The inherited bleeding disorder first described by von Willebrand in 1926 is now known to include several types characterized by all or some of the followings: a prolonged bleeding time, a reduced platelet adhesion to glass beads and to connective tissue, a defective ristocetin-induced platelet aggregation (RIPA), and a decreased level of factor VIII-coagulant activity (VIII:C), factor VIII-related antigen (VIII R:AG) and ristocetin cofactor activity (VIII R:RC). It has been recognized that these abnormal findings are caused by qualitative and quantitative defects of factor VIII/von Willebrand factor protein (F VIII/vWF), i. e., a complex of factor VIII-related polymer (VIII R) and factor VIII-coagulant protein (VIII:C).
This paper described a brief review of current knowledge of von Willebrand's disease. Based on the mode of inheritance and clinical findings, the disease may be divided into two main states; homozygous disease and heterozygous disease. The former is inherited from both parents and clinically severe. All the F VIII/vWF-related activities are extremely reduced. The latter is inherited in an autosomal dominant manner and clinically less severe. This latter form of the disease appears to be heterogeneous. On the basis of the structure-function relationship of F VIII/vWF, it can be divided into two main categories; classical form (type I) and variant form (type II). In type I, there is a quantitative defect of F VIII/vWF. Reductions in VII:C, VIII R:AG and VIII R:RC are concordant, but SDS gel electrophoretic analysis revealed all kinds of VIII R multimer. On the other hand, type II is characterized by qualitative abnormalities of F VIII/vWF. The level of VIII R:RC is lower disproportionately to that of VIII:C or VIII R:RG. The large multimers of VIII R are absent or reduced. The patients with type II are further subdivided into at least four groups based on the behavior of RIPA and analysis of VIII R multimer series. In type II A, RIPA is defective and the concentration of smallest multimer increased. Type II B is characterized by increased RIPA which is caused by the abnormality of VIII R multimer in plasma. Recently, a bleeding disorder resembling type II B is reported as ‘pseudo-von Willebrand's disease’ or platelet-type von Willebrand's disease, because the basic defect is considered to exist in platelets. Another new variant of von Willebrand's disease (II C) was reported by Ruggeri et al. (1982). This disorder is characterized by a repeating doublet unit of each multimer, in contrast to the repeating triplet unit seen in normal subjects and in patients with II A and II B variants. Thus, some possibility still remains that additional variant forms might be observed by further studies of function and structure of F VIII/vWF in patients with von Willebrand's disease.

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Incidence and severity of thromboembolism (T. E.) associated with various types of valve prostheses were surveyed. A total of 576 patients who survived 1 month or longer after isolated mitral valve replacement was divided into three groups depending on flow characteristics of valve prosthesis implanted Group I had the lateral flow type valves, such as Starr-Edwards ball valve and SAM valve (85 cases); Group II had semi-central flow type valves of tilting disc prostheses (345 cases) and Group III had central flow type valve of porcine bioprostheses (146 cases). Severity of T. E. was classified as follows; I° when symptoms were improved within 1 month after onset, II° when they persisted 1 month or longer, and III° when T. E. caused fatality. T. E. occurred in 40 patients among the 576 operative survivors (6.9%). Incidence was highest in group I (16/85, 18.8%; 2.9%/patient-year). By contrast, both of groups II and III showed equally low incidence; that is, 16/345, 4.6%; 1.2%/pt-yr in group II and 11/146, 7.5%; 1.8%/pt-yr in group III. Prognosis of T. E, was poorest in group I in which 8 patients showed II° and the remaining 8 were in III°. Symptoms and prognosis of T. E. were milder in group III than in group II. None of the group III was subjected to fatal cerebral embolism, while two patients of group II were lost due to massive brain infarction.
These results suggest that the flow characteristics of the valve prosthesis is importantly involved not only in incidence but also in severity of thromboembolism following mitral valve replacement.

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Effects of lysine, 6-aminohexanoic acid (=EACA), tranexamic acid (t-AMCHA) on fibrinolysis and complement systems were studied. 50% inhibition of fibrinolysis was at 10^-6M of t-AMCHA, and 10^-5M of EACA, and 100% inhibition was 5×10^-5M of t-AMCHA, and at 10^-3M of EACA. The enhancement of UK-activation of Glu-plasminogen began at 10^-5M (peak at 10^-3M) of t-AMCHA, and at 10^-5M (peak at 10^-2M) of EACA. The curve of the emission of fluorescence had its peak at 10^-3M of t-AMCHA, and 10^-2M of EACA. Both t-AMCHA and EACA showed a competitive inhibition of UK. Lysine inhibited the activation of Cl at low ionic strength and at the interaction with sensitized erythrocytes at lower concentration than t-AMCHA or EACA.

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Effects of positively charged cationized ferritin (CF) on platelet aggregation have been examined in rabbit or human gel-filtered platelets under electron microscopy. Rabbit or human gel-filtered platelets were exposed to CF in a platelet aggregometer and fixed to obtain electron microscopic specimens. Five second after the addition of CF, rabbit gel-filtered platelets showed discoidal form and cluster formations of CF particles on the surface of platelets were observed. Afterward, platelets showed spheroidal form with pseudopods, and were aggregated each other through the connection of surface-located CF particles 1min after the addition of CF. At 3min, platelet aggregates increased in size and numerous CF particles were located in the inter-platelet spaces in the central region of aggregates. In the periphery of aggregates, CF particles on the surface decreased in number. Similar changes were also observed in human gel-filtered platelets. Platelet aggregation induced by CF observed using a lumi-aggregometer showed a biphasic aggregation curve in which ATP-release occured in the secondary wave. The secondary aggregation curve was inhibited by either PGE₁, PGI₂, aspirin, NEM or apyrase. Heparin which has negative charge prevented the initial aggregation. Therefore, it is suggested that the change of surface nagative charge of platelets might participate in the triggering mechanism of platelet aggregation.

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A morphometric analysis of platelets from 5 patients with primary thrombocythemia (PT) was performed with a manual optical picture analyzing system. We have measured the platelet profile area, the number of dense granule (dg) and atypical dense granule (d'g: organelles with a very electron dense granular and/or reticular structure), and also examined the platelet volume with the coulter counter channelyzer and the platelet functions. In this study, parameters were platelet counts, mean platelet area (MPA: total platelet area/total platelet number) and frequency of dg and d'g (F. DG: number/platelet area 100cm²).
The change of MPA including pseudopods showed parallel with the platelet volume measured with the coulter counter channelyzer. F. DG in all patients with PT was increased independently of aspirin ingestion, and MPA was increased in PT without aspirin ingestion. These findings were the common features of myeloproliferative disorders. There were a tendency of positive correlationship between F. DG and platelet counts, and a tendency of negative correlationship between F. DG and MPA, however, no correlationship platelet functions and F. DG. The effects of aspirin ingestion seemed to be the decrease of the platelet volume and the increase of F. DG.

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The time-sequential relationships between Ca²⁺ fluxes and phospholipid metabolism have been examined in activated human platelets. Thrombin-activation caused a marked acceleration of ⁴⁵Ca²⁺ influx and a decrease in extracellular Ca²⁺ concentration measured by murexide dye, which occurred in pallalel with the accumulation of phosphatidic acid (PA). The incorporated ⁴⁵Ca²⁺ was found mainly in cytosolic fraction. The influx of Ca²⁺ was observed to precede to the onset of lysophospholipids formation and subsequent liberation of arachidonic acid. These data provide evidence that PA. generated upon platelet activation, may serve as a calcium ionophore.

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We have previously reported that the actin gelation inhibitor, derived from platelets is a protein of MW 90, 000.
By affinity chromatogaphy in the presence of 0.1mM CaCl₂, a protein of MW 20, 000 was obtained in addition to the gelation inhibitor (MW 90, 000) and actin (MW 45, 000). As the protein of MW 20, 000 was gel-electrophoresised in accordance with brain calmodulin in the presence of EGTA or CaCl₂, it was thought to be calmodulin. But in the presence of CaCl₂, the brain calmodulin could not activate the gelation inhibitor activity. On the other hand when, in the presence of EGTA, the sample containg the gelation inhibitor was mixed with [³H] calmodulin and then chromatographied by Sephacryl S-200gel filtration, the radioactivity of the isotope of calmodulin was detected in accordance with the protein peak of the sample. These results suggest the possibility that the actin gelation inhibitor binds to calmodulin in the presence of EGTA, not in the presence of CaCl₂.

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Interaction of platelet and vessel wall is one of the most important problems on the development of thrombotic disorder, and from the aspect of arachidonic acid metabolism, whether the platelet PG endoperoxides may be utilized as a substrate for PGI₂ biosynthesis in vessel wall has been a point of discussion. This paper reports the possible mechanism of conversion of platelet PG endoperoxides to PGI₂ synthesis in cyclo-oxygenase inhibited aortic ring. Aortic ring and Acetyl Salicylic Acid (ASA)-treated aortic ring were incubated with plateletpoor plasma (PPP), platelet-rich plasma (PRP), or OKY-1581, a thromboxane A₂ (TXA₂) synthetase inhibitor, treated PRP. TXA₂ and PGI₂ were measured by RIA as TXB₂ and 6-keto-PGF_1α respectively. There was no increase of PGI₂ synthesis in the intact aortic ring, when the platelet TXA₂ synthesis was inhibited by OKY, however the increased PGI₂ synthesis was observed in ASA-treated aortic ring. Marked increase of PGI₂ synthesis was observed in ASA-treated aortic ring with the existence of OKY-treated PRP. Arterial microsome also significantly increased PGI₂ synthesis in OKY-treated PRP comparing with PPP or PRP. When ASA-treated aortic ring was incubated with PGH₂, PGI₂ synthesis was significantly increased, while there was a little PGI₂ synthesis, when it was incubated without PGH₂ as control. These results indicate the possible salvage pathway for PGI₂ synthesis from PG endoperoxides of the platelet in cyclo-oxygenase inhibited aortic ring.

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Human platelet aggregation induced by arachidonic acid (AA, 800μM) and collagen (1μg/ml) was inhibited completely by 400μM of eicosapentaenoic acid (EPA). The acid also inhibited the secondary phase of ADP-induced (3μM) aggregation at the dose, but did not affect the primary phase of that up to 1.6mM. These results consisted with the inhibitory effects of EPA on the biosynthesis of PG endoperoxide by sheep seminal vesicle microsomes and that of thromboxane (TX) A₂ by horse platelet microsomes, which both were bioassayed as rabbit aorta contracting activities.
The PGH₂-induced (0.8-3.2μM) aggregation and the release reaction, measured as the ATP release, were not inhibited by indomethacin (IND 25μM) and OKY-1581 (10μM). EPA significantly inhibited the PGH₂-induced (1.6μM) aggregation at 100μM, but did not abolish it even at 800μM. These results suggest that PGH₂ itself can induce the aggregation without conversion to TXA₂ and the inhibitory effect of EPA on the PGH₂-induced aggregation cannot be explained by the inhibition of TXA₂ synthetase. TXA₂ induced biphasic aggregation; a primary phase was reversible and not affected by IND, although a secondary phase was irreversible and inhibited by IND. The release reaction was also biphasic. EPA completely inhibited the secondary phase at 100μM, and gradually inhibited the primary phase at higher than 200μM.
These results suggest that EPA not only inhibit the AA metabolism, but also affect the action of the AA metabolites on human platelets.

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Effects of a new PGI₂ derivative, OP-41483, [5(E)-6, 9-deoxa-6, 9α-methylene-15-cyclopentyl-16, 17, 18, 19, 20-pentanor-PGI₂] on platelet functions and experimentally induced thrombosis were studied. In in vitro, OP-41483 inhibited ADP-induced aggregation of human, rhesus monkey and guinea-pig PRP, and their IC₅₀ were 2.4, 2.1 and 6.2ng/ml, respectively. The relative activity of OP-41483 to PGI₂ and carbacyclin were 1/5-1/7 and 3.5-11, respectively. An intravenous infusion of OP-41483 at doses higher than 300ng/kg/min caused reduction of platelet adhesiveness in guinea-pigs. OP-41483 also inhibited ADP-induced platelet aggregation and thrombus formation induced by electrical stimulation of mesenteric artery in guinea-pigs. Anti-platelet and antithrombotic activities of intravenously infused OP-41483 were 1/3 and 1-3 times more potent than PGI₂ and carbacyclin, respectively. An oral administration of OP-41483 at doses higher than 1mg/kg inhibited platelet adhesiveness in guineapigs, but PGI₂ and carbacyclin did not inhibit at 10mg/kg. The maximum inhibition by OP-41483 was observed at 30min after the administration and the effect was lasted for 3hr. Platelet aggregation and thrombus formation of mesenteric artery in guinea-pigs were also inhibited by OP-41483 at the doses higher than 1mg/kg, p. o. In rabbit extracorporeal shunt model, intravenous infusion of OP-41483 at 30-300ng/kg/min inhibited the reduction of platelet count, hematocrit and fibrinogen in circulating blood. OP-41483 also reduced the thrombus volume in the shunt. Thus, OP-41483 may be a potentially useful drug for thrombotic diseases.

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The effect of OP-41483, 15-cyclopentyl-ω-pentanor-5E-6, 9-methano-PGI₂ on platelet aggregation and thrombus formation on subendothelium was studied.
Extracorporeal circulation in rabbits was carried out with a perfusion chamber containing everted segment of de-endothelialyzed rabbit aorta. OP-41483 administered intravenously significantly inhibited the thrombocytopenia due to platelets adhesion and thrombus formation at doses of 0.3 and 1.0μg/kg/min. Scanning electron microscopy revealed the reduction of platelet aggregates at the dose of 1.0μg/kg/min.
Furthermore, OP-41483 orally administered to Japanese monkeys was found to exert an inhibitory effect on ADP-induced platelet aggregation ex vivo with less changes in the blood pressure and heart rate even at the dose of 3.0mg/kg.
These results suggest that OP-41483 shows anti-platelet activity after either intravenous or oral administration accompanying less cardiovascular effects and it may be a more useful agent for thrombotic diseases in man than PGI₂.

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Nocodazole, a microtubule inhibitor, was tested for its effects on aggregation and release in human platelets. Nocodazole inhibited only the release reaction induced by ADP or ristocetin and inhibited the aggregation and release reaction induced by the other reagents tested (collagen, thrombin, adrenaline, polylysine, lectins [WGA and RCA], arachidonic acid, A23187, and PAF).
Nocodazole had no effect on the intracellular calcium release induced by thrombin which was measured by the decrease of the fluorescence of chlortetracycline. The drug inhibited the MDA generation of platelets induced by collagen, and it also inhibited the release of arachidonic acid from the phospholipids in the membrane.
From these results, nocodazole was indicated to inhibit the release reaction of platelets, and one of the steps inhibited by this drug was suggested to be at the level of the phospholipases.

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GLM-3401 (GLM) is phyto-steryl-glucoside containing β-sitosteryl-β-D-glucoside, stigmasteryl-β-D-glucoside and campesteryl-β-D-glucoside, which is extracted from the plants. In animal experiment, it was shown that GLM has the effect of enhancement of vascular integrity and inhibition of increased permiability of capillary wall and the effect of hemostasis without significant influence on platelet function and blood coagulation system.
We investigated the effect of GLM on human platelets. One hundred twenty mg of GLM per day was administered orally for 7 days to 11 healthy persons (6 males and 5 females). The following laboratory tests were performed before and after administration of GLM, —platelet count, mean platelet volume (MPV), template bleeding time (TBT), platelet adhessiveness and aggregation, β-TG, PF-4, ATP release, prothrombin time, activated partial thromboplastin time, fibrinogen and antithrombin II.
GLM showed no significant effect on these tests except for TBT. The average value of TBT was 6.4±2.3min before administration of GLM and was 4.9±1.4min. after administration of GLM. This difference was statstically significant (p<0.05).
Since GLM showed shortening effect on TBT without significant effects on the other platelet function tests and coagulation tests, it is assumed that GLM has some influence on the interaction between platelets and vascular wall.

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The contribution of vasoactive substances to secretion of PGI₂ from coronary vessel wall was examined in the isolated perfused dog hearts by a modification of the method of Langendorff.
Infusion of bradykinin (5μM) or thrombin (25u/ml) into the heart for 30sec resulted in transient release of an inhibitor of platelet aggregation. The inhibitor was reported to be PGI₂ (Ref. 1, 2). The inhibitor was not observed when acetylcholine, noradrenalin, isoproterenol (25μM, respectively), ATP (10μM), adenosine (5μM), angiotensin II (1μM), histamine (25μM) or serotonin (1μM) was infused.
Bradykinin (5×10^-9M to 5×10^-6M) and thrombin (10^-9M to 10^-7M) caused dose-dependent release of PGI₂ which was assayed by a radioimmunoassay for 6 keto PGF_1α.

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We studied the response of plasma catecholamine release, platelet functions and prostaglandin abnormalities during myocardial ischemia induced by different type of stress testing in patients with chronic stable angina. Pacing stress testing (PAC) was performed in 17 patients and treadmill testing (TM) in 10 patients. Aortic pressure was recorded and ratio of arer of systolic and diastolic phase (DPTI/TTI) was calculated. Radioimmunoassay of β-thromboglobulin (β-TG), thromboxane B² (TxB₂) and 6-keto-prostaglandin F_1α (6-keto-PGF_1α) were performed. Plasma norepinephrine (NE) level was measured by THI method.
Result: In TM systolic blood pressure (SBP) was remarkably increased (156±6 to 190±9mmHg p<0.05) but in PAC SBP was not changed significantly. DPTI/TTI was decreased in both testing at the maximun point and returned to the resting levels after cessation of stress (1.13±0.11 at rest 0.74±0.08max pac in PAC, 1.42±0.08 at rest 0.63±0.10max ex inTM). β-TG increased in both testing. TxB₂ levels were increased in PAC (630±188 to 780±189pg/ml in coronary sinus) as well as in TM (354±94 to 536±141pg/ml p<0.05), whereas 6-keto-PGF1α levels were modestly decreased in both testing. Plasma NE levels were remarkably increased in TM than PAC (250±50 to 400±7ng/l p<0.01 in TM, 260±40 to 280±40ng/l in CS in PAC).
This study suggests that physical exercise stress (TM) could simulate stympathetic tone with strenuous hemodynamic changes whereas platelet function during stress did not change significantly the difference between two types of stress testing.

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Changes in the platelet function and its shape were examined in 19 patients after prosthetic heart valve replacement. All patients were under warfarin treatment, and four of them were also administered dipyridamole simultaneously.
The following results were obtained:
(1) The platelet count was slightly decreased in 3 patients, and the prolonged bleeding time was found in one of these 3 patients.
(2) Platelet retention rate (Hellem II method) was below the normal range in 4 patients. Platelet aggregation induced by ADP, collagen, or arachidonate were diminished in 3 patients.
(3) Spherothrombocytosis without pseudopod formation was noted in 8 patients.
(4) Mean platelet volume was increased in 8 patients.
(5) There was no significant difference in the parameters mentioned above between patients with normal and abnormal level of LDH, patients with and without antiplatelet drug, and patients with and without thrombo-embolic episodes.
These results demonstrated the presence of platelet abnormalities which might be induced by platelet activation in these patients, and suggested that antiplatelet agents might be useful in some patients.

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Platelet functions and blood coagulability in the administration of antiplatelet drugs were investigated to find the best method of antithrombogenic therapy at the early postoperative period in 49 patients with prosthetic valves.
The administration modus of antiplatele drugs was divided into three groups; Group A (control), Group B (dipyridamole 300mg/day), Group C (ticlopidine 300mg/day), Group D (ticlopidine 600mg/day). Together with antiplatelet drugs, warfarin was given all patients 3 days after surgery, and prothrombin time PT was maintained at about 30 percent.
Results: PT was recovered to about 80% at 3p. o. d. and Pl aggregation also recovered within 5p. o. d. Both parameters showed thereafter significant increases. Pl. with larger size than 25μ were increased after prosthetic valve replacement, and this increase was also suppressed by antiplatelet drugs. In general Pl. activity and blood coagulability showed a significant increase at the early period after operations. Therefore, antithrombogenic therapy using antiplatelet drugs should be started as soon as plssible after the operation.

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Open mitral commissurotomy for mitral stenosis and Bentall's procedure for annulo-aortic-ectasia with aortic regurgitation were performed. Swan-Ganz catheter was monitored immediately after operation. Pulmonary embolisms of left lung occurred 2 and 3 days after operations respectively. Both cases were diagnosed by RI pulmonary scintigraphy. For the treatment of pulmonary embolilm, urokinase was injected intervenously 120, 000-240, 000 IU per day and anticoagulant therapy by warfarin started. Two cases were recovered uneventfully 2 weeks after operation. The prophylactic treatments of pulmonary embolism are necessary for the long time monitoring of Swan-Ganz catheter. They are, for instance, 1) the catheter is not inserted deeply so far as the wedge of pulmonary artery, 2) high density fluid is not infused through catheter, 3) urokinase and heparin are used continuously in using Swan-Ganz catheter, 4) the catheter of antithrombic material is better, 5) anticoagulant therapy by warfarin is better, 6) the catheter is removed as soon as possible.

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The mechanisms of the injury of vessel wall to initiate the blood coagulation were studied, using rabbit vessels.
Häutchen preparations, i. e. the strips of cellulose acetate paper adhering several samples of the endothelium, subendothelium and adventitia, respectively, to the surface of each of them, were submerged in barbital buffered saline, and vascular thromboplastin was eluated. Its activities were estimated by a chromogenic substrate.
Vascular thromboplastin activities were detected to some degree in every elusion from the endothelium and the adventitia of thoracic aorta, abdominal aorta and inferior vena cava, and in the elusion from the subendothelium of abdominal aorta. And the level of activity was highest in the elusion from the adventitia.
The level of PPK in human normal plasma time dependently declined more apparently in contact with the subendothelium of thoratic aorta lacking endothelium than in the control group with endothelium intact aorta. The level of PPK rapidly declined in F. XII deficient plasma, F. XI deficient plasma and HMW-kininogen deficient plasma, independent of the existence of endothelium.
The vascular thromboplastin may act on the extrinsic coagulation system as a trigger, and endothelium denuded vessels are likely to activate the contact phase to initiate the intrinsic system. PPK, when incomplete in forming a complex with F. XII or HMW-kininogen, might be unstable.

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The effect of dilazep (1, 4-bis [3-(3, 4, 5-trimethoxy benzoyloxy)-propyl] perhydro-1, 4-diazepine) on the aortic intimal thikening was examined. New Zealand white rabbits were used. The intimal injury was induced by insertion of polyethylene tubing which was drawn out on the next day. Dilazep was intramuscularly administerd in a dose of 50mg/kg three times a day. In Experiment I, rabbits were sacrificed immediately after the drawing out of tubing. In Experiment II, each animal of the experimental and control groups which were composed of ten animals respectively were sacrificed 10 days after the drawing out of tubing. Five sections from the thoracic aorta were embedded in Epon and the thickness of the thrombi in Experiment I and of the intima in Experiment II was measured.
In Experiment I, the thickness of the thrombi in the dilazep group was smaller than that in the control group (p<0.05). In Experiment II, the average thickness of the intima in the dilazep group was smaller than that in the control group (p<0.2), but the difference was not statistically significant as that of Experiment I.
Thus it was considered that the degree of intimal thickening after mechanical injury might not be proportional only to the amount of aggregated platelets and platelet derived growth factor.

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Antithromobotic therapy is necessary and important to maintain the effective blood circulation in vascular surgery. In this report, MD-805, a new synthetic thrombin inhibitor, was evaluated as an anticoagulant agent for vascular surgery.
Fifteen patients with peripheral arterial occlusive disease underwent MD-805, therapy on the schedule described in method after vascular reconstruction The prognosis was resulted in 11 patients with patency and in 4 occlusion, as shown in Table 1. The blood examinations were as follows:
1. In the intravenous administration of 10-20mg/day, partial thromboplastin time (PTT), prothrombin time (PT) and thrombin time significantly prolonged and platelet aggregability due to ADP and collagen were depressed. Fibrinogen remarkably increased. The fibrinolytic system was almost unaffected.
2. In the oral administration of 300mg/day, coagulative and fibrinolytic systems did not manifest any change.
These results were detailed in Table 2.
Intravenous administration of 20mg/day of MD-805 seems to be enough to prevent thrombus formation. MD-805 therapy is considered to be a useful anticoagulant agent for vascular surgery.

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Mesangial hypercellularity and sclerosis is one of the major pathological findings observed in the glomeruli, where the deposition of fibrin may be associated occasionaly, in many cases of glomerulonephritis.
We investigated the effects of fibrinogen and fibrinogen degradation products (FDP) on the growth of cultured glomerular mesangial cells. Fibrinogen FOP-D and E did not enhance ³H-thymidine uptake by cultured mesangial cells during the experimental period. The second peak obtained after the separation of low molecular weight FDP on Sephadex G-25 column showed decrease in ³H-thymidine uptake and increase in ⁵¹Cr release from cultured mesangial cells.
The results of this experiment showed that low molecular weight FDP possessed an suppressve effect on the growth of mesangial cells. It was thus suggested that low molecular weight FDP may promote mesangial cell injury.

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The contents of anti-Fragment D-dimer antibody-reacting antigen (Frag. D-dimer) in the serum of normal subjects and patiemts were determined by radioimmunoassay using specific antiserum against Frag. D-dimer. The content of Frag. D-dimer in normal subjects was 0.26±0.07μg/ml and that in patients with elevated levels of fibrinogen degradation products (FDP) distributed from 0.30 to 28μg/ml. They include patients with various malignant tumors, chronic renal diseases, sepsis, arterial diseases and liver cirrhosis with hepatoma. It was found that the amount of Frag. D-dimer and that of FDP did not necessarily change in paralell.
Plasma plasminogen and alpha-2 plasmin inhibitor were decreased in all disease groups except chronic renal disease. No remarkable decrease of alpha-2 macroglobulin was observed in any groups.

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Level of Fibrinopeptide A (FPA) in plasma is considered to be the most sensitive indicator of thrombin activity.
Since Nossel and his colleagues described a radioimmunoassay (RIA) for FPA, several attempts have been made by other workers to overcome the problems relating to the original alcohol/dialysis method. Recently, Woodhams et al. devised a rapid RIA for FPA using Bentonite as an adsorbant of fibrinogen. We applied this method to FPA measurement and compared with Nossel's original method. A clinical assessment was made of FPA in various thrombotic disorders. The results were obtained as follows:
1) The RIA using Bentonite was simple and sensitive. Good reproducible results and higher recoveries were obtained in this method. The normal range for plasma FPA (0.1-2.6ng/ml) is similar to that reported using the original method. There was a good correlation between results obtained by the Bentonite and original method on same samples from patients, although the Bentonite method tended to give slightly lower values.
2) Among various thrombotic disorders, acute venous thrombosis tended to show higher FPA values compared with acute arterial occlusion. Risk factors of postoperative deep vein thrombosis (DVT) were investigated on 10 patients undergoing hip surgery. DVT was assessed by using mesurement of β-Thromboglobulin, FPA, and ¹²⁵I-fibrinogen uptake test etc. DVT was found postoperatively in 6 of 10 cases. Measurement of FPA was the most reliable test for screening of DVT.

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Crude drugs of Wakan-Yakus (traditional herbal drugs) such as Gaiyoh (Artemisiae folium), Sanshishi (Gardeniae fructus), Taiso (Zizyphi fructus), Kizutsu (Aurantii fructus immaturus) and Akyoh (Glutinum) were investigated to analyse the effects on blood coagulation system.
(1) Gaiyoh (Artemisiae folium) showed the effects of anticoagulant, antifibrinolytic and anti-platelet aggregation, and the anticoagulant effect was strong prominently. When the crude drug of Gaiyoh was purified by the Sephadex G-100 column chromatography, four peaks were found. The strong antocoagulant effect was found to the third peak. We settled “Inhibition unit” of Gaiyoh from statistic studies, and 2.5mg/ml of Gaiyoh in the final concentration was evaluated to be 10 inhibition units.
(2) Sanshishi (Gardeniae fructus) showed strong fibrinolytic effect characteristically.

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Albumin-deficient rat mutant was discovered among Sprague-Dawley rat (SDR) with hypercholosterolemia by Nagase in 1977. In these Nagase's analbuminemic rats (NAR), albumin in plasma is congenitally lacking and an increase in serum globulin concentration is observed. Extreme hyperlipidemia can be induced in NAR by cholesterol-rich diet. In this study, levels of procoagulants, heparin cofactor (antithrombin III), immediate antiplasmin and platelet aggregability of twenty-seven female NAR were compared with those of nine female SDR. In NAR, levels of factors XII, XI, IX and VIII, fibrinogen, antithrombin III and immediate antiplasmin in plasma were significantly higher than in SDR. There was no significant increase in concentrations of factors X, V, II and XIII and platelet aggregability induced by ADP or collagen between SDR and NAR. Levels of factors XII, V, II and XIII, antithrombin III and immediate antiplasmin were higher in SDR and NAR than in human, whereas activities of factors XI, IX, VIII and platelet aggregability were higher in human than in SDR and NAR. Parallel increase in levels of procoagulants and antithrombin III in NAR compared with SDR suggests the presence of homeostatic balance in coagulability of blood in these rat mutants.

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We have studied the changes of kallikrein-kinin system in diabetes mellitus. (D. M.)
Plasma prekellikrein and kallikrein inhibitor levels were elevated in the patients with DM., but there were reduced in the patients of DM with micro-angiopathies.
Plasma kallikrein-like activity was elevated in the patients with DM, but urine glandular kallikrein level was reduced in the patients with DM.
Both heavy and light chain of plasma high molecular-weight kininogen levels were elevated in patients with DM, but light chain of high molecular weight kininogen level was sometimes reduced in patients of DM with micro-angiopathies.
Serum kininase II activity was elevated in most DM patients.
There was a close correlation between urinary C-peptide and glandular kallikrein activity in glucose tolerance test of DM. These findings suggested that kinins themselves exhibited some sort of insulin like activity in normal and diabetic man.

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In the present study, the authors first succeeded in isolating low molecular weight-plasmin by L-lysine-sepharose affinity and Sephadex G-75 column chromatographies from patient plasma with acute pancreatitis followed by disseminated intravascular coagulation. It had an apparent molecular weight of 52, 000 as measured by sodium dodecyl sulphate-polyacrylamide gel disc electrophoresis. Also, pancreatic elastase was purified in the free form from patient plasma by Sephadex G-100 and isoelectric focusing column chromatographies and it was confirmed that there are only a little amount of α2-plasmin inhibitor and less amount of α2-macroglobulin in patient plasma when compared with those in normal plasma.

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Hyperuricemia is known to be frequently accompanied by hypertension, hyperlipidemia, diabetes mellitus, obesity and arteriosclerosis. But there is no reprot on the relationship between serum uric acid (SUA) and blood viscosity which is known to be an important factor of thrombosis. We measured blood viscosity, SUA, hematocrit and other general blood chemistry in 84 healthy volunteers. There was a significant correlation between SUA and blood viscosity. This apparent correlation was found to be mediated by higher hematocrit values in persons with higher SUA values, Actually, it is known that hyperuricemics have higher concentration of hemoglobin than normals.
Treatment with 200mg allopurinol/day of hyperuricemic patients for 2 weeks decreased blood and plasma viscosities in 6 out of 7 patients, but not signifcantly. The incubation of red blood cells with UA (12mg/dl) containing buffer did not change the red cell filtrability to a filter with 5μ pores.
Hyperuricemics are said to have high incidence of thrombotic diseases. This could partly be explained by our findings on the relationship between SUA and blood viscosity.

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