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 ... 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).
Quick and Hussey (1962) described congenital hypoprothrombinemia. In a patient reported by Quick and Hussey (1962), Lanchantin et al. (1968) found no identifiable prothrombin protein, consistent with true deficiency or hypoprothrombinemia. This finding was distinct from a related ... Quick and Hussey (1962) described congenital hypoprothrombinemia. In a patient reported by Quick and Hussey (1962), Lanchantin et al. (1968) found no identifiable prothrombin protein, consistent with true deficiency or hypoprothrombinemia. This finding was distinct from a related disorder, dysprothrombinemia, in which a biologically dysfunctional protein can been detected by immunoassay. Poort et al. (1994) reported a family with congenital prothrombin deficiency and severe bleeding. Clinical features included epistaxis and soft tissue, muscle, and joint bleedings in all, and severe menorrhagia in the 2 women. Laboratory studies of the proband showed factor II activity of about 2% and antigen levels of about 5% of normal controls, consistent with hypoprothrombinemia. Rubio et al. (1983) reported a 5-year-old Cuban girl who presented with umbilical bleeding after birth, followed by easy bruising and bleeding tendency throughout her life. Laboratory studies showed prolonged prothrombin and partial thromboplastin times. Prothrombin activity was less than 10% of normal, but immunologic studies showed about 50% protein levels. Family studies showed that the father had approximately 50% prothrombin activity and antigen, whereas the mother had 45% prothrombin activity and almost 100% prothrombin antigen. Rubio et al. (1983) concluded that the girl was compound heterozygous for a true prothrombin deficiency allele inherited from the father and for an abnormal dysprothrombinemia allele inherited from the mother. The hypoprothrombinemia allele was called prothrombin Habana. Rocha et al. (1986) reported a 21-year-old Spanish man, born of consanguineous parents, who presented simultaneously with hemarthrosis of the left knee and an extensive hematoma following a minor trauma. Prothrombin time and activated partial thromboplastin time were prolonged. Prothrombin activity was very low (range 7 to 23% by various methods), whereas antigen levels were low-normal (64%), consistent with dysprothrombinemia. Both parents had about 50% reduced prothrombin activity. The variant, which showed an abnormal band on immunodiffusion, was termed prothrombin Segovia. Rocha et al. (1986) stated that only 15 families with structural abnormalities of prothrombin had been described. Dumont et al. (1987) described a newborn girl with congenital dysprothrombinemia who presented severe bleeding from the second day of life. Routine coagulation tests showed very prolonged prothrombin time and activated partial thromboplastin time, with prothrombin activity ranging from 2 to 35%. The prothrombin antigen level was 47% and showed abnormal migration on immunoelectrophoresis. Tests of thrombin generation showed that the abnormal prothrombin was slowly and incompletely activated. Family studies showed both the abnormal and normal prothrombin in the father, mother, and brother. The proposita was thought to be homozygous for a 'lazy' dysprothrombin, termed prothrombin Poissy. Lutze et al. (1989) described a family in which 7 members in 3 generations had an abnormal prothrombin. Five of the 7 persons had a slightly increased bleeding tendency manifested especially in more marked or prolonged posttraumatic and postoperative bleeding. Laboratory studies showed decreased clotting activity compared to antigen levels. The variant was referred to as prothrombin Magdeburg.
In affected members of a family with congenital prothrombin deficiency, Poort et al. (1994) identified a homozygous mutation in the F2 gene (Y44C; 176930.0014).
The allelic variants causing dysprothrombinemia are usually indicated according to the city ... In affected members of a family with congenital prothrombin deficiency, Poort et al. (1994) identified a homozygous mutation in the F2 gene (Y44C; 176930.0014). The allelic variants causing dysprothrombinemia are usually indicated according to the city or area where they were described for the first time: see, e.g., prothrombin Barcelona (176930.0002) and prothrombin Tokushima (176930.0003). The abnormalities are usually caused by a defect in activation of the protease, such as prothrombin Barcelona, or a defect in the protease itself, such as prothrombin Quick (176930.0004; 176930.0005) and prothrombin Tokushima (reviews by Girolami et al., 1998 and Lancellotti and De Cristofaro, 2009). Montgomery et al. (1980) described a form of dysprothrombinemia that they referred to as prothrombin Denver. The proband had a severe hemophilia-like bleeding disorder treated with weekly prophylactic factor replacement. Lefkowitz et al. (2000) found that the patient was a compound heterozygote for 2 mutations in the F2 gene: glu300-to-lys (E300K; 176930.0010 and E309K; 176930.0011). In an Iranian girl with a mild form of dysprothrombinemia characterized sporadic ecchymosis and 1 episode of buttock hematoma following a major trauma, Akhavan et al. (2000) identified a homozygous substitution in the prothrombin gene (R382H; 176930.0012).