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1.  Haemolytic uraemic syndrome: therapeutic effect of plasma infusion. 
The therapeutic effect of plasma infusion was evaluated in 10 children and seven adults with haemolytic uraemic syndrome. All but one patient responded to this treatment with rapid disappearance of haematological abnormalities. The patient who apparently failed to respond to plasma infusion obtained complete remission of the disease after plasmapheresis. Although 15 of the 17 patients were anuric or oliguric on admission, renal function recovered completely in eight children and two adults. Seven patients showed residual chronic renal failure and two required long-term maintenance haemodialysis. Treatment with plasma was also successful in patients with relapses or recurrent episodes. Plasma infusion is a promising therapeutic approach for the haemolytic uraemic syndrome and deserves further study in clinical trials.
PMCID: PMC1500200  PMID: 6812686
2.  Haemolytic Uremic Syndrome a Hitherto Unreported Complication of Humpnosed Viper Envenomation 
Merrem’s humpnosed viper bite is known to cause incoagulable blood, acute renal failure, acute respiratory distress syndrome, Raynaud’s phenomenon and gangrene of the distal limb. Venom-induced consumptive coagulopathy (VICC) is the commonest coagulopathy that occurs following snake envenomation which is characterised by prolonged clotting times. In a small proportion of patients with VICC, microangiopathy is also seen. The authors report a novel case of haemolytic uraemic syndrome following a merrem’s humpnosed viper bite, which highlights the need for comprehensive and serial haematological evaluation to detect the condition and initiate timely plasma exchange. The authors recommend screening of all victims of humpnosed viper bite for haemolytic uremic syndrome which might otherwise be overlooked and stress the need for further studies to see the role of haemolytic uremic syndrome following humpnosed viper bite.
doi:10.1007/s12288-012-0156-9
PMCID: PMC3636351  PMID: 24426353
Humpnosed viper; Haemolytic uraemic syndrome; Acute kidney injury
3.  Inhibitor of prostacyclin production in sporadic haemolytic uraemic syndrome. 
Archives of Disease in Childhood  1983;58(9):703-708.
Prostacyclin (PGI2) production was diminished when rat aortic rings were incubated with plasma from 5 of 6 patients with the sporadic form of haemolytic uraemic syndrome but was normal in the presence of plasma from 7 patients with the epidemic form of haemolytic uraemic syndrome or from patients with other renal diseases. The reduced PGI2 production was caused by an unstable inhibitor, extractable into polar lipid solvents, in sporadic haemolytic uraemic plasma. These results suggest that there may be at least 2 different pathogenetic mechanisms in epidemic and sporadic haemolytic uraemic syndrome and that the reduced PGI2 production observed in the sporadic type is due to an inhibitor of PGI2 production rather than a deficiency of stimulating factors.
PMCID: PMC1628234  PMID: 6354101
4.  Verotoxin and neuraminidase induced platelet aggregating activity in plasma: their possible role in the pathogenesis of the haemolytic uraemic syndrome. 
Journal of Clinical Pathology  1985;38(4):438-441.
Certain strains of Escherichia coli producing verotoxin have been isolated in the stools of patients with the haemolytic uraemic syndrome. A platelet aggregating activity has been found in normal plasma after incubation with verotoxin at 37 degrees C for 24 h. This activity, unlike neuraminidase, has an effect that is independent of changing factor VIII related antigen, but requires the IIA and IIIB platelet surface glycoprotein (deficient in thrombasthenia) to mediate its effect. Prostacyclin totally inhibited this effect, but other antiplatelet drugs and heparin were without inhibitory effects.
PMCID: PMC499173  PMID: 2859303
5.  Haemolytic-Uraemic Syndrome in Typhoid Fever 
British Medical Journal  1974;2(5910):84-87.
Among 48 patients with a typhoid infection 6 (12·5%) developed the haemolytic-uraemic syndrome. Neither glucose-6-phosphate dehydrogenase deficiency nor therapy with chloramphenicol could be incriminated as the causal factor. Evidence presented here suggests that the mechanism is localized intravascular coagulation.
The presence of leucocytosis in typhoid fever suggests a complication and should alert one to the possibility of the haemolytic-uraemic syndrome. Furthermore, in our area typhoid should be suspected as a cause in any patient presenting with acute renal failure.
PMCID: PMC1610716  PMID: 4824945
6.  Abnormalities of factor VIII related protein multimers in the haemolytic uraemic syndrome. 
Archives of Disease in Childhood  1984;59(12):1135-1140.
Factor VIII related activities and factor VIII related antigen multimeric analysis have been assessed in two sporadic and eleven epidemic cases of haemolytic uraemic syndrome. In all patients factor VIII related antigen was raised and had an abnormal multimer pattern at presentation. The return to normal of factor VIII related antigen values and multimeric analysis patterns paralleled clinical improvement and, therefore, may be useful in monitoring patients with haemolytic uraemic syndrome. We postulate that endothelial cell damage releases the abnormal high molecular weight factor VIII related antigen multimers and that this may cause platelet agglutination in vivo.
Images
PMCID: PMC1628917  PMID: 6441524
7.  Nationwide study of haemolytic uraemic syndrome: clinical, microbiological, and epidemiological features 
Archives of Disease in Childhood  2001;85(2):125-131.
AIMS—To establish the incidence and aetiology of haemolytic uraemic syndrome (HUS) in Australia and compare clinical and microbial characteristics of sporadic and outbreak cases.
METHODS—National active surveillance through the Australian Paediatric Surveillance Unit with monthly case notification from paediatricians, July 1994 to June 1998. Children under 15 years presenting with microangiopathic haemolytic anaemia, thrombocytopenia, and acute renal impairment were identified.
RESULTS—Ninety eight cases were identified (incidence 0.64 per 105 children <15 years/annum and 1.35 per 105 children <5 years/annum). Eighty four were associated with diarrhoea (64 sporadic, 20 constituting an outbreak) and 14 were atypical. Shiga toxin producing Escherichia coli (STEC) O111:H− was the most common isolate in sporadic HUS and caused the outbreak. However O111:H− isolates from outbreak and sporadic cases differed in phage type and subtyping by DNA electrophoresis. STEC isolates from sporadic cases included O26:H−, O113:H21, O130:H11, OR:H9, O157:H−, ONT:H7, and ONT:H−. STEC O157:H7 was not isolated from any case. Only O111:H− isolates produced both Shiga toxins 1 and 2 and possessed genes encoding E coli attaching and effacing gene (intimin) and enterohemolysin. Outbreak cases had worse gastrointestinal and renal disease at presentation and more extrarenal complications.
CONCLUSIONS—Linking national surveillance with a specialised laboratory service allowed estimation of HUS incidence and provided information on its aetiology. In contrast to North America, Japan, and the British Isles, STEC O157:H7 is rare in Australia; however, non-O157:H7 STEC cause severe disease including outbreaks. Disease severity in outbreak cases may relate to yet unidentified virulence factors of the O111:H− strain isolated.


doi:10.1136/adc.85.2.125
PMCID: PMC1718875  PMID: 11466187
8.  Atypical haemolytic uraemic syndrome presenting initially as suspected meningococcal disease: a case report 
Background
Haemolytic uraemic syndrome (HUS) is the most common cause of acute renal failure in children and is usually linked with Escherichia coli O157 infection. With a fatality rate of around 5%, some reports have associated antibiotic treatment with a worsening prognosis.
Case Presentation
We describe a female infant patient, initially treated for suspected meningococcal septicaemia, who went on to develop renal complications and thrombocytopenia characteristic of HUS. A subsequent positive stool sample for E. coli O157 confirmed HUS as an appropriate diagnosis, although there was no evidence of diarrhoea or vomiting throughout the course of her management.
Conclusion
The urgency of early recognition and treatment for suspected meningococcal disease in very young children while entirely appropriate can initially divert attention from other serious conditions. Evidence of infection with E. coli O157 infection in this case also highlights what can be a blurred distinction between atypical (non-diarrhoeal) HUS from classical HUS of infective origin.
doi:10.1186/1752-1947-1-122
PMCID: PMC2170447  PMID: 17971197
9.  Atypical Haemolytic Uraemic Syndrome Associated with a Hybrid Complement Gene 
PLoS Medicine  2006;3(10):e431.
Background
Sequence analysis of the regulators of complement activation (RCA) cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH) and the genes for the five factor H-related proteins (CFHL1–5; aliases CFHR1–5). CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS). The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS.
Methods and Findings
In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1–21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A) that has been previously described in association with aHUS.
Conclusions
CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene.
Tim Goodship and colleagues have identified a heterozygousCFH/CFHL1 hybrid gene which encodes a protein product identical to one previously described in association with atypical hemolytic uremic syndrome.
Editors' Summary
Background.
Atypical hemolytic uremic (aHUS) syndrome is a rare, chronic disease that can run in families. People with the condition are prone to developing kidney failure and high blood pressure, and are likely to have a shorter life span than healthy people. Previous work done by a group of researchers in Newcastle-on-Tyne, UK looked at the genetic underpinnings of aHUS in three families suffering from the condition. They found a region of the genome that was linked with the disease in all three families. That region was known to contain a gene for a protein called “factor H,” as well as a number of other genes for proteins that are involved in the same pathway as factor H in controlling an ancient defence system called complement. This system helps antibodies to kill invaders by marking any cell that is not protected by proteins such as factor H. Our own cells would be under constant threat without protective proteins such as factor H. Later studies found simple genetic mutations in people with aHUS, in the genes coding for factor H. However, other work suggested that in some families with aHUS, simple genetic mutations might not be the cause; instead more complicated rearrangements of the genome might occur which would then result in an abnormal factor H that incorporated part of the gene for another protective protein called factor H related protein 1.
Why Was This Study Done?
The researchers knew that it was important to understand the exact genetic mutations linked with aHUS in different families. This was because the exact type of mutation would help them predict whether a kidney transplant is likely to be successful in treating an individual with aHUS who has developed kidney failure. In people with mutations affecting proteins produced by the kidney, a kidney transplant would be likely to work; but in people with mutations affecting factor H, which is produced by the liver, the disease would probably recur after a kidney transplant.
What Did the Researchers Do and Find?
In this study, the researchers went back to one of the three families with aHUS they had previously studied. The researchers had shown before that in this family, the disease was linked with the genome region containing factor H, but no precise mutation in that region had been found. This time, the researchers screened the genome of the family members and looked in particular for a specific rearrangement of the genome that they suspected might be involved. They found that the genomes in this family had been shuffled in the factor H region, resulting in an abnormal version of factor H being produced.
What Do These Findings Mean?
The mutation these researchers identified is likely to result in development of aHUS that does not get better after a kidney transplant, because the abnormal factor H would still be produced in the liver after a transplant had been done. Therefore, the researchers suggest that patients with aHUS be checked for this particular mutation before it is decided whether to go ahead with a transplant.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030431.
US National Institutes of Health Office of Rare Diseases information about atypical hemolytic uremic syndrome
The Online Mendelian Inheritance in Man (OMIM) contains an entry on hemolytic uremic syndrome. OMIM is a database of human genes and genetic disorders developed by the US National Center for Biotechnology Information
The US National Kidney and Urologic Diseases has a page about hemolytic uremic syndrome
The Wikipedia has a page about HUS (note that Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030431
PMCID: PMC1626556  PMID: 17076561
10.  L-Arginine/NO Pathway Is Altered in Children with Haemolytic-Uraemic Syndrome (HUS) 
The haemolytic uraemic syndrome (HUS) is the most frequent cause of acute renal failure in childhood. We investigated L-arginine/NO pathway in 12 children with typical HUS and 12 age-matched healthy control subjects. Nitrite and nitrate, the major NO metabolites in plasma and urine, asymmetric dimethylarginine (ADMA) in plasma and urine, and dimethylamine (DMA) in urine were determined by GC-MS and GC-MS/MS techniques. Urinary measurements were corrected for creatinine excretion. Plasma nitrate was significantly higher in HUS patients compared to healthy controls (P = 0.021), whereas urine nitrate was borderline lower in HUS patients compared to healthy controls (P = 0.24). ADMA plasma concentrations were insignificantly lower, but urine ADMA levels were significantly lower in the HUS patients (P = 0.019). Urinary DMA was not significantly elevated. In HUS patients, nitrate (R = 0.91) but not nitrite, L-arginine, or ADMA concentrations in plasma correlated with free haemoglobin concentration. Our results suggest that both NO production and ADMA synthesis are decreased in children with typical HUS. We hypothesize that in the circulation of children with HUS a vicious circle between the L-arginine/NO pathway and free haemoglobin-mediated oxidative stress exists. Disruption of this vicious circle by drugs that release NO and/or sulphydryl groups-containing drugs may offer new therapeutic options in HUS.
doi:10.1155/2014/203512
PMCID: PMC3976927  PMID: 24757496
11.  A clinical and experimental study of platelet function in chronic renal failure 
Journal of Clinical Pathology  1972;25(9):745-753.
Coagulation and platelet function studies were performed on 24 normal subjects and 29 patients with chronic renal failure due to various causes. Thrombocytopenia was uncommon in the uraemic patients but there was reduced platelet retention in glass bead columns and platelet aggregation with adenosine diphosphate (ADP) and thrombin was slower and less complete than normal. The rate of platelet disaggregation in uraemic patients was significantly reduced. The abnormalities tended to be more severe in more uraemic subjects. In normal subjects no inter-relationships were observed between the various measurements of platelet activity. In patients there were significant interrelationships between the measurements of platelet aggregation with ADP and thrombin and between the measurements of aggregation and retention in glass bead columns. It is suggested that if a common pathway is involved in these reactions it is adversely affected in uraemia.
Plasma coagulation defects were uncommon and present in only five of the uraemic subjects. Impaired prothrombin consumption apparently due to defective platelet function was present in half the patients but was not detected by a kaolin activation method. Although platelet coagulation function was activated during ADP aggregation and disaggregation in normal and uraemic subjects, it did not correlate in the latter with impairment of aggregation. It is suggested that aggregation and activation of platelet coagulant activity are not necessarily related aspects of platelet function. An effect of uraemic plasma on normal platelets was demonstrated by mixing experiments consistent with a humoral cause for the uraemic platelet defects.
PMCID: PMC477502  PMID: 5086216
12.  Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome 
Journal of Medical Genetics  2006;44(3):193-199.
Introduction
Abnormal control of the complement alternative pathway (CAP) (factor H, factor I and membrane cofactor protein (MCP) deficiencies) is a well established risk factor for the occurrence of haemolytic uraemic syndrome (HUS). In some instances, HUS may be associated with an unusual glomerulonephritis with isolated C3 deposits (glomerulonephritis C3). We determined whether HUS and glomerulonephritis C3 share common genetic susceptibility factors.
Methods
We identified 19 patients with glomerulonephritis C3. We measured levels of circulating complement components, performed assays for the detection of C3 nephritic factor (C3NeF) and screened factor H, factor I and MCP coding genes for the presence of mutations.
Results
Patients were divided in two groups based on renal pathology findings: group I (n = 13) had typical features of type I membranoproliferative glomerulonephritis (glomerulonephritis C3 with membranoproliferative glomerulonephritis (MPGN)) and group II (n = 6) was characterised by mesangial and epimembranous C3 deposits in the absence of mesangial proliferation (glomerulonephritis C3 without MPGN). Mutations in complement regulatory genes were detected in 4/6 patients with glomerulonephritis C3 without MPGN (heterozygous mutations in factor H gene (two patients) with low factor H antigenic level in one case, heterozygous mutations in factor I gene (two patients)) and in only 2/13 patients with glomerulonephritis C3 with MPGN (heterozygous mutations in factor H gene (one patient) and double heterozygous mutation in CD 46 gene (one patient)). In contrast, C3NeF was present in 5/13 patients with glomerulonephritis C3 with MPGN and in 2/6 patients with glomerulonephritis C3 without MPGN, one of whom had a factor H mutation.
Conclusion
HUS and glomerulonephritis C3 without MPGN share common genetic risk factors. Constitutional or acquired dysregulation of the CAP is probably associated with a wide spectrum of diseases, ranging from HUS to glomerulonephritis C3 with MPGN.
doi:10.1136/jmg.2006.045328
PMCID: PMC2598029  PMID: 17018561
13.  Cholestatic jaundice in the haemolytic-uraemic syndrome: a case report. 
Gut  1985;26(3):315-319.
The haemolytic-uraemic syndrome is the term used to describe the symptom complex of acute oliguric renal failure, haemolysis, and thrombocytopaenia. The pathogenesis of the syndrome is unknown though several factors have been postulated as important. Gastrointestinal disease is now recognised as a regular feature of the syndrome but hepatic involvement is uncommon and limited to occasional jaundice, hepatosplenomegaly and rises in serum transaminase values. A patient is described in whom cholestatic jaundice occurred during the prodromal illness. Its presence is unexplained but might indicate infection with an unrecognised hepatotropic agent or else lack of enteral nutrition during the prodromal phase.
PMCID: PMC1432642  PMID: 3972281
14.  Cisplatin-induced haemolytic uraemic syndrome associated with a novel intronic mutation of CD46 treated with eculizumab 
Clinical Kidney Journal  2013;6(4):421-425.
A 2-year-old patient with a neuroblastoma developed haemolytic uraemic syndrome (HUS) following treatment with cisplatin and carboplatin. Following treatment with eculizumab, there was a substantial improvement in renal function with the recovery of the platelet count and the cessation of haemolysis. Subsequent investigations showed a novel, heterozygous CD46 splice site mutation with reduced peripheral blood neutrophil CD46 expression. Withdrawal of eculizumab was followed by the recurrence of disease activity, which resolved with re-introduction of therapy. Abnormal regulation of complement may be associated with other cases of cisplatin-induced HUS and treatment with eculizumab may be appropriate for other affected individuals.
doi:10.1093/ckj/sft065
PMCID: PMC3888095  PMID: 24422172
CD46; cisplatin; eculizumab; haemolytic uraemic syndrome
15.  Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries 
Journal of Medical Genetics  2003;40(9):676-681.
Background: The aetiology of atypical haemolytic uraemic syndrome (aHUS) is, in contrast to classical, Shiga-like toxin induced HUS in children, largely unknown. Deficiency of human complement factor H and familial occurrence led to identification of the factor H gene (FH1) as the susceptibility gene, but the frequency and relevance of FH1 mutations are unknown.
Methods: We established a German registry for aHUS and analysed in all patients and 100 controls the complete FH1 gene by single strand confirmational polymorphism and DNA sequencing. In addition, complement C3 and factor H serum levels were assayed. Demographic data at onset of aHUS and follow up were compared for the mutation positive and negative groups.
Results: Of 111 patients with aHUS (68 female, 43 male, mean age 33 years) 14% had FH1 germline mutations, including two of eight patients with familial aHUS.For each of these eight patients, both parents were tested, and we were able to trace the mutation for five cases. In the other three cases (one with the mutation 3749 C/T, one with 3200 T/C, and one with 3566+1 G/A), we could not detect the mutation in either parent, although paternity was proven by genetic fingerprinting, suggesting that these subjects have new mutations. C3 was decreased in five mutation carriers but also in two non-carriers, and factor H was decreased in none of the carriers, but elevated in six carriers and 15 non-carriers. Clinical parameters including associated medications and diseases, and outcome of aHUS and of post-aHUS kidney transplantation were similar in the mutation positive and negative groups.
Conclusion: FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.
doi:10.1136/jmg.40.9.676
PMCID: PMC1735586  PMID: 12960213
16.  Non-iterative sampling-based Bayesian methods for identifying changepoints in the sequence of cases of haemolytic uraemic syndrome 
Summary
Diarrhoea-associated Haemolytic uraemic syndrome (HUS) is a disease that affects the kidneys and other organs. Motivated by the annual number of cases of HUS collected in Birmingham and Newcastle of England, respectively, from 1970 to 1989, we consider Bayesian changepoint analysis with specific attention to Poisson changepoint models. For changepoint models with unknown number of changepoints, we propose a new non-iterative Bayesian sampling approach (called exact IBF sampling), which completely avoids the problem of convergence and slow convergence associated with iterative Markov chain Monte Carlo (MCMC) methods. The idea is to first utilize the sampling inverse Bayes formula (IBF) to derive the conditional distribution of the latent data given the observed data, and then to draw iid samples from the complete-data posterior distribution. For the purpose of selecting the appropriate model (or determining the number of changepoints), we develop two alternative formulae to exactly calculate marginal likelihood (or Bayes factor) by using the exact IBF output and the point-wise IBF, respectively. The HUS data are re-analyzed using the proposed methods. Simulations are implemented to validate the performance of the proposed methods.
doi:10.1016/j.csda.2009.02.006
PMCID: PMC2678871  PMID: 20161336
Bayes factor; Changepoint problem; Haemolytic uraemic syndrome; IBF sampling; MCMC; Non-iterative Bayesian approach; Poisson distribution
17.  Cytokines in haemolytic uraemic syndrome associated with verocytotoxin-producing Escherichia coli infection 
Archives of Disease in Childhood  1997;77(2):145-147.
Accepted 6 May 1997

The proinflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-8 were measured in plasma and urine samples from 19 children with verocytotoxin-producing Escherichia coli (VTEC) induced haemolytic uraemic syndrome (HUS) and 30 controls. TNF-α was detected in the plasma of two cases and one control; IL-6 in the plasma of one, and the urine of two cases, and in the plasma of one control. IL-1β and IL-8 were each identified in eight of the 19 cases and in one and two controls respectively. Urinary IL-8 was found in seven cases, four of whom had plasma concentrations below the limit of detection suggesting renal secretion of this cytokine. Cytokine concentrations did not correlate with peripheral blood neutrophil count at onset of disease. These data confirm the systemic release of cytokines responsible for the coordination of acute inflammatory processes in some children with VTEC induced HUS.


PMCID: PMC1717278  PMID: 9301354
18.  An evaluation of treatment with heparin in the haemolytic-uraemic syndrome successfully treated by peritoneal dialysis. 
Archives of Disease in Childhood  1980;55(5):393-397.
Nine children had 10 attacks of the haemolytic-uraemic syndrome in an 11-month period. One child had 2 slight episodes. The remaining 8 children each had a severe attack which required peritoneal dialysis and, of these, the first 4 were also treated with heparin. All the patients survived without sequelae and the rate of recovery of dialysed patients was unaffected by the use of heparin. Peritoneal dialysis alone is therefore recommended as a simple and effective form of treatment for the haemolytic-uraemic syndrome. No infective aetiological agent could be identified and the distribution of HLA antigens among the children were unremarkable.
PMCID: PMC1626866  PMID: 7436475
19.  Bothrops jararaca Venom Metalloproteinases Are Essential for Coagulopathy and Increase Plasma Tissue Factor Levels during Envenomation 
Background/Aims
Bleeding tendency, coagulopathy and platelet disorders are recurrent manifestations in snakebites occurring worldwide. We reasoned that by damaging tissues and/or activating cells at the site of the bite and systemically, snake venom toxins might release or decrypt tissue factor (TF), resulting in activation of blood coagulation and aggravation of the bleeding tendency. Thus, we addressed (a) whether TF and protein disulfide isomerase (PDI), an oxireductase involved in TF encryption/decryption, were altered in experimental snake envenomation; (b) the involvement and significance of snake venom metalloproteinases (SVMP) and serine proteinases (SVSP) to hemostatic disturbances.
Methods/Principal Findings
Crude Bothrops jararaca venom (BjV) was preincubated with Na2-EDTA or AEBSF, which are inhibitors of SVMP and SVSP, respectively, and injected subcutaneously or intravenously into rats to analyze the contribution of local lesion to the development of hemostatic disturbances. Samples of blood, lung and skin were collected and analyzed at 3 and 6 h. Platelet counts were markedly diminished in rats, and neither Na2-EDTA nor AEBSF could effectively abrogate this fall. However, Na2-EDTA markedly reduced plasma fibrinogen consumption and hemorrhage at the site of BjV inoculation. Na2-EDTA also abolished the marked elevation in TF levels in plasma at 3 and 6 h, by both administration routes. Moreover, increased TF activity was also noticed in lung and skin tissue samples at 6 h. However, factor VII levels did not decrease over time. PDI expression in skin was normal at 3 h, and downregulated at 6 h in all groups treated with BjV.
Conclusions
SVMP induce coagulopathy, hemorrhage and increased TF levels in plasma, but neither SVMP nor SVSP are directly involved in thrombocytopenia. High levels of TF in plasma and TF decryption occur during snake envenomation, like true disseminated intravascular coagulation syndrome, and might be implicated in engendering bleeding manifestations in severely-envenomed patients.
Author Summary
Although the abundance of reports about hemostatic disturbances in snakebites, few studies have addressed how crude snake venoms evoke blood coagulation disturbances in vivo. Snake venoms contain several components that disturb hemostasis, and the prevailing model claims that coagulation disturbances observed in patients are triggered directly by those toxins. However, taking into account the physiological mechanisms that activate the coagulation cascade, tissue factor might also be generated and decrypted during snake envenomation. We investigated herein if tissue factor and protein disulfide isomerase, an enzyme that controls the encryption/decryption of tissue factor, were altered during experimental envenomation in rats. We observed increased activity/expression of tissue factor at the site of venom injection, as well as in lungs, and decreased expression of protein disulfide isomerase at the site of venom injection. Moreover, tissue factor levels were raised in plasma, demonstrating thereby that this via may be crucial to activate blood coagulation in patients, especially in those more severely envenomed. We also noticed that snake venom metalloproteinases accounted for most fibrinogen consumption. Our results clarify the mechanisms that activate blood coagulation during envenomation, evidencing that true intravascular coagulation syndrome, due to increased tissue factor expression, might occur during snake envenomation in human beings.
doi:10.1371/journal.pntd.0002814
PMCID: PMC4022520  PMID: 24831016
20.  Severe bleeding tendency caused by a rare complication of excessive fibrinolysis with disseminated intravascular coagulation in a 51-year-old Japanese man with prostate cancer: a case report 
Introduction
Disseminated intravascular coagulation causes thrombotic tendency leading to multiple organ failure and occurs in a wide variety of diseases including malignancy. Disseminated intravascular coagulation is a latent complication in people with prostate cancer.
Case presentation
A 51-year-old Japanese man with advanced castration-resistant prostate cancer was admitted to our hospital because of extensive purpura and severe anemia. Prolonged plasma coagulation time, hypofibrinogenemia and normal platelet count suggested that a decrease in fibrinogen induced a bleeding tendency causing purpura. However, elevated plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers, with positive fibrin monomer test, manifested disseminated intravascular coagulation and subsequent fibrinolysis. Plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers decreased after administration of low-molecular-weight heparin. However, low fibrinogen and α2-antiplasmin levels were not improved and plasmin-antiplasmin complex did not decrease, which revealed excessive fibrinolysis complicated with disseminated intravascular coagulation. We suspected that prostate cancer cell-derived urokinase-type plasminogen activator caused excessive fibrinolysis. Administration of tranexamic acid for fibrinogenolysis was added together with high-dose anti-androgen therapy (fosfestrol) for prostate cancer. Thereafter, prostate-specific antigen and plasmin-antiplasmin complex decreased, followed by normalized fibrinogen and α2-antiplasmin levels, and the patient eventually recovered from the bleeding tendency. Immunohistochemical staining of the biopsied prostate tissue exhibited that the prostate cancer cells produced tissue factor, the coagulation initiator, and urokinase-type plasminogen activator.
Conclusion
This patient with rare complications of disseminated intravascular coagulation and excessive fibrinolysis is a warning case of potential coagulation disorder onset in patients with prostate cancer. We propose that combined administration of tranexamic acid and low-molecular-weight heparin together with high-dose anti-androgen therapy is a useful therapeutic option for patients with this complicated coagulation disorder.
doi:10.1186/1752-1947-6-378
PMCID: PMC3514400  PMID: 23130841
Castration-resistant prostate cancer; Disseminated intravascular coagulation; Excessive fibrinolysis; Low-molecular-weight heparin; Tranexamic acid
21.  Renal functional reserve compared in haemolytic uraemic syndrome and single kidney. 
Archives of Disease in Childhood  1990;65(7):728-731.
Creatinine clearance and microalbuminuria were measured before and after an oral protein load in 17 children with a history of haemolytic uraemic syndrome, 11 with a single kidney, and 15 controls, all of them normotensive and without evidence of renal damage, to look for indirect evidence of glomerular hyperfiltration. While creatinine clearance increased significantly after the protein load in controls, it did not change in patients with either haemolytic uraemic syndrome or a single kidney. Basal microalbuminuria was significantly higher in those with haemolytic uraemic syndrome when compared with those with a single kidney and controls. It increased significantly in all groups after a water load; this increase was significantly higher in haemolytic uraemic syndrome. After the protein load microalbuminuria returned to baseline. In conclusion, children with a history of haemolytic uraemic syndrome have an abnormal renal functional reserve like children with a single kidney. Only patients with haemolytic uraemic syndrome exhibited an increased microalbuminuria, however, suggesting that it may be the expression of a pathophysiological mechanism involved in haemolytic uraemic syndrome and not in single kidney, that could account for their different prognosis.
PMCID: PMC1792424  PMID: 2386378
22.  Haemolytic-uraemic syndrome complicating shigella dystentery in south Indian children. 
British Medical Journal  1978;1(6126):1518-1521.
Shigella dysentery caused 65% of all cases of acute renal failure (ARF) seen in children treated at the Christian Medical College Hospital, Vellore, during the 33 months ending September 1977. In the 40 children with ARF secondary to shigella dysentery, haematological findings suggested that they were suffering from the haemolytic-uraemic syndrome, and glomerular hypercellularity and fibrin deposition were present in all 12 patients whose renal histology could be studied. Peritoneal dialysis was the main element of treatment: 43% of children who underwent dialysis improved, compared with only 25% of those who did not undergo dialysis. The haemolytic-uraemic syndrome precipitated by bacillary dystentery is therefore the most important cause of ARF in children aged under 5 years in Tamil Nadu and the adjoining area of Andhra Pradesh.
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PMCID: PMC1605041  PMID: 350345
23.  Coagulopathy in patients with hemorrhagic fever with renal syndrome. 
Hemorrhagic fever with renal syndrome in Korea (Korean hemorrhagic fever) is an acute viral disease characterized by fever, hemorrhage and renal failure. In Korean patients, the disease manifests more distinctive bleeding tendencies than those of hemorrhagic fever with renal syndrome found in western countries. To investigate the nature and role of the coagulation, fibrinolysis, kinin and immune system in the pathogenesis of such a hemorrhagic manifestation, alterations of these systems were assessed from the early phase of the disease. Decreased platelet count and shortened platelet survival were observed with giant platelets in the peripheral blood. The marked prolongations of bleeding time, prothrombin time and partial thromboplastin time were noticed with the decreased plasma activities of coagulation factors II, V, VIII, IX and X. Shortened half life of fibrinogen, increased fibrinogen-fibrin degradation product, with decreased plasma levels and activities of plasminogen, alpha 2-plasmin inhibitor and antithrombin III were found. On thrombelastogram, the existence of procoagulant activity was confirmed, and prolonged reaction time and clot formation time with decreased maximum amplitude were observed. The appearance of circulating immune complexes was found along with decreased C3 and normal C4 in the serum. Significant decrease of serum C3 was evident in the patients with disseminated intravascular coagulation. These findings of coagulopathy were normalized within ten days of the illness in most cases. Therefore, it can be concluded that disseminated intravascular coagulation and thrombocytopenia in the early phase, and azotemia developing later might play an important role in the pathogenesis of bleeding tendency in Korean hemorrhagic fever.
PMCID: PMC3053648  PMID: 3151765
24.  Vitamin E treatment of haemolytic uraemic syndrome. 
Archives of Disease in Childhood  1984;59(5):401-404.
Because low plasma vitamin E concentrations have been reported in patients with haemolytic uraemic syndrome and there is accumulating evidence of lipid peroxidation in this disease, treatment with the antioxidant vitamin E was undertaken in 16 consecutive children with the syndrome. Twelve children had features at presentation suggesting a poor prognosis for recovery but despite this all 16 patients survived and are well three months later. Fifteen children now have normal values for serum creatinine, blood pressure, and urinalysis for protein but one has slight renal impairment. Although this is not a report of a controlled trial, it seems that patients treated with vitamin E have fared considerably better than our previously treated patients with haemolytic uraemic syndrome, even in the presence of early, adverse prognostic features. We suggest that vitamin E alters the natural history of the disease, and in view of the absence of any observed side effects further experience with this treatment is being sought.
PMCID: PMC1628506  PMID: 6732268
25.  Haemolytic-uraemic Syndrome Treated with Heparin 
British Medical Journal  1970;3(5716):188-191.
Three children with the haemolytic-uraemic syndrome were treated with intravenous heparin. Peritoneal dialysis was required for two of them, one of whom died after 26 days of therapy. Renal biopsy specimens from the two survivors showed widespread glomerular disease, which appeared permanent in one case, but only occasional thrombi. It is suggested that heparin therapy, by preventing further intrarenal thrombosis, allowed the normal fibrinolytic mechanisms to remove previously formed thrombi.
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PMCID: PMC1701113  PMID: 5448778

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