Phase I study was conducted to evaluate the pharmacokinetics and safety of two dose levels of recombinant factor Vila (rF VIIa, NN-007) in two hemophilia A patients with inhibitor. The mean half-life of rF Vila was 2.5±0.5 hours. rF VIIa shortened the activated partial thromboplastin time (APTT) and the prothrombin time (PT). No adverse events were observed.
Phase III study was conducted to evaluate the safety, efficacy and also pharmacokinetics of rF VIIa in 17 hemophilia A or B patients with inhibitor. The mean half-life of rF VIIa was 2.6±0.5 hours. Both the APTT and the PT were significantly shortened by rF VIIa. In 407 bleeding episodes treated with rF VIIa the efficacy rate of hemostatic effect was 72.7%. No adverse events including laboratory or clinical DIC were observed during the study. There was no indication of new antibody formation against rF VIIa, BHK protein, murine IgG and bovine serum protein.
These results indicate that rF VIIa is safe and effective for the hemostatic management in hemophiliacs with inhibitor.

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The antithrombotic effects of low molecular weight heparin (LMWH) were evaluated in the experimental microvascular thrombosis model using the hamster cheek pouch and were compared to unfractionated heparin (UFH). The platelet-rich thrombus was produced in the venules by the irradiation of the filterd ultraviolet light in combination with the intravascular administration of fluorescein sodium. The antithrombotic activities of these agents were evaluated with respect to the time required for the initiation of thrombus formation (Ti: sec) and the time to stop the blood flow by thrombus (Ts: sec), together with anti-Xa activity (a-Xa: U/ml), anti-IIa activity (a-IIa: U/ml), PT, aPTT and bleeding time (BT: sec) immediately (0), 1 hour (1) and 2 hour (2) after the administration of LMWH or UFH (500 a-XaU/kg).
The values of Ti after administration of LMWH or UFH were (0) 122.5±27.8, 114.6±17.5, (1) 97.3±18.9, 87.1±16.8 and (2) 80.1±16.9, 63.2±9.5 (mean±SD) respectively. The values of Ts were (0) 757.2±137.3, 697.7±63.9, (1) 672.1±77.1, 516.1±64.5 and (2) 599.2±47.5, 429.6±54.8, respectively. The levels of a-Xa activity were (0) 0.98±0.05, 0.95±0.03, (1) 0.54±0.08, 0.23±0.12, and (2) 0.24±0.11, 0.08±0.12, respectively. Antithrombotic activity of LMWH was maintained longer than UFH. Significant correlation was found between the antithrombotic activity and a-Xa activity. Moreover, LMWH showed significantly less effect for prolongation of aPTT and BT than UFH.
From these results LMWH was suggested to be more beneficial than UFH in clinical use. And this microvascular thrombosis model will contribute to the evaluation of the antithrombotic effects of various agents in vivo.

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We studied the effects of nonenzymatic glycation on human α₂-plasmin inhibitor (α₂-PI) in vitro. Purified human α₂-PI (14.9μM/l) was incubated with glucose (55.5mM/l) at 37°C for 4 days. α₂-PI was significantly glycated, and then the activity of glycated α₂-PI decreased, while the levels of α₂-PI antigen did not change. The amount of complexes which were formed between glycated α₂-PI and plasmin (5.0U/ml) were less than that of control (control: 167.0-354.8nM/l, glycated α₂-PI: 25.2-105.4nM/l, p<0.01). α₂-PI formed a complex of molecular weight in the region of 170KD with plasmin revealed by SDS-PAGE analysis. However, glycated α₂-PI did not form a complex with plasmin. On crossed immunoelectrophoresis containing anti α₂-PI antiserum in the second dimension, plasmin-α₂-PI complex showed a major peak. On the contrary, glycated α₂-PI demonstrated two major peaks including the slow moving one. The results are indicating that a glycated α₂-PI is a form of non-binding for plasmin. Furthermore, when plasmin was added to the mixture of α₂-PI and LBS I (500μg/ml), the residual plasmin activity increased as the concentration of LBS I was increased. However, in case of glycated α₂-PI, LBS I had no effect on the residual plasmin activity. In addition, α₂-PI was similarly glycated by incubating with glucose and LBS I.
From these observations, it is suggested that nonenzymatic glycation causes a chemical modification of KBS (Kringle Binding Site) and ABS (Active Binding Site) of α₂-PI, and it is caused by poor formation of complex with plasmin and makes activity of α₂-PI decrease.

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An 8 years old Japanese boy born in non-sanguineous parents has been in good health until he was found to have macrothrombocytic thrombocytopenia when he developed purpura after common cold and ingestion of aspirin. His hearing ability and renal function were normal. He had no cataract. Hematological studies revealed normal hemoglobin, normal white cell counts with normal differentials and mild thrombocytopenia (94×10³/μl). Numerous giant platelets larger than red cells were identified on blood films. Döhle bodies and other inclusion bodies were not found in his neutrophils. The patient's platelet in platelet-rich plasma did not aggregate spontaneously and caused normal aggregation/agglutination in response to epinephrine, ADP, collagen and ristocetin, respectively. Major platelet membrane glycoproteins such as GPIa/IIa, Ib/IX, IIIa, and so on were indistinguishable from those of normal platelets. Clot retraction and coagulation studies were normal. However, calpain activity in the patient's platelets solubilized with 1% Triton X-100 was found to be 218.3% of that in platelets from normal control donors (n=6) when calculated per platelet and 135.7% of the controls when calculated per protein concentration. The patient's mother also showed moderate numbers of giant platelets and moderately increased activity of platelet calpain. Thus, the patient's platelets can not be classified into any congenital platelet disorder so far known and seem to be a new congenital disease in which giant platelets are associated with increased platelet calpain acitvity.

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