade.Blood belongs strictly inside its arteries, veins or capillaries. When acut, bruise or laceration lets it escape from these vessels, an elaborateprocess of coagulation kicks in to "bandage" the wound with clots,while preserving the bloodstream's free flow.Clotting Cascade's Balancing ActWhen blood is shed, enzymes cleave a prothrombin to form thrombin.This then activates fibrinogen to form fibrin, the stuff of clots. To keepclotting from going too far, the protein C anticoagulant feedbackpathway also goes into action. As the Nature paper outlines,"Procoagulant thrombin binds to endothelial thrombomodulin,converting thrombin to an anticoagulant protease." This turns onprotein C, a plasma protease, to turn into activated protein C (APC).Then, along with protein S, its non-enzyme cofactor, APC inactivatescoagulation factors Va and VIIIa.Biochemist Rogier Bertina, first author of the Nature paper, heads agroup at the Thrombosis Research Center of the University of LeidenHospital in the Netherlands. He found that two unrelated homozygoticthrombosis patients _ with resistance to APC inherited from bothparents _ had the same single point mutation, which converts arginineto glutamine in the gene for Factor V.This aberrant gene is predicted to encode a crippled Factor V moleculethat is not properly inactivated by APC, so tips the delicate bloodbalance toward clotting. The Leiden team then developed a PCR testfor the mutant gene, and applied it for linkage analysis genotyping ofsusceptible family members.Detecting Thrombosis-Prone CarriersLast March, in Snowbird, Utah, Bertina told an internationalconference on the genetic causes of thrombosis that 2 to 4 percent ofthe Dutch population carry the mutant APC allele. Swedish carriers,said another statistic, run as high as 7 percent; similar prevalence holdsfor the U.S.In thrombosis-prone families, Bertina reported, the mutation runs muchhigher, 13 to 25 percent, suggesting that more than one defective genemay be involved. He supported this supposition by citing that infamilies with mutations of both Factor V and protein C, an individual'srisk was 71 percent."We have during the past years become aware that thrombosis isprobably a multiple-gene disorder," Bertina told BioWorld Today."Each of the genetic defects contributes its own penetrance to thethrombotic risk."But most of these carriers, he added, do not actually suffer a thromboticepisode, if they can avoid the environmental co-factors, such asinfection, injury or physical immobilization.Of 500 consecutive patients with first-episode, deep-vein thrombosis,20 percent had the genetic defect, Bertina said. "We have a large panelof patients referred to our center for analysis during the past 10 years.Of these individuals, selected because of a family history ofthrombosis, 50 percent carry the mutation."Because we can find this abnormality in many families with familialclustering of thrombosis," Bertina concluded, "it's very helpful that wecan identify individuals who carry at least one gene mutation. That willmake it much more easy to use linkage analysis, and find other genedefects _ the line that we are pursuing at present."He doesn't think prenatal diagnosis is relevant, "at this very moment,because homozygotes can lead a very nice life, apart from thisthrombotic episode. But in the future, when we can make a betterassessment of the risk to different individuals in the family, based onthe presence of genetic and other risk factors, then genetic counselingwill be increasingly important."Clotting Mutation Not Just in DutchBiochemist John Griffin, of the Scripps Institute's (of La Jolla, Calif.)molecular and experimental medicine department, told BioWorldToday that his laboratory has found the same Factor Va mutation in 12of 13 patients (92 percent), "which has just astounded us."The astonishment, he explained, stems from this 92 percent evidencethat "the mutation Bertina finds in his patients is not unique to someDutch founder effect or genetic pool. Our 12 mutation-positive patientsincluded one black subject, two Ashkenazi Jews and 10 assortedEuropean Caucasians _ which makes it ubiquitous."As Griffin has recently reported at several scientific meetings,"between 54 and 60 percent of Americans under 50 years of age whopresent with unexplained venous thrombosis, have this resistance toactivated protein C"

-- David N. Leff Science Editor

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