Tacrolimus (FK506) associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in lung transplant salvage with a plasmapheresis and cyclosporin

Thrombotic microangiopathy (TMA), a microvascular hemolytic disorder is a rare, but well described complication in organ transplant patients receiving immunosuppressant drugs. We report a 56-year-old female with a history of left lung transplant that presented to the hospital with microangiopathic hemolytic anemia and thrombocytopenia while receiving tacrolimus (FK 506) for 36 months. The patient was diagnosed with tacrolimus-induced TTP/HUS and started on daily plasmapheresis, and replacement of FK506 with cyclosporine. After thirteen plasmapheresis procedures, her platelet count, lactate dehydrogenase, and hematocrit were normalized. The ADAMTS-13 activity was subnormal and no inhibitory antibody was detected. The combination of daily plasmapheresis with fresh frozen plasma as a source of ADAMTS-13 and cyclosporine may be used as a rescue therapy in patients with FK506-induced TTP/HUS.     

Thrombotic microangiopathy and cytomegalovirus in liver transplant recipients: a case-based review

Background. Thrombotic microangiopathy (TMA) is a rare but potentially lethal complication encountered in solid organ and bone marrow transplant recipients, requiring rapid recognition, diagnosis, and initiation of therapy. Several potential causes have been identified in this setting, including viral infections and medications. Methods. We report a case of TMA in a liver transplant recipient with active cytomegalovirus (CMV) gastritis. A 41‐year‐old female presented 3 months after liver transplantation with a 5‐week history of nausea, vomiting, anorexia, and diarrhea. CMV serology was donor seropositive and recipient seronegative (D+/R?). The immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisone. Evaluation revealed CMV viremia with a high viral load and intravenous ganciclovir was started. A decline in hemoglobin and platelets with an increase in lactate dehydrogenase (LDH) warranted hematologic evaluation, which revealed findings consistent with microangiopathic hemolytic anemia. Ganciclovir and tacrolimus were discontinued. Intravenous immunoglobulin was administered and daily plasmapheresis was initiated. As the patient's blood counts and LDH started to improve, ganciclovir was cautiously reinstituted. The patient's gastrointestinal symptoms gradually resolved and her blood counts continued to improve with prolonged plasmapheresis (a total of 23 plasmapheresis sessions). Tacrolimus and possibly CMV infection were suspected to be the cause for her TMA, and cyclosporine was substituted. Conclusions. TMA is an important entity in the differential diagnosis of acute hemolytic anemia in liver transplant recipients. Many cases seem to be medication‐induced. However, in treatment‐resistant or relapsing cases, a possibility of concomitant CMV infection should be considered.     

Immune thrombocytopenia after umbilical cord progenitor cell transplant: response to vincristine.

An 8-month-old male with X-linked lymphoproliferative disease underwent an unrelated, partially matched (with major mismatch at DR locus), cord blood stem cell transplant. Four months following the transplant, he developed immune thrombocytopenia with hemolytic anemia (Evans syndrome). He received multiple courses of intravenous immunoglobulin, anti-Rh D immunoglobulin, a pulse of high-dose corticosteroids and cyclosporine with some improvement of hemolytic anemia, but no improvement of the thrombocytopenia. Addition of vincristine, resulted in long-term resolution of thrombocytopenia and anemia. No major toxicity was observed during treatment. Vincristine should be considered as a treatment for refractory immune thrombocytopenia after hematopoietic stem cell transplantation.     

Thrombotic microangiopathy in sickle cell disease crisis

Thrombotic microangiopathy (TMA) in patients with sickle cell disease (SCD) is a rare complication. These patients manifest microangiopathic hemolytic anemia (MAHA) with laboratory evidence of hemolytic anemia, schistocytosis, and thrombocytopenia. This is the first report of the syndrome in a group of these patients. A retrospective chart analysis of 10 consecutively diagnosed patients in SCD crisis who were referred for therapeutic plasma exchange (TPE) after developing MAHA was done. Patients had chest pain, respiratory distress, fever, pulmonary infiltrates, jaundice, and neurological dysfunction with abnormal liver function and coagulation tests. MAHA was diagnosed after a median hospital stay of 5 days. Nine patients recovered completely following TPE with fluid replacement by fresh frozen plasma with or without cryo-poor plasma. Incomplete response to TPE in one case was due to the development of fresh complications. During a median follow-up period of 77 months, there was one recurrent episode and one death in SCD crisis but without evidence of MAHA. TMA is not a very rare complication among Bahraini SCD patients in crisis. Characteristic features of this disorder are acute chest syndrome, organ failure, leuco-erythroblastosis, and a combination of thrombocytopenia, LDH level >1,000 U/l, and schistocytes in blood smears. Management with TPE usually leads to complete recovery with little chance of short-term recurrence. Multiple pathogenetic mechanisms leading to increased von Willebrand factor and its multimers may form the basis of this syndrome.     

Pulmonary Tumor Thrombotic Microangiopathy: Report of 3 Cases and Review of the Literature

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinical entity where tumor cell embolisms in pulmonary circulation induce thrombotic microangiopathy (TMA), respiratory failure, and subacute cor pulmonale.We describe 3 cases of PTTM that presented as the initial manifestation of metastatic gastric adenocarcinoma with TMA and pulmonary infiltrates.All 3 cases had similar clinical and laboratory features, which included moderate thrombocytopenia without renal failure, hemolysis with extremely high serum lactate dehydrogenase levels, leukoerythroblastosis in peripheral blood smear, altered coagulation tests, lymphadenopathies, and interstitial pulmonary infiltrates. All patients died within 2 weeks of diagnosis. Two cases were initially misdiagnosed as idiopathic thrombotic thrombocytopenic purpura and treated with plasma exchange with no response. One patient had bone marrow infiltration by malignant cells. Autopsies revealed PTTM associated with gastric disseminated adenocarcinoma (signet-ring cell type in 2 patients and poorly differentiated type in 1).PTTM should be considered in the differential diagnosis of patients with fulminant microangiopathic hemolytic anemia, such as atypical thrombotic thrombocytopenic purpura, mainly those with pulmonary infiltrates, disseminated intravascular coagulation, or Trousseau syndrome.     

Severe thrombotic microangiopathy associated with brucellosis: successful treatment with plasmapheresis.

Brucellosis is a disease that may lead to changes in hematologic parameters such as anemia, neutropenia, and thrombocytopenia; however, thrombotic microangiopathy (TMA) is a rare finding. Severe TMA may be associated with life-threatening hematologic, renal, and neurologic disorders. To prevent this mortality caused by brucellosis, prompt recognition of this complication and prompt therapy are essential. A patient with TMA associated with Brucella melitensis is presented who initially presented with fever, skin purpura, epistaxis, confusion, microangiopathic hemolytic anemia, and thrombocytopenia. TMA was treated with plasmapheresis with cryosupernatant plasma replacement, energetically. A rapid improvement in platelet count, lactate dehydrogenase level, hemolytic anemia, and neurologic symptoms was observed with this treatment. For cases with infection-induced thrombotic microangiopathy, short-term plasmapheresis may be applied as an urgent therapy in addition to antimicrobial therapy.     

Transplantation-associated thrombotic microangiopathy: twenty-two years later

A syndrome of microangiopathic hemolytic anemia, renal dysfunction and neurological abnormalities was first noted in bone marrow transplant recipients 22 years ago. Now known as transplantation-associated thrombotic microangiopathy (TA-TMA) to distinguish it from other thrombotic microangiopathies, this disorder responds poorly to conventional treatments for thrombotic thrombocytopenic purpura. In this review, we discuss the incidence and risk factors for TA-TMA and describe a pathophysiologic model of the disorder based on results obtained from laboratory models of the thrombotic microangiopathies. We conclude by suggesting possible approaches to the early diagnosis and treatment of TA-TMA based on this model that may warrant testing in future clinical trials.     

Therapeutic Plasma Exchange Improved Pregnancy-associated Thrombotic Microangiopathy but not the Pregnancy Outcome in Patient with Systemic Lupus Erythematosus

Thrombotic microangiopathy (TMA) is a rare but life-threatening complication of systemic lupus erythematosus (SLE) and is associated with adverse pregnancy outcomes. We herein report a 30-year-old pregnant woman with SLE complicated by TMA. Because her condition was unresponsive to initial corticosteroid and fresh-frozen plasma infusion treatment, we attempted plasma exchange (PE). Although thrombocytopenia and microangiopathic hemolytic anemia gradually improved, fetal death was confirmed at 23 weeks of gestation. This case suggests that PE is an effective therapeutic option but might be insufficient to maintain pregnancy in patients with SLE complicated by TMA.     

Thrombotic microangiopathy in hematotoxic snakebites and its impact on the prognosis: an entity often overlooked

Journal of Thrombosis and Thrombolysis - Snakebite associated thrombotic microangiopathy (TMA) is a spectrum of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia and...     

产后溶血尿毒症综合征1例报告及文献复习

目的：探讨产后溶血尿毒症综合征(PHUS)的临床特征、诊断治疗及预后情况。方法：报告1例PHUS患者，并复习有关文献就PHUS的临床特征、诊断治疗及预后等情况进行讨论。结果：该患者于正常分娩后第4天出现微血管病性溶血性贫血，血小板减少，肾功能急剧恶化，经血浆置换及血液透析等治疗无效，于发病后第14天死于多器官功能衰竭。结论：正常妊娠及分娩后发生微血管病性溶血性贫血、急性肾功能衰竭、血小板减少为PHUS的临床特征。早期诊断、及时正确治疗，对于降低PHUS患者死亡率至关重要。     

Atypical Hemolytic‐Uremic Syndrome: An Update on Pathophysiology,Diagnosis, and Treatment

Atypical hemolytic uremic syndrome (aHUS), a rare variant of thrombotic microangiopathy, is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. The condition is associated with poor clinical outcomes with high morbidity and mortality. Atypical HUS predominantly affects the kidneys but has the potential to cause multi‐organ system dysfunction. This uncommon disorder is caused by a genetic abnormality in the complement alternative pathway resulting in over‐activation of the complement system and formation of microvascular thrombi. Abnormalities of the complement pathway may be in the form of mutations in key complement genes or autoantibodies against specific complement factors. We discuss the pathophysiology, clinical manifestations, diagnosis, complications, and management of aHUS. We also review the efficacy and safety of the novel therapeutic agent, eculizumab, in aHUS, pregnancy‐associated aHUS, and aHUS in renal transplant patients.     

Thrombotic microangiopathy

The term 'thrombotic microangiopathy' (TMA) describes syndromes of microangiopathic hemolytic anemia, thrombocytopenia, and variable signs of organ impairment, due to platelet aggregation in the microcirculation. The term 'hemolytic uremic syndrome' (HUS) has entered clinical use to describe childhood cases of TMA dominated by renal impairment, while the term 'thrombotic thrombocytopenic purpura' (TTP) refers to adult cases of TMA with predominant neurological abnormalities. HUS and TTP show the same histological lesion characterized by widening of the subendothelial space and microvascular thrombosis and their different manifestations are secondary to the different distribution of the microvascular lesions. Available evidence orients towards endothelial injury as an important factor in the sequence of events leading to the microangiopathic process. Here we provide an overview of the pathophysiology, epidemiology, clinical manifestations, and management of TMA.     

A case of thrombotic microangiopathy complicated with systemic lupus erythematosus

A woman was admitted to the hospital with joint pain. She was also found to have pericardial effusion, renal dysfunction, pancytopenia, and positive antinuclear antibody; a diagnosis of systemic lupus erythematosus (SLE) was made. Although she had neither neurological symptoms nor fever, laboratory tests showed microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Therefore, we diagnosed her illness as SLE complicated by thrombotic microangiopathy (TMA). Plasmapheresis was performed in addition to immunosuppressive therapy. TMA improved rapidly and renal function improved gradually. The number of patients with SLE complicated by TMA is relatively small and the mortality rate is extremely high. A diagnosis of TMA is difficult to determine in patients with SLE because of the overlapping clinical symptoms. The data suggest that prompt induction of plasmapheresis in addition to immunosuppressive therapy is necessary in SLE patients having symptoms suspicious of TMA even before they fulfill the 5 symptoms typical of TMA.     

Thrombotic microangiopathy caused by severe graft dysfunction after living donor liver transplantation: report of a case

Thrombotic microangiopathy (TMA) is a life-threatening complication after transplantation including liver transplantation, and its typical clinical picture is characterized by hemolytic anemia, thrombocytopenia, renal dysfunction, neurological abnormalities, and fever. We report the case of a 56-year-old female with end-stage liver disease who underwent living donor liver transplantation (LDLT), and whose postoperative course was characterized by renal failure and progressive hyperbilirubinemia. Two weeks after LDLT, she started to show progressive thrombocytopenia, anemia, oliguria, and encephalopathy. From these clinical manifestations, she was diagnosed as having TMA and underwent plasma exchanges with continuous hemodialysis under temporary holding calcineurin inhibitors. The patient promptly responded to the treatment, with improved hematological, hepatic, and renal conditions, and was discharged from hospital a month later in a stable condition. We describe this case of TMA after LDLT with poor graft function and extensively review the disease in liver transplant recipients.     

Evans syndrome associated with idiopathic mixed-type autoimmune hemolytic anemia

A 60-year-old man was admitted to our hospital with severe anemia and blood findings showed hemolytic anemia. Further serological examination revealed both warm-reactive autoantibody and cold agglutinin against erythrocytes. The cold agglutinin showed a low titer, 1 : 32 at 4 degrees C, and had a high thermal amplitude of 30 degrees C or higher, resulting in sufficient activity for hemolysis. Since no underlying disorders could be detected, the diagnosis was idiopathic mixed-type autoimmune hemolytic anemia. Although thrombocytopenia (Evans syndrome) subsequently appeared, corticosteroid was extremely effective for both anemia and thrombocytopenia. In this report we describe a rare case of Evans syndrome associated with mixed-type autoimmune hemolytic anemia, which had a dramatic response to corticosteroid therapy.     

Thrombotic thrombocytopenic purpura in a patient with rapidly progressive scleroderma

A 57-year-old man presented with palpitations, shortage of breath on exertion, and rapidly progressive scleroderma. On admission, a computed tomographic scan of his lung showed active interstitial pneumonia. We treated him with d-penicillamine and intravenous pulse methylprednisolone. After this treatment, severe abdominal pain, microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal involvement appeared. We diagnosed him as having systemic sclerosis (SSc) complicated by thrombotic thrombocytopenic purpura. At postmortem, thromboses of capillaries, arterioles, and small arteries were found in several organs. As well as the differential diagnosis of SSc with thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and renal involvement, we diagnosed scleroderma renal crisis (SRC), normotensive renal crisis (NRC), and SSc complicated by TTP. Typical SRC and NRC were excluded because his blood pressure was in the normal range without elevation of plasma renin activity or azotemia over his clinical course. Although distinguishing TTP from renal crisis is difficult, an evaluation of ultra-large multimers of von Willebrand factor (UL-vWF) concentration may be helpful in these situations. Received: November 10, 1999 / Accepted: September 18, 2000     

Severe microangiopathic hemolytic anemia and thrombocytopenia in a child with Brucella infection

We present a case of severe microangiopathic hemolytic anemia and thrombocytopenia with epistaxis, gross hematuria, hemoglobinuria, and skin purpura in a child with Brucella septicemia proven by culture. The patient showed the features of this illness: leukopenia, severe hemolytic anemia, thrombocytopenia, fragmentation of erythrocytes in the peripheral blood smear, increased erythropoiesis, megakaryopoiesis, and granulomata cell invasion in the bone marrow. The patient was treated with rifampin and doxycycline. Platelets and leukocyte numbers rose to normal values by the 6th day. She was discharged on the 14th day. Follow-up of the patient 1 year later showed normal bone marrow morphology. Differential diagnosis, pathogenesis, and therapy of Brucella infection are discussed.     

皮肤淤斑、血小板减少伴肾功能损害

47岁男性患者,急性起病,临床表现为微血管病性溶血性贫血、血小板减少、高血压及肾功能损害,补体C3减低,血浆ADAMTS13活性极度缺乏,肾活检证实病理改变为血栓性微血管病;大剂量血浆及甲泼尼龙(累计5g)治疗后血液学缓解,ADAMTS13酶活性恢复正常,但病情反复,肾功能继续恶化,8个月后进入维持性血液透析。     

von Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience

Severe deficiency of von Willebrand factor (VWF)-cleaving protease (ADAMTS-13) activity (<5% of normal) is a specific finding for acute idiopathic thrombotic thrombocytopenic purpura (TTP), a disorder that presents as thrombocytopenia, microangiopathic hemolytic anemia, and often organ dysfunction such as neurological disturbances or renal failure, and fever. Between January 2001 and July 2003, ADAMTS-13 activity was determined in plasma samples of 396 consecutive patients referred to our laboratory for diagnostic purposes. Plasma samples with ADAMTS-13 activity less than 5% were in addition tested for the presence of inhibitory antibodies. Patients were assigned to 10 predefined clinical categories according to information provided by the referring clinician: thrombotic microangiopathy (TMA) not further specified; neoplasia- or chemotherapy-associated TMA; TMA following hematopoietic stem cell transplantation; TMA with additional/alternative disorder; idiopathic TTP; hemolytic-uremic syndrome (HUS) not specified; HUS with diarrhea prodrome (D+HUS); atypical HUS; other hematological disorder; and no clinical information available. Severe ADAMTS-13 deficiency was found in 69 (17%) patients, including 42 with acquired idiopathic TTP, either at initial presentation or at relapse, 14 with confirmed or suspected hereditary TTP, 10 with TMA not further specified, two with neoplasia- or chemotherapy-associated TMA, and one in continued clinical remission 3.4 years after splenectomy for plasma-refractory TTP. Forty-three (62%) patients with ADAMTS-13 activity less than 5% displayed inhibitory antibodies. Severe ADAMTS-13 deficiency was found in 60% of patients diagnosed with acute idiopathic TTP, but in none of 130 patients diagnosed with HUS or in any of the 14 patients with hematopoietic stem cell transplantation-associated TMA. Thus, plasma ADAMTS-13 activity less than 5% does not identify all patients clinically diagnosed with TTP, and severe ADAMTS-13 deficiency is not invariably associated with clinical manifestations of microvascular platelet clumping.