Prodrome Of Bloody Diarrhea Research Articles

First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur?

Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare cause of thrombocytopenia and hemolysis characterized by life-threatening end-organ ischemia due to platelet microthrombi. TTP arises from severe deficiency of ADAMTS13 (< 10% activity). Although neurologic symptoms are considered classical of TTP, they are not present in all patients. Previous studies have described other manifestations in a significant percentage of the patients, related or not to hemolysis and anemia.1 Therefore, physicians must have a high level of suspicion in order to diagnose TTP. Delay to refer a patient for therapeutic plasma exchange (TPE) is potentially fatal.2 Following Institutional Review Board’s approval, we reviewed the records of all adults diagnosed with a first episode of TTP at the University of Alabama at Birmingham (UAB) and the Oklahoma TTP-HUS Registry from January 1, 2007 to June 30, 2010 to answer a specific question: What are the first symptoms of TTP and when do they occur? TTP was defined as thrombocytopenia, microangiopathic hemolytic anemia, and ADAMTS13 activity of < 10% . Patients with underlying conditions such as: pregnancy/postpartum, stem cell transplantation, sepsis, systemic malignancy, autoimmune disease, or a bloody diarrhea prodrome, were excluded, even if their ADAMTS13 activity was <10%. Thirty-four patients met eligibility criteria (23 from UAB and 11 from the OK Registry). Their mean age was 46 years, and 76% were female. Their laboratory data are shown in Table 1. Table 2 displays the initial symptoms and the number of days until the first TPE. While neurologic complaints were the most common (44%), they varied from mild, such as headache or lightheadedness, to serious, such as seizures and focal deficits. The single most common symptom was abdominal pain (23.5%), with or without nausea/vomiting. Less than 10% of patients reported bleeding secondary to thrombocytopenia. The mean number of days prior to TPE was 12, the median was 5.5, and 62% were treated within 7 days. Table 1 Laboratory characteristics of patients with TTP: Table 2 Initial symptoms and time to first therapeutic plasma exchange (TPE): Our data confirm that patients with TTP present with a wide range of symptoms, not immediately suspicious for TTP, such as abdominal pain, nausea and vomiting. We postulate that some of these symptoms reflect an underlying disease that may have triggered TTP. Influenza, for example, has been shown to induce antibodies to ADAMTS13 and clinical TTP.3 Moreover, we suggest that abdominal pain, not considered classic of TTP, represents intra-abdominal ischemia, as it has been rarely described.4-6 In the past year, we have seen two patients with ADAMTS13 deficiency that died with massive gastrointestinal ischemia and hemorrhage, confirmed by autopsy. Unfortunately, the nonspecific nature of signs and symptoms of TTP are likely to hamper a physician’s ability to suspect it on clinical grounds alone. Unless a complete blood cell count is ordered and the combination of severe thrombocytopenia and microangiopathic hemolytic anemia is noted, it is concerning that some patients may experience a delay in diagnosis. We did not collect any information on how many clinic or emergency room visits our patients had prior to being diagnosed with TTP. Anecdotally, we know that many patients are seen by several physicians until the constellation of history, laboratory values and consultation with colleagues in hematology or apheresis medicine eventually leads to the correct diagnosis of TTP. Indeed, patients included in this study had one or more of the following diagnoses prior to being referred for TPE: meningitis, arthritis, gastroenteritis, systemic lupus erythematosus, immune thrombocytopenia, stroke, urosepsis, diabetic non-ketotic hyperosmolar acidosis, pernicious anemia, pancreatitis, and antiphospholipid antibody syndrome, confirming our concerns.

Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic‐uremic syndromes

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent multiple disorders with diverse etiologies. We compared the gender and race of 335 patients enrolled in the Oklahoma TTP-HUS Registry across 21 years for their first episode of TTP or HUS to appropriate control groups. The relative frequency of women and white race among patients with TTP-HUS-associated with a bloody diarrhea prodrome and the relative frequency of women with quinine-associated TTP-HUS were significantly greater than their control populations. The relative frequency of women and black race among patients with idiopathic TTP and TTP-associated with severe ADAMTS13 deficiency was significantly greater than their control populations. The relative frequency of black race among patients who had systemic lupus erythematosus (SLE) preceding TTP was significantly greater than among a population of patients with SLE, and the relative frequency of black race among patients with other autoimmune disorders preceding TTP was significantly greater than their control population. No significant gender or race disparities were present among patients with hematopoietic stem cell transplantation-associated thrombotic microangiopathy, TTP associated with pregnancy, or TTP associated with drugs other than quinine. The validity of these observations is supported by the enrollment of all consecutive patients across 21 years from a defined geographic region, without selection or referral bias. These observations of different gender and race disparities among the TTP-HUS syndromes suggest the presence of different risk factors and may serve as starting points for novel investigations of pathogenesis.

Sporadic Bloody Diarrhea-Associated Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) in Adults in Oklahoma: Comparison to Adults with Severe Adamts13 Deficiency and to Children with Typical HUS.

The frequency, presenting features and clinical outcomes of sporadic TTP-HUS following a prodrome of bloody diarrhea in adults are not described. The Oklahoma TTP-HUS Registry enrolled 237 consecutive patients over age 18 years with their first episode of clinically diagnosed TTP from 11-13-1995 (the date of our initial ADAMTS13 measurement) to 12-31-2006 for whom plasma exchange treatment (PEX) was requested. ADAMTS13 activity was measured on 218 (92%) patients immediately before their first PEX. 16 (7%) of these 218 patients presented with a prodrome of acute bloody diarrhea. 42 (19%) patients had ADAMTS13 activity <10%. 2 patients who presented with acute bloody diarrhea had ADAMTS13 activity <10%; they are analyzed with the bloody diarrhea patients; ADAMTS13 activity in the remaining 14 patients was 40–100%. Children with typical HUS are not usually treated with PEX and therefore are not all included in the Registry. Data on children were retrieved from the Children's Hospital of Oklahoma for 2002–2006 to identify all children with typical HUS; 28 children were identified. E. coli O157:H7 infection was identified in 5 adults (of 12 tested) and 19 children (of 25 tested). No source for E. coli O157:H7 infection was identified. There were no case clusters except for one family with 2 affected children. In 2 of the adults with bloody diarrhea, a colectomy was performed before the correct diagnosis was made.Patient characteristicsAdults, bloody diarrhea prodrome (n=16)Adults, ADAMTS13 deficiency (n=40)Children, diarrhea prodrome (n=28)Age (years, median)5840*3.8**Female (%)80%81%64%Race (% white)94%53%*75%Severe neurologic abnormalities†63%45%7%**Platelet count (/μL)‡24,00010,000*34,000Hematocrit (%)‡222118**LDH (/UL) ‡141014311161Creatinine (mg/dL)‡2.71.0*3.7Acute renal failure§50%8%*57%Response to PEX (%)81%85%NADialysis (%)31%3%*57%Death (30 days)31%15%0%**Relapse (%)0% (0/10)38% (13/34)*NA* p≤0.05 for adult bloody diarrhea prodrome compared to adult ADAMTS13 deficient patients; ** p≤0.05 for adult bloody diarrhea prodrome compared to children bloody diarrhea prodrome patients; †seizure, stroke, coma, focal abnormalities anytime during the course; ‡most abnormal values on the day of diagnosis ± 7 days; median §defined by ↑ Cr ≥ 0.5 mg/dL x 2 days or Cr ≥4.0 and dialysis.Conclusions:1.TTP-HUS following bloody diarrhea is an endemic, sporadic disorder among adults that is less common and less familiar than in children.2.Distinct from children, adults with bloody diarrhea have a higher frequency of severe neurologic abnormalities and death; distinct from adults with severe ADAMTS13 deficiency, adults with bloody diarrhea are primarily white, have a higher frequency of acute renal failure, and have not relapsed.3.Although the role of PEX in the recovery of adult patients presenting with bloody diarrhea is unclear, PEX may be appropriate initial treatment since the mortality is high, many patients appear to respond, and patients with severe ADAMTS13 deficiency may also present with bloody diarrhea apparently caused by intestinal ischemia.

Predicting Risk for Relapse in Patients Who Have Recovered from Thrombotic Thrombocytopenic Purpura (TTP).

The greatest concern for patients who have recovered from an acute episode of TTP is the risk for relapse. We have analyzed the experience of The Oklahoma TTP-HUS Registry to estimate the risk for relapse and to identify the time to relapse and factors that determine the risk for relapse. The Registry has complete follow-up data on 333 of 335 consecutive patients who had their first episode of clinically diagnosed TTP, 1989–2005. Patients who were discovered to have an alternative diagnosis for their signs of TTP, patients whose TTP followed bone marrow transplantation and patients with drug-induced TTP were not analyzed. Among the 219 remaining patients, 172 achieved a remission (defined as survival >30 days after the last plasma exchange treatment) and were at risk for relapse. Among these 172 patients, 22 (21%) of 107 patients with idiopathic TTP relapsed and 5 (8%) of 65 patients in other clinical categories (pregnancy associated, bloody diarrhea prodrome, autoimmune disease) relapsed (P<0.02). ADAMTS13 has been measured at the time of diagnosis of the first episode in 92% of consecutive patients since November 1995. Among patients who had ADAMTS13 activity <10% at the time of their initial diagnosis, 13 of 30 (43%) relapsed compared to 2 of 81 (2%) patients who had initial ADAMTS13 activity of ≥10% (P<.001). These 30 patients have been followed a median of 63 months (range, 6–124 months). Nine of the 13 patients who have relapsed have had only 1 relapse; the others have had 2–4 relapses. Nine patients had their first relapse within one year of their initial episode; the others had their first relapse within 4 years. Eleven patients followed > 4 years have never relapsed. [Display omitted] The Table compares the clinical features of the 13 ADAMTS13 deficient patients who relapsed to the 17 patients who did not relapse.Comparison between ADAMTS13 deficient patients who did and did not relapseClinical featuresRelapseNo RelapsePn=13n=17Age (years)46390.04Race (% black)62%29%0.08Sex (% men)38%0%0.01Severe neurological abnormality (%)46%35%0.55Hematocrit (%)21%21%0.82Platelets (/μL)7,00010,0000.68Creatinine (mg/dL)1.01.00.66LDH (U/L)136314340.62ADAMTS13 inhibitor (% moderate/strong)38%53%0.43Number of plasma exchanges22140.23Data are median values from the initial episode. Severe neurologic abnormalities were coma, stroke, seizure, or focal signs.CONCLUSIONS: Patients with idiopathic TTP have a greater risk for relapse than other patients. Patients who initially have severely deficient ADAMTS13 activity (<10%) have the highest risk for relapse. Most initial relapses occur within the first year following the initial episode; all occurred within 4 years. Most patients have only 1 relapse. Among patients who have ADAMTS13 deficiency (<10%), the only features that predict a greater risk for relapse are older age and male sex.

Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) in Adults Following a Prodrome of Bloody Diarrhea.

Diarrhea, often bloody diarrhea caused by infection with E. coli 0157:H7, is the prodrome for typical HUS in children. In adults, HUS has been reported following epidemics of enteric infections, however the frequency and clinical features of sporadic HUS or TTP in adults following a prodrome of bloody diarrhea have not been characterized. In the Oklahoma TTP-HUS Registry, January 1, 1989 to December 31, 2003, 19 (6%) of 301 consecutive patients had a prodrome of bloody diarrhea. The 19 cases were separated by time and location, indicating no common source outbreak. 5/10 patients who were appropriately tested had positive stool cultures for E. coli O157:H7. Although more cases (12/19, 63%) occurred in warm months, April–September, a seasonal difference was not significant (p= 0.25). We compared the clinical features of these 19 patients to the 119 patients who had no apparent etiologies or associated conditions and were therefore defined as idiopathic TTP-HUS.Bloody DiarrheaIdiopathicp-value(n=19)(n=119)Age (years)59480.109Race (% Black)5%25%0.073Gender (% female)79%74%0.781Obesity (BMI≥30 kg/m2)21%40%0.120Severe neurologic abnormalities63%49%0.243Platelet count26130.010Hematocrit22220.931LDH141013050.115Acute renal failure68%29%<0.001Response to PE84%82%1.000ADAMTS13 deficiency (<5%)0% (0/13)30% (20/67)0.031Death32%19%0.233Relapse in 30 day survivors0%20%0.119Median values are presented for continuous data. Laboratory data: most abnormal value at diagnosis of TTP-HUS ± 7 daysAlthough women predominated in both groups, 18/19 patients with a prodrome of bloody diarrhea were White, consistent with the predominance of White subjects among children with diarrhea-associated HUS, but distinct from the significantly higher incidence of Blacks among adult patients with idiopathic TTP-HUS (compared to the incidence among other races, p<0.0001). 3 patients with a prodrome of bloody diarrhea never had an abnormal serum creatinine, therefore the term TTP-HUS, rather than HUS, may better describe these patients. The only significant differences in presenting features and outcomes were the severity of thrombocytopenia, the relative frequency of acute renal failure, and the relative frequency of severe ADAMTS13 deficiency (<5% activity). ADAMTS13 activity was measured in 13 of the 19 patients with a prodrome of bloody diarrhea (median 50%, range 5–100%). We conclude that there is a continuous occurrence of TTP-HUS in adults preceded by a prodrome of bloody diarrhea, presumably related to Shiga toxin-producing enteric infections, even in the absence of recognized outbreaks. Plasma exchange is an appropriate treatment for adult patients with a prodrome of bloody diarrhea since they cannot be accurately distinguished from patients with idiopathic TTP, they have a high mortality rate, and they apparently respond to plasma exchange treatment.

The Incidence of TTP-HUS: Racial Disparity among Patients with Severe ADAMTS13 Deficiency.

Previous studies have estimated the U.S. incidence of TTP to be 3.7/106/year, based on U.S. death certificates (Am J Hem 1995; 50:84), and 3.8/106/year, based on claims submitted to a national health insurer (Epidemiol 2004; 15:208). These methods are indirect and require extrapolation to determine incidence rates. We estimated the incidence directly from the Oklahoma TTP-HUS Registry. The Registry accrues all patients treated with plasma exchange (PE) for a clinical diagnosis of TTP or HUS (therefore excluding only children with typical HUS) in central, western, and southeastern Oklahoma since the Oklahoma Blood Institute (OBI) is the sole provider for PE in this region of 2.3 million people. Our estimates are based on patients who had their initial episode from 1/1/1996, after routine ADAMTS13 measurements began, to 6/30/2004. During these 8.5 years ADAMTS13 activity was measured in 189 (90%) of 209 consecutive patients. Prior to 1996, the number of patients accrued in the Oklahoma TTP-HUS Registry increased each year, similar to other data (JAMA 2003; 290:1351); since 1996, there has been no consistent change in the annual number of patients accrued.CategoriesIncidence (new cases/106population/year)1All patientsBlack race1Other race1CasesIncidence1CasesIncidence1CasesIncidence1All patients20910.644024.081699.40Urban211712.712927.638810.79Rural2928.821117.99818.25Idiopathic3773.922112.64563.12ADAMTS13 deficient (<5%)271.37127.22150.831Population data are from the 2000 US Census for the Oklahoma counties served by the OBI. Black race includes Black alone and in combination with one or more other races. Other race refers to all other racial designations. 2Urban or rural designations were determined by county of residence. Urban is the Oklahoma City Metropolitan Statistical Area; all other counties are rural. 3Excludes patients after BMT, pregnant/postpartum, drug-associated, bloody diarrhea prodrome, and additional or alternative diagnoses.The incidence of all patients with TTP-HUS from the Oklahoma Registry (10.64/106/year) was greater than previous reports, perhaps because of our inclusion of all patients in a defined geographic region who were treated with PE. The incidence of patients with idiopathic TTP-HUS (3.92/106/year) was similar to the previous reports for TTP. The incidence of patients with severe ADAMTS13 deficiency (<5% activity) was 1.37/106/year. For all patients with TTP-HUS the incidence of patients living in an urban area was 1.4-fold the incidence of patients living in rural areas. The rate of urban excess was greater for patients with idiopathic TTP-HUS (1.8-fold) and patients with ADAMTS13 deficiency (3.2-fold) (data not shown). Part of the urban excess may reflect better recognition of TTP-HUS because of familiarity with the Registry. However much of the urban excess can be attributed to the racial disparity that is greatest among patients with severe ADAMTS13 deficiency. Although the number of patients with severe ADAMTS13 deficiency in the Oklahoma TTP-HUS Registry is small, the incidence among the Black population was 8.7-fold the incidence among the non-Black population (95% CI, 4.1–18.5, p<0.0001). The explanation for why Black race is a risk factor for TTP is unknown, but may be related to the reasons why there is a greater prevalence of other vascular and thrombotic diseases among Blacks.

Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

Recurrent thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) during a subsequent pregnancy is an important concern because pregnancy may increase the risk for relapse. Outcomes of all pregnancies after recovery from TTP-HUS in the Oklahoma TTP-HUS Registry, a cohort of 301 consecutive patients during the period of 1989 through 2003, were assessed and compared to the total published experience. In the Oklahoma Registry, 3 of 7 (43%) women with idiopathic TTP-HUS, 2 of 11 (18%) women who were pregnant/postpartum, and 0 of 1 (0%) woman with a bloody diarrhea prodrome at their initial presentation were diagnosed with TTP-HUS during a subsequent pregnancy; all 5 women recovered. In published reports, 10 of 11 (91%) women with idiopathic TTP-HUS and 11 of 18 (61%) women who were pregnant/postpartum at their initial presentation, and all 11 (100%) women with congenital TTP-HUS were diagnosed with TTP-HUS during a subsequent pregnancy. Rates of recurrence in the Oklahoma Registry may be less because of case report bias for exceptional patients. Recurrent TTP-HUS was difficult to diagnose because other pregnancy-related complications were frequent. Although pregnancies in these women were often complicated, a future pregnancy may be a safe and appropriate decision for women who have recovered from TTP-HUS.

Platelets: Thrombotic Thrombocytopenic Purpura

Abnormalities of plasma von Willebrand factor (VWF) have been recognized to be associated with thrombotic thrombocytopenic purpura (TTP) for over 20 years. Patients with chronic, relapsing TTP have VWF multimers that are larger than normal, similar in size to those secreted by cultured endothelial cells. Recent observations have documented that a deficiency of a VWF-cleaving protease (termed ADAMTS13) may be responsible for the presence of these unusually large VWF multimers. Multiple mutations of the ADAMTS13 gene can result in ADAMTS13 deficiency and cause congenital TTP; autoantibodies neutralizing ADAMTS13 protease activity have been associated with acquired TTP. In Section I, Dr. Evan Sadler reviews the structure, biosynthesis, and function of the ADAMTS13 protease. He describes the mutations that have been identified in congenital TTP and describes the relationship of ADAMTS13 deficiency to the development of both congenital and acquired TTP. Dr. Sadler postulates that the development of TTP may be favored by conditions that combine increased VWF secretion, such as during the later stages of pregnancy, and decreased ADAMTS13 activity. In Section II, Dr. Bernhard Lämmle describes the assay methods for determining ADAMTS13 activity. Understanding the complexity of these methods is essential for understanding the difficulty of assay performance and the interpretation of assay data. Dr. Lämmle describes his extensive experience measuring ADAMTS13 activity in patients with TTP as well as patients with acute thrombocytopenia and severe illnesses not diagnosed as TTP. His data suggest that a severe deficiency of ADAMTS13 activity (< 5%) is a specific feature of TTP. However, he emphasizes that, although severe ADAMTS13 deficiency may be specific for TTP, it may not be sensitive enough to identify all patients who may be appropriately diagnosed as TTP and who may respond to plasma exchange treatment. In Section III, Dr. James George describes the evaluation and management of patients with clinically suspected TTP, as well as adults who may be described as having hemolytic-uremic syndrome (HUS). Dr. George presents a classification of TTP and HUS in children and adults. Appropriate evaluation and management are related to the clinical setting in which the diagnosis is considered. A clinical approach is described for patients in whom the diagnosis of TTP or HUS is considered (1) following bone marrow transplantation, (2) during pregnancy or the postpartum period, (3) in association with drugs which may cause TTP either by an acute immune-mediated toxicity or a dose-related toxicity, (4) following a prodrome of bloody diarrhea, (5) in patients with autoimmune disorders, and (6) in patients with no apparent associated condition who may be considered to have idiopathic TTP. Patients with idiopathic TTP appear to have the greatest frequency of ADAMTS13 deficiency and appear to be at greatest risk for a prolonged clinical course and subsequent relapse. Management with plasma exchange has a high risk of complications. Indications for additional immunosuppressive therapy are described.

Renal transplantation in adults with autosomal recessive inheritance of hemolytic uremic syndrome

When hemolytic uremic syndrome (HUS) is occasionally inherited in an autosomal recessive mode, this occurs mainly in infants and children. We describe four families in which two adult siblings were affected with HUS in each kindred. HUS first occurred between the ages of 19 to 36 years, and the intervals between the onset of HUS in each sibling pair ranged from 6 months to 6 years. None of the patients had a typical prodrome of bloody diarrhea, and one had a recurrence of HUS before transplantation. All eight patients developed renal failure requiring dialysis and transplantation, and seven patients received kidney transplants. Donor kidneys were from parents, siblings, and cadavers. The initial renal transplants were performed from 6 months to 6 years after the onset of the syndrome. HUS recurred in six of the seven patients 2 weeks to 6.5 years after transplantation regardless of the interval between the onset of HUS and transplantation, the origin of the allograft, or the use of cyclosporin A. The only marker for autosomal recessive HUS is the occurrence of the syndrome in a second sibling several months to many years after its occurrence in the proband. In patient with the autosomal recessive form of HUS, the risk for a recurrence in an allograft is high regardless of the source of the kidney.

High-Dose Intravenous Gamma Globulin Infusions in Hemolytic-Uremic Syndrome: A Preliminary Report

Sir. —The classic form of hemolyticuremic syndrome (HUS) follows a prodrome of bloody diarrhea due to verotoxin-producing Escherichia coli infection. 1 Verotoxin damages endothelial cells 2 and releases factor VIII, von Willebrand factor (vWF) antigen, and large multimers of vWF. 3 These large vWF multimers, in the presence of a platelet agglutinating factor, may facilitate platelet aggregation, resulting in microthrombi and thrombocytopenia. A platelet agglutinating factor has been reported in HUS 4 and can be inhibited by IgG obtained from adults only. 4,5 Anecdotal reports suggest a beneficial effect of intravenous infusions of human gamma globulins (IVGG) in thrombotic thrombocytopenic purpura. 6 Because the inciting factors and clinical manifestations of thrombotic thrombocytopenic purpura and HUS are similar, it is likely that both represent a spectrum of disease with a common mechanism 7 and both might improve with IVGG therapy. In our preliminary study, eight consecutively treated children (three boys, five girls;

The histopathology of the hemolytic uremic syndrome associated with verocytotoxin-producing Escherichia coli infections

Verocytotoxin-producing Escherichia coli (VTEC) infection was present in three cases of hemolytic uremic syndrome (HUS), two fatal and one non-fatal, in which detailed histopathologic investigations were conducted. Two patients had a prodrome of bloody diarrhea, one of whom required a hemicolectomy for severe bleeding. The renal histopathology was characterized primarily by glomerular thrombotic microangiopathy (TMA) with greater than 95% of glomeruli showing changes of capillary wall thickening, endothelial cell swelling, and narrowing or thrombosis of the capillary lumen. Preglomerular arterioles were frequently thrombosed, and abnormalities of the medium-sized vessels, including endothelial cell damage and thrombosis, were also commonly observed. Gastrointestinal involvement was prominent in all three cases. The colon was most severely involved, with marked mucosal and submucosal edema and hemorrhage, in the absence of significant inflammation or widespread ulceration. Microvascular angiopathy was present in all cases, with changes ranging from endothelial cell damage to overt thrombosis. Similar pathology was seen throughout the small bowel, including the presence of TMA. In one patient, typical morphologic changes of pseudomembranous enterocolitis were found in the absence of infection with Clostridium difficile. The nature of vascular involvement in the kidneys and intestinal tract supports the hypothesis that HUS is mediated by systemic toxemia, and that endothelial cells are the primary target cells for the action of verocytotoxin.