Prenatal diagnosis in rare bleeding disorders-An unresolved issue?

Intracranial haemorrhage (ICH) is the most dreadful complication, and the main cause of death among patients with rare bleeding disorders (RBD) and prenatal diagnosis (PND) is a preventative lifesaving program. A total of 39 PNDs were reported in the literature through a search on PubMed, EMBASE, SCOPUS and Web of Science databases, most often for congenital factor (F) XIII and FVII deficiencies and rarely in FX, FV deficiencies and afibrinogenemia. The main cause to request a PND is ICH and related morbidity and mortality. Different molecular methods including direct sequencing and linkage analysis as well as polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for a specific mutation are the most common used methods for PND, while factor assay and combination of molecular and factor assay also were used. In this research, 7 severely affected foetuses were identified during PND including 3 foetuses with FXIII deficiency, 3 with FVII deficiency and 1 with FX deficiency. Out of these 7 cases, intrauterine ICH occurred in 1 case with FXIII deficiency, 1 was electively aborted and 1 case with severe FVII deficiency received intrauterine factor transfusion. Postdelivery ICH was reported for 1 patient with severe FVII deficiency within the first month of life. All other pregnancies were uneventful.

Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients.

All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.

Analysis of factors affecting hemorrhagic diathesis and overall survival in patients with acute promyelocytic leukemia.

BACKGROUND/AIMS: This study investigated whether patients with acute promyelocytic leukemia (APL) truly fulfill the diagnostic criteria of overt disseminated intravascular coagulation (DIC), as proposed by the International Society on Thrombosis and Haemostasis (ISTH) and the Korean Society on Thrombosis and Hemostasis (KSTH), and analyzed which component of the criteria most contributes to bleeding diathesis. METHODS: A single-center retrospective analysis was conducted on newly diagnosed APL patients between January 1995 and May 2012. RESULTS: A total of 46 newly diagnosed APL patients were analyzed. Of these, 27 patients (58.7%) showed initial bleeding. The median number of points per patient fulfilling the diagnostic criteria of overt DIC by the ISTH and the KSTH was 5 (range, 1 to 7) and 3 (range, 1 to 4), respectively. At diagnosis of APL, 22 patients (47.8%) fulfilled the overt DIC diagnostic criteria by either the ISTH or KSTH. In multivariate analysis of the ISTH or KSTH diagnostic criteria for overt DIC, the initial fibrinogen level was the only statistically significant factor associated with initial bleeding (p = 0.035), but it was not associated with overall survival (OS). CONCLUSIONS: Initial fibrinogen level is associated with initial presentation of bleeding of APL patients, but does not affect OS.

[Is a different view on the pathophysiology of sepsis the key for novel therapeutic options?]. / Sepsis: neue Erkenntnisse, andere Perspektiven - neue Therapieoptionen?

Sepsis remains a critical problem in virtually all fields of clinical medicine. Despite intensive scientific and clinical efforts no significant progress has emerged in the fight against sepsis mortality. Solely the algorithm of the "surviving sepsis campaign" has proven to result in significantly enhanced survival of sepsis patients when consequently adopted. Novel research in the field of the complex immunological alterations in sepsis suggests that ongoing immunosuppression is the critical determinant underlying sepsis mortality. Therefore, it was proposed that immunostimulation might be a successful approach to improve outcome in individually selected patients. Others favor a different view on the pathophysiology of sepsis and support the notion that the manifestation of organ failure may be the dominant therapeutic target. Due to the fact that breakdown of the microcirculation and disruption of the microvascular barrier are critical events preceding organ failure, experimental therapeutic efforts to address these events led to promising results. Taken together, in view of the many initially promising experimental data and the failure to translate them into successful clinical therapies, a different view on the pathophysiology of sepsis is warranted to obtain the key for novel therapeutic options.

PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice.

Cellular senescence restricts the proliferative capacity of cells and is accompanied by the production of several proteins, collectively termed the "senescence-messaging secretome" (SMS). As senescent cells accumulate in tissue, local effects of the SMS have been hypothesized to disrupt tissue regenerative capacity. Klotho functions as an aging-suppressor gene, and Klotho-deficient (kl/kl) mice exhibit an accelerated aging-like phenotype that includes a truncated lifespan, arteriosclerosis, and emphysema. Because plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor (SERPIN), is elevated in kl/kl mice and is a critical determinant of replicative senescence in vitro, we hypothesized that a reduction in extracellular proteolytic activity contributes to the accelerated aging-like phenotype of kl/kl mice. Here we show that PAI-1 deficiency retards the development of senescence and protects organ structure and function while prolonging the lifespan of kl/kl mice. These findings indicate that a SERPIN-regulated cell-nonautonomous proteolytic cascade is a critical determinant of senescence in vivo.

Matrix metalloproteinase 9 mRNA: an early prognostic marker for patients with acute stroke.

OBJECTIVES: To investigate matrix metalloproteinase 9 (MMP9) mRNA as a prognostic marker in stroke. DESIGN AND METHODS: MMP9 mRNA concentrations in 126 stroke patients were analyzed using quantitative reverse transcription-polymerase chain reaction. RESULTS: The normalized MMP9 mRNA concentration was almost 3 times higher in non-survival patients compared to survival patients (P=0.0002); and 1.9-fold higher in patients with post-stroke modified Rankin score (mRS) >2 than patients with mRS≤2 (P<0.05). CONCLUSIONS: MMP9 mRNA was a predictor of poor outcome and mortality in stroke.

Aplastic anemia as a cause of death in a patient with glioblastoma multiforme treated with temozolomide.

BACKGROUND: Standard treatment of glioblastoma multiforme consists of postoperative radiochemotherapy with temozolomide, followed by a 6-month chemotherapy. Serious hematologic complications are rarely reported. CASE REPORT AND RESULTS: The authors present the case of a 61-year-old female patient with glioblastoma multiforme treated with external-beam radiation therapy and concomitant temozolomide. After completion of treatment, the patient developed symptoms of serious aplastic anemia that eventually led to death due to prolonged neutro- and thrombocytopenia followed by infectious complications. CONCLUSION: Lethal complications following temozolomide are, per se, extremely rare, however, a total of four other cases of aplastic anemia have been reported in the literature so far.

Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes.

OBJECTIVES: Most patients with myelodysplastic syndromes (MDS) present with single or multiple lineage cytopenias in peripheral blood despite a hypercellular bone marrow. Thrombocytopenia, attributable to ineffective platelet production by dysfunctional megakaryocytes, has been estimated to occur in 40-65% of patients. However, there are hardly any studies on the clinical relevance of low platelet counts in MDS. METHODS: We retrospectively analysed data from 2900 patients in the Duesseldorf MDS Registry who were diagnosed at our laboratory between 1982 and 2007. RESULTS: At the time of diagnosis, 43% of the patients had a platelet count lower than 100 000/microL. Platelets were lower than 20 000/microL in 7% of the patients, especially in those with advanced stages of MDS, who showed a higher frequency of thrombocytopenia and platelet transfusion dependency. On multivariate analysis, platelet anisometry, hypocellularity of megakaryopoiesis, maturational defects of megakaryocytes and platelets <20 000/microL were independent variables showing a statistically significant correlation (P < 0.05) with clinical signs of bleeding. Platelets lower than 100 000/microL were associated with significantly shortened survival (P < 0.00005), because of an increased risk of progression to acute myeloid leukaemia (AML) (30% vs. 21%) (P < 0.02) and bleeding (16% vs. 8%) (P = 0.0005). CONCLUSIONS: Thrombocytopenia is a strong predictor of short survival, with or without haemorrhagic complications.

Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study.

Prior to 1990, many patients with inherited bleeding disorders were infected with hepatitis C virus (HCV). This study assessed the risk of end-stage liver disease (ESLD) in patients with hemophilia with chronic hepatitis C. Patients were infected between 1961 and 1990 and were followed up to August 2005. Of 847 anti-HCV(+) patients, 160 (19%) spontaneously cleared HCV and 687 (81%) developed chronic hepatitis C. Coinfection with HIV was present in 210 patients. After 35 years of infection the cumulative incidence of ESLD was 11.5% (95% CI, 8.2%-14.8%) in HIV(-) patients and 35.1% (95% CI, 29.2%-41.0%; P < .001) in patients coinfected with HIV. Independent risk factors of ESLD were HIV coinfection (hazard ratio 13.8; 95% CI, 7.5-25.3), older age at infection (hazard ratio 2.3 per 10 years; 95% CI, 2.0-2.8), alcohol abuse (hazard ratio 4.9; 95% CI, 2.5-9.6), and presence of HCV genotype 1 (hazard ratio 2.2; 95% CI, 1.1-4.2). With longer duration of HCV infection, the risk of developing ESLD is emerging in patients with inherited bleeding disorders. Risk factors for rapid progression to ESLD are alcohol abuse, coinfection with HIV, older age at infection, and presence of HCV genotype 1.

Community-based surveillance: a pilot study from rural Cambodia.

OBJECTIVE: This study seeks to assess the performance of a community-based surveillance system (CBSS), developed and implemented in seven rural communes in Cambodia from 2000 to 2002 to provide timely and representative information on major health problems and life events, and so permit rapid and effective control of outbreaks and communicable diseases in general. METHODS: Lay people were trained as Village Health Volunteers (VHVs) to report suspected outbreaks, important infectious diseases, and vital events occurring in their communities to local health staff who analysed the data and gave feedback to the volunteers during their monthly meetings. RESULTS: Over 2 years of its implementation, the system was able to detect outbreaks early, regularly monitor communicable disease trends, and to provide continuously updated information on pregnancies, births and deaths in the rural areas. In addition, the system triggered effective responses from both health staff and VHVs for disease control and prevention and in outbreaks. CONCLUSION: A CBSS can successfully fill the gaps of the current health facility-based disease surveillance system in the rapid detection of outbreaks, in the effective monitoring of communicable diseases, and in the notification of vital events in rural Cambodia. Its replication or adaptation for use in other rural areas in Cambodia and in other developing countries is likely to be beneficial and cost-effective.

Embolia pulmonar no paciente idoso internado / Pulmonary embolism in ederly patients admited into a hospital

Introdução: A prevalência da embolia pulmonar(EP)aumenta com a idade, porém pouco se conhece a respeito dos fatores associados ao óbito no idoso.Objetivo: Identificar as características clínicas e os fatores que se associam com a mortalidade por EP confirmada, internados, entre Março de 2000 a Maio de 2004. A associação com a mortalidade foi analisada pelo teste exato de Fisher e pelo teste t, considerando-se 5 por cento como nível de significância estatística.Resultados: A média de idade foi de 80 anos(máximo 98 anos, mínimo 65 anos) e do Escore APACHE 13, seno 72 por cento do sexo feminino. O seguimento foi de 6 meses. A mortalidade diretamente relacionada à EP foi de 21 por cento. Os demais óbitos foram por choque séptico ou diátese hemorrágica. Houve associação significtiva com mortalidade por EP com: neoplasia (p igual 0,024), acidente vascular encefálico(p igual 0,024), pressão sistólica inferior a 100mmhg(p igual 0,005), e com o intervalo entre o início dos sintomas e a internação(p igual 0,0001).Conclusão: Conclui-se que na EP, fatores associados como a neoplasia, acidente vascular encefálico, hipotensão e intervalo entre o início dos sintomas e a internação correlacionaram-se com a mortalidade

Your bleeding heart: lessons from low tissue factor expression in mice.

Tissue factor (TF) is the cellular receptor and cofactor for blood coagulation factor VII (FVII). Exposure of flowing blood to cells that express TF leads to the initiation of blood coagulation. A recent study of mice expressing low levels of TF has demonstrated the importance of TF and FVII in maintaining adequate haemostasis within the heart. In addition, the study indicates that the heart is subject to a succession of minor bleeds most probably as a result of repetitive minor mechanical injury to the blood vessels.

Angiosarcoma of the colon developing in a capsule of a foreign body. Report of a case with associated hemorrhagic diathesis.

A case of angiosarcoma of the colon is reported. The tumor developed in the fibrous capsule of a retained sponge that was lost 25 years earlier during a gynecologic surgical procedure. The postoperative course was dominated by a fatal consumptive thrombohemorrhagic disorder. Angiosarcoma associated with a retained foreign body and development of hemorrhagic diathesis in angiosarcoma are discussed.

Lethal complications in 30 patients after allogeneic BMT (BMT) and autografted (ABMT) patients (1980-1986) examined by autopsy.

Lethal and accompanying complications from 29 allogeneic, 8 autologous, and 1 syngeneic transplanted pts., died between 1980 and 1986 at the BMT-Center Leipzig were revisited. An important problem was that of systemic and local infections. We observed a predominance of bacterial and fungal infections within the first 3 weeks p.t., and later on a period of predominantly virus-associated infections. The most common early death (up to 3 months p.t.) was related to ICP, as a rule caused by CMV. GvHD was a common finding at autopsy, and GvHD of the bowel seems to facilitate infectious inflammations of the bowel. There was a positive correlation between severe GvHD and the occurrence of ICP. Neither of the died BMT pts. showed signs of relapse. After ABMT ICP did not occur. The lethal complications were septicaemia, local infections, relapse and haemorrhagic diathesis. A toxic effect of DMSO in 3 pts. must be taken into account. In conclusion, a rather small number of lethal factors indicates the steps in improving results of transplantation in the future.