Blood clots, however useful in wound healing, can beextremely hazardous, not just to health but to life itself.When clots dam the flow through coronary arteries, theheart starves to death. In stroke, their blood-vesselblockage deprives the brain of vital nourishment. Andremote blood clots deep in veins of the leg often travel tothe lungs, to choke off their breath of life.
Pulmonary embolisms kill anywhere from 50,000 to100,000 people a year in the U.S. alone. Of every 100elderly patients hospitalized with such a clot in the lung,21 will die in the hospital, and another 39 within the year.
When the diagnosis is deep-vein thrombosis (DVT) _frequent precursor of lung clots _ 30 percent of olderpersons successfully treated for the disorder will comedown with a recurrence, and 20 or more will die in 12months.
Although DVT most often strikes people over 65, old ageper se is not the only risk factor. Cancer sufferers andsurvivors of surgery are likely candidates, as are pregnantwomen and persons immobilized by prolonged periods ofbed rest.
But these and other risk factors still leave "a majority ofdeep-vein thrombosis cases unexplained," observesmolecular hematologist David Rees of OxfordUniversity's Radcliffe Hospital.
Clotting disorders represent, in a sense, the flip side ofhemophilia, in which components of the coagulationcascade, usually factors VIII and IX, fail to thicken bloodsufficiently to prevent hemorrhage during injury.Conversely, in venous thrombosis, the blood becomesunduly sticky, causing clots to form.
In 1993, researchers in the Netherlands discovered amutation in the gene for coagulation factor V. The DNAdefect renders blood so thick that it clots without anapparent cause. This point mutation _ dubbed factor VLeiden _ exchanges an arginine for a glutamine in factorV's amino acid chain. This renders it resistant to aprotein, protein C, which has the job of preventing unduecoagulation by inhibiting formation of too much factor V.
Rees is first author of a paper in the current issue of TheLancet, dated Oct. 28, titled, "World distribution of factorV Leiden."
In it he writes that "21 percent of deep-vein thrombosesin the under-70's . . . heterozygotes [carriers, who inheritthe defective gene from one parent only] have a sevenfoldincreased risk of venous thrombosis, and homozygotes[who get a double dose, from both parents] are 80 timesmore susceptible."
Mutation Occurred Recently In Europe
Noting that "venous thrombosis is common amongEuropeans [but] rare among individuals of most otherracial backgrounds," Rees analyzed DNA from the 3,380chromosomes of 1,690 unrelated people, representingindigenous populations in virtually every inhabited regionof the planet. He found 50 heterozygotes plus twohomozygotes among 618 Europeans.
In Africa, Asia, Australia and the Americas, he countedzero for both categories, except for a lone heterozygote inIndia.
Rees told BioWorld Today that "the mutation occurredrecently in the European founding population _ perhapswithin the last 100,000 years _ and has been dispersedby migration." He speculated that early in humanevolution, carrier status for venous thrombosis may havebenefited premenopausal women, reducing menstrualblood and iron loss, and reducing postpartumhemorrhage.
However, by testing the factor V gene in the DNA of sixchimpanzees and a gorilla, he determined that theunmutated gene "is the ancestral state."
In the U.S., cardiologist Paul Ridker has followed 14,916American physicians for 8.6 years, and recorded theirhistories of clot-related disorders in the New EnglandJournal of Medicine, dated April 6, 1995. He reportedthat "121 had deep venous thrombosis, pulmonaryembolism or both; 374 had myocardial infarctions; 209had strokes."
Seeking Answers To The Million-Dollar Question
Ridker, who directs clinical trials at Harvard MedicalSchool's preventive medicine division, told BioWorldToday: "Until the discovery of factor V Leiden, only in1993, if you wanted to predict the likelihood of a bloodclot, forget it. You couldn't do it. Now along comes thismutation in the gene for coagulation factor V, whichcarries a sevenfold increased risk of having a DVT eventin a person over 60 with the gene."
He explained: "At least one in 13 presumably CaucasianNorth Americans of European extraction have it. That'swhat the Lancet paper, which I found fascinating, istrying to tell us."
For Ridker, this raised "a quandary. If you look at apopulation that's suffered a first blood clot _ thus, avery, very high-risk group _ what are their odds ofhaving a second DVT in the future? That's the million-dollar question."
Standard care for a first-time DVT patient, he observed,"is heparin injections for four or five days in hospital,then outpatient warfarin [an oral anti-coagulant] for threemonths." But in the light of the newly testable risk factor,the factor V Leiden mutation, "perhaps we're mistreatingpeople. Perhaps the thing to be doing is screen for thegene after a first event, then put the gene-positive patientson lifelong anti-coagulation, not just three months."
Ridker is now "in the process of trying to find funding todo a randomized clinical trial. We would take patientswho come in with a first-time DVT, screen for the gene,then randomize the gene-positives to standard three-month care vs. lifelong anti-coagulation, and see if wecan actually prevent the second event."
He concluded, "Our present plan is to include allgenetically positive comers, regardless of ethnicbackground." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.