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Greengard et al.,
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glutamine mutation at position 506 in the factor V gene. On the basis of this report and others,2,3,4 one can estimate that there are hundreds of thousands of homozygotes in Europe and the United States. Many of them probably come from families in which the heterozygous state is asymptomatic, since the mutation is very common in the general population.1,2,3,4 At present, it is not known whether homozygous members of such families have an increased risk of thrombosis. We examined a family from Burgenland in eastern Austria (Figure 1). With functional assays, we detected no deficiency in antithrombin III, protein C, protein S, or coagulation factor XII. Plasma concentrations of plasminogen-activator inhibitor 1 and heparin cofactor II were in the normal range. We tested for the factor V gene mutation, as previously described.5 The activated protein C ratios2 were between 2.4 and 3.7 in the noncarriers, between 1.7 and 2.4 in the heterozygotes, and markedly lower in the two homozygotes (1.2 and 1.3). Coagulation-based tests sensitive to lupus anticoagulant and immunologic assays for anticardiolipin antibodies were negative in all heterozygous and homozygous subjects.
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Unlike the findings reported by Greengard et al., our data suggest that homozygotes for the factor V mutation may have no symptoms or a late onset of disease. It is interesting that, like the asymptomatic homozygous members of the family we studied, the asymptomatic homozygous family members described by Greengard et al. were both females. Whether this is purely coincidental needs to be clarified. In any case, an increased thrombotic tendency among homozygous members cannot be ruled out, even in families with numerous carriers and no history of thrombosis.
Pierre Hopmeier, M.D.
Walter Krugluger, M.D.
Rudolfstiftung Hospital
A-1030 Vienna, Austria
References
Gln mutation in the gene for factor V. N Engl J Med 1994;331:1559-1562. glutamine mutation at position 506. No other genetic defects, including defects in antithrombin III, protein C, protein S, and plasminogen, as well as hyperhomocystinemia, could be detected in these patients. Seven of the 10 homozygotes presented with thrombotic manifestations (Table 1). in three instances only superficial phlebitis occurred. The mean (±SD) age of the symptomatic patients was 32.4±10.3 years, and their mean age at the time of the first thrombotic event was 23.1±14.5 years.
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Resistance to activated protein C presents a puzzling coagulation problem. The clinical presentation in homozygotes with this defect is clearly different from that in homozygotes with defects of protein C, protein S, or antithrombin III; in comparison with these conditions, resistance to activated protein C appears to be a relatively weak prothrombotic condition. Follow-up of the asymptomatic and symptomatic carriers of the factor V Leiden mutation will provide more information about the clinical relevance of the defect.
Paolo Simioni, M.D.
Alberta Scudeller, M.D.
Antonio Girolami, M.D.
University of Padua Medical School
35100 Padua, Italy
References
The essential inactivating cleavage of human factor Va occurs after the cleavage at Arg506 in the connecting region between the A1 and A2 domains at Arg306. The previously reported cleavage site at Arg506 facilitates cleavage at Arg306 but has little direct effect on the activity of factor Va. Thus, the statement that activated protein C "inactivates factor Va . . . by cleaving a single peptide bond, Arg506–Gly507" is in error. Unlike factor Va, the procofactor factor V is inactivated in the presence of a membrane by direct cleavage at Arg306.5
During the performance of the assay for resistance to activated protein C, plasma is incubated with the reagent used to determine the activated partial-thromboplastin time, activated protein C is added together with Ca2+, and the clotting time is measured. Prolongation of the clotting time with plasma from normal persons is associated with inactivation of factor Va by activated protein C. In plasma from a person with resistance to activated protein C, a shorter prolongation of the clotting time is observed. Since only factor Va, not factor V, is procoagulant-active, all clot-based assays rely on the in situ or adventitious activation of factor V to support the clotting reaction. Both factor V activation (by factor Xa) and factor V or Va inactivation (by activated protein C) are lipid-dependent. In addition, the performance of the assay for resistance to activated protein C is highly sensitive to the status of factor V activation in the plasma sample. Since factor V inactivation occurs by an initial cleavage at Arg306 and factor Va inactivation results from a sequential cleavage at Arg506 followed by Arg306,5 the status of factor V activation can compromise the assay for resistance to activated protein C. Thus, a patient with resistance to activated protein C in whom plasma factor V is not properly activated to factor Va will have a normal ratio for sensitivity to activated protein C (arbitrarily set at >2), and the defect will escape detection.
Michael Kalafatis, Ph.D.
Kenneth G. Mann, Ph.D.
University of Vermont
Burlington, VT 05405
References
Moreover, in a report not cited by Dr. Hajjar, Dahlbäck2 indicates that when factor V is activated by thrombin, three peptide bonds are cleaved, resulting in two terminal fragments and two central fragments. In contrast to the process shown in Dr. Hajjar's diagram, it is the two terminal fragments that join to form factor Va, according to Dahlbäck.
These two representations do not appear to be compatible. Is it possible to have Dr. Hajjar clarify what appears to be an inconsistency?
Robert R. Belliveau, M.D.
University Medical Center of Southern Nevada
Las Vegas, NV 89102
References
To the Editor: The letters in response to our report underscore the variable thrombotic tendency in patients with homozygosity for the arginine glutamine mutation at position 506 in factor V. Hopmeier and Krugluger describe an Austrian family in which a homozygous woman had an initial episode of venous thrombosis at 56 years of age and her older sister has not had such an event. Simioni et al. report on 10 additional homozygous patients, from seven different Italian families, 70 percent of whom had venous thrombosis at relatively young ages — a substantially higher frequency than that among their heterozygous patients. Investigators from Sweden1 and the Netherlands2 have recently documented that homozygous patients are at increased risk for venous thrombosis. As expected, the risk for homozygotes is significantly higher than that for heterozygotes, who are also more likely to have such events than normal persons.3
Recent biochemical studies show that purified plasma Gln506–factor Va, generated by either thrombin or factor Xa, is only relatively resistant to activated protein C, since the mutant factor Va is inactivated approximately 10 times more slowly than normal factor Va.4 Cleavage of both mutant and normal factor Va molecules by activated protein C at Arg306 occurs readily and causes complete loss of procoagulant activity. Thus, the down-regulation of factor Va by activated protein C is modulated but not ablated by the arginine glutamine mutation at position 506. These findings may explain why homozygous resistance to activated protein C due to this mutation results in a weaker prothrombotic condition than a homozygous deficiency of protein C or protein S, which causes a complete loss of function of the protein C anticoagulant mechanism.
In our article we estimated the incidence of homozygosity too high by a factor of four, because the likelihood of two heterozygotes bearing a homozygous offspring is only one in four. Since heterozygosity for the arginineglutamine mutation at position 506 in factor V has a prevalence of 3 to 7 percent in the general population, the correct estimate for the prevalence of homozygosity in the general population is between 0.02 percent (1 in 5000 people) and 0.12 percent (1 in 800).
Kenneth A. Bauer, M.D.
Brockton–West Roxbury Veterans Affairs Medical Center
West Roxbury, MA 02132
John H. Griffin, Ph.D.
Scripps Research Institute
La Jolla, CA 92037
References
Dr. Belliveau notes that activation of factor Va results from the noncovalent association of the two terminal domains of factor V, after the thrombin-mediated release of the central B domain. This is certainly correct, and the figure in my editorial was intended to illustrate this process. At the risk of oversimplification, however, I omitted the third intra–B-domain thrombin cleavage site for clarity. Dr. Belliveau suggests further that an alternative reference would have directed the reader to a more thorough discussion of the thrombin-mediated activation of factor V. Although it is true that the reference I cite3 in my editorial does not provide a comprehensive review of mechanistic details, it does assert that "thrombin generated at sites of vascular injury activates factors V and VIII," referring the reader to another source4 for further detail. The reference I cite3 was chosen for its clinical viewpoint, since the phenotypic expression of factor V Leiden is the main subject of my editorial.
Katherine A. Hajjar, M.D.
Cornell University Medical College
New York, NY 10021
References
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