MedGen

Miscarriage, the commonest complication of pregnancy, is the spontaneous loss of a pregnancy before the fetus has reached viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation. Recurrent miscarriage, defined as 3 or more consecutive pregnancy losses, affects about 1% of couples; when defined as 2 or more losses, the scale of the problem increases to 5% of all couples trying to conceive (summary by Rai and Regan, 2006). Pregnancy losses have traditionally been designated 'spontaneous abortions' if they occur before 20 weeks' gestation and 'stillbirths' if they occur after 20 weeks. Subtypes of spontaneous abortions can be further distinguished on the basis of embryonic development and include anembryonic loss in the first 5 weeks after conception (so-called 'blighted ovum'), embryonic loss from 6 to 9 weeks' gestation, and fetal loss from 10 weeks' gestation through the remainder of the pregnancy. These distinctions are important because the causes of pregnancy loss vary over gestational ages, with anembryonic losses being more likely to be associated with chromosomal abnormalities, for example. Possible etiologies for recurrent pregnancy loss include uterine anatomic abnormalities, cytogenetic abnormalities in the parents or fetus, single gene disorders, thrombophilic conditions, and immunologic or endocrine factors as well as environmental or infectious agents (summary by Warren and Silver, 2008). [from OMIM]

Prothrombin thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism. The clinical expression of prothrombin thrombophilia is variable; many individuals heterozygous or homozygous for the 20210G>A F2 variant never develop thrombosis, and while most heterozygotes who develop thrombotic complications remain asymptomatic until adulthood, some have recurrent thromboembolism before age 30 years. The relative risk for DVT in adults heterozygous for the 20210G>A variant is two- to fivefold increased; in children, the relative risk for thrombosis is three- to fourfold increased. Heterozygosity for 20210G>A has at most a modest effect on recurrence risk after a first episode. Although prothrombin thrombophilia may increase the risk for pregnancy loss, its association with preeclampsia and other complications of pregnancy such as intrauterine growth restriction and placental abruption remains controversial. Factors that predispose to thrombosis in prothrombin thrombophilia include: the number of 20210G>A alleles; presence of coexisting genetic abnormalities including factor V Leiden; and acquired thrombophilic disorders (e.g., antiphospholipid antibodies). Circumstantial risk factors for thrombosis include pregnancy and oral contraceptive use. Some evidence suggests that the risk for VTE in 20210G>A heterozygotes increases after air travel. [from GeneReviews]

A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. It is said to be the third leading cause of death in the United States. Gunel and Lifton (1996) noted that about 20% of strokes are hemorrhagic, resulting in bleeding into the brain. Ischemic strokes, resulting from vascular occlusion, account for the majority of strokes. Bersano et al. (2008) reviewed genetic polymorphisms that have been implicated in the development of stroke. Candidate genes include those involved in hemostasis (see, e.g., F5; 612309), the renin-angiotensin-aldosterone system (see, e.g., ACE; 106180), homocysteine (see, e.g., MTHFR; 607093), and lipoprotein metabolism (see, e.g., APOE; 107741). See also hemorrhagic stroke, or intracerebral hemorrhage (ICH; 614519). [from OMIM]

Prothrombin deficiency is an extremely rare autosomal recessive bleeding disorder characterized by low levels of circulating prothrombin; it affects about 1 in 2,000,000 individuals. There are 2 main types: type I deficiency, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia. Type II deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein. Bleeding symptoms are more variable, depending on the amount of residual functional activity. Variant prothrombin gene alleles can result in 'hypoprothrombinemia' or 'dysprothrombinemia,' and individuals who are compound heterozygous for these 2 types of alleles have variable manifestations. Heterozygous mutation carriers, who have plasma levels between 40 and 60% of normal, are usually asymptomatic, but can show bleeding after tooth extraction or surgical procedures (review by Lancellotti and De Cristofaro, 2009). [from OMIM]