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Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, and remains a global issue due to its high incidence and mortality. Many randomized controlled trials have investigated sepsis, but no specific treatments have been established. This is due to "heterogeneity," which indicates that a diagnosis of sepsis includes various pathophysiological states. To resolve this issue, efforts are being made to identify subclasses of sepsis. Past studies have selected different variables, such as expressed genes, cytokines, and vital signs, and identified subclasses based on clinical or biomarker-expression features. We also identified subclasses of sepsis with different coagulation features, and found that a specific anticoagulant agent (recombinant human thrombomodulin) was associated with improved survival rates in only one subclass. We also developed a model that could predict the subclass. However, none of the reported subclasses had shared characteristics, and they are not in clinical use. Further research is required to identify subclasses that are strongly associated with the pathophysiological mechanism and reproducible in any cohort.

Disseminated intravascular coagulation (DIC) is defined as systemic intravascular coagulation activity that has been acquired in the presence of various underlying diseases and is outside local or compensatory control, and is a fatal condition. Although the pathogenesis, diagnosis, and treatment of DIC are well known in Japan, each clinician has a different understanding of DIC, which makes it difficult to standardize diagnosis and treatment. Even at the international level, perception of DIC varies widely. This makes it difficult for residents and novice clinicians to standardize routine care for DIC. To meet the demands of the times, my colleagues and I are currently working on a globally unprecedented project to develop guidelines for the treatment of DIC for each underlying disease (tentative title). This article will also review the status of past guidelines from inside and outside Japan.

A 43-year-old man with pancytopenia was diagnosed with acute promyelocytic leukemia (APL). On the first day of induction therapy with all-trans retinoic acid (ATRA) alone, he presented with high fever and was found to have coronavirus disease 2019 (COVID-19) infection by SARS-CoV2 antigen test. While it is generally recommended to delay treatment for APL patients with COVID-19 unless urgent APL treatment is required, this patient needed to continue treatment due to APL-induced disseminated intravascular coagulation (DIC). Considering the challenge of distinguishing between differentiation syndrome (DS) and COVID-19 exacerbation, the ATRA dosage was reduced to 50%. The patient was able to continue treatment without development of DS or exacerbation of DIC, leading to his recovery from COVID-19 and remission of APL.

A 43-year-old man presenting with oral bleeding was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy consisting of all-trans retinoic acid and idarubicin was initiated, and disseminated intravascular coagulation (DIC) was treated with fresh frozen plasma and recombinant thrombomodulin infusions. The patient was free from neurological symptoms throughout the clinical course. However, cerebral hemorrhagic lesions were detected incidentally on magnetic resonance imaging performed to screen for leukemic central nervous system invasion at 2 weeks after treatment initiation. Imaging findings suggested subacute or later-phase cerebral hemorrhage. Platelet transfusions and other supportive care was provided. Serial imaging evaluations confirmed reduction of the hemorrhagic lesions. Hematological remission was achieved after induction chemotherapy, and no symptoms due to cerebral hemorrhage developed during the subsequent consolidation therapy. As patients with APL characteristically experience hemorrhagic events due to bleeding tendency caused by DIC, physicians should be aware of the possibility of asymptomatic cerebral hemorrhage in these patients.

Aortic regurgitation, a thoracoabdominal aortic aneurysm, chronic myeloid leukemia, and chronic kidney disease were all being treated at two hospitals for an 83-year-old man. He was admitted to the Department of Orthopedics at our hospital with a lumbar compression fracture. Later, he experienced melena, for which the Department of Internal Medicine was consulted. Due to the aberrant results of PT-INR (7.1) and a PTT > 200 seconds on a coagulation test, we suspected the presence of an autoimmune coagulation factor deficiency, and prednisolone immunosuppressive therapy medication was started right away. Due to a sharp decline in FV/5 activity, the presence of FV/5 inhibitors, and the presence of anti-FV/5 autoantibodies, a final diagnosis of autoimmune coagulation factor V (FV/5) deficiency was made. After the start of immunosuppressive therapy, the FV/5 inhibitor and anti-FV/5 autoantibodies disappeared, and the FV/5 activity progressively returned to normal. Disseminated intravascular coagulation-which may have been caused by a known aortic aneurysm-worsened while tapering off prednisolone. Due to the patient's advanced age and other problems, the aneurysm was extensive and inappropriate for surgical repair. The coagulation test findings improved gradually upon initiation of warfarin therapy. Herein, the patient had autoimmune FV/5 deficiency, a rare disorder that made diagnosis and therapy difficult because of the patient's several coexisting conditions.

During the treatment of disseminated intravascular coagulation (DIC) associated with hematopoietic malignancies (particularly, acute leukemia), fatal bleeding, such as cerebral, alveolar, and gastrointestinal hemorrhages at diagnosis or immediately after initiating treatment, determines the patient's prognosis. DIC should always be suspected in such cases, and the diagnosis should be made on the basis of the former Ministry of Health and Welfare DIC diagnostic criteria or the 2017 Japanese Society on Thrombosis and Hemostasis DIC diagnostic criteria. This treatment requires the use of appropriate anticoagulants and replacement therapies. The anticoagulant should be chosen based on the patient's risk of bleeding. Here we present the recent evidence of DIC complicating hematopoietic malignancies with antithrombin agents and recombinant human soluble thrombomodulin. Moreover, prognostic markers during the course of therapy have been reported. The effect of treatment, including withdrawal from DIC, should be carefully assessed. In the future, detailed evidence regarding the tumor subtype, tumor burden, and disease severity will be required to ensure appropriate drug choice for the treatment.

Peliosis hepatis (PH) is a condition involving benign tumors pathologically characterized by multiple blood-filled cavities, mostly affecting the liver and spleen. Androgenic-steroids are widely used in patients with bone marrow failure syndromes (e.g.: aplastic anemia) and these patients are at increased risk of developing PH. Although patients with PH are generally asymptomatic, PH can progress to liver failure and even fatal spontaneous intraabdominal hemorrhage. Therefore, early diagnosis is critical in order to prevent life-threatening complications of PH. We herein report a patient with PH which had been treated with danazol, who presented with liver dysfunction and multiple hepatic lesions on imaging studies at the time of diagnosis. Although the patient presented with disseminated intravascular coagulation (DIC), a bone marrow biopsy revealed no evidence of leukemic transformation. The patient was diagnosed as having danazol-induced PH, and these abnormalities spontaneously resolved after the discontinuation of danazol. PH is one of the most important complications of long-term administration of androgenic-steroids. Although the mechanisms remain unclear, the multiple blood-filled cavities characteristic of PH may be responsible for the development of DIC. Therefore, monitoring of coagulation markers might also be a key strategy for early diagnosis of PH.

Disseminated intravascular coagulation (DIC) is a pathological state in which varying degrees of fibrinolytic activation are seen simultaneously as systemic, persistent, and marked coagulation activation in the presence of an underlying disease. Suppressed-fibrinolytic-type DIC usually develops in patients with sepsis. Coagulation activation is severe, while fibrinolytic activation is mild. Enhanced-fibrinolytic-type DIC usually occurs with acute promyelocytic leukemia (APL). Both coagulation activation and fibrinolytic activation are severe in affected patients. Balanced-fibrinolytic-type DIC is usually seen in patients with solid tumors, and has a pathogenesis intermediate between those of the two aforementioned types. In animal DIC models, lipopolysaccharide (LPS)-induced forms of DIC are similar to suppressed-fibrinolytic-type DIC, whereas models of tissue factor (TF)-induced DIC have features similar to those of enhanced-fibrinolytic/balanced-fibrinolytic DIC. We are moving in the direction of more appropriate selection of treatment based on DIC type.

Thrombosis is generally considered to be harmful because it compromises the blood supply to organs. However, recent studies have suggested that thrombosis during infection might play a physiological role in the early immune defense against invading microorganisms. This defensive role of thrombosis is now referred to as immunothrombosis. Detection of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by immune cells triggers tissue factor expression and neutrophil extracellular trap (NET) release, promoting immunothrombosis. Sepsis-associated disseminated intravascular coagulation (DIC) is considered to be an advanced stage of pathological immunothrombosis, in which the immune system is no longer able to restrict the spread of pathogens, inflammation, and coagulation. In this stage, thrombosis is detrimental in part because it causes multiple organ failure. Recombinant thrombomodulin (rTM) is a therapeutic option for the treatment of sepsis-associated DIC in Japan. rTM binds thrombin, and switches its substrate specificity from coagulation factors V, VIII, and XIII to anticoagulant protein C. In addition to the activated protein C (APC)-dependent anticoagulant action, rTM has APC-independent anti-inflammatory actions, i.e., the sequestration of PAMPs and DAMPs. Thus, rTM is useful for resolving PAMP-and DAMP-mediated DIC, although further studies are needed to confirm the effectiveness of rTM in terms of clinical outcomes.

An 80-year-old man with autoimmune hemolytic anemia (AIHA) received immunosuppressive therapy with prednisolone (1 mg/kg). One month later, his hemoglobin level had normalized, and the prednisolone dose was tapered. The next day, he complained of acute and progressive back pain. He was admitted to our hospital for further examination approximately 24 h after the pain had started. Computed tomography revealed only localized pneumonia. However, he showed signs of severe disseminated intravascular coagulation (DIC), liver dysfunction, and respiratory failure. Empiric broad-spectrum antibacterial therapy was started with a presumptive diagnosis of severe bacterial infection. However, his condition rapidly deteriorated, and he died 17 h after admission. Varicella-zoster virus (VZV) was detected by quantitative PCR in the peripheral blood sample and by immunohistochemistry in all organs except for the brain at autopsy. Visceral VZV infection is a severe disease with a high mortality rate. Although appropriate diagnosis and treatment is crucial, in cases without the characteristic skin rash the diagnosis is difficult. The possibility of visceral VZV infection should be taken into consideration when administering prednisolone to patients with AIHA.

The clinical features noted in individuals with disseminated intravascular coagulation (DIC) complicated by hematological malignancies include life threatening hemorrhage that is associated with thrombocytopenia and consumptive deficiency of coagulation factors. Exacerbation of DIC after the initiation of chemotherapy is also related to fatal hemorrhage. The Japanese Society of Thrombosis and Hemostasis recently proposed provisional DIC diagnostic criteria allowing evaluation of hypercoagulable markers such as soluble fibrin and thrombin-antithrombin complex to help physicians to diagnose DIC and initiate treatment in the early phase of coagulopathy. A phase III clinical trial showed that human soluble recombinant thrombomodulin (rTM) more potently improved DIC than unfractionated heparin and was approved for treatment of DIC in 2008 in Japan. rTM exerts anti-inflammatory and cytoprotective actions and may improve clinical outcomes of DIC patients.

We retrospectively investigated treatment outcomes with soluble recombinant thrombomodulin (rTM) for disseminated intravascular coagulation (DIC) associated with hematological malignancies (acute leukemia and malignant lymphoma) at our hospital. After rTM administration, DIC scores improved in 29 of 39 cases with hematological malignancies (74.36%). Although one case with recurrent and refractory APL died due to cerebral bleeding during rTM administration, no bleeding-associated adverse events were observed in the other 38 cases. DIC improvement was augmented in cases with acute leukemia when rTM was introduced in the pre-DIC state. CRP decreased in 26 of 36 cases with hematological malignancies (72.22%) after rTM introduction, and CRP decreased particularly significantly in cases with malignant lymphoma, suggesting rTM to exert anti-inflammatory activity. Taken together, these observations indicate that rTM, which rarely causes bleeding-associated adverse events, is an excellent agent in terms of both efficacy and safety for treating DIC associated with hematological malignancies, and the potential anti-inflammatory activity of this agent was also suggested.

A 62-year-old man had a history of acute aortic dissection (Stanford type A) and had been diagnosed with polycystic kidney disease three years earlier, and then developed end-stage renal failure. He was referred with chief complaints of difficult hemostasis and consecutive hemorrhagic episodes at the puncture site of the shunt soon after dialysis introduction. We suspected chronic disseminated intravascular coagulation (DIC) due to mild thrombocytopenia and a fibrinolytic system abnormality. Plasma factor XIII activity was decreased, but no inhibitor was detected. In addition, contrast-enhanced computed tomography showed exacerbation of a dissecting aortic aneurysm. We finally diagnosed chronic DIC and secondary factor XIII deficiency associated with the aortic aneurysm. We selected treatment involving recombinant human soluble thrombomodulin (rTM) because he was on maintenance dialysis and required long-term follow-up bofore the operation. Hemostatic function improved with regular administration of rTM, and was well-controlled preoperatively.

An 82-year-old female with a history of aortic dissection was admitted to our hospital for evaluation of thrombocytopenia and a bleeding tendency. Blood coagulation test data demonstrated that the patient had disseminated intravascular coagulation (DIC) secondary to aortic dissection. We initiated anti-fibrinolytic therapy with tranexamic acid. After this anti-fibrinolytic therapy, thrombocytopenia and the levels of fibrinogen and fibrinogen degradation products improved. In addition, we reviewed 7 other patients who were treated with tranexamic acid for DIC associated with aortic dissection. Anti-fibrinolytic therapy with tranexamic acid is effective for treating DIC secondary to aortic dissection.

Recombinant human soluble thrombomodulin (rTM) is a new drug for the treatment of disseminated intravascular coagulation (DIC), although the effects on obstetric DIC have not yet been fully elucidated. We report herein three patients with obstetric DIC caused by placental abruption, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and atonic bleeding, respectively. In all three cases, treatment with rTM proved successful, suggesting that rTM is an efficient method for treating obstetric DIC.

An 87-year-old man was referred to our hospital because of sustained bleeding from head skin lesions after trauma. Examination of peripheral blood showed severe thrombocytopenia, a nearly normal coagulation test, and elevated PAIgG. Based on the tentative diagnosis of immune thrombocytopenic purpura (ITP), immunosuppressive drugs and high-dose immunoglobulin were administered; however, the platelet count did not recover, and was followed by severe DIC, resulting in a fatal outcome due to massive bleeding from the scalp. Histopathological examination of autopsy samples of skin lesions revealed angiosarcoma, suggesting that Kasabach-Merritt syndrome (KMS) complicated with DIC, but not ITP, was the primary cause of thrombocytopenia. Although KMS is commonly accompanied with hemangioma in infants, it is extremely rare in patients with angiosarcoma, which is an uncommon malignant neoplasm. In this case, our correct diagnosis of thrombocytopenia was difficult because of the unusual clinical setting, indicating that careful interpretation of physical, laboratory and pathological examinations is mandatory for correct diagnosis of thrombocytopenia of unknown etiology.

An 83-year-old woman had been suffering from palpitations and fatigue for a month. An annual screening test revealed an increased WBC count so she was referred to our hospital. CBC showed extremely elevated WBC count (186,300/microl), in which the population of blastic eosinophils was over 90%. The eosinophils expressed CD7/13/33/34/DR, and the karyotype demonstrated 47,XX,+8. The fusion gene of FIP1-LP/PDGFRalpha in peripheral blood was negative. As plural effusion due to the underlying disease progressively worsened, she was given prednisolone and hydroxyurea, but the effect was limited. Steroid pulse therapy and imatinib (100 mg/day) were administrated. As a result, a prompt response was observed. The WBC count rapidly decreased, but tumor lysis syndrome led to acute renal failure and disseminated intravasucular coagulation appeared. Supportive therapies such as artificial dialysis and transfusions were conducted, but unfortunately she died because of alveolar hemorrhage.

Patients receiving splenectomy are at risk of a fatal fulminant infection called overwhelming post-splenectomy infection (OPSI). Here we report a rare case of toxic shock syndrome (TSS) evoked by group B streptococcus (GBS) in an asplenic young woman, which we considered a case of OPSI. A 34-year old woman consulted our hospital complaining of vomiting, diarrhea and fever that developed early in the morning. As the physical examination and routine laboratory tests did not disclose any serious abnormalities, she returned home after symptomatic treatment under a provisional diagnosis of acute enterocolitis. However, the next morning, she was transferred to the hospital complicated by acute renal failure, severe liver damage, respiratory insufficiency, disseminated intravascular coagulation and hypotension. She was admitted to ICU and treated with intravenous antibiotics, frequent transfusions of platelet concentrates, hemodialysis, and non-invasive positive pressure ventilation. Blood cultures grew gram-positive cocci, which later proved to be Streptococcus agalactiae (GBS). We diagnosed the patient with TSS due to GBS. Organ damage and symptoms improved gradually with intensive treatment, she was discharged from the hospital 26 days after admission. Although cases of TSS due to GBS are very rare, we must be aware of the potential risk of OPSI in a splenectomized patient.

We report here two patients with chronic disseminated intravascular coagulation (chronic DIC) secondary to aortic aneurysm, who were successfully treated with continuous subcutaneous infusion of heparin. The patients were 69- and 89-year-old males, who were admitted to our hospital because of thrombocytopenia and marked bleeding tendency. The underlying conditions were aortic dissection and aortic aneurysm, respectively. Coagulation test demonstrated that these patients had DIC, and a diagnosis of chronic DIC secondary to aortic aneurysm was made. Anti-coagulation treatment with oral camostat mesylate and daily subcutaneous infusion of heparin calcium was started. However, the treatment was insufficient to control chronic DIC, and these patients developed recurrent severe subcutaneous hemorrhages. Therefore, we attempted continuous subcutaneous infusion of heparin using a mobile infusion pump. This delivery of heparin markedly improved the coagulopathy, and the hemorrhagic episode disappeared with good compliance in the use of infusion equipment in these patients. Continuous subcutaneous infusion of heparin using a mobile infusion pump is effective and useful for long term treatment of chronic DIC by the outpatient department.

A 14-year-old boy presented with a short history of general fatigue. Laboratory examination of the peripheral blood revealed white blood cells 11,300/microl, hemoglobin 10.4 g/dl, platelets 45,000/microl, fibrinogen < 50 mg/dl, fibrin/fibrinogen degradation products 536 microg/ml and lactate dehydrogenase 1,684 U/l. A bone marrow aspirate contained 89.6% of undifferentiated tumor cells. A hematological malignancy was suspected and the patient was treated with idarubicin and cytarabine. However, further examination revealed that tumor cells were positive for CD56 and lacked lineage markers of lymphoid or myeloid cells. They were positive for PAS, HHF35 and desmin, and negative for MPO. Reverse transcriptase polymerase chain reaction demonstrated PAX3/FKHR fusion transcripts, confirming the diagnosis of alveolar rhabdomyosarcoma. Radiological examination revealed only one enlarged lymph node being 1.5 cm in diameter at the paraaortic region in the abdomen, and failed to find a primary tumor. After three courses of chemotherapy containing etoposide, cyclophosphamide, pirarubicin, cisplatin and vincristine, tumor cells were eradicated from the bone marrow. The patient received an allogeneic bone marrow transplantation eight months after diagnosis, although he died of hepatic veno-occlusive disease on day 21. Alveolar rhabdomyosarcoma often develops in older children and younger adults, and its bone marrow infiltration may mimic acute leukemia.

A 19-year-old man was referred to our hospital with pancytopenia and disseminated intravascular coagulation (DIC). Bone marrow aspiration revealed 93.6% of atypical promyelocytes and marked hemophagocytosis by macrophages. The diagnosis of acute promyelocytic leukemia (APL) associated with hemophagocytic syndrome (HPS) was made. As there was no evidence of infection, collagen diseases, or abuse of medicine, his HPS was classified as malignancy-associated HPS (MAHS). The DIC improved after administration of idarubicin and all-trans-retinoic acid (ATRA). On the 11th day, however, DIC and elevation of serum LDH recurred with the appearance of hepatosplenomegaly. Although APL cells had decreased in the bone marrow, hemophagocytes persisted. After administration of dexamethasone and etoposide, DIC and HPS improved, and complete remission of APL was obtained. ATRA was implicated in the aggravation of APL-induced MAHS in the present case.

A 17-year-old female was admitted to our hospital because of pyrexia and thrombocytopenia in May 2002. Laboratory examination showed a platelet count of 50,000/microliter with an increased level of fibrinogen degradation product, leading to a diagnosis of disseminated intravascular coagulation (DIC). Gabexate mesilate was intravenously administrated without any effects. Several days later, erythema, joint pain and neck lymphadenopathy developed sequentially. The patient was diagnosed as having adult-onset Still disease (AOSD) complicated with DIC. Moreover, serum inflammatory cytokine levels had increased and activated macrophages were observed in the bone marrow, suggesting the presence of macrophage activation syndrome. After additional treatments with dalteparin and aspirin, the clinical symptoms and laboratory findings associated with AOSD and DIC disappeared. Although this was a severe case of AOSD associated with preceding DIC, the AOSD symptoms resolved in this patient with the treatment of the DIC and with aspirin only without any relapse.

A 71-year-old man with acute myelogenous leukemia (AML, M2) developed signs of chest oppression, and was diagnosed as having acute myocardial infarction (AMI). At the same time, his leukemia relapsed in association with disseminated intravascular coagulation (DIC). The patient's risk factors for AMI were hyperlipidemia, hyperglycemia, and a history of smoking. Coronary angiography showed occlusion of the circumflex branch. Percutaneous transluminal angioplasty (PTCA) was performed successfully, followed by administration of heparin. After chemotherapy, the patient's DIC improved and a second remission was attained. When elderly patients with AML show evidence of DIC, we should be aware of AMI as a possible complication. PTCA is a safe operation for such patients.

A 44-year-old man was admitted to our hospital because of purpura, increased serum alkaline phosphatase, and thrombocytopenia. He had undergone subtotal gastrectomy for gastric cancer 11 years earlier. A biopsy specimen of the bone marrow revealed metastatic mucin-forming, moderately differentiated adenocarcinoma. Because the primary tumor was not detected in any other organ, the gastric cancer the patient was treated for 11 years earlier was suspected as the primary tumor. Microangiopathic hemolytic anemia and disseminated intravascular coagulation developed during the clinical course, and the patient deteriorated despite treatment with anticoagulants. Finally, he died of pulmonary carcinomatous lymphangitis. Autopsy revealed a small number of adenocarcinomatous cells in the lymphoduct of the remaining stomach in spite of its mucosa being intact. We concluded that the bone marrow was infiltrated by cancer cells which originated in the stomach 11 years before. It is unclear why adenocarcinoma cells remained dormant for as long as 11 years in the gastric lymphoduct and bone marrow.

We report a 82-year-old woman with adult onset Still's disease (AOSD), who presented with high fever, skin rash, swollen axillary lymph nodes, accelerated erythrocyte sedimentation rate, leukocytosis, abnormal liver function tests, hypoalbuminemia, negative antinuclear antibody and rheumatoid factor, and lack of renal involvement. Disseminated intravascular coagulation (DIC) was also diagnosed on admission. An antipyretic relieved high fever and DIC soon improved. Three years later, AOSD relapsed accompanied by hypercoagulation and hyperfibrinolysis. The patient developed subdural hematoma and DIC due to a brain contusion. High titers of serum soluble adhesion molecules and soluble thrombomodulin were noted on the first episode of DIC. These findings indicated that endothelial cells were damaged in AOSD complicated by DIC.

A 66-year-old woman complained of chest discomfort in January 1995. In March the accelerated phase of chronic myeloid leukemia (CML) was diagnosed. Chromosomal analysis demonstrated negative Ph and positive t(9;16) (q34;p11) with positive major BCR/ABL chimeric mRNA. Administration of hydroxycarbamide was initiated, but in May she developed high fever and severe left hypochondralgia. Her WBC was 62,100/microliter (blast 64%), and LDH was 3,590 IU/l. Bone marrow examination showed 78.6% blasts, with a nucleated cell count of 74 x 10(3)/microliter. Blasts were negative for esterase stain and partially positive for both peroxidase stain and PAS reaction. Surface marker analysis revealed that blasts were positive for CD13, CD19, CD33, CD34, and HLA-DR. A diagnosis of blast crisis was made and she was treated with the VDS-CP regimen with heparin for DIC. After temporary improvement her disease recurred rapidly with severe DIC. Treatment with low molecular weight heparin and fresh frozen plasma failed to control DIC and she died of subarachnoid hemorrhage on the 48th hospital day. This is the first veprted of case Ph-negative, M-BCR/ABL-positive CML with t(9;16) accompanied by severe DIC.

We report a case of acute promyelocytic leukemia (APL) following ulcerative colitis (UC). A 23-year-old man was diagnosed as UC in January 1991 and had been treated with salazosulfapyridine and prednisolone with good effect. In September 1993, he developed bleeding tendency and a diagnosis of APL with disseminated intravascular coagulation was made based on the results of bone marrow aspiration and coagulation profile. Complete remission was achieved with All-trans retinoic acid together with combined chemotherapy. He died of sepsis during consolidation chemotherapy in December 1993. Autopsy revealed no recurrence of UC.

Disseminated intravascular coagulation (DIC) is characterized by extreme activation of intravascular coagulation, and clinical manifestations such as bleeding and/or multiple organ failure is sometimes observed in advanced cases of DIC. The balance of coagulation and fibrinolysis activation varies according to the underlying diseases of DIC. DIC cases are classified as the type with predominant coagulation activation and the type with predominant fibrinolysis activation in former type plasma levels of thrombin-antithrombin III complex (TAT) are greatly increased, and those of plasmin-alpha 2 plasmin inhibitor complex (PIC) are slightly increased. In addition plasma levels of plasminogen activator inhibitor 1 (PA1) are greatly increased, multiple organ failure is a major clinical manifestation in advanced cases and sepsis is a representative underlying disease. In the second type both plasma levels of TAT and PIC are greatly increased, plasma levels of PA1 are almost within normal limits. Bleeding is a major clinical manifestation in advanced cases and acute promyelocytic leukemia (APL) is a representative underlying disease. The classification of DIC should be considered when choosing treatment with DIC. Diagnosis of pre-DIC status is based on gradually decreasing platelets counts in sepsis and on mild elevation of FDP and D dimer in APL, leukemia and cancer.

A 20 year-old female patient with Kasabach-Merrit syndrome, suffered from chronic consumption coagulopathy due to localized intravascular coagulation in the tumors. She had been diagnosed as Kasabach-Merrit syndrome immediately after birth and below knee amputation of her right lower leg was performed at the age of 2 years because of her giant hemangioma on the right foot and lower leg. After the operation, she had often complained of severe pain and enlargement of the residual tumors due to continuous thrombus formation within the tumors. She was admitted to the third Department of Tohoku University Hospital in order to initiate oral anticoagulant therapy with Warfarin at the age of 12 years. After the administration of 2.5 mg/day Warfarin, she has maintained good clinical condition until now, despite the occasional occurrence of coagulation abnormalities. We believe that the results of this case indicate the efficacy of oral anticoagulant therapy in the treatment of chronic consumption coagulopathies complicated with other diseases.

We describe a 39 years-old male hemophilia A patient with acquired immunodeficiency syndrome (AIDS) developing to disseminated intravascular coagulation (DIC) due to gastric carcinoma. He had been diagnosed as human immunodeficiency virus (HIV) sero-positive in 1990. Since then, he has been treated by the oral administration of zidovudine (AZT), dideoxyinosine (ddI) and intravenous administration of glycyrrhizin. In September 1990, he suddenly complained abdominal pain with bloody stool. His condition deteriorated in spite of our intensive treatment for DIC. He died of multiple organ failure (MOF) due to DIC. The autopsy findings showed gastric carcinoma, defined of signet ring cell carcinoma histopathologically. But neither opportunistic infection nor other cause of DIC were observed.

In order to elucidate the activation of the coagulation cascade in patients with malignant neoplasms, we measured the levels of plasma prothrombin fragment F1 + 2, which is liberated in the process of thrombin generation. Twenty healthy adults (Group A), 29 patients with malignancies not complicated with DIC (Group B) and 4 patients with DIC (Group C) were evaluated. The values of F1 + 2 in Group C (2.38 +/- 0.55 nmol/l) were significantly higher (p < 0.01) than those in Group A (0.52 +/- 0.19 nmol/l) and B (0.86 +/- 0.68 nmol/l). Many patients in Group B showed higher levels of F1 + 2 compared to normal subjects, however, no significant differences were found between Group A and B. With respect to other coagulation molecular markers such as TAT, D-Dimer and PIC, F1 + 2 levels revealed positive correlation to those levels. Concerning the clinical course of DIC, elevated levels of F1 + 2 normalized much rapidly than those of TAT and D-Dimer by continuous administration of heparin. In conclusion, the measurement of plasma F1 + 2 is important in monitoring the activation of coagulation system in patients with malignancies, especially with respect to early detection and treatment of DIC.

Pneumocystis carinii pneumonia (PCP) is a major opportunistic infection in acquired immunodeficiency syndrome (AIDS) and is treated with co-trimoxazole, pentamidine and others. The severe adverse reactions, including bone marrow suppression, by these therapeutic agents often preclude their continued use. A 14-year-old male HIV-positive hemophilia A patient, who was complicated by disseminated intravascular coagulation syndrome (DIC) following acute pancreatitis during treatment for PCP, was treated with proteinase inhibitors and anticoagulant agents. He was improved and discharged. As pentamidine may cause pancreatitis and develop DIC, it is important that pancreatic enzymes should be carefully followed when this agent administrated. In this case, granulocyte colony-stimulating factor and erythropoietin were effective for the bone marrow suppression, suggesting that importance of these agents for the prophylaxis of other secondary infections during the treatment.

A 36-year-old woman with disseminated intravascular coagulation syndrome (DIC) was admitted to the Third Department of Internal Medicine of the National Defense Medical College Hospital. Even after she recovered from DIC, she had a low level of C1-inactivator. Her past history, family history and family study revealed that she and her family showed hereditary angioneurotic edema (HANE). There have been no reports of HANE associated with DIC. She had two HANE attacks after discharge. We used nafamostat mesilate, a strong inhibitor of activated first complement component, to treat the attacks. She obtained subjective relief and her serological data were improved. Nafamostat mesilate was considered effective for HANE attack.

We examined fibrinolytic substances in homogenate of leukemic cells, normal granulocyte or mononuclear cells fraction. Plasminogen activators (PA) were significantly low in normal cells, but they were slightly increased in lymphoblastic leukemia cells and markedly increased in myeloblastic leukemia cells. In almost leukemic cells homogenate, the antigen ratio of tissue type PA (t-PA)/urokinase type PA (u-PA) was about 2.0. In especially AMMoL and AMoL, PA activity had discrepancy between euglobulin lysis time and amidolytic assay using chromogenic substrate. As PA inhibitor (PAI)-II was markedly increased in them. PAI might effect the PA assay. PA activity of leukemic cells homogenate was similar to that without t-PA stimulator and leukemic cells homogenate significantly stimulated t-PA. As both PA activity and antigen were statistically increased in leukemic cells homogenate of patient with disseminated intravascular coagulation (DIC), PA and PA stimulator in leukemic cell might play an important role in hypofibrinogenemia or DIC.

A 57-year-old man was admitted to our hospital with high fever and nasal obstruction. The diagnosis of T cell type malignant lymphoma (T-ML) was made by the biopsy of left nasal cavity tumor. After admission, his general condition was improved by chemotherapy and radiotherapy, but relapsed a month later. He was then treated with chemotherapy, and the partial remission was obtained. During the clinical course, he had a high fever again without any significant infections or exacerbation of T-ML. The data of coagulation system showed DIC. The levels of serum ferritin and LDH were extremely elevated. Bone marrow aspiration showed markedly increased hemophagocytic histiocytes. These data suggested that he was complicated by DIC and hyperferritinemia closely associated with hemophagocytic histiocytosis a part from the underlying T-ML. Causes of DIC and hyperferritinemia associated with hemophagocytic histiocytosis in the present case were discussed.