Prothrombin Deficiency Research Articles

Variable Manifestations of Severe Hypoprothrombinemia (Factor II Deficiency): 2 Cases

Case 1 is a 28 months female child, who has been symptomatic from 8 month of age with multiple, painful bruises over legs once in 5 to 6 weeks. Her complete blood picture was normal.PT and APTT were prolonged with normal fibrinogen and liver function. Case 2, became symptomatic from day 2 of life. He was treated for blood stained vomiting and black coloured stool and severe anaemia. Second episode was subdural hemorrhage and seizures. Investigations revealed abnormal PT and APTT with normal fibrinogen and liver function. Hereditary prothrombin deficiency is one of the rare congenital coagulation defect encountered in clinical practice. High index of suspicion is required to diagnose this condition with systematic approach as the facility to check factor 2 levels are not freely available in many centres. Bleeding manifestations are dependent on factor level. Children with severe deficiency are prone for life threatening bleeds. We report couple of children who had severe form of hereditary prothrombin deficiency with variable clinical manifestations. In both the cases, coagulation profile was suggestive of common pathway defect, PT and APTT were prolonged. Fibrinogen and Liver function tests were normal. No evidence of sepsis, no response to vitamin K. Further evaluation revealed low prothrombin activity (<1%). Factor v and x were normal.

Congenital Prothrombin Deficiency: An Update

Prothrombin (factor II [FII]) deficiency is a rare inherited coagulation disorder, having a prevalence of approximately 1 in 2,000,000. Two phenotypes can be distinguished: (1) true hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of the zymogen antigen; and (2) dysprothrombinemia (type II deficiency), characterized by the normal or near-normal synthesis of a dysfunctional protein. In the latter case, recent studies showed that particular mutations in the catalytic domain of active thrombin can even impair the enzyme interaction with antithrombin, favoring thromboembolic diseases. In some cases, hypoprothrombinemia associated with dysprothrombinemia was also described in compound heterozygous defects. Prothrombin is essential for the development of mammalian organisms. No living patient with undetectable plasma prothrombin has been reported to date. Prothrombin is encoded by a ≈21 kb gene located on chromosome 11 and containing 14 exons. Thirty-nine different mutations have been identified and characterized in prothrombin deficiency. Many of these are present in the catalytic site, whereas some involve regulatory domains, such as the anion-binding exosite I, the Na+-binding loop, and the light A-chain. Most hypoprothrombinemia-associated mutations are missense, but nonsense mutations leading to stop codons and one single nucleotide deletion have also been identified. Finally, recent developments in the therapy of congenital prothrombin deficiency are presented and discussed.

Two novel mutations in the prothrombin gene identified in a patient with compound heterozygous type 1/2 prothrombin deficiency

Two novel mutations in the prothrombin gene identified in a patient with compound heterozygous type 1/2 prothrombin deficiency

Trends in the Antiphospholipid Syndrome Criteria

Copyright: © 2013 Forastiero R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The Antiphospholipid Syndrome (APS) is an autoimmune disease characterized clinically by the occurrence of either venous or arterial thrombosis in different vascular beds, and/or recurrent miscarriages in the first trimester, or fetal death in the second or third trimesters, or severe pre-eclampsia requiring delivery of a premature infant before 34 weeks of gestation. Cerebrovascular infarction is the most common clinical feature within the arterial circulation, whereas lower limb deep venous thrombosis and pulmonary embolism are the main locations within the venous circulation [1]. The detection of persistently elevated levels of antiphospholipid antibodies (aPL) is a requisite laboratory feature for the diagnosis of APS. The positivity for at least one aPL test: lupus anticoagulant (LA) by clotting assays and/or IgG/IgM anticardiolipin (aCL) and/ or IgG/IgM anti-β2 glycoprotein I antibodies (aβ2GPI) by Enzyme-Linked Immunosorbent (ELISA) assays must be detected. aPL must be found on two or more occasions at least 12 weeks apart. In the 2006 updated APS criteria it is advised to classify APS patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, LA present alone; IIb, aCL present alone; IIc, aβ2GPI present alone [2]. aPL can occur in isolation or in association with other autoimmune conditions, particularly Systemic Lupus Erythematosus (SLE). The catastrophic APS is a rare variant of APS characterized by microthrombi in multiple organs. It is commonly triggered by several factors including infection, trauma, surgery, and the withdrawal of oral anticoagulation. Less than 1% of patients with the APS develop the catastrophic complication but it has a life-threatening clinical course. Sometimes aPL coagulopathy may start with a hemorrhagic syndrome when a severe thrombocytopenia, or an acquired thrombocytopathy, factor VIII inhibitor, or prothrombin deficiency is present.

Prophylactic administration of prothrombin complex concentrates for congenital prothrombin deficiency with a novel frameshift mutation, prothrombin saitama

Prothrombin (Factor II, FII) deficiency is an extremely rare autosomal recessive condition with an estimated incidence of 1:2 million. As severe and life-threatening bleeding is rare in FII deficiency, on demand therapy with administration of prothrombin complex concentrates (PCCs) or fresh frozen plasma is generally performed, and prophylactic therapy for FII deficiency has been reported in only three cases. Thus, its optimal dosage and schedule has remained uncertain. Here we report a case of severe prothrombin deficiency with a novel frameshift mutation of the F2 gene, who was started on prophylactic administration.

A 24-Year-Old Man with Previously Diagnosed Hemophilia

A 24-year-old Middle Eastern man diagnosed with hemophilia at the age of 4 or 5 years presented to the hematology clinic for follow-up after a recent hospitalization for excessive bleeding from an accidental knife cut. The patient reported a history of prolonged bleeding after teeth extractions, an upper gastrointestinal bleed 3 years previously, and excessive bruising since childhood. He denied hemarthroses but reported chronic pain in his ankles and joints. The patient reported having been treated for episodes of excessive bleeding with fresh frozen plasma (FFP)3 and factor VIII during past hospitalizations. Because of poor continuity of care, his disease had not been monitored or treated on an ongoing outpatient basis. The patient's family history is noteworthy for consanguineous parents (first cousins) and a sister who also experienced excessive bleeding, although her diagnosis was uncertain. Initial laboratory test results included a normal complete blood count, including platelets, a prolonged activated partial thromboplastin time (aPTT), and a prolonged prothrombin time (PT) (Table 1). Fibrinogen activity was normal. A 1:1 mixture of the patient's plasma with pooled normal plasma demonstrated full correction of the PT and aPTT, a result consistent with factor deficiency. View this table: Table 1. Patient's laboratory results (citrated plasma). ### ADDITIONAL PATIENT DATA AND DIFFERENTIAL DIAGNOSIS Patients with isolated hemophilia A, B, or C (due to deficiencies in factors VIII, IX, and XI, respectively) or factor VIII deficiency due to von Willebrand disease typically have a prolonged aPTT but a normal PT. In the absence of anticoagulation therapy or suspected vitamin K deficiency, a prolonged PT in this patient's initial workup should raise clinical suspicion for a bleeding disorder of a different etiology. Given the patient's clinically notable bleeding symptoms since childhood, a genetic disorder should be considered. The differential diagnosis includes dysfibrinogenemia, prothrombin deficiency, factor V deficiency, combined deficiency of factors V and VIII (F5F8D), factor X deficiency, and hereditary combined deficiency of …

Bleeding in the antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune disease characterized clinically by the occurrence of venous or arterial thrombosis, and/or pregnancy morbidity. The detection of persistently elevated levels of antiphospholipid antibodies (aPL) is a requisite laboratory feature for the diagnosis of APS. The positivity for at least one aPL test: lupus anticoagulant and/or IgG/IgM anticardiolipin and/ or IgG/IgM anti-β2glycoprotein I antibodies must be detected. Sometimes aPL coagulopathy may start with a hemorrhagic syndrome when a severe thrombocytopenia, or an acquired thrombocytopathy, or an acquired fator VIII inhibitor, or an acquired prothrombin deficiency is present. aPL-associated thrombocytopenia is usually moderate without clinical manifestations. Except in the occasional situations in which thrombocytopenia is associated with thrombotic microangiopathy, such as catastrophic APS, bleeding is uncommon in APS patients. When platelet counts are less than 30×109/L and there are symptoms of bleeding, the treatments used are the same for idiopathic thrombocytopenic purpura. In rare occasions a hemorrhagic diathesis due to the occurrence of non-neutralizing anti-prothrombin antibodies causing severe hypoprothrombinemia (HPT) can be observed. Levels of prothrombin in plasma are less than 10-20% in cases with HPT-related bleeding requiring transfusion and/or corticosteroid treatment. The APS mainly causes thrombosis, and pregnancy losses. However, other clinical manifestations are also associated with the presence of persistent autoimmune aPL. Bleeding is uncommon but can be the first clinical manifestation in patients having severe thrombocytopenia or prothrombin deficiency.

Prothrombin Mumbai causes severe prothrombin deficiency due to a novel Cys90Ser mutation

Dear Editor, Prothrombin (coagulation factor II) is a zymogen which is proteolytically cleaved to form its active derivative, thrombin, a serine protease, in the penultimate step of the coagulation cascade. The prothrombin gene is located on chromosome 11 (11p11-q12) [1]. Homozygous prothrombin deficiency is a rare autosomal recessive bleeding disorder occurring approximately in one of two million individuals. The Human Genome Mutation Database shows reports of only 32 mutations causing prothrombin deficiency [2]. The molecular basis is diverse, and mutations or polymorphisms in f2 gene are known to lead to both thrombosis and bleeding [3, 4]. A 5-month-old female child from Nepal, born of nonconsanguinous marriage, was referred with acute intracranial hemorrhage (Fig. 1a). Since birth, the baby had few episodes of bleeding ranging from hematemesis, umbilical stump bleed, and right-sided subdural hematoma. During these episodes, the baby was given an injection of vitamin K, fresh frozen plasma, and whole blood. Coagulation investigations done during these episodes showed consistently deranged prothrombin time (PT) and activated partial thromboplastin time (APTT); however, no reports of factor assays were available. Both the parents were clinically normal with neither any history of bleeding nor thrombosis during their life time. Blood samples of the patient and parents were collected in 3.2 % tri-sodium citrate after an informed consent. All the coagulation tests were performed in a semi-automated coagulometer using commercial reagents and calibrators (Diagnostica Stago, Asnieres, France). All the 14 exons and their flanking intronic regions were amplified using 12 sets of primers as described earlier [5]. The amplicons were sequenced using BigDye Terminator cycle sequencing kit in a ABI 3130XL genetic analyzer (Applied Biosystems, Foster City, CA, USA). The primary amino acid sequences of prothrombin from Homo sapiens (NC_000011.9), Pan troglodytes (NC_006478.2), Macaca mulatta (NC_007871.1), and Mus musculus (NC_000068.6) were obtained from NCBI gene [6]. Multiple sequence alignment was performed with ClustalW [7] to study the conservation of amino acids mutated by missense variations. Ensembl Genome Browser [8] was used to refer to the reported variations in the prothrombin gene. PolyPhen, Sorting Intolerant from Tolerant (SIFT), and Panther were used to predict the severity of the amino acid substitution on the protein function. The coagulation parameters of the patient were as follows: PT 27 s/control 14.5 s, APTT 40 s/control 29 s, thrombin time (TT) 18 s/control 15 s, fibrinogen 222 g/dL (normal range, 150–400 mg/dL). Mixing studies were normal for PT, APTT, and TT. Factor II (prothrombin) was found to be <1% on assay, with other factors being within normal limits. PCR amplification of all 14 exons followed by DNA sequencing in the patient showed a homozygous c.G269C variation in exon 4 of the patient. Both the parents were B. Kulkarni :K. Ghosh : S. Shetty (*) National Institute of Immunohaematology (I.C.M.R.), 13th floor, New building, K.E.M. Hospital Campus, Parel, Mumbai 400012, India e-mail: shrimatishetty@yahoo.com

A severe neonatal presentation of factor II deficiency

Prothrombin deficiency is an autosomal recessive disorder associated with moderate or severe bleeding tendency. In this study, a three-month-old boy with non-consanguineous parents was referred for convulsions because of intracerebral hemorrhage. Standard coagulation tests revealed that the patient's plasma prothrombin activity was 12%, while his father's and mother's levels were 55% and 70%, respectively. Analysis of the prothrombin gene revealed that this patient is a compound heterozygote for two missense mutations: one maternally inherited point mutation in the propeptide (p.Arg4Gln) and one paternally inherited mutation in the kringle-2 (p.Arg220Pro) domain. Structural analysis was performed and confirmed that the resulting mutations were inferred to respectively affect the cleavage of the propeptide from the Gla domain, and the stability of the kringle-2 domain, both resulting in a severe hypoprothrombinemia. In unusually bleeding newborn of non-consanguineous parents, rare severe homozygous bleeding disorders need to be considered to facilitate early diagnosis and treatment.

Pregnancy and rare bleeding disorders

Rare bleeding disorders include deficiency of fibrinogen, prothrombin, factor V, factor VII, factor X, factor XI and factor XIII together with combined deficiency disorders, factor V+VIII deficiency, and deficiency of the vitamin K-dependent factors (factor II, VII, IX and X). They account for 3-5% of all inherited coagulation disorders. Due to their rarity, information about pregnancy complications and management is limited and mostly derived from case reports. Deficiency of fibrinogen and FXIII are both found to be strongly associated with increased risk of recurrent miscarriage and placental abruption. Factor replacement is used to reduce these risks. However, the risk of miscarriage and ante-partum complications is less clear in women with other bleeding disorders. Haemostatic abnormalities in women with rare bleeding disorders seem to persist throughout pregnancy especially if the defect is severe. Therefore women affected with these disorders are at risk of post-partum haemorrhage. The fetus can also be affected and potentially at risk of bleeding complications. Specialised multidisciplinary management is essential to minimise the potential maternal and neonatal complications and ensure an optimal outcome. This paper presents literature review for pregnancy complications in each of the rare bleeding disorders. In addition general principles for management of pregnancy, labour and delivery are discussed.

Congenital Prothrombin Deficiency

Prothrombin deficiency is among the rarest inherited coagulation disorders, with a prevalence of approximately 1:2,000,000. Two main phenotypes can be distinguished: (1) hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen; and (2) dysprothrombinemia (type II deficiency), characterized by the normal or near-normal synthesis of a dysfunctional protein. In some cases, hypoprothrombinemia associated with dysprothrombinemia was also described in compound heterozygous defects. No living patient with undetectable plasma prothrombin has been reported to date. Prothrombin is encoded by a gene of approximately 21 kb located on chromosome 11 and containing 14 exons. Forty different mutations have been identified and characterized in prothrombin deficiency. Many of them surround the catalytic site, whereas another "hot spot" is localized in the recognition domain called anion binding exosite I, also called fibrinogen recognition site. Recently, mutations were identified also in the Na (+)-binding loop and in the light A-chain of thrombin. Most hypoprothrombinemia-associated mutations are missense, but there are also nonsense mutations leading to stop codons and one single nucleotide deletion. Finally, the main aspects of clinical manifestations and therapy of congenital prothrombin deficiency are presented and discussed.

The clinical significance of the lack of arterial or venous thrombosis in patients with congenital prothrombin or FX deficiency

Several reports have dealt with the occurrence of both arterial and venous thrombosis in patients with haemophilia A, haemophilia B, and von Willebrand disease. Similar thrombotic events have been occasionally reported also in rare congenital coagulation disorders, particularly in fibrinogen or FVII deficiencies. On the contrary no sure venous or arterial thrombotic event has ever been reported in congenital prothrombin or Factor X deficiency. The significance of this observation is discussed. This discrepancy cannot be explained on the basis of the rarity of the two conditions, since in similarly rare congenital bleeding disorders such as FV or FXIII deficiency a few patients with thrombosis have been described. It appears that only these two defects are able to allow a sure protection from thrombosis. These observations may indirectly support the rationale for the use of direct thrombin or Factor X inhibitors in the prophylaxis and/or therapy of thrombotic manifestations.

Genetic Elimination of Prothrombin in Adult Mice Results in Fatal Spontaneous Hemorrhage in the Heart and Central Nervous System

Thrombin-mediated proteolysis is central to hemostasis, directly controlling both platelet activation and fibrin deposition as well as positively- and negatively-regulating further thrombin generation through the activation of factors XI, VIII, V and protein C. Thrombin also appears to be important in multiple processes distinct from traditional hemostasis, but detailed genetics-based studies have been impeded by the uniform embryonic and perinatal failure of mice with constitutive prothrombin (fII) deficiency. To develop an experimental setting to explore the importance of fII in vascular biology, tissue repair, the inflammatory response and disease processes in adult animals, we have generated mice carrying a conditional prothrombin knockout allele (fIIlox). In the absence of Cre-mediated recombination, homozygous fIIlox/lox mice or compound heterozygous mice carrying one fIIlox allele and one constitutive-null allele were found to carry ~20% and ~10% the normal level of circulating prothrombin, respectively. These fIIlox/lox and fIIlox/− mice exhibited normal developmental and reproductive success, survived well into adulthood and young adults exhibited no appreciable spontaneous bleeding events or other pathologies. However, one-year-old fIIlox/− mice developed modest focal hemosiderin deposits and fibrosis within the heart, consistent with chronic low grade hemorrhage in this tissue. No gross or microscopic pathologies were observed in any other tissue examined in mice carrying an intact conditional knockout allele, regardless of age or gender. The induction of Cre recombinase in adult fIIlox mice using the poly I:C-inducible Mx1-Cre system resulted in the rapid and near-complete recombination of the fIIlox allele within the liver, loss of hepatic fII mRNA, elimination of detectable circulating prothrombin, and profound derangements in coagulation function. The life-expectancy in adults genetically-depleted of prothrombin was found to be very short (generally 5–7 days), and the loss of viability was associated with the development of severe hemorrhagic events within multiple tissues, most prominently in the heart (100% phenotypic penetrance) and brain (~50% phenotypic penetrance). Microscopic analysis of hearts from mice following deletion of the fII allele revealed widespread hemorrhage within the myocardium, particularly in the subepicardial region, focal ischemia and necrosis, neutrophil infiltrates and early granulation tissue. Gross evidence of blood was observed within the pleural cavity in nearly half of Cre-induced fIIlox/− mice at autopsy, and the lack of appreciable hemorrhage within lung tissue favored the heart as the source of this free blood. Less common hemorrhagic events were observed several other tissues, including skeletal muscle, intestines and testes. Examination of brains from mice lacking fII revealed widespread bleeding in the central nervous system, including dural-based hemorrhage and bleeding into both the brain parenchyma and ventricles. These results imply that a robust hemostatic system is essential to limit spontaneous bleeding events in tissues under repetitive mechanical or pulsatile stress. These findings also demonstrate that low levels of fII are compatible with long-term survival in adult mice, affording the ability to examine fII in a diverse spectrum of disease and physiologic processes. As evidence of this concept, mice lacking fII were challenged with S. aureus peritonitis prior to the onset of hemorrhage. Similar to mice lacking fibrinogen, these animals were found to have a profound deficit in their ability to control this infection, pointing to the need for polymerized fibrin for the effective clearance of this bacteria from the peritoneal cavity.

Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment

Prothrombin (factor II) deficiency is a rare autosomal recessive coagulation disorder that occurs in approximately 1 in 1-2 million people. Prothrombin is activated to thrombin, which in turn proteolytically cleaves fibrinogen to fibrin and contributes to forming a stable fibrin clot. The haemostatic level of prothrombin is thought to be between 20 and 40%, and the half-life is approximately 3 days. There are more than 40 known mutations in prothrombin. Both hypoprothrombinemia and dysprothrombinemia have been described. Low prothrombin activity typically prolongs both the activated partial thromboplastin time and prothrombin time. Clinical manifestations are predominantly mucosal or surgical- or trauma-associated bleeding, but joint bleeding and intracranial haemorrhages have been reported. No purified prothrombin products are available for replacement therapy. Both fresh frozen plasma and prothrombin complex concentrates contain prothrombin and may be used for treatment.

True Congenital Prothrombin Deficiency Due to a ‘New’ Mutation in the Pre-Propeptide (ARG-39 GLN)

True Congenital Prothrombin Deficiency Due to a ‘New’ Mutation in the Pre-Propeptide (ARG-39 GLN)

A natural variant with a point mutation resulting in a homozygous Arg to His substitution at position 388 in prothrombin

Prothrombin deficiency is probably the rarest inherited bleeding disorder with two phenotypes: (i) hypoprothrombinemia, with a concomitant decrease in prothrombin antigen and activity; (ii) dysprothrombinemia, with a decrease in prothrombin activity but normal or sub-normal antigen levels. Bleeding

Acquired prothrombin deficiency in a patient with follicular lymphoma

HaemophiliaVolume 14, Issue 3 p. 634-636 Acquired prothrombin deficiency in a patient with follicular lymphoma J. ALAMELU, J. ALAMELU The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, London, UKSearch for more papers by this authorA. McCORMICK, A. McCORMICK The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, London, UKSearch for more papers by this authorG. W. MOORE, G. W. MOORE The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, London, UKSearch for more papers by this authorB. MADAN, B. MADAN The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, London, UKSearch for more papers by this author J. ALAMELU, J. ALAMELU The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, London, UKSearch for more papers by this authorA. McCORMICK, A. McCORMICK The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, London, UKSearch for more papers by this authorG. W. MOORE, G. W. MOORE The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, London, UKSearch for more papers by this authorB. MADAN, B. MADAN The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, London, UKSearch for more papers by this author First published: 18 March 2008 https://doi.org/10.1111/j.1365-2516.2008.01671.xCitations: 2 Bella Madan, The Centre for Haemostasis and Thrombosis, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK.Tel.: +0207 1882794; fax: +0207 4013125;e-mail: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume14, Issue3May 2008Pages 634-636 RelatedInformation

Response to Girolami et al.

American Journal of HematologyVolume 83, Issue 6 p. 518-519 LetterFree Access Response to Girolami et al. Stephen Kling, Stephen Kling Division of Hematology, University of Utah Health Sciences Center, Salt Lake City, UtahSearch for more papers by this authorGeorge Rodgers, George Rodgers Division of Hematology, University of Utah Health Sciences Center, Salt Lake City, UtahSearch for more papers by this author Stephen Kling, Stephen Kling Division of Hematology, University of Utah Health Sciences Center, Salt Lake City, UtahSearch for more papers by this authorGeorge Rodgers, George Rodgers Division of Hematology, University of Utah Health Sciences Center, Salt Lake City, UtahSearch for more papers by this author First published: 13 February 2008 https://doi.org/10.1002/ajh.21169AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 Kling SJ,Jones KA,Rodgers GM. A second case of prothrombin Puerto Rico I in the United States. Am J Hematol 2007; 82: 661– 662. 2 Lefkowitz JB,Weller A,Nuss R, et al. A common mutation, Arg457-->Gln, links prothrombin deficiencies in the Puerto Rican population. J Thromb Haemost 2003; 1: 2381– 2388. 3 Wu W,Bancroft JD,Suttie JW. Structural features of the kringle domain determine the intracellular degradation of under-γ-carboxylated prothrombin: studies of chimeric rat/human prothrombin. Proc Natl Acad Sci USA 1997; 94: 13654– 13660. 4 Kotkow KJ,Deitcher SR,Furie B,Furie BC. The second kringle domain of prothrombin promotes factor Va-mediated prothrombin activation by prothrombinase. J Biol Chem 1995; 270: 4551– 4557. 5Prothrombin deficiency, 2008. CEINGE—Biotecnologie Avanzate. 23 January 2008 <http://www.ceinge.unina.it/index.php?option=com_content&task=view&id=60&Itemid=26&lang=en>. Volume83, Issue6June 2008Pages 518-519 ReferencesRelatedInformation

Mutations are no substitutes for clotting, chromogenic and immunological assays in patients with congenital prothrombin deficiency

Mutations are no substitutes for clotting, chromogenic and immunological assays in patients with congenital prothrombin deficiency

A second case of prothrombin puerto rico I in the united states

Prothrombin deficiency is a very rare autosomal recessive bleeding disorder associated with mild to severe bleeding symptoms. We identified this bleeding disorder in a US-born patient as due to prothrombin Puerto Rico I. Unlike other prothrombin deficiencies, prothrombin Puerto Rico I is a series of concordant polymorphisms found in people of Puerto Rican descent with a much higher frequency than those prothrombin deficiencies found in the general population. This case underscores the importance of family history in identifying rare bleeding disorders.