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Thrombotic microangiopathies are rare disorders characterized by the concomitant occurrence of severe thrombocytopenia, microangiopathic hemolytic anemia, and a variable degree of ischemic end-organ damage. The latter particularly affects the brain, the heart, and the kidneys. The primary forms, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), although their clinical presentations often overlap, have distinctive pathophysiologies. TTP is the consequence of a severe ADAMTS-13 deficiency, either immune-mediated as a result of circulating autoantibodies, or caused by mutations in ADAMTS-13. HUS develops following an infection with Shiga-toxin producing bacteria, or as the result of excessive activation of the alternative pathway of the complement system because of mutations in genes encoding complement system proteins., (© 2018 International Society on Thrombosis and Haemostasis.)

Thrombocytopenia-associated multiple organ failure (TAMOF) is a clinical phenotype that encompasses a spectrum of syndromes associated with disseminated microvascular thromboses, such as the thrombotic microangiopathies thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) and disseminated intravascular coagulation (DIC). Autopsies findings in TTP, HUS, or DIC reveal specific findings that can differentiate these 3 entities. Von Willebrand factor and ADAMTS-13 play a central role in TTP. Shiga toxins and the complement pathway are vital in the development of HUS. Tissue factor is the major protease that drives the pathology of DIC. Acute kidney injury (AKI) is a common feature in patients with TAMOF., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease often related to uncontrolled complement activation. The use of eculizumab has changed the management and the outcome of aHUS, becoming the frontline treatment of the acute disease and for the prevention of relapses. We report the case of a male patient with aHUS due to complement factor H gene mutation who was shifted from plasmatherapy to eculizumab for preventing disease relapses. The shift to eculizumab was associated with a significant decrease in proteinuria, revealing disease activity otherwise unsuspected, being the classic criteria of disease activity (platelet, haptoglobin, LDH, schistocytes), all in the normal range.The condition of proteinuria as the only sign of thrombotic microangiopathy activity is here designated as "cryptic activity of aHUS.", (Copyright © 2014 by the American Academy of Pediatrics.)

The complement system contains a great deal of biological "energy". This is demonstrated by the atypical hemolytic uremic syndrome (aHUS), which is a thrombotic microangiopathy (TMA) characterized by endothelial and blood cell damage and thrombotic vascular occlusions. Kidneys and often also other organs (brain, lungs and gastrointestinal tract) are affected. A principal pathophysiological feature in aHUS is a complement attack against endothelial cells and blood cells. This leads to platelet activation and aggregation, hemolysis, prothrombotic and inflammatory changes. The attacks can be triggered by infections, pregnancy, drugs or trauma. Complement-mediated aHUS is distinct from bacterial shiga-toxin (produced e.g. by E. coli O:157 or O:104 serotypes) induced "typical" HUS, thrombotic thrombocytopenic purpura (TTP) associated with ADAMTS13 (an adamalysin enzyme) dysfunction and from a recently described disease related to mutations in intracellular diacylglycerol kinase ε (DGKE). Mutations in proteins that regulate complement (factor H, factor I, MCP/CD46, thrombomodulin) or promote (C3, factor B) amplification of its alternative pathway or anti-factor H antibodies predispose to aHUS. The fundamental defect in aHUS is an excessive complement attack against cellular surfaces. This can be due to 1) an inability to regulate complement on self cell surfaces, 2) hyperactive C3 convertases or 3) complement activation and coagulation promoting changes on cell surfaces. The most common genetic cause is in factor H, where aHUS mutations disrupt its ability to recognize protective polyanions on surfaces where C3b has become attached. Most TMAs are thus characterized by misdirected complement activation affecting endothelial cell and platelet integrity., (Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

The hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are rare diseases that manifest with thrombocytopenia and microangiopathic hemolytic anemia accompanied by renal and neurologic dysfunction. Most childhood cases of HUS are caused by Shiga-toxin-producing bacteria and have a good prognosis. The other form, atypical HUS (aHUS), accounts for 10% of cases. Prognosis of aHUS and TTP has changed over time from fatal disorders to 60% to 80% survival in the plasma therapy era. In the past 10 years the molecular bases of aHUS and TTP have been discovered that mostly lead to uncontrolled activation of the complement system in aHUS and to abnormal von Willebrand factor processing in TTP. Identification of the underlying abnormality in an individual patient can provide prognostically significant information in predicting long-term outcome, response to therapies, and transplant outcome. It also paves the way for the use of specific new therapies in the near future., (Copyright 2010 Elsevier Inc. All rights reserved.)

Patients with atypical haemolytic uremic syndrome (aHUS) with a mutation in the gene encoding membrane cofactor protein (CD46) are known to have a better prognosis than those with mutations in factor H (CFH) or factor I (CFI), but a small number of the former still proceed to end-stage renal failure. Plasma therapy (PE) is the recommended approach to treat both acute episodes and prevent recurrences in aHUS, but studies have yet to show PE efficacy in aHUS associated with a CD46 mutation. The factors determining failure to treatment are not clear and may be related to the mutation involved or to insufficient treatment. Our experience of PE in a family of three sisters with CFH-associated aHUS suggests that intensive and prophylactic PE allows renal function to be maintained in both native kidneys and allografts. The success of this strategy has led us to use it in all cases of aHUS. Here, we describe the effect of this strategy in a child with aHUS and a CD46 mutation. The initial episode was treated with daily PE, resulting in the recovery of renal function. However, over the next 4 years, there was a progressive decline in renal function to end-stage renal failure, with evidence of an on-going thrombotic microangiopathy despite continuous prophylactic PE. Prophylactic PE does not influence the natural course of aHUS and CD46 mutation.

Factor V Leiden (FVL) mutation and prothrombin G20210A mutation are common hereditary risk factors for venous thrombosis. In the current study, 40 patients (mean age +/- standard deviation, 35 +/- 11 years) and 764 healthy control subjects (mean age +/- standard deviation, 37 +/- 14 years) were enrolled to assess the potential role of these mutations in the manifestation of thrombotic microangiopathies. Compared with controls, neither the heterozygous FVL mutation (7.5% vs 8.5%; P = 1) nor the heterozygous prothrombin mutation (2.5% vs 2.8%; P = 1) was more prevalent in the patients. The findings do not support a significant role of FVL and prothrombin mutations as risk factors for the manifestation of thrombotic microangiopathies. Thus, screening for these mutations does not allow the identification of individuals at increased risk for these rare thrombotic disorders.

In this study, we assessed the potential role of the TT genotype of the gene of the methylenetetrahydrofolate reductase for the manifestation of thrombotic microangiopathies, enrolling 40 affected patients (mean age [+/- standard deviation] 35 +/- 11 years). As a result, the methylenetetrahydrofolate reductase 677TT genotype was more prevalent in patients with thrombotic microangiopathies compared with controls (adjusted odds ratio = 2.58, 95% confidence interval = 1.2-5.7, P = .018), particularly in those suffering from the hemolytic uremic syndrome. A hemolytic more severe clinical course of thrombotic microangiopathies in carriers of the methylenetetrahydrofolate reductase 677TT genotype was not observed. In summary, our findings suggest a significant influence of the methylenetetrahydrofolate reductase genotype on the manifestation of thrombotic microangiopathies. The 677 TT genotype of this polymorphism appears to be a risk factor for manifestation of these rare thrombotic disorders, possibly explained by endothelial activation and increased oxidative stress.

The Oklahoma TTP-HUS Registry provides a complete community perspective of thrombotic thrombocytopenic purpura (TTP). This is possible because plasma exchange is the essential treatment for TTP and the Oklahoma Blood Institute provides all plasma exchange procedures for a region encompassing most of the State, including 58 of Oklahoma's 77 counties. The Registry is an inception cohort of consecutive patients for whom plasma exchange treatment was requested for a diagnosis of either TTP or hemolytic uremic syndrome (HUS). All 382 patients identified from January 1, 1989 to December 31, 2007 have consented to be enrolled. Complete follow-up is available for 380 of 382 patients. Patients are described both by clinical categories, related to their associated conditions and clinically apparent etiologies, and by the presence of severe ADAMTS13 deficiency. ADAMTS13 activity has been measured on 235 (93%) of 254 patients since 1995. Registry data have provided new perspectives on the definition and diagnoses of these syndromes as well as their outcomes. Long-term follow-up has documented that relapse is common among patients with ADAMTS13 deficiency but rarely occurs in patients without ADAMTS13 deficiency. Long-term follow-up has also documented persistent abnormalities of health-related quality-of-life and cognitive function. In addition to providing new perspectives on the natural history of these syndromes, The Oklahoma TTP-HUS Registry provides a support group for our patients, information about evaluation and management for community physicians, and a resource for research and educational programs.

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.

Background: Unlike acquired thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome, which are often intractable, thrombotic microangiopathy in patients with Upshaw-Schulman syndrome (USS)--a congenital deficiency of von Willebrand factor-cleaving protease (ADAMTS13) activity--responds very well to plasma infusion and does not even require plasma exchange. However, the symptoms significantly vary in each individual and thus clinicians often overlook this diagnosis., Methods: A 31-year-old adult male patient with thrombotic microangiopathy, which was complicated with repeated episodes of acute renal failure, is reported. We suspected that the patient had USS and performed assays of ADAMT13 activity and its inhibitor, followed by ADAMTS13 gene analysis of the patient and his parents., Results: The patient had extremely low ADAMTS13 activity and has no inhibitors of ADAMTS13. Through an ADAMTS13 gene analysis of this family, we found two novel mutations responsible for the disease: a missense mutation in exon 7 [702 C --> A (H234Q)] from the father and a nonsense mutation in exon 26 [3616 C --> T (R1206X)] from the mother., Conclusions: Our experience appears to indicate the importance of assays of ADAMTS13 activity and its inhibitor in patients who have episodes of renal insufficiency in association with thrombotic microangiopathy, for diagnosis and choice of treatment.

During the last decade, major progresses have been performed in the understanding and classification of hereditary haemolytic uremic syndromes and thrombotic thrombocytopenic purpura. The identification of patients with congenital thrombotic thrombocytopenic purpura due to hereditary deficiency of von Willebrand factor protease (Adamts 13) is of primordial importance, as fresh frozen plasma infusions prevent relapses and the risk of visceral (mainly cerebral and renal) involvement. The identification of patients with haemolytic uremic syndromes due to mutations in the genes that encode complement alternative pathway regulatory proteins (factor H, factor I, MCP) opens the way to new physiopathologic and therapeutic advances.

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) disorder characterised by the association of haemolytic anaemia, thrombocytopenia and acute renal failure. Atypical forms (non-related to shigatoxin) may be familial or sporadic, with frequent recurrences and most of them lead to end stage renal failure. During the last years, different groups have demonstrated genetic predisposition of atypical HUS involving complement components factor H (FH), CD46 [or membrane co-factor protein (MCP)] and factor I. These three proteins are involved in the regulation of the alternative pathway of the complement system. Several series have reported mutations in the FH gene (called HF1) in between 10 and 22% of atypical HUS patients. At this time, four pedigrees corresponding to 13 cases have been reported with an MCP mutation and four cases with a sporadic disease presented factor I mutation. Whereas FH mutations were reported in both familial and sporadic forms of HUS, CD46 mutations were restricted to familial HUS, and factor I mutations were only observed in cases of sporadic HUS. We speculate that the penetrance of the disease may be variable regarding the identified susceptibility factors. Recently, the analysis of single nucleotide polymorphisms in both HF1 and MCP in three large cohorts of HUS patients identified significant association between atypical HUS and HF1 and MCP particular alleles. All these results, together with the finding of anti-FH antibodies in some atypical HUS patients, strongly suggest that an abnormality in the regulation of the alternative pathway participates in the patho-physiological mechanisms of atypical HUS. The recent progress made in the determination of susceptibility factors for atypical HUS has permitted the development of new diagnostic tests and may eventually lead to new specific treatments to block the pathological process.

Background: Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are now considered to be variants of one single syndrome called thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Key features are thrombocytopenia, hemolytic anemia, and subsequently impaired function of different organs, especially the kidneys and the central nervous system (CNS). One possible reason is the deficiency of von Willebrand factor-cleaving protease (vWF-CP) resulting in persistence of uncleaved, ultralarge von Willebrand factor multimers (ULvWFM)., Methods: We report a patient who was initially diagnosed with Evans syndrome (hemolytic anemia and autoimmune thrombocytopenia) as infant. At 10 years of age he developed HUS-like disease with gastrointestinal tract infection, hemolytic anemia, thrombocytopenia,and acute renal failure. However, enteropathogenic Escherichia coli-like or Shiga-like toxins were not detected., Results: Further investigations revealed severe deficiency (<3%; normal >40%) of vWF-CP activity caused by compound heterozygosity of two novel ADAMTS13 gene mutations (1170 G>C [W390C] and 3735 G>A [W1245X]. vWF-CP autoantibodies were not detected. Periodic (every 2 weeks) treatment with fresh frozen plasma (FFP) maintained both platelet level and kidney function within normal range and prevented new episodes of TTP/HUS., Conclusion: Enteropathogenic E. coli- and Shiga-like toxin-negative patients who present with hemolytic or thrombocytopenic episodes and HUS like symptoms should be tested for vWF-CP deficiency and other noninfectious reasons for TTP/HUS since plasma substitution possibly provides an efficient therapeutic option for this subgroup of patients.

A total of 290 Japanese patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) were analyzed with respect to ADAMTS-13 activity and its inhibitor. Twenty-one patients (17 families) had Upshaw-Schulman syndrome, and 12 patients (six families) had familial HUS of undetermined etiology. The number of patients with acquired HUS and TTP was 44 and 213, respectively. In acquired TTP, patients with severe deficiency of ADAMTS-13 activity secondary to the presence of an inhibitor were high responders to plasma exchange, but others were low responders to plasma exchange. The former patients were associated with "idiopathic" TTP, drugs, and pregnancy, and the latter patients with malignancy and stem cell transplantation. Patients with autoimmune disease-associated TTP fit into both groups.

Mutations in complement factor H (HF1) gene have been reported in non-Shiga toxin-associated and diarrhoea-negative haemolytic uraemic syndrome (D-HUS). We analysed the complete HF1 in 101 patients with HUS, in 32 with thrombotic thrombocytopenic purpura (TTP) and in 106 controls to evaluate the frequency of HF1 mutations, the clinical outcome in mutation and non-mutation carriers and the role of HF1 polymorphisms in the predisposition to HUS. We found 17 HF1 mutations (16 heterozygous, one homozygous) in 33 HUS patients. Thirteen mutations were located in exons XXII and XXIII. No TTP patient carried HF1 mutations. The disease manifested earlier and the mortality rate was higher in mutation carriers than in non-carriers. Kidney transplants invariably failed for disease recurrences in patients with HF1 mutations, while in non-mutated patients half of the grafts were functioning after 1 year. Three HF1 polymorphic variants were strongly associated with D-HUS: -257T (promoter region), 2089G (exonXIV, silent) and 2881T (963Asp, SCR16). The association was stronger in patients without HF1 mutations. Two or three disease-associated variants led to a higher risk of HUS than a single one. Analysis of available relatives of mutated patients revealed a penetrance of 50%. In 5/9 families the proband inherited the mutation from one parent and two disease-associated variants from the other, while unaffected carriers inherited the protective variants. In conclusion HF1 mutations are frequent in patients with D-HUS (24%). Common polymorphisms of HF1 may contribute to D-HUS manifestation in subjects with and without HF1 mutations.

Purpose of Review: In recent years there has been a substantial increase in the understanding of the genetics and pathogenesis of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura., Recent Findings: In diarrhoeal associated haemolytic uraemic syndrome it has been established that the virulence of Escherichia coli O157 is related to intimin adhesion and the transport of verocytotoxin on polymorphonuclear cells. It has been shown that early changes in the coagulation pathway predate the onset of diarrhoeal haemolytic uraemic syndrome. Mutations in factor H, a fluid-phase regulator of the alternative complement pathway, have been identified in 10-20% of patients with both familial and sporadic (non-diarrhoeal-associated) haemolytic uraemic syndrome. The mutations mainly cluster in the C terminal part of factor H, a region that is important for both binding to C3b and also polyanionic structures on cell surfaces. The identification of antibodies against a plasma metalloproteinase responsible for cleaving ultralarge von Willebrand factor multimers in thrombotic thrombocytopenic purpura has been followed by the elucidation of the identity of the proteinase. It has been shown to be a member of the ADAMTS family, and mutations have been identified in the gene in families with inherited thrombotic thrombocytopenic purpura., Summary: The molecular pathogenesis of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura is an exciting and rapidly evolving field. These recent advances will lead to logical, targetted changes in the management of these conditions.

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.

Two siblings with chronic relapsing TTP/HUS from early childhood are presented. An onset of the disease was probably neonatal period and it did not involved the organ until puberty. During puberty the course of the disease aggravated with renal involvement and became fulminant in a girl who died disseminated TTP. Her older brother had episode of severe atypical HUS responding to plasma therapy. Now, his renal function is normal but the symptoms are depend an regular, prophylactic plasma infusions.

Patients with thrombotic thrombocytopenic purpura (TTP) have a deficiency of von Willebrand factor (vWF)-cleaving protease, whereas patients with hemolytic-uremic syndrome (HUS) show normal activity of this protease. Present methods for assaying vWF-cleaving protease by immunoblotting are time-intensive and cumbersome. We therefore developed a new functional assay based on the preferential binding of high-molecular-weight forms of vWF to collagen. In this assay, the diluted plasma sample to be tested is added to normal human plasma in which protease activity had been abolished. The vWF present in the protease-depleted plasma is digested by the vWF-cleaving protease in the test plasma. The proteolytic degradation leads to low-molecular-weight forms of vWF, which show impaired binding to microtiter plates coated with human collagen type III. The collagen-bound vWF is quantified using a peroxidase-conjugated rabbit antibody against human vWF. The values of vWF-cleaving protease activity in tested plasma samples are read from a calibration curve achieved by incubating the vWF-substrate with dilutions of a normal human plasma pool (NHP). Testing of plasma from patients with TTP and HUS showed that the assay can be used to distinguish between these two syndromes. The presence of an inhibitor can be detected by carrying out the test after incubation of NHP with the patient plasma sample, thus enabling differentiation of patients with familial TTP from those with nonfamilial TTP.

We investigated here the changes in von Willebrand factor (vWF) multimers in recurrent, sporadic and familial forms of hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP) to see whether they are actually proteolyzed in vivo in these patients. Molecular determinants of fragments in vWF were also characterized to identify possible sites of cleavage of the subunit. Unusually large vWF multimers were found in blood of 8 of 10 patients with recurrent HUS/TTP, both in the acute phase and in remission, but never in familial and sporadic cases. Instead, all of the groups showed evidence of enhanced fragmentation of vWF multimers during the acute phase. Increased fragmentation was also shown by decrease in native 225-kD vWF subunit. In recurrent and sporadic HUS/TTP, enhanced fragmentation normalized at remission, but the abnormality persisted in familial HUS/TTP patients. The latter findings suggest that patients with familial HUS/TTP may have a congenital abnormality in vWF processing. Analysis with specific monoclonal antibodies showed the presence of the normal vWF fragments with apparent molecular mass of 189, 176, and 140 kD in all patients; however, in 6 recurrent and in 5 familial cases, novel fragments that differed in size from normal ones were found. The size of these abnormal fragments differed from one patient to another and none of them was ever found in normal plasma. These results documented, for the first time in HUS/TTP, an abnormal cleavage of the vWF subunit that might account for the increased fragmentation observed in these patients.

Familial hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) carry a very poor outcome and have been reported in association with decreased serum levels of the third complement component (C3). Uncontrolled consumption in the microcirculation, possibly related to genetically determined deficiency in factor H--a modulator of the alternative pathway of complement activation--may account for decreased C3 serum levels even during disease remission and may predispose to intravascular thrombosis. In a case-control study by multivariate analysis, we correlated putative predisposing conditions, including low C3 serum levels, with history of disease in 15 cases reporting one or more episodes of familial HUS and TTP, in 25 age- and gender-matched healthy controls and in 63 case-relatives and 56 control-relatives, respectively. The relationship between history of disease, low C3, and factor H abnormalities was investigated in all affected families and in 17 controls. Seventy-three percent of cases compared with 16% of controls (P < 0.001), and 24% of case-relatives compared with 5% of control-relatives (P = 0.005) had decreased C3 serum levels. At multivariate analysis, C3 serum level was the only parameter associated with the disease within affected families (P = 0.02) and in the overall study population (P = 0.01). Thus, subjects with decreased C3 serum levels had a relative risk of HUS or TTP of 16.56 (95% confidence interval [CI], 1.66 to 162.39) within families and of 27.77 (95% CI, 2.44 to 314.19) in the overall population, compared to subjects with normal serum levels. Factor H abnormalities were found in four of the cases, compared with three of the healthy family members (P = 0.02) and none of the controls (P = 0.04) and, within families, factor H abnormalities were correlated with C3 reduction (P < 0.05). Reduced C3 clusters in familial HUS and TTP is likely related to a genetically determined deficiency in factor H and may predispose to the disease. Its demonstration may help identify subjects at risk in affected families.

Background: Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor-cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders., Methods: Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we measured the protease activity in normal plasma after incubation with plasma from the patients., Results: We examined 30 patients with thrombotic thrombocytopenic purpura and 23 patients with the hemolytic-uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with nonfamilial hemolytic-uremic syndrome, 11 had normal levels of activity of von Willebrand factor-cleaving protease during the acute episode, whereas in 2 patients, the activity was slightly decreased. All 6 patients with familial thrombotic thrombocytopenic purpura lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients., Conclusions: Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with the hemolyticuremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protease.

Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome occurred 6 1/2 years apart in HLA-identical brothers. This unique occurrence supports the concept that the two disorders may be varieties of a basic disease process and suggests the possibility of an inherited predisposition for them.

Two brothers and one sister had three variants of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome (the 'TTP-HUS' complex). The sister had a chronic fatal variant of thrombotic thrombocytopenic purpura with severe neurological manifestation. One brother had a chronic relapsing disease but the kidneys were not affected, and the other brother had haemolytic uraemic syndrome. This occurrence in one family supports the hypothesis that haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura are actually two variants of the same disease.