Further specificity characterization of von Willebrand factor inhibitors developed in two patients with severe von Willebrand disease

Circulating inhibitors against von Willebrand factor (vWF) that show the properties of heterologous IgG antibodies have been described in a few patients with severe von Willebrand disease (vWD). The present study provides further characterization of inhibitors from two patients with severe vWD. Inhibitors in both, like polyclonal rabbit antibody, detected all sizes of multimers and the complex structure of each multimer from platelets and plasma of normal individuals as well as from plasma of patients with IIA, IIB, and IIC vWD. Both inhibitors and the rabbit antibody reacted mainly with the intact 225-Kd vWF subunit and the 189-H and 140-Kd fragments in contrast to monoclonal antibodies specific for vWF fragments that detected a higher relative proportion of 176-Kd fragment. Furthermore, all these antibodies recognized fragment III, although one inhibitor and rabbit polyclonal antibody reacted poorly and the other inhibitor did not react at all with reduced fragment II of vWF digested with Staphylococcus aureus V-8 protease. These data suggest that although human inhibitors from severe vWD patients may behave, to some extent, as polyclonal heterologous antibodies against native vWF, the former show striking differences in their target specificity as well as a much broader specificity than that described for human factor VIII inhibitors.     

Venous thromboembolism in patients with liver diseases

Essentials

• Emerging evidence shows that patients with liver disease are not protected from thrombotic events.
• We assessed the risk of venous thromboembolism (VTE) in patients with liver disease.
• The presence of VTE resulted in an increase in mortality for patients with liver disease.
• Hospitalized patients with moderate‐severe liver disease had low risk of VTE during admission.

Summary

Background and Aims

Patients with liver disease were traditionally believed to be protected against development of blood clots, but some studies have shown a potential increased risk of venous thrombotic complications. We assessed the risk of venous thromboembolism (VTE) in patients with liver disease.

Methods

Data in discharge reports of patients with liver disease and control patients without liver disease were analyzed from the national inpatient sample. Incidence of VTE was compared in patients with mild, moderate‐severe or no liver disease, and the impact on in‐hospital mortality and length of stay was calculated.

Results

The overall incidence of VTE for patients with no liver disease, mild liver disease and moderate‐severe liver disease was 2.7, 2.4 and 0.9 per 100 patient discharges, respectively. In the presence of VTE, in‐hospital mortality was 10.8%, 5.8%, and 21.7% for the no liver disease, mild disease and moderate‐severe liver disease, respectively. The presence of VTE resulted in an increase in mortality for patients with no liver disease (OR, 1.16; 95% CI, 1.14–1.18) and moderate‐severe liver disease (OR, 1.63; CI 95%, 1.42–1.88).

Conclusions

Patients with moderate‐severe liver disease have a lower risk of VTE than those without liver disease. Development of thrombosis during admission increased the risk of in‐hospital mortality.

     

Effects of Fecal Microbiota Transplantation on Composition in Mice with CKD

Background: Chronic kidney disease (CKD) is a renal disorder characterized by the accumulation of uremic toxins with limited strategies to reduce their concentrations. A large amount of data supports the pivotal role of intestinal microbiota in CKD complications and as a major source of uremic toxins production. Here, we explored whether fecal microbiota transplantation (FMT) could be attenuated in metabolic complication and uremic toxin accumulation in mice with CKD. Methods: Kidney failure was chemically induced by a diet containing 0.25% (w/w) of adenine for four weeks. Mice were randomized into three groups: control, CKD and CKD + FMT groups. After four weeks, CKD mice underwent fecal microbiota transplantation (FMT) from healthy mice or phosphate buffered saline as control. The gut microbiota structure, uremic toxins plasmatic concentrations, and metabolic profiles were explored three weeks after transplantation. Results: Associated with the increase of alpha diversity, we observed a noticeable improvement of gut microbiota disturbance, after FMT treatment. FMT further decreased p-cresyl sulfate accumulation and improved glucose tolerance. There was no change in kidney function. Conclusions: These data indicate that FMT limited the accumulation of uremic toxins issued from intestinal cresol pathway by a beneficial effect on gut microbiota diversity. Further studies are needed to investigate the FMT efficiency, the timing and feces amount for the transplantation before, to become a therapeutic option in CKD patients.     

Clustering of genomic breakpoints at the MLL locus in therapy‐related acute leukemia with t(4;11)(q21;q23)

Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy‐related acute leukemias (t‐AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t‐AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t‐AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL‐AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130‐32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215‐17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non‐homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy‐related acute leukemia with MLL‐AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites. © 2013 Wiley Periodicals, Inc.     

Influence of obesity and malnutrition on acute heart failure

Introduction and objectives

Obesity is an independent risk factor for the development of heart failure. Several recent studies have found better outcomes of heart failure for obese patients, an observation termed as the “obesity paradox.” On the other hand, the negative effect of malnutrition on the evolution of heart failure has also been clearly established.

Methods

Data from the Minimum Basic Data Set were analyzed for all patients discharged from all the departments of internal medicine in hospitals of the Spanish National Health System between the years 2006 and 2008. The information was limited to those patients with a primary or secondary diagnosis of heart failure. Patients with a diagnosis of obesity or malnutrition were identified. The mortality and readmission indexes of obese and malnourished patients were compared against the subpopulation without these diagnoses.

Results

A total of 370 983 heart failure admittances were analyzed, with 41 127 (11.1%) diagnosed with obesity and 4105 (1.1%) with malnutrition. In-hospital global mortality reached 12.9% and the risk of readmission was 16.4%. Obese patients had a lower in-hospital mortality risk (odds ratio [OR]: 0.65, 95% confidence interval [95%CI]: 0.62-0.68) and early readmission risk (OR: 0.81, 95%CI: 0.78-0.83) than nonobese patients. Malnourished patients had a much higher risk of dying while in hospital (OR: 1.83 95%CI: 1.69-1.97) or of being readmitted within 30 days after discharge (OR: 1.39, 95%CI: 1.29-1.51), even after adjusting for possible confounding factors.

Conclusions

Obesity in patients admitted for HF substantially reduces in-hospital mortality risk and the possibility of early readmission, whereas malnutrition is associated with important increases in in-hospital mortality and risk of readmission in the 30 days following discharge.Full English text available from:www.revespcardiol.org