Effect of CV-4151, a thromboxane A₂ synthase inhibitor, on antithrombotic and thrombolytic agents-induced bleeding time prolongation was examined in rats. CV-4151, ticlopidine, ozagrel and warfarin singly at doses greater than 0.3, 300, 1 and 0.5mg/kg, p. o. respectively, significantly prolonged bleeding time. Aspirin (10mg/kg, p. o.) also prolonged bleeding time. Tissue-type plasminogen activator (TPA, 2×10⁴ IU/kg/min i. v. infusion) and urokinase (UK, 4×10⁴IU/kg/min i. v. infusion) showed significant prolongation of bleeding time. Prologing effect of CV-4151 on bleeding time was weaker than those of warfarin and thrombolytic agents.
In combined experiments with CV-4151 and other agents, CV-4151 moderately enhanced ticlopidine-induced bleeding time prolongation, and markedly enhanced warfarin-, TPA-and UK-induced bleeding time prolongation. On the other hand, CV-4151 had no effect on aspirin-induced bleeding time prolongation.
Thus, CV-4151 markedly enhanced bleeding time prolongation caused by an oral anticoagulant and thrombolytic agents in rats.

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Continuous intravenous infusion of factor VIII (FVIII) concentrate has been reported to be effective and safe to achieve a stable plasma level of FVIII activity as well as reduction of FVIII consumption. We have used continuous infusion of a monoclonal-antibody purified FVIII concentrate (M-FVIII) for the treatment of 6 patients with hemophilia A, 5 of whom underwent major surgery and 1 with subcortical cerebral hemorrhage. The age of the patients were ranged from 16 to 68. Duration of continuous infusion was 3 to 27 days. In vitro study of the FVIII activity in the M-FVIII showed that it retained over 80% of initial FVIII activity for the period of 24 hours at room temperature in a plastic syringe. The patients required bolus shot of 63.4±29.4U/kg followed by 4.25±1.49U/kg/hr continuous infusion to keep the initial plasma factor VIII level of 100% that result in 102.3±19.0% of actual activity in the plasma of over 2 hours after starting the infusion. Subsequently, dose of continuous infusion was reduced stepwise so that the achieved plasma level of FVIII gradually decreased to 60% in 7 to 10 days after the operation, followed by bolus infusion. All the patients showed excellent hemostasis with no remarkable adverse reactions during and after the operation. 28% of the total dose of M-FVIII was reduced as compared with theoretical dose of bolus infusion of twice a day for the first 3 days. We conclude that the use of continuous infusion of M-FVIII is practical and effective replacement therapy especially for hospitalized patients with hemophilia A for elective surgery.

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Advances in molecular biology have improved the screening for carriers and the prenatal diagnosis of many genetic disorders, including hemophilia B. For instance, based on the eight described dimorphic restriction fragment length polymorphisms within the factor IX gene, a Caucasian female has a 94% chance of being heterozygous (informative) for at least one of these markers. However, ethnic limitations of molecular genetic techniques have been found in diagnosing hemophilia B families in the Japanese and other populations. Previously, we heve demonstrated that three dinucleotide polymorphisms, which locate in the 5' flanking region at nucleotide-793 (FIX-793), in intron A at nucleotide 192 (FIX192), and in the 3' flanking region (FIXHhaI), of the factor IX gene, are present in normal Japanese. Each of these polymorphisms was able to be rapidly ascertained by the polymerase chain reaction technique.
In this study, we analyzed 23 Japanese families with hemophilia B, and found that 19 families (82.6%) were heterozygous for at least one of these polymorphisms. Using these polymorphisms together with the extragenic DXS99/Sac I PFLP, which was previously reported as a useful gene marker for Japanese hemophilia B, the informative rate impproved to 87.0%. Carrier detection and the prenatal diagnosis of hemophilia B can be achieved effectively and rapidly in Japanese with these polymorphisms. In fact, we have successfully performed the prenatal diagnosis in two Japanese families with hemophilia B by using FIXHhaI or FIX192 polymorphism analysis. These polymorphisms may also be present and useful for hemophilia B carrier detection in other Oriental population.

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We report a missense mutation of protein C (PC) gene in a family with type II congenital. PC deficiency. The proband was a 17-year-old high school student with deep venous thrombosis and pulmonary embolism. Hemostatic examinations revealed normal amidolytic activity and PC antigen level measured by a chromogenic snake venom assay and an EIA utilizing a polyclonal antibody, respectively. However, anticoagulant activity measured by the activated partial thromboplastin time method and immunological antigen level estimated by a monoclonal antibody recognizing the Ca²⁺-dependent conformational change were reduced. Two other members. of this family (father and paternal grand-mother) showed the identical defect, but they had been asymptomatic. The functional abnormalities were most likely to be due to alternation in the Gla domain. Subsequently, a polymerase chain reaction (PCR) strategy and an allele-specific oligonucleotide (ASO) hybridization were used to evaluate exon 3 of the PC gene. Sequence analysis following amplification of exon 3 and its flanking regions showed a single G to A transition, resulting in the conversion of Glu²⁶ codon (GAG) to Lys²⁶ codon (AAG). Since this missense mutation generated no new restriction site, the PCR-amplified exon 3 fragments from this family member were hybridized with ASOs corresponding to the normal and mutated sequences. An identical mutation was detected in the affected family members of the proband by the ASO hybridization. These data indicate that conversion of the Glu²⁶ codon (GAG) to Lys²⁶ codon (AAG) was responsible for the type II congenital PC deficiency inherited in this Japanese family.

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A 27-year-old man had been diagnosed as Evans syndrome (ITP+immune hemolytic anemia) at the age of 17 and treated with prednisolone, to which he became refractory. Splenectomy at the age of 24 failed to maintain normal platelet counts after a year. One and half years after the splenectomy, he was admitted because of ecchymoses, macroscopic hematuria and serious thrombocytopenia (3×10³/μl). Pulse therapy with methyl-prednisolone (m-PSL) (1.0g/day for 3 days) rapidly increased platelet counts to 105×10³/μl and improved hematuria. However, one week later, platelet counts again decreased to 3×10³/μl and the patient complained of serious colicky abdominal pains. Colonoscopy showed moderate colitis. The same m-PSL pulse therapy was again administrated, which increased platelet counts to 149×10³/μl but gave no effect on the abdominal pains. His blood levels of factor XIII antigen and activity were abnormally low (both 40% of normals). Based on a presumptive diagnosis of Schönlein-Henoch purpura, treatment with i. v. Factor XIII (Fibrogammin P, 6A/day) for 5 days dramatically improved abdominal pains. His platelet counts gradually decreased but he did not complain of an abdominal pain. Thereafter, the patient had another two attacks of colicky pains associated with abnormally decreased Factor XIII that were successfully treated with Fibrogammin.

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