Factor XII (F. XII), prekallikrein (PK), high molecular weight kininogen (HMW-K), plasminogen (PLG), antithrombin III (AT-III), α₂-plasmin inhibitor (α₂-PI) and C1-inactivator (C1-INH) levels were assayed of 102 sequential plasma samples from 8 patients with acute promyelocytic leukemia (APL), 8 with metastasized malignancies, 6 with septicemia, all of whom were associated with DIC, and from 8 with advanced cancer without metastasis and 6 with acute myocardial infarction (AMI), who were not with DIC. F. XII and HMW-K activities were assayed by one-stage PTT method with each deficient plasma as a substrate. The activities of PK, PLG, AT-III and α₂-PI were measured by amidolytic method with chromogenic substrates (Teatzym) specific to each factor, and the antigen levels of the latter 3 proteins and F. XII were also measured by single radial immunodiffusion technique. C1-INH was measured by the same method.
In patients with DIC due to APL and metastasized malignancies, the activities of F. XII, PK and HMW-K were nearly normal in the early to moderately advanced stages of the underlying diseases, although they were reduced to around 50% of normal in the terminal stages with poor nutrition and hepatic dysfunctions. In patients with septic DIC, however, marked and uniform reduction of these activities was noted from the beginning and in patients with advanced cancers without DIC, these were also decreased in various degrees. No significant changes of these factors were found in the plasmas of patients with AMI collected within 7 days after the attack. In DIC, regardless of its precipitating pathologies, the changes of F. XII, PK, HMW-K and PLG levels were similar to each other with significant correlation coefficient.
AT-III and α₂-PI, in both activities and antigen levels, were decreased not only in DIC but also in patients with advanced cancers without DIC. A mild but significant reduction of AT-III was also demonstrated in patients with AMI. C1-INH levels, on the other hand, were markedly elevated in DIC, moderately elevated in advanced cancers and normal in AMI.
From these results it may be concluded that in DIC with septicemia which activates the intrinsic pathways of blood coagulation, fibrinolysis and kinin formation, F. XII, PK, HMW-K and PLG are markedly and invariably decreased due to rapid activation and resultant consumption of these proteins, and that in DIC associated with APL and metastasized malignancies which activate the extrinsic pathways of coagulation and fibrinolysis, F. XII, PK and HMW-K do not become reduced unless decreased synthesis of these proteins are overt in the terminal conditions. Low levels of AT-III and α₂-PI seem to be useful parameters for the early diagnosis of DIC of either pathology, but hepatic dysfunction and poor nutrition can also influence these levels. C1-INH level was increased in APL, septicemia and malignancies with and without DIC and this protein seems to be one of the acute phase reactants.

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There is increasing evidence that certain hereditary abnormality of coagulation systems and fibrinolytic system result in a predisposition to thromboembolism.
These abnormalities include antithrombin III deficiincy, dysfibrinogenemia and molecular abnormality of plasminogen. However all these affected members have not had thrombotic problems, and it is reasonable to assume that another thrombogenic risk factor such as age, trauma, operation, infection, pregnancy, hyperestrogenemia, varix or hyperlipidemia might be involved.
In this presentation, these aspects together with the author's studies on hereditary molecular abnormality of plasminogen in a patient with recurrent thrombosis were discussed.

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Increasing knowledge of immunology has shown that immune mechanism, especially humoral reaction including antibody and complement, plays a part in the clotting mechanism. Fibrin clot has been demonstrated in the tissue of Arthus phenomenon or in the glomerulus of nephritic kidney. So-called acute or hyperacute rejection in tissue transplantation has been explained to be due to clot formation around the transplanted tissue. Recently, disseminated intravascular coagulation (DIC) has been reported in patients with immune complex diseases. These evidences strongly support the participation of immune reaction in coagulation mechanism.
Complement system has been demonstrated to play an important role in the coagulation mechanism, through the investigation of C6-deficient rabbit and complement-depleted animals. In order to understand the mechanism of hypercoagulable stage through the activation of complement system, it seems reasonable to explain in the following manner. (1) Destruction of vascular endothel mainly due to the deposition of immune complex results in the activation of contact system (Hageman factor) as well as the enhancement of platelets aggregation. (2) Destruction or aggregation of platelets can easily occur by the action of complement through its classical or the alternative pathway and results in the release of platelet factors. (3) Tissue factor is released when tissue damage is produced by complement. In addition, activation of plasmin or kinin through Hageman factor dependent pathway also activate complement system and enhances above mentioned coagulation mechanisms.
From the clinical standpoint, estimation of complement gives valuable informations in the managing the patients with DIC. Serum complement (CH 50) and complement components C3 and C4 revealed marked reduction after the onset of DIC, and those who survived restored their complement level. Titration of complement in patients with hypercoagulable stage was strongly recommended.

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Platelet aggregation and blood coagulation originally take actions in hemostasis. However, when the damage of vascular endothelial cells occurred, these systems are activated at the vessel walls.
In inflammation, increase in vascular permeability causes extravasation of plasma protein into interstitial space, where Factor XII is considered to be activated and then plasma prekallikrein is converted to active plasma kallikrein. In fact, in rat carrageenin-induced pleurisy, plasma kallikrein-kinin system was activated only in the pleural cavity, although this system was not activated in plasma of rats with pleurisy.
The release reaction of platelet aggregation was accompanied with release of prostaglandins (PG) and thromboxane (TX). In pleural fluid, 6-keto PGE₁α, PGE₂, TXB₂ showed their peaks successively between 1 and 7 hours after carrageenin. 6-keto PGE₁α is a stable metabolite of PGI₂ and might be related to vasodilatation and anti-aggregation, whereas TXB₂ might be result of platelet aggregation. TXA₂, however, is also released during phagocytosis and the peak of TXB₂ in pleural fluid agreed with that of polymorphonuclear leucocytes in pleural fluid. The main PG responsible to exudation was PGE₂. Thus, in inflammatory reactions, due to invasion of incitors, blood coagulation and thrombus formation seems to be hardly involved, unless bleeding occurred.
On the contrary, thrombus formation plays important roles in rejection of the skin graft. Blood flow to the skin graft reopened 6-9 days after implantation, but several days later, blood flow ceased suddenly by thrombus formation in arterioles and small veins at the boarder of the graft skin.
Arachidonic acid (C, 20: 4) is important as precursor of PG in platelet aggregation and in the inhibition by vascular endothelial cells. In take of fishes results in increase of eicosapentaenoic acid (C 20: 5) in phospholipids, which causes prevention of the thrombus formation.

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A clinical study of coagulation-fibrinolytic abnormalities in 96 patients with primary lung cancer, 12 patients with metastatic lung cancer and 27 patients with leukemia was undertaken.
Patients with lung cancer in advanced stages were found to be in the hypercoagulable state, which consisted of intravascular coagulation and secondary fibrinolysis. It was noted that the measurements of fibrinogen, FPA, ATIII and FDP were useful and important to analyze the pathophysiology.
It was suggested that DIC was the final condition of intravascular coagulation and secondary fibrinolysis exhausted of various factors, and that DIC might be considered to be a presenting pattern of the hypercoagulable state in a broad sense.
Heparin therapy was considered to be the most important way against the hypercoagulable state in malignancy. Our data indicates that the beneficial clinical effects of heparin can be obtained by keeping the heparin level 0.73±0.51 IU/ml in blood. And it is also necessary to measure fibrinogen, FPA, ATIII, FDP and PF₄.

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Hypercoagulability seems to be intimately correlated to atherosclerosis in terms of its pathogenesis and complications. When the aorta of the rabbit was desquamated by catheterization of polyethylene tube, many platelets adheared to the denudated area, where intimal thickening with proliferation of smooth muscle cells subsequently occured. Immunofluorescence and electron microscopy revealed extensive insudation of fibrinogen and lipoproteins, which seemed to lead to formation of atheroma. Our experiments also revealed that fibrin activated mesenchymal proliferation. Therefore, thrombosis may lead to atherosclerosis in the aorta, even when the level of serum cholesterol remains low. Hypercoagulability following rupture of the atheroma is seen with keen interest. Occulusive thrombosis due to rupture of the atheroma of coronary artery is a major cause of myocardial infarction. It may be caused by the release of thromboplastin from ruptured intima and inhibitory action of LDL to plasminogen tissue activator.

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We have been trying to treat acute leukemic children with BCG-CWS as a nonspecific immunotherapy for preventing hematological relapse occurring after cessation of chemotherapy maintained over two and half years complete remission.
The period of observation was from one month to fifty months (Median duration: 18 months). It has been reported that hematological relapse rates in patients without any treatments after stopping chemotherapy was 16 to 18% and that most of them relapsed within one year after the cessation of chemotherapy. But, we found only one of seventeen patients treated with CWS immunotherapy developed hematological relapse at 18 months (about 6%).
Although our cases are small in number, we would say that administration of CWS immunotherapy following cessation of chemotherapy might prevent hematological relapse. One patient who had not received prophylactic cranial irradiation developed meningeal leukemia and the other one showed ovarian relapse.
From this, CWS immunotherapy seems to prevent hematological relapse, but its effect on the Blood-Brain-Barrier and Blood-Gonad-Barrier is doughtful.
We have to design safer and more effective treatment against these barriers in future.

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The peripheral lymphocytes in liver cirrhosis were evaluated for the percent of T-cells judged by the rosette formation with sheep RBC, the responsiveness to stimulation of phytohemagglutinin (PHA), pokeweed mitogen (PWM) or concanavalin-A (Con-A) in 72 hours cultures, the percent of immunoglobulin (Ig) synthesizing cells and IgG secretion into the medium after in vitro 8 days cultures with or without PWM.
Ig synthesizing cells were enumerated by counting the cytoplasmic Ig positive cells staining with fluorescein-conjugated anti human Ig antiserum, and the secreted IgG into the medium by radioimmunoassay technique.
The percent of T-cells and the responsiveness of lymphocytes to PHA, PWM or Con-A were about the same in both healthy and liver cirrhosis.
Liver cirrhosis lymphocytes contained markedly increased numbers of Ig synthesizing cells after 8 days cultures without PWM, the lymphocytes contained a mean of 0.36±0.10%, while healthy lymphocytes contained a mean of 0.11±0.02%. However, liver cirrhosis lymphocytes were deficient in their capacity to respond to PWM with differentiation into Ig synthesizing cells and IgG secretions, the lymphocytes contained a mean of 1.75±0.56%, and secreted IgG 392+88 ng/1×10⁶ lymphocytes, while healthy lymphocytes contained a mean of 3.92±0.84% and secreted IgG 1699±492 ng/1×10⁶ lymphocytes.

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VENP-therapy—vincristine sulfate 1 or 2 mg/w IV (push), cyclophosphamide 50∼100 mg/d PO or 200∼500 mg×2/w IV (push), procarbazine 50∼100 mg/d PO and prednisolone 20∼30 mg/d PO—was indicated for initial remission induction of 13 cases with acute lymphocytic leukemia, from 14 to 67 (median 31)-year old at diagnosis.
Of 13 patients 9 obtained a complete remission (CR), 1 partial remission and 3 failure. The initial remission length was 2 2/3∼33 (median 5) months and the median survival time of patients attaining CR was 19 (7∼48+) months, as compared with 8 (4∼16 1/2+) months for patients not attaining CR. The three patients older than 60 years all obtained a CR and survived over 17 months. The median period to reach CR was 30 days from the beginning of the treatment. On the other hand, as to hematological changes in CR cases, the median time spent to recover was 23 days in WBC over 3,000/cmm and 16 days in plt. over 100,000/cmm, from day 1 of VENP respectively.
Thus, myelosuppression was mild compared to leukemocydal effect in VENP, which should be one of the most recommendable chemotherapies for aged patients with acute lymphocytic leukemia.

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Four-drug combination treatment, consisting of adriamycin, vincristine, ifosfamide, and prednisolone (AVIP) was performed to 43 patients with malignant lymphoma, who had been previously treated on other chemotherapy regimens, but relapsed in 10 and refractory in 33 cases. Complete remission rate was 57% (4/7) in Hodgkin's disease (HD), 29% (7/24) in reticulum cell sarcoma (RCS), and 33% (4/12) in lymphosarcoma (LS). No relapse had been observed in 4 complete responders of HD in the following-up period of 2∼45 months. Five of 7 patients (71%) with RCS remained free of disorder for 3∼47 months, but 3 of 4 patients with LS who were brought in complete remission state relapsed within 8 months after the remission. Average surviving time from the initiation of the AVIP therapy was more than 14 months in HD, 7 months in RCS, and 6.5 months in LS. Myelosuppressive toxicity was limited within tolerable range, although 2 cases were suffered from bacterial infections and 7 from herpes zoster (16%). This study indicated that the AVIP therapy was effective to increase survival time, bestowing satisfactory drug response to patients with malignant lymphoma, especially relapsed or refractory types.

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Fifty patients with advanced malignant lymphoma were treated with combined administration of 4 drugs, vincristine, bleomycin, cyclophosphamide, and prednisolone. Complete remission rate was 53% (8/15) in Hodgkin's disease (HD), 52% (14/27) in reticulum cell sarcoma (RCS), and 25% (2/8) in lymphosarcoma (LS). Median duration of their complete remission was 15.3 months in HD and 2 of these 8 cases remained free of disorder for 63 and 65 months. Seven of 14 cases with RCS, who were cured to complete remission, relapsed within 10 months, while the remainders were further free of signs for 15∼56 months during the following-up period of median 28 months; the median duration of remission was more than 17 months (designated as 17+, hereafter). Median surviving time of HD cases was 30+ months; e.g. 39+months for complete responders, and 24 months for partial and nonresponders. That of RCS cases was 20 months; e.g. 25+ months for complete, 12.5 months for patrial, and 3.5 months for nonresponders. On the other hand, that of LS cases was 8.5 months (range of 3 to 39+ months). Bleomycin pneumonitis was observed in 5 patients and was fatal for 2. Myelosuppressive toxicity was mild, being observed in only 3 cases during this chemotherapy. This study indicated that combination chemotherapy of these agents was effective to increase complete remission rate and prolong survival time of HD as well as RCS cases.

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An extreme hyperkalemia, hyperphosphatemia and hypocalcemia were developed following the induction therapy with prednisolone and vincristine in a case of acute lymphatic leukemia Serum potassium reached to 9.1 mEq/L. and phosphate to 12.5 mg/dl. and calcium decreased to 6.3 mg/dl. These electrolyte abnormalities changed in parallel with the increase of blood urea-nitrogen, creatinine and uric acid. At the same time, plasma renin activity and aldosterone levels increased in parallel with blood pressure. There were also the vasopressin-resistent polyuria. Before these changes occurred, the leukemic cells in peripheral blood decresed rapidly from 523,000/cmm to 25,000/cmm within four days.
The cause of these changes was suspected to be a result of the sudden lysis of a large number of leukemic cells. Sudden occurrence of hyperkalemia and the presence of polyuria denied the idea that the electrolyte changes were simply due to the renal inssufficiency.

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A 54-year-old woman born in Miyazaki Prefecture was admitted because of dyspnea, fever, erythroderma and generalized lymphnode enlargement. The leucocyte count in the peripheral blood was 45,100/cmm with 9% atypical lymphocytes showing pleomorphism and deeply indented or lobulated neuclei. 93.6% of the peripheral lymphocytes formed E-rosettes. The chest radiographs showed extensive mixed shadow of alveolar and interstitial pattern bilaterally.
The diagnosis of adult T-cell leukemia was made and treatment with vincristine, cyclophosphamide and prednisolone was instituted, but her general state deteriorated rapidly. She died of respiratory failure 15 days after admission.
Autopsy revealed leukemic cell infiltration into almost all organs including thymus. It was confirmed histologically that the abnormal shadow of chest radiographs was caused by leukemic infiltration.

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A case of Letterer-Siwe disease in a 1-year-1-month-old girl with an enlarged liver, markedly swollen gums and seborrhoic eruptions is reported.
She died from pyopneumothorax in spite of treatment with prednisolone and vinblastine.
Lipids of the patient's liver were analyzed. It was found that there was remarkable increase in concentration of free fatty acid, which is not present in normal human liver, and cholesterol ester was also accumlated in the liver. The concentration of phospholipids and glycerides, however, was low and lysophospholipid was found in her liver.
It was assumed that an accelerated lipolysis had undergone in the proliferating reticuloendothelial cells.

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It is well known that thromboembolism is one of the most serious side effects of oral contraceptives. In Japan, however, reports of thromboembolism following use of oral contraceptives are rare, since their clinical use in Japan is restricted to treatment of menstrual abnormalities.
We reported here on two patients affected with cerebrovascular occlusive diseases associated with the administration of oral contraceptives.
The first case was that of of 32-year-old woman, who developed headache, paresis and dysesthesia of the right limbs following daily taking over a period of 20 days of oral contraceptives, one tablet containing 0.15 mg of mestranol and 5 mg of lynestranol. Neurological symptoms as well as examinations led to the diagnosis of a kind of thalamic syndrome due to cerebral thrombosis.
The second case was that of a 37-year-old woman, who developed right hemiparesis following daily consumption over a period of 21 days of oral contraceptives as given above. Clinical symptoms and neurological examinations led to the diagnosis of right hemiparesis due to cerebral thrombosis.
The pathogenesis of cerebral thrombosis caused by taking of oral contraceptives was discussed mainly in connection with coagulation and fibrinolysis. Certain evidences suggesting that hypercoagulability may play major roles in pathogenesis of thromboembolism during taking oral contraceptives have been derived from the works of other investigators. It is true that estrogen in this compound may induce a state in which an increase of coagulation factors together with a decrease of antithrombin III combine to produce hypercoagulation; laboratory tests with our patients, however, produced nothing compatible with a state of hypercoagulability.

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A 48-year-old man was admitted on Oct. 29, 1977, because of anemia and hemorrhagic tendency. Fourteen months before admission, he had epigastric pain, and 5 months later, upper GI series and gastrofiberscopic examination showed gastric cancer (Borrmann III) on the lesser curvature of the antrum. On June 8, 1977, partial gastrectomy was performed. The histology of the lesion was anaplastic adenocarcinoma. After surgery, he was treated with anti-cancer drugs for about a month. A month before admission, examination showed anemia, reticulocytosis and hemorrhagic tendency.
On admission, hematuria, thrombocytopenia, prolonged prothrombin time, delayed erythrocyte sedimentation, hypofibrinogenemia, hyperbilirubinemia, elevated FDP, elevated LDH and abnormal renal function were evident. The diagnosis of disseminated intravascular coagulation (DIC) with microangiopathic hemolytic anemia (MHA) was made and he was treated with heparin and prednisolone but he was expired on Dec. 18, 1977.
Postmortem examination revealed fibrin thrombi in the kidneys and hemorrhagic diathesis but neither primary cancer nor metastatic lesion was found.
It was suspected that anti-cancer drug therapy on the hypercoagulable state after surgery elicited DIC with MHA.

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A family of congenital factor VII deficiency is presented. The proband is a 46-year-old male who had been suffering from recurrent epistaxis and easy bruising until 20 years old, when he started to be less hemorrhagic and his youngest brother had the same hemorrhagic diathesis.
They were born of a consaguineous marriage and presented marked prolongation of one stage prothrombin time, normal partial thromboplastin time and normal stypven clotting time.
Their factor VII levels were 5.2% and 6.0%, respectively. Including these 2 patients, 11 members of the family were investigated. Three had normal factor VII activity, and 6 had 36∼54% of normal who were thought to be heterozygotes.
Factor VII activities of the proband were assayed with the use of several different kinds of tissue thromboplastin, where there was no significant difference between them.
Two thousand units of factor VII concentrate (Factor VII Concentrate Human IMMUNO) was given to the proband. The activity immediately reached to the expected value, which continued for 180 minutes and then decreased slowly. According to this infusion trial, the half life of factor VII in vivo was estimated to be 240∼300 minutes, which was quite similar to the result reported by us in 1976.
The levels of other coagulation factors were within normal ranges. Routine liver function tests, liver scintigram and laparoscopic findings were also normal. From these results, the posibility of acquired factor VII deficiency was ruled out.
To the best of our knowledge, there have been 14 reported cases of congenital factor VII deficiency in Japan which were reviewed briefly in this paper.

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