The newborn infant, because of the physiologic deficiency of various regulatory proteins, is particularly predisposed to both hemorrhage and thrombosis. For both anticoagulant proteins and most procoagulant factors, the more premature the infant, the greater the deficiency. The sick newborn infant is particularly at risk because interventions to provide support often include placement of large indwelling catheters into major veins or arteries. Those with hereditary deficiencies of anticoagulants may have major symptoms. After the neonatal period, young children seem to have some resistance to clinical thrombosis, even if they have a heterozygous hereditary deficiency of an anticoagulant protein. When a thrombus is identified in the young child, particularly when the family history is abnormal, a thrombotic evaluation should be initiated. In children and teenagers, thromboses are often triggered by major medical or surgical challenges.
A hereditary predisposition to thrombosis can be caused by deficiencies of the regulatory proteins protein C, protein S, antithrombin III, and plasminogen; synthesis of a procoagulant protein unable to be inhibited by its regulatory protein, factor V Leiden; elevated levels of procoagulant protein; prothrombin mutation (G20210A); and elevated levels of a toxic organic acid, homocystinemia.
The hereditary mutation of factor V, factor V Leiden, results in a factor V molecule that, when activated, is not subsequently inactivated by activated protein C. This leaves the patient with unregulated “active” factor V and so-called resistance to activated protein C. Furthermore, after proteolysis by activated protein C–inactivated factor Va (Vai) is a functional anticoagulant that inhibits clotting. Individuals with the prothrombin mutation (G20210A) have a mutation in the 3?-untranslated end of the messenger RNA for prothrombin that results in increased levels of prothrombin synthesis. Children with these hereditary mutations have an increased frequency of venous thrombosis.
Heterozygous deficiency of anticoagulant proteins, protein C, protein S, or antithrombin III, induces a tendency toward venous thromboembolic disease at an early age. The special case of neonatal purpura fulminans, characterized by necrotic purpura of the skin and thromboses of major vessels, is caused by homozygous protein C deficiency. Such infants were probably overlooked in the past because the symptoms were believed to be secondary to sepsis and disseminated intravascular coagulation. Because the newborn is physiologically deficient in protein C, its absence is difficult to determine, except in a laboratory that has established normal ranges for neonates and preterm infants. If an individual has undetectable levels of protein C, this is most likely a hereditary disorder. However, the physiologic deficiency of protein C in the newborn, coupled with true sepsis, may also lead to nearly undetectable levels of protein C.
There are no screening tests for a hereditary predisposition to thrombosis; thus, specific testing is required for protein C, protein S, antithrombin III, factor V Leiden, and prothrombin 20210. A careful family history may reveal thromboembolic diseases in family members at a young age, but the absence of a positive history does not rule out a hereditary predisposition to thrombosis.
Homozygous deficiency of protein C presents with purpura fulminans in the first few hr of life. Fresh frozen plasma (FFP) is the only immediately available source of protein C. Amelioration of symptoms usually requires 10–15 mL/kg of FFP every 8–12 hr. Clinical trials are in progress using a plasma protein C concentrate, which eliminates the need for large amounts of FFP. A recombinant activated protein C concentrate (drotrecogin-?) has been approved for the treatment of adult sepsis, but it has not been approved for treating hereditary deficiency. There are a few case reports wherein activated protein C concentrate has been successfully used to treat homozygous protein C deficiency. After the infant’s symptoms have improved, the amount of FFP or protein C concentrate is adjusted by monitoring of protein C levels. When the infant is beyond the neonatal period, high-dose warfarin (to achieve an INR of 3–5) may prevent most of the thrombotic problems, but acute intermittent thromboses require additional FFP or protein C concentrate