Factor V Leiden and Neonatal Intracranial Hemorrhage
ABSTRACT & COMMENTARY
Synopsis: Three newborns with clinical thrombosis or infarction were shown to have factor V leiden mutation. Those and other "hypercoagulable" states must be considered in instances of neonatal thrombosis.
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 adults1 and children.2
Thorarensen and associates 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 of age; 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).
COMMENT BY ROSARIO TRIFILETTI, MD, PhD
Although, as a rule, it is difficult to infer too much from a small case report, this paper has considerable merit. Clearly, factor V leiden must be considered in a variety of neonatal strokes, where bland, hemorrhage, or the punctate hemorrhage are often seen with periventricular leukomalacia. Sometimes, there is a family history of thrombotic diathesis that, 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. (Dr. Trifiletti is Assistant Professor of Pediatric Neurology, New York Hospital, Cornell Medical Center.) v
References
1. Ridker, et al. N Engl J Med 1995;330:517-522.
2. Sifontes, et al. J Pediatr 1996;128:324-328.
28. Which of the following is true regarding Factor V Leiden or Factor V Leiden trait?
a. Unlike "wild type" Factor V (seen in > 90% of the population), Factor V Leiden activates protein C.
b. It may predispose to bland or hemorrhagic infarctions in neonates.
c. Factor V Leiden trait is much less common than Protein C or Protein S deficiency.
d. All babies with Factor V Leiden and stroke have a strong family history of recurrent thrombosis.
e. Activated protein C cleaves Factor V Leiden but not "wild-type" Factor V.
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