Plasma therapy in von Willebrand factor protease deficiency

We report a patient with relapsing hereditary hemolytic uremic syndrome (HUS) that began in the neonatal period with life-threatening jaundice and hemolytic anemia. He progressed to end-stage renal failure at 14 years of age and had a cerebrovascular accident while on dialysis. The cause of HUS was a constitutional deficiency in the von Willebrand factor cleaving protease. Hematological features of HUS significantly improved following bilateral nephrectomy. After renal transplantation, he had an early recurrence of HUS associated with two episodes of retinal and cerebral ischemia. Long-term treatment with fresh-frozen plasma exchanges prevented recurrence of HUS, cerebrovascular attacks, and early loss of the graft.     

Hemolytic uremic syndrome with systemic lupus erythematosus

Hemolytic uremic syndrome (HUS) as an initial presentation of systemic lupus erythematosus (SLE) is a rare finding. We report a 25-year-old female patient who presented to our hospital with complaint of fever, joint pain, anasarca, hematuria and nose bleed. Her diagnostic workup revealed renal failure, microangiopathic hemolytic anemia and thrombocytopenia due to SLE with HUS. The patient initially responded well to treatment with steroids, plasmapheresis with cryosupernatant and cyclophosphamide but finally succumbed to enterococcus septicemia.     

The successful treatment of atypical hemolytic uremic syndrome with plasmapheresis

A seven and a half-year-old boy presented with idiopathic atypical hemolytic uremic syndrome (HUS). He initially appeared to respond to plasma infusions. When he became refractory to plasma infusion, plasmapheresis was initiated. The treatment with plasmapheresis dramatically reversed the deterioration in glomerular filtration rate and platelet count. The use of plasma infusion and plasmapheresis in HUS is discussed. The authors advise the use of plasmapheresis in idiopathic atypical HUS.     

Plasmapheresis and antiplatelet agents in the treatment of the hemolytic uremic syndrome secondary to mitomycin

Four patients with the hemolytic uremic syndrome secondary to mitomycin therapy were treated with intense plasmapheresis and antiplatelet agents. All four patients had a hematologic response and three had slow, but steady, improvement in renal function. These results suggest an important role for these agents in mitomycin-induced hemolytic uremic syndrome.     

Renal failure due to scleroderma with thrombotic microangiopathy developing in a woman treated with carboplatin for ovarian cancer

Acute renal failure in association with microangiopathic hemolytic anemia and the pathological finding of thrombotic microangiopathy may occur in a number of conditions including hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and systemic sclerosis. Distinguishing between these conditions on clinical grounds may be difficult, and further investigations, including serological tests, are normally helpful. We present a patient who was treated with 5 doses of monthly carboplatin chemotherapy for stage IIb ovarian carcinoma and who subsequently developed acute renal failure and microangiopathic hemolysis together with some cutaneous features of systemic sclerosis. Initial serological tests, including anti-nuclear antibody titers measured using rat hepatocytes, were normal, and renal biopsy showed features of microangiopathic hemolysis, fibrinoid change, patchy tubular atrophy, and concentric intimal proliferation. A clinical diagnosis of diarrhea-negative hemolytic uremic syndrome was made and she was treated with plasma exchange and fresh frozen plasma infusion. However, she remained dialysis-dependent. Several weeks later she died following a cardiac arrest. Post-mortem examination revealed medial hypertrophy, concentric intimal proliferation, and thrombi within the small arteries of the kidneys and lungs. Subsequent results from tests taken at the time of her presentation with acute renal failure revealed a normal von Willebrand factor qualitative distribution, and a positive anti-nuclear antibody titer (using a human cell line) in association with positive autoantibodies to RNA polymerase types I, II, and III. Taken together, the clinical, laboratory, and post-mortem findings were suggestive of a diagnosis of systemic sclerosis. We discuss the differential diagnoses, and the associations between these and malignancy and chemotherapy. Finally, we consider the serological tests used for the diagnosis of systemic sclerosis that were, in this case, initially misleading.     

Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome

Several studies have demonstrated genetic predisposition in non-shigatoxin-associated hemolytic uremic syndrome (HUS), involving regulatory proteins of the complement alternative pathway: Factor H (FH) and membrane co-factor protein (CD46). Regarding the observations of thrombotic thrombocytopenic purpura patients, in whom a von Willebrand factor protease (ADAMST-13) deficiency may be inherited or acquired secondary to IgG antibodies, it was speculated that HUS might occur in a context of an autoimmune disease with the development of anti-FH antibodies leading to an acquired FH deficiency. The presence of FH autoantibodies was investigated by an ELISA method using coated purified human FH in a series of 48 children who presented with atypical HUS and were recruited from French university hospitals. Anti-FH IgG antibodies were detected in the plasma of three children who presented with recurrent HUS. The anti-FH specificity was conserved by the Fab'2 fraction. The plasma FH activity was found to be decreased, whereas plasma FH antigenic levels and FH gene analysis were normal, indicating that the presence of anti-FH antibodies led to an acquired functional FH deficiency. This report supports for the first time that HUS may occur in a context of an autoimmune disease with the development of anti-FH-specific antibody leading to an acquired FH deficiency. This new mechanism of functional FH deficiency may lead to the design of new approaches of diagnosis and treatment with a particular interest in plasma exchanges or immunosuppressive therapies.     

Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura

The term thrombotic microangiopathy (TMA) defines a lesion of vessel wall thickening (mainly arterioles or capillaries), intraluminal platelet thrombosis, and partial or complete obstruction of the vessel lumina. Depending on whether renal or brain lesions prevail, two pathologically indistinguishable but somehow clinically different entities have been described: the hemolytic uremic syndrome (HUS) and the thrombotic thrombocytopenic purpura (TTP). Injury to the endothelial cell is the central and likely inciting factor in the sequence of events leading to TMA. Loss of physiological thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal von Willebrand factor release and fragmentation, and increased vascular shear stress may then sustain and amplify the microangiopathic process. Intrinsic abnormalities of the complement system and of the von Willebrand factor pathway may account for a genetic predisposition to the disease that may play a paramount role in particular in familial and recurrent forms. Outcome is usually good in childhood, Shiga toxin-associated HUS, whereas renal and neurological sequelae are more frequently reported in adult, atypical, and familial forms of HUS and in TTP. Plasma infusion or exchange is the only treatment of proven efficacy. Bilateral nephrectomy and splenectomy may serve as rescue therapies in very selected cases of plasma resistant HUS or recurrent TTP, respectively.     

Rituximab therapy in two children with autoimmune thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare disease among pediatric patients, in whom it may be mistaken for hemolytic uremic syndrome (HUS) and idiopathic thrombocytopenic purpura (ITP). Familial forms are caused by mutations in the ADAMTS13 gene, whereas acquired forms may result from an inhibitory antibody directed against ADAMTS13, a metalloprotease that cleaves very large multimers of Von Willebrand factor (VWF), thereby preventing platelet aggregation in blood vessels. We report two cases of TTP. The first was a 15-year-old girl with her first episode of TTP that failed to respond after 10 days of plasmapheresis and was treated with rituximab; she has remained in remission at 12 months of follow-up. The second was a 6-year-old boy with acquired relapsing TTP previously managed with plasmapheresis and prednisolone, who presented with a third relapse that was treated with plasmapheresis and rituximab; he remains in remission 17 months after treatment. Rituximab has been used by pediatricians for treating B cell malignancy, autoimmune diseases and antibody-mediated diseases, such as the Factor VIII inhibitors in hemophilia A, and may also have a promising role in children with acute refractory or chronic relapsing TTP.     

Goodpasture’s syndrome associated with thrombotic thrombocytopenic purpura secondary to an ADAMTS-13 deficit

A 27-year-old man was hospitalized for acute kidney injury associated with antiglomerular basement membrane antibodies (anti-GBM). He underwent immunosuppression and plasma exchange therapy, without recovery of renal function. Later on, he was again admitted to the hospital with seizures. Evidence of microangiopathic hemolytic anemia, with schistocytes in peripheral blood, was present, as well as a persistent low platelet count and activity of von Willebrand factor from adherence to protease (ADAMTS-13) less than 1 %. The presence of IgG antibodies against ADAMTS-13 was documented, leading to a diagnosis of thrombotic thrombocytopenic purpura (TTP) in the context of Goodpasture’s syndrome. The TTP was treated with rituximab and plasmapheresis with a good response. We conclude that early measurement of ADAMTS-13 activity dictated the most appropriate therapy and achieved excellent results in this patient.     

Hemolytic Uremic Syndrome Following Cisplatin,Bleomycin, and Vincristine Chemotherapy

This report describes a patient who developed the hemolytic uremic syndrome while undergoing chemotherapy with cisplatin, bleomycin, and vincristine, for metastatic squamous cell cancer of the floor of the mouth. In spite of dialysis and plasmapheresis, the patient died. This complication has rarely been reported in association with cisplatin, bleomycin, or vincristine therapy. The etiology of this syndrome is uncertain but may be related to scleroderma-like endothelial injury and vasospasm caused by bleomycin combination chemotherapy. It is notable that the development of the hemolytic uremic syndrome in conjunction with this combination of agents has been fatal in all patients over the age of 50 with squamous cell cancers.     

Hemolytic uremic syndrome following cisplatin, bleomycin, and vincristine chemotherapy: a report of a case and a review of the literature

This report describes a patient who developed the hemolytic uremic syndrome while undergoing chemotherapy with cisplatin, bleomycin, and vincristine, for metastatic squamous cell cancer of the floor of the mouth. In spite of dialysis and plasmapheresis, the patient died. This complication has rarely been reported in association with cisplatin, bleomycin, or vincristine therapy. The etiology of this syndrome is uncertain but may be related to scleroderma-like endothelial injury and vasospasm caused by bleomycin combination chemotherapy. It is notable that the development of the hemolytic uremic syndrome in conjunction with this combination of agents has been fatal in all patients over the age of 50 with squamous cell cancers.     

Postoperative thrombotic thrombocytopenic purpura in an infant: case report and literature review

Thrombotic thrombocytopenic purpura is caused by an imbalance of von Willebrand factor and its cleaving protease, which leads to the formation of microthrombi in end-organs. It rarely occurs in the pediatric population. Plasma exchange can significantly reduce mortality and morbidity. We present a 14-month-old infant in whom clinical and laboratory abnormalities compatible with thrombotic thrombocytopenic purpura were noted several days after resection of a large pelvic tumor. Treatment with double volume plasma exchange on postoperative day 5 led to complete resolution of the renal failure, thrombocytopenia, anemia, and neurological manifestations. ADAMTS13 inhibitors were negative and no mutations were found in factor H, factor I, membrane cofactor protein, and thrombomodulin to account for genetic predisposition to thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome. Postoperative anemia, thrombocytopenia, fever, and neurological deficits in children should raise the suspicion of thrombotic thrombocytopenic purpura. Early diagnosis is important because the disorder is readily and efficiently treated with plasma exchange.     

Treatment of the hemolytic uremic syndrome with plasma.

Two patients with the hemolytic uremic syndrome were treated with plasma exchange an infusion: in both cases, the reduced platelet count reverted to normal values and the microangiopathic anemia ceased within a few days. Systemic blood pressure and requirement for antihypertensive drug therapy were also markedly reduced following treatment with plasma. Venousprostacyclin (antiplatelet aggregating) activity was undetectable in both patients before but was restored after treatment with plasma. The plasma samples collected before, but not those collected at various intervals after replacement therapy, had decreased capacity to stimulate prostacyclin activity in rat aortic rings. It is suggested that in patients with the hemolytic uremic syndrome or with other clinical conditions which can be included under this rubric (such as thrombotic thrombocytopenic purpura) a plasma factor is lacking which stimulates prostacyclin activity. Plasma would supply such a missing factor, thus representing a rational treatment for some of the life-threatening manifestations (thrombocytopenia, hemolytic anemia, hypertension) of this severe syndrome.     

Atypical relapse of hemolytic uremic syndrome after transplantation

Atypical hemolytic uremic syndrome (HUS) frequently leads to end-stage renal failure and can relapse after transplantation. A 12-year-old girl presenting with familial atypical HUS with a factor H mutation was successfully transplanted 6 years after a first transplant that had failed because of immediate recurrent HUS. Prophylactic plasma exchange before and after transplantation was used. Two months after transplantation, concomitant with a reduction in plasma exchange frequency, the plasma creatinine increased from 70 micro mol/l to 194 micro mol/l in 2 weeks without thrombocytopenia or signs of hemolytic anemia. The patient had minimal clinical symptoms and a presumptive diagnosis of graft rejection was made. Despite treatment with six daily pulses of methylprednisolone, plasma creatinine continued to increase and a graft biopsy was therefore undertaken. This showed the typical appearance of a thrombotic microangiopathy without any evidence of rejection. Despite daily plasmapheresis and replacement of cyclosporine with tacrolimus, there was no improvement and transplant nephrectomy was undertaken. This patient demonstrates that HUS can recur in a kidney transplant without the diagnostic hematological features and emphasizes the need for early transplant biopsy in such patients showing a decline in transplant function.     

Update on evaluating complement in hemolytic uremic syndrome

PURPOSE OF REVIEW: The last few years have seen the decoding of the genetic basis for atypical hemolytic uremic syndrome. RECENT FINDINGS: Mutations in complement factor H were the first to be associated with atypical hemolytic uremic syndrome. These mutations cluster in the C-terminus of complement factor H. This year has seen the publication of a transgenic mouse model lacking the C-terminus of complement factor H, which spontaneously develops atypical hemolytic uremic syndrome. This mouse model regulated C3 activation in plasma but failed to bind to endothelial cells in an analogous manner to the mutations seen in atypical hemolytic uremic syndrome patients. This year has also seen the emergence of genotype-phenotype correlations in atypical hemolytic uremic syndrome. Patients with membrane cofactor protein mutations have a good prognosis and in those who do develop endstage renal disease, recurrence after transplantation is rare. By contrast, the outcome for patients with complement factor H and complement factor I mutations is poor and the rate of recurrence after transplantation is high. New complement genes associated with atypical hemolytic uremic syndrome have also been described in the past year including factor B, C3, C4b-binding protein, FHR1 and FHR3. SUMMARY: Genetic screening is now providing prognostically significant information in predicting survival, renal recovery and transplant outcome. It paves the way for the use of complement inhibitors in the future.     

Successful management of severe refractory acquired immune bleeding disorder: Prior to insisting surgery

INTRODUCTION

Acquired bleeding disorders are rare and may be missed before surgery. Additionally, they may be refractory to conventional treatments.

PRESENTATION OF CASE

A 50-year-old patient experienced prolonged post-operative bleeding when his bleeding disorder was missed prior to his undergoing inguinal herniorrhaphy. Post-operative investigations revealed severe acquired von Willebrand syndrome associated with a monoclonal gammopathy of undetermined significance. A few months later, he required umbilical herniorrhaphy, but he did not respond to attempts to raise his von Willebrand factor antigen and activity levels using conventional therapies, including desmopressin, cryoprecipitate, intravenous immunoglobulin, and Von Willebrand factor concentrate. A triple therapy combination of dexamethasone, intravenous immunoglobulin, and mycophenolate mofetil was administered, with a successful and sustained response, lasting about 2 months. The surgery was performed safely, without any complications.

DISCUSSION

Conventional acquired von Willebrand syndrome treatment is usually aimed at replacing von Willebrand factor or stimulating its secretion from storage in endothelial cells. In the present case, the alternative treatment was directed against both the humoral and cell-mediated immune mechanisms.

CONCLUSION

This case of acquired bleeding disorder showed that more attention must be given to a patient''s coagulation profile, even if only very minor laboratory coagulation derangements are detected prior to surgery, to avoid missing such rare disorders. The described triple therapy demonstrated good effects and may be considered for inclusion in a controlled randomized study to determine its usefulness for other surgeries delayed due to severe acquired bleeding disorders. To the best of our knowledge, this triple combination treatment has not been previously used for the treatment of severe acquired bleeding disorders that are refractory to conventional therapies.Abbreviations: APTT, activated partial thromboplastin time; VWF Ag, von Willebrand factor antigen; VWF Act, von Willebrand factor activity; IgG, immunoglobulin G; aVWS, acquired von Willebrand syndrome; VWF, von Willebrand factor; MGUS, monoclonal gammopathy of undetermined significance; MMF, mycophenolate mofetil; DIM, dexamethasone, intravenous immunoglobulin, mycophenolate mofetil; VWD, von Willebrand disease     

Abnormal prostacyclin metabolism in the hemolytic uremic syndrome: equivocal effect of prostacyclin infusions

In a child with the hemolytic uremic syndrome, plasma 6 keto-prostaglandin F1 alpha levels remained undetectable throughout the acute phase of the disease. The patient's plasma failed to stimulate prostacyclin production by "exhausted" rat aorta rings. In vitro study of the patient's vessels indicated that they retained the capacity to synthesize prostacyclin from exogenous arachidonic acid but that their endogenous arachidonic acid stores were either depleted or non-available. The response to repeated infusion of exogenous prostacyclin was equivocal, suggesting that abnormal prostacyclin metabolism in the hemolytic uremic syndrome may not be the only factor in its pathogenesis.     

The molecular biology of thrombotic microangiopathy

Thrombotic microangiopathy, which includes thrombotic thrombocytopenic purpura (TTP), shiga-toxin-associated hemolytic uremic syndrome (Stx-HUS) and atypical HUS, is characterized by the development of hyaline thrombi in the microvasculature resulting in thrombocytopenia, microangiopathic hemolysis, and organ dysfunction. Renal failure is a predominant complication of both Stx-HUS and atypical HUS, whereas neurological complications are more prominent in TTP. Other disorders such as lupus or bone marrow transplantations may occasionally present with features of thrombotic microangiopathy. Recent studies have found autoimmune inhibitors or genetic mutations of a von Willebrand factor (VWF) cleaving metalloprotease ADAMTS13 in patients with TTP. In approximately 30-50% of patients with atypical HUS, mutations have been detected in complement factor H, membrane cofactor protein (CD46), or factor I. All three proteins are involved in the regulation of complement activation. Additionally, autoantibodies of factor H have been described in patients without genetic mutations. These advances illustrate that dysregulation of VWF homeostasis or complement activation owing to genetic or autoimmune mechanisms may lead to the syndrome of thrombotic microangiopathy.     

Hemolytic uremic syndrome: glomerular filtration rate, 6 to 11 years later measured by 99mTc DTPA plasma slope clearance

Thirty-seven patients who had been discharged from hospital six to eleven years after an acute episode of hemolytic uremic syndrome were studied. Glomerular filtration rates were measured by plasma slope clearance using 99mTc DTPA. Eleven patients had GFRs below 60 ml/min/1.73 m2. Hemolytic uremic syndrome may result in an appreciable deterioration in GFR undectable by routine laboratory tests and without clinical signs.     

Hemolytic uremic syndrome in solid-organ transplant recipients

Post-transplant hemolytic uremic syndrome characterized by microangiopathic hemolysis, thrombocytopenia, and renal failure is an infrequent but potentially serious complication in organ transplant recipients. Hemolytic uremic syndrome developed in 2% (2/100) of our consecutive liver transplants. We report our patients and review a total of 91 cases of hemolytic uremic syndrome in adult solid organ transplant recipients reported in the literature. Ninety percent were observed in renal transplant recipients, 8% in liver, and 1% each in lung and heart transplant recipients. Eighty percent and 96% of cases occurred within 90 days and 1 year, respectively, post-transplantation. In renal transplant recipients, 23% of cases were due to post-transplant recurrence of hemolytic uremic syndrome. In 50% of renal transplant recipients and in all norenal solid-organ transplant recipients, hemolytic uremic syndrome was attributed to cyclosporin or tacrolimus therapy. Notably, infections were not a significant precipitating factor for post-transplant hemolytic uremic syndrome. Graft loss attributable to hemolytic uremic syndrome occurred in 43% of renal transplant recipients while renal transplantation and hemodialysis were required in the lung and heart transplant recipients due to hemolytic uremic syndrome induced renal failure. The overall mortality was 13% (12/91). Physicians caring for transplant recipients need to be aware of this potentially severe graft and life-threatening disorder since prompt recognition and removal of identifiable risk factors is critical in the management of post-transplant hemolytic uremic syndrome.