Factor V Leiden and Neonatal Intracranial Hemorrhage

ABSTRACT & COMMENTARY
Source: Thorarensen O, et al. Factor V Leiden mutation: An unrecognized cause of hemiplegic cerebral palsy, neonatal stroke and placental thrombosis. Ann Neurol 1997;42: 372-375.

Recently, the factor v leiden trait has been shown to be an important risk factor for venous thrombosis in both adults (Ridker, et al. N Engl J Med 1995;330:517-522) and children (Silfontes, et al. J Pediatr 1996;128:324-328).

Thorarensen et al now report three neonates with Factor V Leiden deficiency presenting with a clinical picture of thrombosis or infarction. Case 1 was an infant with a bland focal infarction presenting as right hemiplegia first diagnosed at 6 months; in retrospect, a left hand preference was present since birth. The father had a history of deep vein thrombosis. Both patient and father were wild type (wt)/Leiden at the factor V locus. Case 2 was a term infant with a neonatal hemorrhagic infarction discovered on the third day of life. Both the baby and mother (who had no history of thrombotic or bleeding disorders) were wt/Leiden. Case 3 was a term infant who developed seizures on the first day of life. The patient was found to have hemorrhagic periventricular leukomalacia. The infant was found to be wt/Leiden. Placental exam revealed evidence of placental thrombosis.

Coagulation involves a delicate system of checks and balances between anti- and procoagulant proteins; Activated Protein C (APC) is an important anti-coagulant factor. APC, along with its cofactor Protein S, produces anti-coagulation by inactivating Va (factor V, activated) and VIIIa. The inactivation of Va by APC involves cleavage at a particular site in the Va protein. Deficiencies in the amount of circulating protein C and S have been well described in cases of venous thrombosis, but they are quite rare causes. Venous thrombosis is much more likely to be associated with a resistance of factor Va to protein C than with deficiencies in the amount of protein C or S.

Factor V Leiden is a variant form of Factor V seen in 2-6% of the population. In this protein variant, there is an arginine to glutamine mutation at the APC cleavage site. Thus, Factor V Leiden has normal procoagulant activity but cannot be inactivated by APC. "Factor V Leiden" patients are actually heterozygotes (wt/Leiden) at the factor V locus (i.e., approximately 50% of their factor Va is resistant to regulation by APC).

COMMENTARY

Although, as a rule, it is difficult to infer too much from a case study, this report has considerable merit. Clearly, Factor V Leiden must be considered in a variety of neonatal strokes, whether bland, hemorrhage, or the punctate hemorrhage often seen with periventricular leukomalacia. There is sometimes a family history of thrombotic diathesis which, when present, may increase the probability of a Factor V Leiden defect. Case 3 illustrates that placental thrombosis can occur in mothers with Factor V Leiden, making this a potential risk factor for periventricular leukomalacia, a condition that is thought to begin in utero during the third trimester. —rt