Acquired hemophilia A in a patient associated with community-acquired pneumonia.

Acquired hemophilia A (AHA) is a rare disease induced by autoantibodies to factor VIII (FVIII) and may be correlated with pregnancy, underlying malignancies, autoimmune diseases or drug administration. An 81-year-old man who presented with cough, expectoration, hemoptysis and multiple ecchymoses was diagnosed with community-acquired pneumonia by computed tomography scan. Respiratory symptoms were ameliorated after the application of antibiotics. Despite repeated infusion of fresh frozen plasma and cryoprecipitate, his prolonged activated partial thromboplastin time (APTT) maintained in the 75-110-s range and ecchymoses were not ameliorated. Then, he was transferred to the department of hematology. Based on a prolonged APTT, decreased level of FVIII and presence of antibodies against FVIII, the patient was diagnosed with AHA. Then the patient was treated with activated prothrombin complex concentrates, prednisone and intravenous immunoglobulin, resulting in a complete remission of the bleeding, recovering the FVIII level and negativity for FVIII antibody titers. Here, we investigate this novel case retrospectively and review the relevant literature.

Pathogen safety of long-term treatments for bleeding disorders: (un)predictable risks and evolving threats.

Substantial improvements in the safety of blood and plasma products for the management of bleeding disorders have been achieved in recent decades. This has led some clinicians to believe that the infectious threat is over and that inhibitor formation is the foremost complication of hemophilia therapy. On the contrary, elimination of all microbes from blood is difficult, potentially impossible, and there are always threats from emerging pathogens. The risk of infection transmission is also increasing due to greater exposure to products, increasing prophylaxis and high-dose regimens for immune tolerance, and longevity of hemophilia patients. Current products can be considered "reasonably safe," but pathogen testing is not all-inclusive, and manufacturing and purification techniques are often not standardized. Although safer nonplasma-derived products are widely used, they are not available for all bleeding disorders, and so there is an ongoing need for plasma-derived products. This review will discuss the evolving risk from emerging pathogens in the context of the issues described. Reducing the risk from emerging infections requires global collaboration to devise ways to monitor and continue to improve blood safety.

Central venous access device-related infections in patients with haemophilia.

AIMS: Fully implantable central venous access devices (CVADs) can offer long-term reliable venous access to facilitate regular factor replacement therapy in haemophilia. However, CVAD-related infection remains a major deterrent to the optimal use of CVAD in this population. This report represents the first review of CVAD use in haemophilia in Australia and aims to examine the rate of complications including CVAD-related infections. METHODS: A retrospective review of medical records was conducted of all haemophilic patients with fully implantable CVADs at the Royal Children's Hospital (RCH), Melbourne, between 1 June 1992 and 30 June 2009. CVAD-related bloodstream infection was defined based on the guidelines from the Centre of Disease Control and Victoria National Nosocomial Infection Surveillance. To further enhance identification of CVAD-related infection in this study, a third criterion of 'suspected infection' was added by the authors. RESULTS: Eighty-one CVADs in 56 patients were managed at the RCH during this time period resulting in a combined study period of 94 756 CVAD days. Median age at first CVAD insertion = 2.16 years (range 0.66 to 13.98 years). CVADs were inserted predominantly due to difficult venous access and prophylaxis initiation (70.4%). Median life-span of a CVAD was 1227 days, equivalent to 3.36 years (n = 50; range 0.22 to 9.44 years). Fifty-seven CVAD-related infections occurred in 37 CVADs (46.3%) in 29 patients (51.8%). Overall incidence of confirmed CVAD-related bloodstream infection = 0.42 per 1000 CVAD days (95% confidence interval (CI): 0.31 to 0.58 per 1000 CVAD days) and indicate better performance compared with the published benchmark of 0.66 per 1000 CVAD days (0.44 to 0.97 per 1000 CVAD days). The incidence of both confirmed (criteria 1, 2) and suspected (criterion 3) CVAD-related infection is 0.60 per 1000 CVAD days (95% CI: 0.46 to 0.78), which is comparable to the international benchmark. The majority of CVAD-related infections (73.7%) were successfully treated with intravenous antimicrobials without necessitating CVAD removal. Klebsiella pneumoniae was the most common organism found in positive blood cultures. CONCLUSION: CVAD-related infection in this Australian population was comparable to rates described in the medical literature. Ongoing surveillance for infection rates is important to provide an up-to-date assessment of risks associated with CVAD use in this population.

Preventing surgical site infection in haemophilia patients undergoing total knee arthroplasty.

UNLABELLED: The rate of infection following primary total knee arthroplasty (TKA) in the general population is 1% on average. However, in persons with haemophilia (PWH), the mean rate of infection following primary TKA is nearly 8%. QUESTIONS: why is the infection rate higher in persons with haemophilia compared with the general population? what should be done to correct this? A PubMed (MEDLINE) search and a Cochrane Library search were performed. The most important articles as judged by the author were selected for this review. The main criteria for selection were that the articles addressed the prevention of infection in PWH undergoing TKA. Patient-related risk factors predisposing to postoperative infection in the general population include immunodepression and previous infection in the knee. Methicillin-resistant Staphylococcus aureus (MRSA) is the most common organism in infected TKAs. Systematic preoperative screening by swab is very important. Prevention of MRSA-positive cases by means of nasal decontamination (mupirocin 3 days) is advisable. Preoperative antibiotic prophylaxis has shown itself to be an efficient method to lower infection rates. Operating theatres ideally should be equipped with laminar flow. In PWH, there are three additional risk factors: insufficient haemostasis, HIV-positive status, and central venous catheters (CVCs). Implementing the preventive measures for the general population and a sufficient level of clotting factor for 2-3 weeks can help diminish the infection in PWH undergoing TKA. In HIV-positive patients with CD4 count less than 200 cells/µl , early, vigorous treatment should be instituted for suspected infection and surgical intervention individualized based on the balance of risks and benefits. Strict adherence to handwashing and aseptic technique are essential elements of catheter care. Caregiver education is an integral part of CVC use and the procedural practices of users should be regularly reassessed. If TKA is contraindicated, arthroscopic knee joint debridement can relieve pain for several years and delay the need for TKA.

Transfusion transmitted infections in patients with hemophilia of Karachi, Pakistan.

The aim of the study was to assess the prevalence of HCV, HBV, and HIV infections among the patients with hemophilia. Patients with Hemophilia A and B were evaluated who visited hospital for factor replacement therapy. The viral markers tested in these patients included anti-HCV-Ab, HBsAg, and anti-HIV-Ab. Seroprevalence was compared from 5717 exchange healthy blood donors for same markers. A total of 173 multitransfused male hemophiliacs showed prevalence of 51.4% for HCV, 1.73% for HBV, and nil for HIV. In blood donors seroprevalence was 1.9% for HCV, 1.81% for HBV, while no HIV-positive case was detected. Prevalence of anti-HCV-Ab was significantly high in patients with hemophilia than normal donors (P = .0005). This study showed that HCV infection was more frequently identified than HBV and HIV infections in multitransfused hemophiliacs. The frequency of hepatitis C among blood donors is also higher than that of hepatitis B which is showing downward trend.

Ethanol lock therapy for the treatment of catheter-related infections in haemophilia patients.

Central venous access devices (CVAD) are increasingly being used for optimal delivery of clotting factor concentrates in patients with haemophilia with poor peripheral venous access. The utility of CVAD is particularly well recognized in young patients starting factor prophylaxis and in patients with inhibitors undergoing immune tolerance induction (ITI). A catheter-related infection (CRI) remains the most common complication of CVAD in haemophilia patients and is the most frequent indication for its removal. Additionally, in some patients the infection results in significant morbidity and mortality and also contributes to failure of the ITI regimen. Ethanol-lock therapy (ELT) is a treatment modality that has been used to treat CRI in patients with indwelling catheters for home parenteral nutrition and chemotherapy. The aim of this study was to report the success in treating CRI in haemophilia patients using ELT. Three severe haemophilia A patients undergoing ITI regimen who developed CVAD infections resistant to conventional management with antibiotics were treated by ELT according to the institutional technique. All three patients responded well to ELT with clearance of the CVAD infection. There were no adverse side effects. To our knowledge, this is the first report of ELT in patients with haemophilia. The role of ELT needs to be investigated in larger studies for treatment of CRI in patients with bleeding disorders.

Factors influencing the long-term outcome of primary total knee replacement in haemophiliacs: a review of 116 procedures at a single institution.

Total knee replacement (TKR) is a safe treatment for alleviating pain and restoring physical function in end-stage arthropathy of the knee. First reports of TKR in haemophiliacs date back to the mid-1970s, however detailed information on long-term outcome is scarce. This study evaluated factors influencing the outcome of 116 primary TKRs performed consecutively over 14 years at a single institution. Haemostatic management is discussed in patients with and without inhibitors. Orthopaedic outcome was measured by using the Hospital for Special Surgery knee-rating scale, knee flexion contracture and range of motion. At the end of follow-up period (median duration: 5.1 years) 96 prostheses (83%) were still in place with a 7-year removal-free survival of 81%, similar between human immunodeficiency virus-positive and -negative patients and lower in inhibitor than non-inhibitor patients (44% vs. 87%; P < 0.05). Sixteen prostheses (14%) were removed for infection (nine) or aseptic loosening (seven) after a median of 4.5 years. Presence of inhibitors, continuous infusion, cementless prostheses and different primary surgeons were associated with an increased risk of infection; however, after adjustment, only primary surgeon was confirmed as an independent risk factor. These results show that TKR represents a safe and effective procedure in haemophiliacs if performed by a highly experienced surgeon.

Emerging viral diseases and infectious disease risks.

New pathogens and antimicrobial-resistant forms of older pathogens continue to emerge, some with the potential for rapid, global spread and high morbidity and mortality. Pathogens can emerge either through introduction into a new population or when the interaction with the vector changes; emergence is also influenced by microbiological adaptation and change, global travel patterns, domestic and wild animal contact and other variants in human ecology and behaviour. Quick, decisive action to detect and control novel pathogens, and thereby contain outbreaks and prevent further transmission, is frequently hampered by incomplete or inadequate data about a new or re-emerging pathogen. Three examples of pathogens that are current causes for human health concern are avian influenza, West Nile virus (WNV) and the severe acute respiratory syndrome (SARS) coronavirus. Pathogens directly or indirectly transmitted by aerosolized droplets, such as avian influenza and SARS, pose considerable containment challenges. Rapid screening tests for other newly described pathogens such as WNV require time for development and may be <100% reliable. The importance of vigilance in the detection and control of newly recognized infectious threats cannot be overstressed. The presence of infectious agents in the blood supply could again have a significant impact on the safe use of both blood and blood-derived products in the care of patients with haemophilia, as did the human immunodeficiency virus in the 1980s. Emerging pathogens will continue to be a reality requiring the collaborative efforts of public health and individual healthcare providers worldwide to contain outbreaks and prevent transmission.

Candida in saliva of Brazilian hemophilic patients

Hemofilia é uma alteração hemorrágica hereditária comum, entretanto pouco se sabe a respeito da microbiota oral destes indivíduos. O objetivo deste estudo foi quantificar a presença de Candida e identificar as suas espécies na saliva de hemofílicos, correlacionando os resultados com fatores clínicos que possam influenciar a presença deste fungo. Foram avaliados 86 hemofílicos do Hemocentro/UNICAMP e 43 indivíduos saudáveis. Todos os pacientes foram submetidos a anamnese, exame clínico intra-oral e coleta de saliva de forma não estimulada. A quantificação e identificação das espécies de Candida foram realizadas nas amostras de saliva. Candida estava presente em 64% dos hemofílicos e em 44% dos indivíduos saudáveis. C. albicans representou 65% e 68% das espécies identificadas, nos hemofílicos e grupo controle respectivamente, e C. tropicalis foi a segunda espécie mais comum. Estes resultados sugerem que pacientes hemofílicos albergam mais freqüentemente Candida na cavidade bucal e em maiores quantidades que os indivíduos do grupo controle, independentemente dos parâmetros clínicos analisados, como infecção viral, próteses dentárias, transfusões de hemoderivados e fluxo salivar.

Helicobacter pylori causes gastrointestinal hemorrhage in patients with congenital bleeding disorders.

Helicobacter pylori (H. pylori) infection is associated with peptic ulcer disease and gastric cancer. The eradication of H. pylori is of special interest in patients with congenital bleeding disorders, for whom treatment of gastrointestinal hemorrhage with factor concentrates is costly. The prevalence of H. pylori varies between different populations and identification of high-risk subgroups may allow for more targeted screening and eradication of the infection. We performed a 5-year retrospective study of gastrointestinal bleeding, combined with screening and treatment for H. pylori and a long-term prospective follow-up in 168 Swedish and 23 Estonian patients with hemophilia or von Willebrand disease. The prevalence of seropositivity was lower in Sweden than in Estonia (28 versus 48%, p = 0.03), lower in native Swedes than in non-Nordic immigrants to Sweden (20 versus 76%, p = 0.0001) and lower in patients less than 40 years of age than older patients (16 versus 38%, p = 0.002). The incidence of gastrointestinal hemorrhages among the 35 Swedish patients with active H. pylori infection, confirmed by a urea breath test, was 6.0 per 100 patient-years before eradication therapy versus 1.7 during the prospective followup. A negative urea breath test one month after therapy always remained negative after one year. Screening, followed by treatment of all infected patients, yielded a reduction of direct costs over a 5-year period of 130 US-$ per screened patient. We conclude that screening and eradication therapy for infection with H. pylori in patients with congenital bleeding disorders is an effective and economic strategy.

Septic arthritis in hemophilia with central venous catheter: a case report.

A case is reported of septic arthritis in a child with human immunodeficiency virus-negative hemophilia A associated with a Staphylococcus aureus catheter-associated septicemia. The infection occurred in relation to the use of a totally implantable central venous catheter. The organism was eventually eradicated with antibiotics injected via the catheter. With increasing use of such catheters in the hemophilic population, clinicians should be alerted to the possibility of septic arthritis for prompt diagnosis and treatment.

Transient factor VIII inhibitor in a hemophilia patient after staphylococcal septic shock syndrome.

We report a transient type I factor VIII inhibitor that arose in a 30-year-old hemophilia patient just after staphylococcal septicemia. This situation usually occurs early in the course of substitution therapy with factor VIII concentrate in hemophilia patients. Although disseminated intravascular coagulation and acute respiratory distress syndrome developed after septic shock, the patient recovered following intravenous administration of antibiotics (meropenem and gentamycin), an antithrombin preparation, high-dose methylprednisolone, and recombinant factor VIII concentrate (rFVIII). During this therapy, however, activated partial thromboplastin time gradually lengthened. On the seventh day of hospitalization, intracranial hemorrhage occurred with right hemiplegia, even though the substitution therapy had continued at the same dosage (30 U/kg per day) of rFVIII. At that point, 4 Bethesda units of the type I inhibitor against factor VIII were detected in the plasma. Increased amounts (46 U/kg per day) of rFVIII and prednisolone were administered, and hypothermic therapy was initiated. Following these treatments, the patient's general condition gradually improved, and within 25 days the inhibitor titer dropped to undetectable levels and did not recur during treatment. These clinical findings suggest that the staphylococcal septic shock may have acted as a trigger in the development of transient factor VIII inhibitor in this patient.

[The characteristics of the causative agents of suppurative-inflammatory complications in hemophiliacs]. / Kharakteristika vozbuditelei gnoino-vospalitel'nykh oslozhnenii u bol'nykh gemofiliei.

Morphological-cultural and physiological-biochemical properties of 24 strains of microorganisms agents of pyo-inflammatory complications of different localization in patients with hemophilia have been studied. Microorganisms strains presented by the following species: Staphylococcus aureus, S. epidermidis, S. saprophyticus, Proteus vulgaris, P. morganii, Hafnia alvei, Serratia marcescens, have been identified. It was found out that in monoculture staphylococci prove to be the leading etiological agent (60.9%), gram-negative enterobacteria (52.2%) and bacterial associations (8.7%) occur more rarely. Special attention was paid to the study of resistance of antibiotics, circulation and pathogenicity factors that had a direct effect on the main disease severity. It was ascertained that high activity of enzymes and presence of pathogenicity factors were the peculiarities of microorganisms isolated from pyo-septic sites in patients with hemophilia. All the strains possessed multiple resistance to antibiotics.

An unusual haemarthrosis in an HIV-seronegative haemophilia A patient.

We report the case of a severe haemophilia A patient with an anti-factor VIII antibody who presented with a thigh haematoma and 1 year later with an elbow haemarthrosis infected by Salmonella enteritidis. These two infections were treated by antibiotics. The probable origin of these infections seems to be an anal fistula. The occurrence of a septic arthritis due to Salmonella is rare, and to our knowledge has never been reported in HIV-negative haemophilic patients. The differential diagnosis of haemarthrosis and septic arthritis in a haemophilic patient is also discussed.

Genetic drift can dominate short-term human immunodeficiency virus type 1 nef quasispecies evolution in vivo.

The evolution of human immunodeficiency virus (HIV) type 1 nef quasispecies in a patient clonally infected with a contaminated batch of blood clotting factor IX was monitored. nef sequences were derived at 11, 25, and 41 months postinfection from infected peripheral blood mononuclear cells after molecular cloning of PCR-amplified proviral DNA. The phylogenetic relationships among a total of 41 informative sequences were established by split decomposition analysis and used as a basis to establish a substitution matrix and to score synonymous (s) and nonsynonymous (ns) substitutions. The number of observed in-phase stop codons within the nef sequences was comparable to that expected on a random basis. Similarly, the numbers of observed s and ns substitutions did not differ significantly from expected values. No codon position was preferentially mutated. The maximum sequence divergence increased in a linear manner, with approximately 4.4 nucleotide and approximately 3.2 amino acid changes per year. It appears that stochastic processes strongly influence short-term HIV nef quasispecies evolution in vivo.

A study of the subgingival microflora of HIV-seropositive and CD4 cell depleted children with hemophilia.

The cultivable subgingival bacterial flora from three HIV-seropositive and CD4 cell depleted children with hemophilia were examined in this study. The numbers of CD4 cells of the subjected children ranged from 4.9 to 16.3 per mm3 blood. Streptococcus species, including, beta-hemolytic streptococcus identified as Streptococcus mutans and Streptococcus sanguis, were predominant in the subgingival plaque samples. Actinomyces species were also frequently found. Gram-negative rods other than Capnocytophaga species were not common in these samples. It is possible that the subgingival microbial flora are influenced by the CD4 cell decrease with HIV infection.

Hepatitis C virus-RNAs in plasma and in peripheral blood mononuclear cells of hemophiliacs with chronic hepatitis C: evidence for viral replication in peripheral blood mononuclear cells.

Hemophiliacs who have been exposed to unheated and/or dry heated pooled clotting factor concentrates are at high risk of chronic hepatitis C. Although the mechanism and site of hepatitis C virus (HCV) replication are not yet known, HCV is thought to replicate through a complementary negative RNA strand, as has been shown for flaviviruses. The detection of negative RNA strands has therefore been regarded as a marker of replication. We investigated the prevalence of HCV-RNA and of negative HCV-RNA strands in peripheral blood mononuclear cells (PBMC) and plasma of hemophiliacs. Forty-three of 47 patients studied (91%) had anti-HCV antibodies and in 36 patients HCV-RNA was detectable in PBMC. In one group of 20 patients negative HCV-RNA strands were present in PBMC and 10 of these patients also had negative HCV-RNA strands in plasma. In another group of nine patients HCV-RNA was detected in PBMC, although cDNA synthesis was carried out in the absence of primers. Only in two of these nine patients negative and positive HCV-RNA strands were demonstrated specifically in PBMC using a modified reverse transcription step. If the presence of negative HCV-RNA strands can be considered as marker of viral replication, the findings indicate that HCV can replicate in PBMC. Furthermore, in certain patients it is impossible to use the currently available technique to detect selectively positive or negative HCV-RNA strands.

Time-course detection of HIV-1 proviral DNA and genomic RNA by polymerase chain reaction in sera from seropositive and seronegative hemophiliacs treated with clotting factor concentrates.

The detection of HIV-1 proviral DNA and genomic RNA was performed by polymerase chain reaction (PCR) in hemophiliacs treated with non-heated clotting factor concentrates. Reamplification with double PCR was performed on those samples that were negative for single PCR. Primer pairs of the gag, env, and pol regions were used for the amplification of HIV-1 proviral DNA sequences. Amplification of the gag region by the SK38/SK39 primer pair was useful for the detection of proviral DNA sequences. With double PCR, 44 of 47 seropositive samples (93.6%) were PCR-positive. All 23 seronegative samples were PCR-negative. Reverse transcription and PCR amplification (RT-PCR) according to the primer pair of the gag region were performed to detect HIV-1 genomic RNA sequences. Double RT-PCR analysis of the HIV-1 RNA sequence in frozen-preserved sera revealed that 49 of 55 seropositive sera (89.1%) were PCR-positive. Although quantification of the PCR method was not performed in this study, we concluded that, in patients in whom proviral DNA or genomic RNA sequences are detected with difficulty with PCR, the onset and progression of HIV-1 infection is delayed.