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Thrombotic thrombocytopenic purpura (TTP) is a fatal thrombotic disease caused by a marked decrease in the activity of ADAMTS13, a von Willebrand factor cleaving protease. In congenital TTP, ADAMTS13 activity is decreased by an abnormality in ADAMTS13, and in acquired TTP, by anti-ADAMTS13 autoantibody. Death from thrombosis in the acute phase has been an issue with conventional treatment of acquired TTP by plasma exchange or immunosuppressive therapy. However, the advent of caplacizumab, an anti-VWF nanobody, has made it possible to suppress thrombus formation and is expected to improve survival rates. In addition, some case series have shown the efficacy of caplacizumab without plasma exchange for acquired TTP, and this approach is being investigated in clinical trials. Fresh-frozen plasma is transfused to supply ADAMTS13 for congenital TTP, but frequent transfusions over a long period of time can lead to problems such as infection and allergic reactions. Novel therapies such as recombinant ADAMTS13 products and gene therapy are now under development, and show promise for future clinical use.

A 27-year-old woman was diagnosed with idiopathic thrombocytopenic purpura in the neonatal period, and was admitted to our hospital after presenting with impaired consciousness, purpura, nausea and vomiting, with a platelet count of 10×10 9 /l. Congenital thrombotic thrombocytopenic purpura (cTTP) was suspected on the basis of recurrent thrombocytopenia and impaired consciousness, so tests for ADAMTS13 activity and inhibitor were performed. ADAMTS13 activity was severely decreased, ADAMTS13 inhibitor was negative, and platelet count increased after transfusion of fresh frozen plasma. These findings and the results of genetic testing done on all family members led to a diagnosis of cTTP. cTTP requires differential diagnosis even in adults. If a patient diagnosed with ITP in childhood has a history or findings that suggest cTTP during follow-up observation, it is necessary to actively consider ADAMTS13 testing.

Immune checkpoint inhibitor (ICI)-induced thrombocytopenias are rare immune-related adverse events (irAE), but ICI-related thrombotic thrombocytopenic purpura (TTP) is extremely rare. A 79-year-old woman with non-small cell lung cancer received maintenance therapy with the anti-human PD-L1 monoclonal antibody durvalumab. Four weeks after the last infusion, she developed overt TTP. Remission was achieved by plasma exchange and prednisolone, and the patient has now been recurrence-free for over 12 months. To our knowledge, this is the first report of TTP occurring as an irAE of durvalumab.

Thrombotic thrombocytopenic purpura (TTP) is a poor prognosis disease caused by platelet thrombi produced in the microvessels throughout the body. The thrombus is mainly composed of von Willebrand factor (VWF) and platelets. Acquired TTP is an autoimmune disease wherein autoantibodies against ADAMTS13, a VWF-cleaving enzyme, are produced and ADAMTS13 activity is markedly decreased. Plasma exchange using fresh-frozen plasma as a replacement fluid effective against acquired TTP was reported in 1991. Since then, plasma exchange and corticosteroids have been the standard of care in Japan. Caplacizumab, which is a monoclonal antibody against the VWF A1 domain, finally became available for use in 2022, and the number of cases is still increasing in Japan. A clinical trial of recombinant ADAMTS13 product is being conducted for congenital TTP, and an era is expected to come in the future when plasma exchange will no longer be necessary.

Thrombotic microangiopathy (TMA) is a pathological condition characterized by platelet thrombi-induced generalized microvascular occlusion, thrombocytopenia, and microangiopathic hemolytic anemia. TMA includes the life-threatening diseases thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). TTP is different from HUS in that it has a severe deficiency in ADAMTS13 activity. Congenital TTP is caused by a lack of plasma ADAMTS13 activity caused by genetic mutations, and acquired TTP is caused by a secondary deficiency caused by autoantibodies. In Japan the only product approved for the treatment of congenital TTP is fresh frozen plasma containing ADAMTS13. Recombinant ADAMTS13 may provide a new treatment option for congenital TTP. The first-line treatment for acquired TTP is plasma exchange. Rituximab treatment should be considered for patients who are refractory or have relapsed. Caplacizumab is a nanobody that specifically targets von Willebrand factor. ISTH recently published guidelines recommending that caplacizumab be added to the initial treatment for acquired TTP. Atypical HUS (aHUS) is related with the dysregulation of the complement alternative pathway. Eculizumab, a monoclonal antibody that inhibits C5, was the first drug approved for aHUS, and it was found to be well-tolerated by patients and effective in clinical use. TMA is classified based on its etiology, and specific treatments for targeting various etiologies are now available.

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially life-threatening disease that is characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and ischemic organ damage resulting from the formation of platelet-rich thrombi in the microvasculature. It is especially related to a severe deficiency of ADAMTS13, the specific von Willebrand factor-cleaving protease. Thus, <10% of the normal activity of ADAMTS13 is an essential diagnostic marker for establishing a diagnosis of TTP. TTP can be of congenital form that is termed the Upshaw-Schulman syndrome (USS) that is caused by genetic abnormality of ADAMTS13 and acquired form that is caused by autoantibodies against ADAMTS13. The congenital form is treated with the infusion of fresh frozen plasma, and the treatment of the acquired form involves plasma exchange combined with immunosuppressive therapy that uses corticosteroids and rituximab. Recently, the efficacy and safety of new drugs caplacizumab, single-domain antibody against ADAMTS13, and recombinant ADAMTS13 products have been reported in large-scale clinical trials conducted in other countries. These results suggested the better outcome in the treatment for the patients with TTP in the near future.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening systemic thrombotic microangiopathy characterized by the presence of anti-ADAMTS13 antibodies (inhibitor). Here we report the case of a patient with refractory aTTP successfully treated with cyclosporine. A 69-year-old man presenting with hematuria and petechiae was referred to our hospital; he was disoriented and febrile. Laboratory results revealed Coombs-negative hemolytic anemia, thrombocytopenia, and renal failure. Undetectable ADAMTS13 activity and presence of anti-ADAMTS13 antibodies (inhibitor) confirmed the diagnosis of aTTP. Despite performing plasma exchange and administering prednisolone and rituximab (375 mg/m 2 ), we were unable to restore his platelet counts to the normal level. Therefore, he was treated with cyclophosphamide (500 mg/bodyweight), vincristine (1.4 mg/m 2 ), bortezomib (1.3 mg/m 2 ), and cyclosporine (2.5 mg/kg). After the cyclosporine therapy, his platelet counts gradually normalized. Continuous cyclosporine maintenance therapy led to complete disappearance of the inhibitor. Therapeutic strategies for refractory aTTP have not yet been established. Further investigations are warranted to establish a therapeutic strategy for refractory aTTP.

In this article, I mainly review the molecular targeted therapy for thrombotic thrombocytopenic purpura (TTP). TTP is one of thrombotic microangiopathies (TMA), which demonstrate hemolytic anemia with red blood cell destruction and thrombocytopenia. Another TTP, hemolytic uremic anemia (HUS) reveals bloody stood and acute kidney failure. As it is difficult to correctly diagnose TTP based on clinical symptoms alone, a confirmation of whether ADAMTS13 activity is lower than 10% is required. In the past few years, TTP was designated as an intractable disease by law, and the clinical application of ADAMTS13 test and rituximab became labeled in Japan. Currently, we are expecting that recombinant ADAMTS13 and caplacizumab for immune TTP will be applied.

The key clinical symptoms of thrombotic thrombocytopenic purpura (TTP) are severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia/infarction due to microthrombi. Hemolytic anemia in TTP is characterized by mechanical damage to red blood cells. TTP is caused by a severe deficiency of ADAMTS13 activity, which is caused by mutations in the ADAMTS13 gene (congenital TTP) or by autoantibodies affecting the function or clearance of ADAMTS13 (immune TTP). Patients with congenital TTP receive fresh frozen plasma (FFP) transfusion for the supplementation of ADAMTS13. Meanwhile, those with immune TTP receive plasma exchange therapy using FFP for the supplementation of ADAMTS13 and the removal of anti-ADAMTS13 autoantibodies. Corticosteroid therapy is concurrently administered to suppress autoantibody production. In terms of novel treatment, the use of rituximab, a humanized anti-CD20 monoclonal antibody, in patients with immune TTP was approved by the Japanese health insurance in 2020. Novel and promising drugs are currently developed. A first-in-human study of recombinant ADAMTS13 for congenital TTP was reported in 2017. Caplacizumab is a humanized nanobody that inhibits the interaction between von Willebrand factor and platelets. This drug can prevent early thrombus formation and organ damage in patients with immune TTP. Therefore, these novel drugs can improve mortality in patients with TTP.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) caused by ADAMTS13 deficiency. Although the name of TTP is well known, most hematologists find its diagnosis and treatment difficult because it is ultrarare. TTP is an acute-onset and fatal disorder. Approximately 90% of TTP patients die within 2 weeks of onset without proper medical treatment. Although most doctors may remember being taught the five TTP symptoms (fever, transient central nervous system symptoms, hemolytic anemia, thrombocytopenia, and kidney dysfunction) at medical school, only 7% of TTP patients present with all five symptoms. Thus, TTP must be suspected in patients with microangiopathic hemolytic anemia and thrombocytopenia, and plasma therapy must be initiated as soon as possible after ordering the ADAMTS13 test. In this article, I describe how to differentially diagnose TMA as well as the standard and the updated therapy, such as rituximab and caplacizumab, for TTP treatment.

A 30-year-old woman who was 14 weeks pregnant was admitted to our hospital due to purpura, nasal bleeding, and abdominal pain. She was diagnosed with acquired thrombotic thrombocytopenic purpura (TTP) based on the presence of hemolytic anemia, thrombocytopenia, decreased ADAMTS 13 activity (<0.01 IU/ml), and high ADAMTS 13 inhibitor levels (4.8 BU/ml). Plasma exchange (PE) and steroid therapy were immediately administered. However, because she did not respond to these therapeutic approaches, rituximab was additionally administered on the sixth day of treatment. The level of ADAMTS 13 inhibitor increased to 12.5 BU/ml on the seventh day. Renal insufficiency, disturbed consciousness, and genital bleeding did not improve in spite of daily PE, steroid therapy, and second dose of rituximab. She finally died after sudden convulsions on the 14th day. Although the treatment outcomes of TTP have remarkably improved, some cases are refractory to therapy. Establishment of adequate treatment strategies for acquired TTP in pregnant women is required.

Both TTP and aHUS are officially designated as intractable diseases by a new Japanese law in 2015. New clinical practice guidelines for TTP and aHUS have been published. Both conditions share some common pathophysiology such as thrombotic microangiopathy. Unfortunately, most professionals in the fields of hematology/oncology are unaware of these diseases. Therefore, I will provide an updated overview of TTP and aHUS in this article.

Although thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease, appropriate diagnosis and treatment result in the higher survival rate of >80%. TTP is usually suspected with thrombocytopenia and hemolytic anemia and is confirmed by a reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) <10%. TTP is classified as acquired if a patient tests positive for anti-ADAMTS13 autoantibodies, and as congenital if ADAMTS13 gene abnormalities are identified. In patients with congenital TTP, fresh frozen plasma (FFP) transfusion for the supplementation of ADAMTS13 is performed. On the other hand, in patients with acquired TTP, plasma exchange therapy using FFP is conducted to supplement ADAMTS13 and remove anti-ADAMTS13 autoantibodies. Besides, corticosteroid therapy is often administered in conjunction with plasma exchange to suppress autoantibody production. In 2017, we aim to provide "diagnostic and treatment guidelines for TTP 2017 in Japan". In this review, we describe new developments in diagnosis and management of TTP, which are not discussed in the guidelines.

An 81-year-old man presenting with fever, neurological symptoms, thrombocytopenia, and hemolytic anemia was diagnosed with acquired idiopathic thrombotic thrombocytopenic purpura (TTP). His disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity was <1% and the ADAMTS13 inhibitor titer was 3.2 BU/ml. He received plasma exchange and steroid administration until remission was achieved. Seven months later, he suffered from paralysis of the right hand, hemolytic anemia, and thrombocytopenia. We confirmed TTP recurrence based on ADAMTS13 activity <1% and an ADAMTS13 inhibitor titer of 19.4 BU/ml. Four infusions of rituximab were administered in addition to plasma exchange and steroid pulse therapy. Platelet count recovery was observed within 5 days. No severe side effects related to rituximab occurred. Although rituximab has not been approved for TTP in Japan, we report the efficacy and safety of rituximab in an elderly patient with recurrent TTP. We suggest that rituximab therapy should be started as soon as possible for recurrent TTP in patients with high titers of ADAMTS13 inhibitor.

Acquired thrombotic thrombocytopenic purpura (TTP) is caused by autoantibodies against ADAMTS13. TTP patients run a rapidly fatal course unless immediate plasma exchange (PEX) is initiated upon diagnosis. Herein, we report a 72-year-old man with TTP, which developed after he underwent artificial blood vessel replacement surgery for an abdominal aneurysm with impending rupture. In the perioperative period, the patient received several platelet transfusions for severe thrombocytopenia (minimum platelet count: 0.6×10(4)/μl). Thereafter, he was admitted to our department for rapidly progressing coma with multiple cerebral infarctions, and was transferred to the ICU. Based on the tentative diagnosis of TTP, we immediately began PEX and steroid pulse therapy. The diagnosis was confirmed thereafter by markedly reduced ADAMTS13 activity (<0.5%) and his being positive for the ADAMTS13 inhibitor. We performed PEX for five consecutive days and administered high-dose prednisolone (PSL). On the second hospital day (HD), his platelet count rose along with improvement of his consciousness level. The ADAMTS13 inhibitor was not detected on the 10th HD. TTP did not relapse and his general condition improved despite tapering of PSL. In this case, by closely monitoring ADAMTS13-related parameters and minimizing the number of plasma exchanges, the patient was able to achieve a remission without the use of boosting inhibitors.

Thrombotic microangiopathies (TMAs) are microvascular occlusive disorders characterized by thrombocytopenia, microangiopathic hemolytic anemia, and systemic or intrarenal aggregation of platelets. TMA includes two major disorders: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). It is now well known that TTP is caused by deficiency of ADAMTS13 activity due to mutations in the ADAMTS13 gene (Upshaw-Schulman syndrome, USS) or by acquired autoantibodies against ADAMTS13. On the other hand, more than 90% of HUS cases are associated with Shiga toxin-producing E. coli infection. The remaining 10% of patients have what is called atypical HUS (aHUS). Most aHUS cases are caused by uncontrolled complement activation due to genetic mutations in the alternative pathway, such as complement factor H, complement factor I, membrane cofactor protein (CD46), and C3. TMAs also develop in association with various underlying diseases and conditions (so-called secondary TMA) including connective tissue disorders, transplantation (hematopoietic stem cell, liver, kidney), malignancy, pregnancy, and certain drugs. Plasma exchange is the first-line therapy for most patients with TMAs. Early plasma exchange improves TMA outcomes. Monoclonal therapies, rituximab in TTP and eculizumab in aHUS, are now frequently being used as second-line treatment options.

An 89-year-old woman presented to our hospital with hemolytic anemia and a high titer of cold agglutinins. Red cell agglutination was observed on a blood smear. Agglutination visibly decreased after warming the blood; therefore, the patient was diagnosed with cold agglutinin disease (CAD). Bone marrow aspiration revealed no infiltration of malignant cells. Computed tomography indicated moderate splenomegaly. The patient had neither an infection nor autoimmune disease. Initial steroid therapy was ineffective and hemolysis worsened. Meanwhile, thrombocytopenia, delirium, fever, and schistocytes in the blood were observed. The progression of hemolysis was attributed not only to CAD but also to coexisting thrombotic thrombocytopenic purpura (TTP) because of the decreased ADAMTS 13 level. Autopsy revealed mild paraaortic lymphadenopathy and splenomegaly. Microscopic examination revealed lymphoma cell infiltration in the spleen, liver, bone marrow, and paraaortic lymph nodes. These observations suggested that TTP and CAD were both secondary complications. This case highlights the importance of an autopsy for the detection of latent lymphoma, which can be difficult to diagnose before the patient's death. Careful examination to exclude lymphomas is important in patients with CAD at the time of diagnosis.

We report here on a case of a 27-year-old woman in her first pregnancy. She was diagnosed with idiopathic thrombocytopenic purpura (ITP) at the age of 14 years. At 36 weeks of gestation, she was admitted to our hospital due to thrombocytopenia. We initially suspected ITP exacerbated by pregnancy. Laboratory results revealed mild anemia, thrombocytopenia (5.0×10(9)/l), and slightly elevated liver enzymes and lactate dehydrogenase. The next day, hemoglobin fell to 6.6 g/dl. Thrombotic thrombocytopenic purpura (TTP) was suspected on the basis of hemolytic anemia with schistocytes and a negative Coombs' test. Plasma exchange and methylprednisolone were initiated immediately. ADAMTS13 analysis showed a severe deficiency in ADAMTS13 activity but no inhibitors. At Day 6, the platelet count rose to 223×10(9)/l and she delivered a live baby by cesarean section. Currently, the patient receives fresh frozen plasma infusions every 2 weeks due to suspected Upshaw-Schulman syndrome.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is a rare complication of thienopyridine treatment, especially clopidogrel. Here we report a case of clopidogrel-associated TTP. A 77-year-old male initially complained of petechiae on his legs 6 weeks after clopidogrel treatment following coronary artery stenting. He was admitted 4 weeks later with slurred speech and low-grade fever. Laboratory findings showed severe thrombocytopenia, hemolytic anemia with fragmented red cells, renal dysfunction and severe deficiency of ADAMTS13 activity with the presence of the inhibitor. Based on the clinical course and laboratory findings, he was diagnosed with TTP and underwent plasma exchange, followed by improvement of symptoms and laboratory abnormalities after 7 courses of plasma exchange. Nevertheless, the patient died of sepsis due to perforated small intestinal diverticulitis 89 days after admission. Thienopyridine-associated TTP usually occurs within 12 weeks after initiation of the therapy. Physicians should therefore be aware of this fatal complication associated with clopidogrel therapy and frequent blood tests, every 2 weeks during the first 12 weeks, is recommended for early diagnosis.

A 47-year-old woman was transported to our hospital because of vomiting and syncope after breakfast. Physical examination revealed icterus and anemia of bulbar conjunctivas, and abnormal neurological findings were detected. Laboratory data indicated marked anemia and thrombocytopenia (Hb 5.2 g/dl, Plt. 0.6×10(4)/μl), but no leukocyte abnormalities were found. Transaminase was slightly elevated, and serum indirect bilirubin in was also elevated. Based on these data, we initially suspected Evan's syndrome, which involves idiopathic thrombocytopenic purpura with autoimmune hemolytic anemia. So we transfused red blood cells, performed platelet transfusion, and administered steroids, but there was no response to these therapies. On the 4th day of admission, she developed a stroke followed by coma. After the stroke, we diagnosed the case as thrombotic thrombocytopenic purpura (TTP) because laboratory findings showed diminished activity of ADAMTS 13 (a disintegrin-like metalloproteinase with thrombospondin type 1 motifs 13) and ADAMTS 13 antigen. It is important to suspect TTP when hemolytic anemia with thrombocytopenia is observed, and to check the activity and antigen of ADAMTS13 immediately for the diagnosis. Platelet transfusion should be done cautiously in these cases.

We report a patient with refractory idiopathic thrombotic thrombocytopenic purpura (TTP) who was successfully treated with rituximab. A 50-year-old woman was referred to our hospital with progressive psychoneurotic symptoms, hemolytic anemia and thrombocytopenia. The diagnosis of TTP was confirmed by the absence of ADAMTS13 activity with the presence of circulating ADAMTS13 inhibitor. High-dose steroid therapy and plasma exchange were performed. Despite 21 sessions of plasma exchange, however, there was no remarkable improvement. We then administered rituximab. Fifteen days after the first infusion of rituximab, she achieved complete remission and ADAMTS13 activity increased up to 14%. The patient has remained in remission for more than 9 months.

A 48-year-old man presented with consciousness disturbance with vasogenic edema in the occipital lobe on brain CT. The diagnosis of reversible posterior leukoencephalopathy syndrome (RPLS) was made. His hypertension was refractory to treatment, and his neurological disabilities and CT abnormalities, along with renal dysfunction, became worse. Hemodialysis and strict management of blood pressure resolved the neurological findings and the lesions on brain CT. However, one week later, consciousness disturbance and brain CT abnormalities recurred. At that time, hemolytic anemia with fragmented erythrocytes, thrombocytopenia, and renal dysfunction became apparent. We therefore diagnosed thrombotic thrombocytopenic purpura (TTP). Plasma exchange and vincristine administration improved not only the clinical findings of TTP, but also consciousness disturbance and brain CT abnormalities. We concluded that latent TTP had caused RPLS in this patient.

A 26-year-old man was referred to our hospital with vomiting and high fever. He was disoriented and laboratory results showed microangiopathic hemolytic anemia (Hb 7.1 g/dl) and severe thrombocytopenia (15 x 10(3)/microl). The diagnosis of thrombotic thrombocytopenic purpura (TTP) was established. The activity of von Willebrand cleaving protease (ADAMTS13) was found to be remarkably low (<0.5%) and the high activity of the inhibitor (11.0 Bethesda U/ml) was detected, confirming the diagnosis of typical acquired TIP. Although he had been successfully treated with daily plasma exchange and methylprednisolone, he relapsed after a week. To this therapeutic strategy we added four weekly doses of rituximab (375 mg/m2) and two weekly doses of vincristine (1 mg/m2) simultaneously. The response was very rapid and complete, that is, the platelet count recovered to normal seven days after the first rituximab and vincristine treatment. The patient maintains complete remission nine months later under the administration of 17.5 mg prednisolone. Recovery of the plasma ADAMTS13 activity was clearly correlated with the decrease or disappearance of the inhibitor activity. Combination of rituximab and vincristine therapy would appear to be very effective against refractory TTP.

We report a patient with severe thrombotic thrombocytopenic purpura (TTP) refractory to plasmapheresis who was successfully treated with rituximab. A 57-year-old male patient was referred to our department for further differential diagnosis and treatment of anemia and severe thrombocytopenia. Progressive psychoneurotic symptoms, hemolytic anemia, thrombocytopenia, renal function insufficiency and fever led us to the diagnosis of TTP. ADAMTS13 activity was below 3% and an inhibitor for ADAMTS13 was detected. Treatment with plasmapheresis and high-dose steroid was initiated but without clinical benefit. Two weeks following the initiation of plasmapheresis, we decided to treat the patient with 7 cycles of rituximab. No severe rituximab-related adverse effects were observed. After treatment with rituximab, the disease remitted, and the ADAMTS13 activity level increased. The patient has remained in complete remission for more than 1 year. Our data suggest that rituximab may be the optimal immunosuppressive therapy for refractory thrombotic thrombocytopenic purpura caused by an anti-ADAMTS 13 inhibitor.

A 19-year-old girl was admitted to our hospital because of general fatigue, headache and purpura. A number of her laboratory findings suggested hemolytic anemia and thrombocytopenia. Direct/indirect Coombs tests gave negative results. Although the patient had no neurological or renal abnormalities, peripheral blood smears showed marked red cell fragmentation, and therefore she was diagnosed as having thrombotic thrombocytopenic purpura (TTP). Fresh frozen plasma (FFP) was transfused daily. The thrombocytopenia and hemolysis immediately improved, but worsened again after reduction of the FFP transfusion. Plasma exchange was instituted every other day, but the patient's condition worsened. Palsy and consciousness disturbance developed, and finally she lapsed into a coma. Daily plasma exchange and methylprednisolone pulse therapy were performed, together with weekly vincristine therapy, and this led to a gradual improvement in the patient's condition. However, several attempts at weaning from plasma exchange resulted in exacerbation of the TTP activity. Therefore oral cyclosporine A was started and splenectomy was performed. After these interventions, despite transient relapse, the patient was successfully weaned off the FFP transfusion, and she is now in remission. Because in this case splenectomy and cyclosporine A resulted in sustained remission of TTP that was refractory to intensive plasma therapy, an autoimmune mechanism may have been involved in the pathogenesis.

On June 29, 1995, a 49-year-old man was admitted with acute onset of fever, petechiae on his legs, and mental confusion He had suffered hypertension since 6 months previously and was on nicardipine (60 mg/day), ifenprodil (60 mg/day) and ticlopidine (300 mg/day). He had been on ticlopidine for 4 weeks and on the other drugs for 6 months. Soon after admission he had frequent grand mal seizures and needed mechanical ventilation. A diagnosis of TTP was made. He was treated with plasmapheresis (50 ml/kg per day), aspirin 81 mg/day and dipyridamole 300 mg/day. On the sixth day his mental status returned to normal. He recovered gradually from microangiopathic hemolytic anemia, thrombocytopenia and elevated serum creatinine. We reviewed the literature and discussed the possible mechanism of TTP related to the use of ticlopidine.

We treated two patients with thrombotic thrombocytopenic purpura (TTP) with multiple plasma exchanges for a short period. Following 6 plasma exchanges during 11 days in patient 1 and the 8 exchanges during 13 days in patient 2, consciousness disturbance and thrombocytopenia improved with a decrease in serum lactate dehydrogenase (LDH) levels in both patients. However, thrombocytopenia rapidly progressed with a rise of serum LDH levels after a few days from cessation of the treatment. They received a few rounds of plasma exchange without beneficial effects and eventually died of massive hemorrhage. The clinical course of these patients indicates that some patients with TTP are refractory to repeated plasma exchanges for a short period. It seems important to determine the target point in blood chemistry values such as the LDH level for plasma exchange at which the treatment could be discontinued without causing relapse of TTP.

A rare case of dermatomyositis and thrombotic thrombocytopenic purpura (TTP), which responded dramatically to high-dose gamma globulin and vincristine is presented. A 42-year old man was admitted for evaluation of polymyalgia and skin change of the face and fingers. Findings of muscle biopsy was consistent with the diagnosis of dermatomyositis. During the course of his hospital stay, he had diffuse purpura, hematuria, high fever, and his consciousness became disturbed. The hemoglobin level and the platelet count decreased. Based on microangiopathic hemolytic anemia, thrombocytopenia and neurological abnormality, a clinical diagnosis of TTP was made. Therapy included high-dose gamma globulin, vincristine, corticosteroids and dextran. One week later, his consciousness became clear, hematological findings improved, and prolonged remission has been maintained for more than 19 months at the time of this report. This case suggests that gamma globulin and vincristine are effective in some with TTP cases. Case reports that have appeared in the Japanese literature are summarized and reviewed in terms of treatment.

A 60-year-old man was admitted to our hospital because of fever, hemorrhagic tendency, anemia and neurological abnormality. A blood count revealed that the hemoglobin was 6.8 g/dl, the reticulocyte was 17.3 percent with 2 erythroblasts per 100 white cells, the white cell count was 7,100/microliters and the platelet count was 0.8 x 10(4)/microliters. Peripheral blood smear demonstrated marked fragmentation of red cells. Bone marrow examination disclosed the marked erythroid hyperplasia. Although the bleeding time was prolonged (14 minutes 30 seconds), the other hemostatic data were within normal limits. The serum bilirubin level was 1.57 mg/dl; LDH level, 1,437 U/l; creatinine level, 0.92 mg/dl; BUN level 14.7 mg/dl. Haptoglobin was below 10 mg/dl. Results of immunological tests were all negative except the result of PAIgG (576.6 ng/10(7) cells). The urinalysis showed proteinuria, microhematuria and trace granular and hyaline casts. A diagnosis of thrombotic thrombocytopenic purpura was made. The patient was initially treated with prednisolone (60 mg), aspirin (1,000 mg), dipyridamole (150 mg), gabexate mesilate (1.5 g), sodium oxagrel (80 mg) daily with little response. The thirty days after admission, infusion of gamma globulin (20 g, daily) was given for 3 days. The clinical state and laboratory findings became dramatically improved shortly after the administration of gamma globulin and the laboratory data came to be normalized after 1 month. After ten months of this treatment, the patient is remained asymptomatic and the hematological data are within normal range without using any drug. A trial seems justified to confirm the value of this mode of therapy.

A 51 year-old woman with severe thrombocytopenia, hemolytic anemia, renal failure and loss of consciousness, and significant decrease in plasma large multimer of von Willebrand Factor (vWF) was diagnosed as having thrombotic thrombocytopenic purpura (TTP). She was treated with plasma exchange, anti-platelet agents and steroids. Although she showed temporary improvement and return of vWF multimer to a normal level, her symptoms reappeared, vWF large multimer level showed a remarkable increase, and she died because of pulmonary bleeding. It would be important that the vWF multimer bands changed in the course of TTP.

A 38-year old female patient with thrombotic thrombocytopenic purpura (TTP) did not respond to plasmapheresis and treatment with corticosteroids and antiplatelet agents but did respond to subsequent high-dose gamma-globulin therapy and vincristine slow infusion therapy. Remission, thought to be due to vincristine, was achieved. The administration schedule of vincristine was 1 or 2 mg once a week by intravenous drip infusion over a period of 6 to 8 hr. Improvement tended to be seen after the 6th administration, and remission was achieved after the 12th administration (total dose: 15 mg), and continues to the time of this writing. In this case, it was thought that vincristine inhibited a certain excessive reaction in the process of PAIgG-related platelet consumption. We conclude that vincristine should be administered at least 5 to 6 times, and the therapeutic method should be established based on the experience in a larger number of clinical cases.

We studied 10 patients with thrombotic thrombocytopenic purpura (TTP) and 5 patients with hemolytic uremic syndrome (HUS). Common cold symptoms were observed in 2 with TTP and 3 with HUS, and SLE was noted or suspected in 3 with TTP, and the onset was after operation in on with TTP and one with HUS. All TTP patients had coma and high fever. Renal failure was noted in 3 with TTP and their prognosis was poor. Seven patients with TTP and 4 patients with HUS survived. Autoantibody was highly positive in TTP but slightly positive in HUS. High molecular weight multimer of von Willebrand factor was decreased in 3 of 6 with TTP, platelet aggregating factor was positive in 4 of 6 with TTP, and microthrombus was observed in 7 of 8 with TTP. Tumor necrosis factor was increased in 5 of 9 with TTP and HUS, Interleukin-1 beta was increased in all TTP and HUS patients, and soluble interleukin 2 receptor and interferon alpha were also increased. Although plasma exchange was generally effective, some patients required combination therapy with steroids. We speculated that an autoimmune mechanism was involved in the on onset of TTP.

We reported a case of 69-year-old female presenting with clinically typical TTP which was treated with Ticlopidine and plasma exchanges four times in total and resulted in successful improvement of her clinical state. The first chromosomal analysis of lymphocytes in the peripheral blood of the patient revealed abnormal patterns of 45, XO/46, XX/47, XXX, the second, 45, XO/46, XX/47, XXX/47.XX, + 21. Measurement of FITC-labelled fibrinogen antibody against the fibrinogen combined with platelet glycoprotein GP IIb/IIIa complex using flow cytometry showed an apparently increased positive rate 76.2% for the platelet of the patient, compared with that of 31.9% for the control. From the comparative study of the platelet agglutination of the platelet rich plasma (PRP) derived from the citrated-added complete blood taken from the patient to whom Ticlopidine was given, added with adenosine-5'-diphosphate (ADP), collagen or acetyl glyceryl ether phosphoryl choline (AGEPC) as the reagents and that of normal control, it was shown that for AGEPC increased. Thus, increased reaction specific to AGEPC in addition to activated platelet was demonstrated in the present study.

A 49-year-old man with a one-week history of general fatigue and several other symptoms, including hematuria, numbness of the mouth, anemia and thrombocytopenia, was admitted because of an episode of convulsions and unconsciousness after blood transfusion. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was then made, and treatment with steroids, anti-platelet agents, transfusion of fresh frozen plasma was started. However, since no improvement was seen, on the third day of admission, treatment with plasma exchange was instituted (total plasma exchange volume was 18.1 iota), and his clinical and hematological conditions improved markedly. Since then, he has been in a remission state for about three years. Laboratory examinations during the acute phase showed increase of vWf: Ag, decrease of RCof/vWf: Ag, increase of vWf large multimers and a high endothelial cell injury activity by the patient's serum. In the next day following the plasma exchange therapy, RCof/vWf: Ag improved, but not to the normal range. One and a half years later, while in the remission phase, the vWf multimers and endothelial cell injury activity normalized. Thus, these findings show further evidence on the involvement of endothelial cell injury and vWf in the pathogenesis of TTP.