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Vol. 20: Fall 2002

Genetic Considerations in Thrombotic Disorders

Fetal and Neonatal Effects of Maternal/Fetal Thrombotic Disorders

The effects of hereditary thrombotic disorders on the developing fetus have not been recognized until recently. Current evidence indicates that maternal/fetal thrombotic disorders play a role in the pathogenesis of several neonatal/pediatric conditions. Maternal (hereditary) thrombophilia has also been implicated as a cause of late and recurrent fetal loss.

Thrombophilia As a Cause of Fetal/Neonatal Disorders

Central nervous system defects

Cerebral palsy is one of the most common and debilitating conditions of childhood. Over 300,000 children in the U.S. are affected with this disorder, and in most cases a causal event is not identified. With the advancement of magnetic resonance scanning and other forms of cranial imaging, a subgroup of patients with cerebral palsy have been diagnosed with cerebral infarction, either due to arterial infarction (middle cerebral artery) or cerebral venous thrombosis. Neonatal stroke may be an incompletely ascertained cause of cerebral palsy, mental retardation, seizures, and pediatric death (Curry et al. 2000). Current estimates indicate that ischemic accidents occur rarely in the pediatric population, with an incidence of 2.5/100,000, while the incidence of neonatal stroke ranges from 0.63-1.2/100,000. Approximately 25% of ischemic cerebrovascular disease in children is due to cerebral venous thrombosis. While many risk factors have been associated with the development of stroke, including congenital heart disease, vascular abnormalities, shock, dehydration, sepsis, and metabolic disorders, in an estimated 30% of cases no specific cause can be identified.

Several recent studies provide evidence that genetic thrombotic disorders are significant risk factors for neonatal stroke. Among these disorders are two newly identified genetic mutations in the clotting factor cascade. In 1994, the most common cause of hereditary venous thrombosis in adults was found to be a point mutation in the factor V gene, called the factor V Leiden mutation. Also called Arg506Gln or R506Q, this causes an arginine to glutamine substitution at position 506 in the cleavage site for activated protein C, and thereby reducing the rate of inactivation of factor V. Factor V Leiden has estimated prevalence of 3-5% among the Caucasian population. The second recently identified gene variant is a polymorphism in the 3’ untranslated region of the prothrombin gene (factor II), a G to A transition at position 20210, called the prothrombin G 20210 A variant, or P-G20210a-V. This causes an elevated level of prothrombin and a nearly 3-fold increased risk of venous thrombosis in adults.

Mercuri et al.. (2001) studied twenty-four infants with perinatal cerebral infarction confirmed by MRI scan and screened for several thrombotic disorders. Twenty-two of these patients had an infarction of the middle cerebral artery, and two had watershed infarctions. Laboratory evaluations included prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen, and vonWillebrand factor antigen. The prothrombotic screen consisted of factor VIIIc, protein C, protein S, and antithrombin. Two DNA mutations, the factor V Leiden mutation and the prothrombin 20210 (G® A transition at position 20210 of the prothrombin gene) were analyzed as well via polymerase chain reaction (PCR). Results were abnormal in 10/24 (42%) of the patients. These included 6 patients with increased factor VIIIc and 5 with heterozygous factor V Leiden. (One patient had both abnormalities.) Parental studies were available for 4/5 children with factor V Leiden, and in all four one parent was heterozygous for this mutation. Of the 6 patients with elevated factor VIIIc, parental studies were normal in 10/11 parents studied. An additional association was found between clinical outcome and abnormal thrombotic profile. In 8/11 (73%) of patients with hemiplegia or developmental delay, an abnormality in the thrombotic profile was detected, compared to 2/13 with normal outcomes who had an abnormal thrombotic profile.

There was a significant association between factor V Leiden and the presence of hemiplegia (Fischer’s exact test, p=.003). All 5 children with factor V Leiden had hemiplegia compared to only 4/20 without this mutation. In addition there was a much higher prevalence of factor V Leiden in this cohort (24%) than in the normal population, estimated to be 2.7-10% in Europe and North America. These results have been confirmed by other studies, including that of Zenz et al. (1998), who studied 33 Austrian children with ischemic stroke and found an 18% incidence of factor V Leiden mutation. This result exceeded the expected prevalence in the Austrian population of 4.6% (Fischer’s exact test p=.001). Curry et al. (2000) looked at 27 patients with neonatal stroke and found 53% had one or more abnormalities in mother, child, or both. The highest frequency was that of prothrombin G20210A, found in 3 children, 2 with factor V Leiden, and 2 with MTHFR homozygosity. In 46% of mothers an abnormality was found, most commonly 6 with anticardiolipin antibodies, 4 with MTHFR heterozygosity, and 3 with factor V Leiden.

Gunther et al. (2000) looked at the role of genetic and acquired prothrombotic risk factors in symptomatic stroke in 91 full term neonates in a multi-center case-control study in Germany. A total of 62 stroke patients had one or more genetic prothrombotic risk factors compared to the healthy age-matched controls (Fischer’s exact test p <.001). Most significant among these was lipoprotein (a) level > 30mg/dl, found in 20 patients (22%) compared to 10 controls (5.5%) (p <.001). Factor V Leiden was again found to be more common among stroke patients than controls (17 vs. 10, p = .0016), and protein C deficiency was found in 6 additional patients. These results were in contrast to those of Zenz et al., who found factor V Leiden to be the most significant risk factor. The authors cited differences in study design and the small number of cases as causes for the discrepancy. This report also looked at additional triggering factors including asphyxia, neonatal septicemia, patient foramen ovale, maternal diabetes, antenatal renal venous thrombosis, and fibromuscular dysplasia. Forty-nine patients had an additional triggering factor; most frequently identified were perinatally acquired asphyxia, neonatal septicemia, and patent foramen ovale. Of this subgroup, 33 had at least one prothrombotic risk factor. The role of thrombotic risk factors has also been studied as a cause of stroke due to cerebral venous thrombosis in children. Carvalho et al.. (2001) retrospectively studied 31 patients with cerebral venous thrombosis, including 19 neonates (61.2% of the total). Clinical risk factors were found in 14, including persistent pulmonary hypertension, congenital heart disease, dehydration, meningitis, sepsis, and central nervous system tumor. Radiographic studies showed that 9 had superior sagittal thrombosis, 3 had sigmoid/transverse sinus thrombosis, and 7 had multiple sinus thrombosis. The clinical presentation in these neonates was generally nonspecific with symptoms such as seizures, fever, respiratory distress lethargy, and decreased oral intake. Eleven of 19 (58%) neonates had stroke; 7 were hemorrhagic and 4 were ischemic. Neurological outcome was also assessed in all 19 patients. Eleven were developmentally delayed, one had a learning disability, and 5 showed no deficits. There were two deaths. Prothrombotic risk factor analysis was performed on 14 patients (although the study does not indicate the percentage of neonates versus pediatric patients). Of this subgroup, 7 (50%) had protein C deficiency, 5 (35) had antithrombin III deficiency, 3 (33%) had factor V Leiden, 2 had protein S deficiency (14%), and 1 (13%) had antiphospholipid antibodies (13%). The authors concluded that the frequency of prothrombotic risk factors in their patients with cerebral venous thrombosis indicates that all of these patients, even in the presence of obvious clinical risk factors, should undergo coagulation evaluation.

Finally, Debus et al. (1998) found evidence to suggest that factor V Leiden is also a risk factor in the development of antenatal porencephaly. Among 24 infants with porencephaly, they found 16 with abnormalities of protein C, protein S, factor V Leiden or lipoprotein (a). Three patients had more than one risk factor.

Limb defects

The relationship between genetic thrombotic disorders and other types of congenital anomalies has not been as thoroughly investigated. One recent study found some evidence that there is an excess of thrombophilic disorders in families with a child with a terminal limb defect, and that they may play a role in the etiology of these limb malformations. Hunter (2000) studied 24 mother-child pairs in which the child had a terminal transverse limb defect, ranging from the phalanges up to the elbow/knee, or had Poland anomaly. He looked at an extensive panel of prothrombotic risk factors, including proteins C and S, antithrombin III, factor V Leiden, prothrombin G20210A, lipoprotein (a), homocysteine, maternal anticardiolipin IgG and IgM, and 5,10-methylenetetrahydrofolate reductase (MTHFR), heterozygote and homozygote. (A cytosine to thymine substitution at position 677 in the MTHFR gene [MTHFR C677T] affects MTHFR, the primary methyl donor in the conversion of homocysteine to methionine and results in an elevated plasma homocysteine level.) His results showed an increased frequency over expected in 6 different prothrombotic factors, with statistically significant increases for protein S (maternal and child) and maternal anticardiolipin IgG. The author noted that, while the patient numbers are small, the patients with protein C or S deficiency had transverse defects, typically with "nubbins of distal tissue," while 2 of the 3 children born to mothers with elevated anticardiolipin IgG had Poland anomaly.

Although this is only preliminary evidence that thrombophilic disorders play a role in the etiology of limb defects, there are numerous reports in the medical literature citing evidence of a vascular pathogenesis for these types of anomalies. Postulated mechanisms have included subclavian artery supply disruption sequence (SADS), twin-embolization-sequence, in utero trauma, partial placental separation as a complication of chorionic villus sampling, and homozygous alpha-thalassemia causing hypoxia. Hunter also postulates that the fetus may be susceptible to maternal thrombotic risk factors, which are not actually inherited by the fetus, but may cause abnormal levels through placental transfer, or by clot or embolus formation at the placental interface.

Maternal Thrombophia As a Cause of Recurrent Fetal Loss

While the risk of early miscarriage is common in pregnancy, with an incidence approximately 1 in every 10 pregnancies, fetal loss after 20 weeks gestation is less frequent, occurring in 1 in every 200 pregnancies. Placental insufficiency is frequently cited as the cause, and is known to be associated with maternal thrombophilic conditions predisposing to thromboembolism, including antithrombin III deficiency, protein C and S deficiencies, and antiphospholipid-antibody syndrome. Several recent studies have also pointed to the genetic variants of the prothrombotic factors discussed above as risk factors for late fetal loss. The factor V Leiden mutation has been associated with third-trimester fetal loss, as well as first and second trimester losses. Women with the MTHFR C677T variant have also been shown to be at an increased risk for late fetal loss, as well as various for obstetrical complications such as preeclampsia, abruptio placentae, and intrauterine growth retardation.

Martinelli et al. (2000) studied 67 women with a first episode of late fetal loss (after 20 weeks gestation) and 232 women with one or more pregnancies and no late fetal losses. They found eleven of the 67 women (16%) and 13 of the 232 control women (6%) had either factor V Leiden or prothrombin G20210A mutation. The relative risks of late fetal loss for these women were 3.2 for the factor V Leiden and 3.3 for the prothrombin G20210A (95%confidence interval, 1.0-10.9 and 1.1 -10.3, respectively). Thirteen percent of the women in the late fetal loss group and 20% of the control women had the MTHFR C677T mutation, for a relative risk of 0.8 (95% confidence interval, 0.5-1.2). They concluded that both the factor V Leiden and prothrombin G20210A mutations carry a 3-fold increased risk of late fetal loss.


Recent evidence points to maternal/fetal thrombotic (thrombophilic) disorders as a cause of both neonatal/antenatal disorders of the central nervous system including neonatal stroke, central venous thrombosis, and porencephaly, They may also play an unrecognized role in some cases of cerebral palsy. In addition, these genetic disorders are also implicated as causes of terminal limb malformations and late fetal loss as well as other pregnancy complications. Future studies may implicate this group of disorders in additional types of congenital malformations. A complete laboratory evaluation for these disorders, for both mother and baby, as outlined below, is indicated in cases of neonatal stroke, central venous thrombosis, late fetal loss, and should be considered in patients with unexplained cerebral palsy.

Suggested laboratory testing for suspected maternal/fetal thrombotic disorders both mother and child or fetus should be tested.

Protein S
Protein C
Antithrombin III
Factor V Leiden
Prothrombin G20210A
Lipoprotein (a)
Anticardiolipin IgG/IgM (maternal)


Carvahlo KS, Bodensteiner JB, Connolly PJ, Garg BP. Cerebral venous thrombosis in children. J Child Neurol 2001. 16(8):574-80.Curry CJ, Holmes J, Catts ZA et al.. Hypercoagulable factors in pregnancy loss and neonatal stroke. Proc Greenwood Gen Ctr 2001. 20:92-3. Gunther G, Junker R, Strater R, Schobess R, Kurnik K, Heller C, Kosch A, Nowak-Gottl U. Symptomatic ischemic stroke in full-term neonates: role of acquired and genetic prothrombotic risk factors. Stroke 2000. 31(10):2437-41.Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, Bozzo M, Mannucci PM. Mutations in coagulation factors in women with unexplained late fetal loss. NEJM 2000. 343(14):1015-1018.Mercuri E, Cowan F, Gupte G, Manning R, Laffan M, Rutherford M, Edwards AD, Dubowitz L, Roberts I. Prothrombotic disorders and abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction. Pediatrics 2001 107(6):100-4.

Zenz W, Bodo Z, Plotho J, Streif, W, Male C, Bernert G, Rauter L, Ebetsberger G, Kaltenbrunner K, Kurnik P, Lischka A, Paky F, Ploier R, Hofler G, Mannhalter C, Muntean W. Factor V Leiden and prothrombin gene G 20120 A variant in children with ischemic stroke. Thromb Haemost. 1998 80(5):763-6.

Contributed by Terri A. Grebe, M.D (AZ)

Genetic Considerations in Thrombotic Disorders
Table of Contents

Adult Thrombotic Disorders
Pediatric Thrombotic Disorders
Fetal and Neonatal Effects of Maternal/Fetal Thrombotic Disorders
Teratogen Hot Topic: Anticoagulants
Heterozygote Counseling for Factor V Leiden mutation


Bob McCurdy