Blood, 1 November 2001, Vol. 98, No. 9, pp. 2875-2875
CORRESPONDENCE
To the editor:
Factor V Leiden and intracranial hemorrhage
The prevalence of factor V Leiden (FVL) in people of northern
and central European descent suggests that FVL bestowed a survival advantage on those populations. In the study by Corral et al, the
presence of FVL reduced the risk of spontaneous intracranial hemorrhage
by 5-fold.1 Specifically, FVL protected against hemorrhagic transformation of ischemic events associated with artherosclerotic cerebrovascular disease in subjects with a mean age of
66.4 years. Although this finding is of interest, it seems unlikely
that this advantage led to the persistence of FVL in European
populations. There is no apparent survival advantage, biologically
speaking, to protecting elders from hemorrhagic stroke. It is more
plausible that this allele protected those of childbearing potential.
Today, acquired hemorrhagic disease is uncommon in young people.
However, it is likely that hemorrhagic disease of the newborn (HDN) was
prevalent thousands of years ago, contributing significantly to
neonatal mortality. HDN is caused by vitamin K deficiency, a common
condition in neonates even today,2 and can result in
life-threatening intracranial hemorrhage. Therefore, one could hypothesize that FVL is prevalent in certain populations because it
lessens the severity of HDN. It is possible that clinically significant
vitamin K deficiency was more common thousands of years ago because
food sources rich in vitamin K were not available year-round and
breast-feeding, which is a significant risk factor for HDN, was more common.
The hemostatic system of the neonate is such that the presence of FVL
could result in enhanced thrombin generation because of the limited
capacity of both the antithrombin and the protein C pathways.
Significant vitamin K deficiency could further enhance this effect. In
the neonate, levels of procoagulant and anticoagulant vitamin
K-dependent proteins are low.3 In the healthy neonate, a
balance is maintained, making bleeding and thrombotic complications uncommon. With worsening vitamin K deficiency, this balance is lost in
favor of bleeding. The presence of factor V Leiden could prevent the
loss of this fine balance by attenuating the protein C pathway.
The study by Corral et al is important in that it lends evidence to the
notion that there is benefit to having factor V Leiden. However,
for a polymorphism associated with disease to persist in a
population, the net effect must favor survival of those most likely to
procreate. Nonetheless, the hypothesis that FVL protects against fatal
intracranial hemorrhage in neonates with HDN would be difficult
to prove; therefore, the elder population with cerebrovascular disease
will have to suffice as an acceptable experimental model.
J. Nathan Hagstrom
Correspondence: J. N. Hagstrom, Hematology-Oncology,
Connecticut Children's Medical Center, 282 Washington St, Hartford, CT
References
1.
Corral J, Iniesta JA, González-Conejero R, Villalón M, Vicente V.
Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage.
Blood.
2001;97:2979-2982[Abstract/Free Full Text].
2.
Bovill EG, Soll RF, Lynch M, et al.
Vitamin K1 metabolism and the production of des-carboxy prothrombin and protein C in the term and premature neonate.
Blood.
1993;81:77-83[Abstract/Free Full Text].
3.
Andrew M, Paes B, Milner R, et al.
Development of the human coagulation system in the full-term infant.
Blood.
1987;70:165-172[Abstract/Free Full Text].
