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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., (Copyright © 2012 Wiley Periodicals, Inc.)

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis. The anticoagulant management of APS thrombosis remains controversial. Few reports on markers of in vivo activation of coagulation have been reported. To determine whether plasma levels of prothrombin fragment 1 + 2 (F1 +2) correlate with thrombotic risk and treatment effect in patients with APS, plasma F1 + 2 levels were followed in 57 patients with this syndrome for more than 2 years. Clinical findings were also observed in these patients. Plasma levels of F1 + 2 in patients with APS were significantly higher when compared with control subjects (p<.05). These results suggest patients with APS are in a hypercoagulable state. Plasma levels of F1 + 2 significantly decreased following treatment with either aspirin, or aspirin plus warfarin (p<.05 and p<.01, respectively). Recurrent thromboses or spontaneous abortions occurred in all eight patients whose plasma levels of F1 + 2 remained higher than 1 nmol/l after treatment with either aspirin alone or no anticoagulants. These patients were subsequently treated with warfarin as well as aspirin, and plasma levels of F1 + 2 decreased to less than 1 nmol/l, with no additional thrombotic events over the remainder of the 2-year follow-up. No fatal bleeding was observed in treated patients. Our results suggest plasma levels of F1 + 2 are useful indicators of successful treatment. It is also suggested that warfarin plus mini-dose aspirin therapy is effective for patients with APS to protect from recurrent thromboses without harmful side effects. Further, prospective cohort studies are needed to substantiate these associations.

Plasma levels of prothrombin fragment F 1 + 2 (PTF) and thrombin-antithrombin III complex (TAT) were assayed in 86 cases of disseminated intravascular coagulation (DIC). A significant elevation of both parameters was observed in most cases of DIC, which suggested that the in vivo generation of thrombin is highly accelerated by the cleavage of the prothrombin molecule by factor Xa. On the contrary, no significant elevation of plasma levels of PTF was observed in cases of DIC with severe hepatic failure or fulminant hepatitis in spite of significant elevation of TAT. Plasma levels of PTF were directly proportional to those of TAT in 86 cases of DIC as a whole (r = 0.682, p < 0.001). The measurement of both parameters was considered to be useful to estimate the hemostatic activation in DIC.

A congenitally dysfunctional form of prothrombin, Prothrombin Himi, shows reduced fibrinogen clotting activity, although it retains full hydrolytic activity toward synthetic substrates. To elucidate the structural abnormality of the variant prothrombin, we first performed genetic analysis of dysprothrombin. Polymerase chain reaction amplification of the exons 8 through 14 of the proband and her family members' prothrombin genes, which code the thrombin moiety, followed by single-strand conformation polymorphism analysis, identified two variant conformers in exon 10 specific to this family. One variant allele detected in the father was inherited by the proband and one of her sisters, and the other detected in the mother was also inherited by them. This result indicates that the proband has two different base pair changes in the gene. Sequencing showed two novel point mutations in the proband's gene. One is a T to C transition at position 8751, resulting in the substitution of threonine for methionine at codon 337 (Thrombin Himi I). The other is a G to A transition at 8904, resulting in the substitution of histidine for arginine at codon 388 (Thrombin Himi II). By sequencing analysis of her parents, it was determined that Thrombin Himi I was inherited from the father and Thrombin Himi II from the mother. These results confirm that Prothrombin Himi is compound heterozygous for two dysfunctional prothrombin molecules.

It is well known that atrial fibrillation (AF) is one of the most important diseases that predispose patients to thrombosis. We have attempted to identify patients with AF in the hypercoagulable state by measuring molecular markers such as thrombin-antithrombin III complex (TAT) and prothrombin fragment 1 + 2 (PTF) and determining the effect of antithrombotic therapy on these markers; 83 patients with AF were studied. Increased levels of plasma TAT and PTF were more frequently observed in patients with AF and associated mitral stenosis than in patients with AF alone. In cases of AF without mitral stenosis, plasma levels of TAT and PTF were significantly lower in those patients receiving antithrombotic agents (aspirin or warfarin) than in those receiving no antithrombotic agents. Furthermore, plasma levels of PTF were significantly lower in patients given warfarin than in those receiving aspirin. These results suggest that (1) patients with AF and mitral stenosis who are not given warfarin are in an extremely hypercoagulable state and (2) some patients with AF without mitral stenosis who are not given antithrombotic agents are also moderately hypercoagulable. In vivo activation of blood coagulation was more effectively controlled in patients receiving warfarin than in those taking aspirin.

An abnormal prothrombin has been detected in a 26-year-old female, who had no history of excessive bleeding. Prothrombin activity was approximately 10% when measured using either the classical one-stage assay or the assay with Echis carinatus venom, whereas prothrombin antigen level was normal. In keeping with current nomenclature practices, the abnormal prothrombin was designated "Prothrombin Himi". The electrophoretic behavior and calcium binding properties of Prothrombin Himi did not differ significantly from normal. Prothrombin Himi was isolated by chromatography on Q-Sepharose. Electrophoretic migration of the purified abnormal prothrombin on SDS-PAGE was normal. Upon prothrombin activation by Echis carinatus venom, the clotting activity produced from Prothrombin Himi was only 37% of the normal level after 90 minutes of the activation time, where as the amidolytic activity was almost the same as normal. The cleavage patterns of Prothrombin Himi by factor Xa or Echis carinatus venom investigated by SDS-PAGE, were found to be normal. These results indicate that Prothrombin Himi was characterized by a defective thrombin enzymatic activity.

. Acquired factor XIII (FXIII) deficiency due to an autoantibody against FXIII is a very rare, yet potentially life-threatening bleeding disorder. As the standard coagulation tests (prothrombin time and activated partial thromboplastin time) are normal, the specialized tests are required to make an accurate diagnosis. Here, we report a case of acquired FXIII deficiency with severe bleeding symptoms. A 75-year-old man was referred to our hospital because of severe bleeding tendency after a tooth extraction. Laboratory findings showed that routine coagulation studies were normal, but factor XIII (FXIII) activity was low (3%). The presence of FXIII inhibitor was detected with dot blotting studies. Although the bleeding tendency was very severe, it was successfully controlled by infusion of FXIII concentrates combined with immunosuppressive treatment (oral prednisolone). Fibrin cross-linking study showed the significant delay of the γ-chain dimer and α-chain polymer formation. Western blotting revealed the marked decrease in FXIII-A level. The mixing study of FXIII activity measured using amine-incorporation assay showed the incomplete inhibition pattern. There seems to be little agreement as to the treatment strategy of acquired FXIII deficiency. In this patient, the use of FXIII concentrates was very useful in the initial treatment of bleeding symptom. The use of steroids was also effective in increasing FXIII activity without any serious complications. [ABSTRACT FROM AUTHOR]