Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 33297000; ORPHA: 325; DO: 2235;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p11.2 | Dysprothrombinemia | 613679 | Autosomal recessive | 3 | F2 | 176930 |
| 11p11.2 | Hypoprothrombinemia | 613679 | Autosomal recessive | 3 | F2 | 176930 |
A number sign (#) is used with this entry because congenital prothrombin deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding coagulation factor II, also known as prothrombin (F2; 176930), on chromosome 11p11.
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 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.
Shapiro et al. (1969) reported a large kindred in which 11 individuals had normal immunoreactive prothrombin antigen, but half-normal biologic prothrombin activity, consistent with dysprothrombinemia. They referred to the defective molecule as prothrombin Cardeza.
Shapiro et al. (1974) discussed 3 prothrombin variants--Barcelona (176930.0002), Cardeza, and San Juan. They presented evidence that San Juan is in fact an example of a genetic compound, i.e., the parents were heterozygous for different prothrombin variants. Prothrombin Barcelona appeared to be an example of mutation at the cleavage site between the 'pro' and 'thrombin' parts of the molecule (Rabiet et al., 1979).
In an editorial on variants of vitamin K-dependent coagulation factors, Bertina et al. (1979) stated that 9 defective variants of factor II (F2), 5 variants of factor X (F10; 613872), and many variants of factor IX (F9; 300746) had been identified.
Board et al. (1982) referenced the functionally abnormal prothrombins that had been reported, noting that functional abnormality was more likely to occur with a mutation affecting the enzymatically active part of the molecule or at sites where activated factor X either splits off the initial profragment or activates the thrombin molecule.
Inomoto et al. (1987) stated that only 16 prothrombin variants leading to congenital dysprothrombinemia had been reported. All dysprothrombinemia variants were characterized by a decrease in the functional level of prothrombin relative to the antigenic level of prothrombin. Five of the prothrombin variants had been purified and characterized. Prothrombin Barcelona (176930.0002) and prothrombin Madrid were found to have specific impairment of 1 of the 2 factor Xa-catalyzed cleavages, whereas prothrombin Quick (176930.0004; 176930.0005), prothrombin Metz, and prothrombin Salakta had a defect confined to the thrombin portion of the molecule. Inomoto et al. (1987) described the first case of dysprothrombinemia in Japan; the prothrombin variant Tokushima (176930.0003) also had a defect in the thrombin portion. The patient was a compound heterozygote; the mother had a dysprothrombinemia allele and the father had a hypoprothrombinemia allele (176930.0008).
Valls-de-Ruiz et al. (1987) described a Mexican Mestizo family in which a mother and all 3 of her children had a functionally normal but structurally abnormal prothrombin variant, termed 'Mexico City.' Laboratory studies showed an abnormal cleavage of the prothrombin molecule by factor Xa, despite a functionally normal thrombin molecule. The family also had multiple exostoses (133700), which was molecularly unrelated to the prothrombin variant.
Josso et al. (1962) reported 2 affected offspring with hypoprothrombinemia who were born of first-cousins, suggesting autosomal recessive inheritance.
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).
Akhavan, S., Mannucci, P. M., Lak, M., Mancuso, G., Mazzucconi, M. G., Rocino, A., Jenkins, P. V., Perkins, S. J. Identification and three-dimensional structural analysis of nine novel mutations in patients with prothrombin deficiency. Thromb. Haemost. 84: 989-997, 2000. [PubMed: 11154146]
Bertina, R. M., Briet, E., Veltkamp, J. J. Variants of vitamin K dependent coagulation factors. (Editorial) Acta Haemat. 62: 1-3, 1979.
Board, P. G., Coggan, M., Pidcock, M. E. Genetic heterogeneity of human prothrombin (FII). Ann. Hum. Genet. 46: 1-9, 1982. [PubMed: 7103409] [Full Text: https://doi.org/10.1111/j.1469-1809.1982.tb00689.x]
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Girolami, A. The hereditary transmission of congenital 'true' hypoprothrombinaemia. Brit. J. Haemat. 21: 695-704, 1971. [PubMed: 5132950]
Girolami, A., Bareggi, G., Brunetti, A., Sticchi, A. Prothrombin Padua: a new congenital dysprothrombinemia. J. Lab. Clin. Med. 84: 654-666, 1974. [PubMed: 4283787]
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Inomoto, T., Shirakami, A., Kawauchi, S., Shigekiyo, T., Saito, S., Miyoshi, K., Morita, T., Iwanaga, S. Prothrombin Tokushima: characterization of dysfunctional thrombin derived from a variant of human prothrombin. Blood 69: 565-569, 1987. [PubMed: 3801671]
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Josso, F., Monasterio De Sanchez, J., Lavergne, J. M., Menache, D., Soulier, J. P. Congenital abnormality of the prothrombin molecule (factor II) in four siblings: prothrombin Barcelona. Blood 38: 9-16, 1971. [PubMed: 4997605]
Josso, F., Rio, Y., Beguin, S. A new variant of human prothrombin: prothrombin Metz, demonstration in a family showing double heterozygosity for congenital hypoprothrombinemia and dysprothrombinemia. Haemostasis 12: 309-316, 1982. [PubMed: 7152370] [Full Text: https://doi.org/10.1159/000214689]
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Lefkowitz, J. B., Haver, T., Clarke, S., Jacobson, L., Weller, A., Nuss, R., Manco-Johnson, M., Hathaway, W. E. The prothrombin Denver patient has two different prothrombin point mutations resulting in glu300-to-lys and glu309-to-lys substitutions. Brit. J. Haemat. 108: 182-187, 2000. [PubMed: 10651742] [Full Text: https://doi.org/10.1046/j.1365-2141.2000.01810.x]
Lutze, G., Frick, U., Topfer, G., Urbahn, H. Hereditaere Dysprothrombinaemie mit geringer Blutungsneigung (Prothrombin Magdeburg). Dtsch. Med. Wschr. 114: 288-292, 1989. [PubMed: 2920673] [Full Text: https://doi.org/10.1055/s-2008-1066590]
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Montgomery, R. R., Corrigan, J. J., Clarke, S., Johnson, J. Prothrombin Denver: a new dysprothrombinemia. (Abstract) Circulation 62 (suppl. III): 279 only, 1980.
Morishita, E., Saito, M., Kumabashiri, I., Asakura, H., Matsuda, T., Yamaguchi, K. Prothrombin Himi: a compound heterozygote for two dysfunctional prothrombin molecules (met-337-to-thr and arg-388-to-his). Blood 80: 2275-2280, 1992. [PubMed: 1421398]
Owen, C. A., Jr., Henriksen, R. A., McDuffie, F. C., Mann, K. G. Prothrombin Quick: a newly identified dysprothrombinemia. Mayo Clin. Proc. 53: 29-33, 1978. [PubMed: 625142]
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Rabiet, M.-J., Elion, J., Benarous, R., Labie, D., Josso, F. Activation of prothrombin Barcelona: evidence for active high molecular weight intermediates. Biochim. Biophys. Acta 584: 66-75, 1979. [PubMed: 444582] [Full Text: https://doi.org/10.1016/0304-4165(79)90236-8]
Rabiet, M. J., Jandrot-Perrus, M., Boissel, J. P., Elion, J., Josso, F. Thrombin Metz: characterization of the dysfunctional thrombin derived from a variant of human prothrombin. Blood 63: 927-934, 1984. [PubMed: 6546700]
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Smith, L. G., Coone, L. A. H., Kitchens, C. S. Prothrombin Gainesville: a dysprothrombinemia in a pair of identical twins. Am. J. Hemat. 11: 223-231, 1981. [PubMed: 7198379] [Full Text: https://doi.org/10.1002/ajh.2830110302]
Valls-de-Ruiz, M., Ruiz-Arguelles, A., Ruiz-Arguelles, G. J., Ambriz, R. Prothrombin 'Mexico City,' an asymptomatic autosomal dominant prothrombin variant. Am. J. Hemat. 24: 229-240, 1987. [PubMed: 3826054] [Full Text: https://doi.org/10.1002/ajh.2830240302]
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Weinger, R. S., Rudy, C., Moake, J. L., Olson, J. D., Cimo, P. L. Prothrombin Houston: a dysprothrombin identifiable by crossed immunoelectrofocusing and abnormal Echis carinatus venom activation. Blood 55: 811-816, 1980. [PubMed: 7362870]