Extremely low therapeutic doses of acenocoumarol in a patient with CYP2C9*3/*3 and VKORC1-1639A/A genotype.

Vitamin-K antagonists (VKAs) have remained the mainstay of oral anticoagulant therapy for the treatment and prevention of thromboembolism. The management of treatment with VKAs is challenging due to their narrow therapeutic index and the wide interindividual variation in response to therapy. Variants of the CYP2C9 and the VKORC1 gene account for 30-50% of the variability in dosing requirements, and it has been proposed that genotyping of these loci could facilitate management of VKA therapy and minimize risk of overanticoagulation, even in very low doses. We present the first reported case of a patient with the compounded genotype CYP2C9*3*3 and VKORC1-1639A/A under treatment with acenocoumarol, and review of other reported cases with analogous genotypic profiles but under treatment with warfarin.

Literature review of apheresis procedures performed perioperatively in cardiac surgery for ASFA category indications.

BACKGROUND: Perioperative therapeutic plasma exchange in patients with cardiovascular diseases poses several challenges, including alterations in intravascular volume, serum electrolytes, the coagulation cascade, and drug pharmacokinetics. METHODS: This review article summarizes different indications of plasma exchange for patients requiring cardiac surgery based on reported case reports and case series. RESULTS: The most common reported indication is plasma exchange for the management of allosensitized cardiac transplant candidate patients in combination with immunosuppressive regimens, which increases the likelihood of obtaining a cross-match-negative allograft, improving post-transplant clinical outcome. The second most common indication is for patients with a history of heparin-induced thrombocytopenia syndrome that permits the use of heparin in cardiopulmonary bypass in an urgent cardiac surgery. Less common indications are restoration of clotting factors for patients with congenital bleeding disorders or removal of cold agglutinins. No severe complications were described in reported cases. CONCLUSION: Therapeutic plasma exchange is an effective and safe procedure that could be performed preoperatively and intraoperatively in urgent cardiac surgery for the management of antibody-mediated disorders including allosensitized cardiac transplant candidate patients or patients with heparin-induced thrombocytopenia syndrome.

Interleukin-17A and B-cell activating factor in chronic hepatitis C patients with or without asymptomatic mixed cryoglobulinemia: effects of antiviral treatment and correlations with vitamin D.

BACKGROUND: Several studies have provided conflicting results regarding the immune responses in chronic hepatitis C (CHC) patients with mixed cryoglobulinemia (MC). The importance of B-cell activating factor (BAFF) in MC has been described, but the role of interleukin (IL)-17A is less clear. METHODS: Serum concentrations of IL-17A, BAFF and 25-OH vitamin D were measured in CHC patients at baseline, end of treatment, and 6 months post-treatment with pegylated interferon-α and ribavirin, versus 12 healthy controls. RESULTS: Thirty-four patients (20 male, mean age 40.7±9.2 years, 12 of genotype 1 or 4, 22 of genotype 2 or 3) were included, of whom 64.7% achieved a sustained virological response (SVR). MC was detected in 52.9% of the patients. Higher levels of both cytokines were found in patients with MC compared to those without. Patients who achieved SVR had higher pretreatment IL-17A and lower BAFF levels compared to those without SVR. IL-17A was downregulated during and following treatment in responders, whereas upregulation was observed in non-responders. CHC patients demonstrated low vitamin D levels compared to HC. Moreover, the changes in IL-17A over the treatment period were significantly associated with vitamin D changes (ß=-0.04, SE=0.02, P=0.046). No difference in IL-17A, BAFF and vitamin D values was seen between patients with cirrhosis (n=14) and those without. CONCLUSIONS: CHC patients with asymptomatic MC have increased levels of IL-17A and BAFF. IL-17A levels decline significantly while BAFF increases during treatment in responders. An interplay between IL-17A and vitamin D concentrations was revealed during the antiviral treatment.

Replacement therapy for coronary artery bypass surgery in patients with hemophilia A and B.

There are only a few cases of patients with hemophilia A and B who have undergone coronary artery bypass surgery. High levels of replacement therapy with factor concentrate either with bolus or continuous infusion are usually required pre-operatively and during the first post-operative days in order to maintain the coagulation deficient factor levels greater than 80% of normal. Heparinization during cardiopulmonary bypass appears to be safe and intra-operative blood salvage using cell saver techniques reduce the need for transfusions.

Autoimmune hemolytic anemia in solid organ transplantation-The role of immunosuppression.

Hemolysis after solid organ transplantation can be caused by both immune and non-immune-mediated mechanisms, and the evaluation must take into account issues distinctive to the post-transplant period. Autoimmune hemolytic anemia usually occurs within the first year and has been attributed to immunosuppressive treatment, infections, or underlying post-transplant lymphoproliferative disorder. Review of the literature revealed 59 cases with autoimmune hemolytic anemia mostly in children after liver transplantation. Almost all of the patients at the time of diagnosis received immunosuppression with tacrolimus, and first-line treatment with steroids and/or intravenous immunoglobulin was ineffective for complete remission. Rituximab was used as second-line treatment especially in patients with underlying lymphoproliferative disorders whereas sirolimus showed encouraging results.

Aspirin vs Heparin for the Prevention of Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy that remains a significant cause of maternal morbidity and mortality worldwide. Preeclampsia can be resolved by delivery, and most of the proposed preventive treatment approaches are based on processes involved in placental development in early pregnancy. Yet, none of these has been established in clinical practice. Low-dose aspirin is the most promising candidate, nevertheless; while some individual randomized controlled trials showed minimal or no statistically significant benefit, recent metanalyses showed that early initiation before 16 weeks of gestation is associated with prevention of early-onset preeclampsia and reduction in prevalence of perinatal death or morbidity of pregnant women. Heparin could be an alternative antithrombotic and anti-inflammatory median to prevent preeclampsia either alone or in combination with aspirin; however, results are conflicting concerning efficacy.

The significance of platelet microparticles in patients with chronic hepatitis C and their association with antiviral treatment and smoking.

BACKGROUND: Platelet microparticles (PMPs) are platelet-derived membrane vesicles involved in cardiovascular diseases and atherosclerosis. Chronic hepatitis C (CHC) is associated with increased atherosclerosis, but the effect of therapy on its atherogenic potential has not been adequately studied. METHODS: We evaluated PMP levels before and after treatment with pegylated-interferon-alfa and ribavirin in 28 CHC patients compared with 20 non-alcoholic fatty liver disease (NAFLD) patients and 20 healthy volunteers (HV). RESULTS: Twenty-four (86%) CHC patients achieved sustained virological response (SVR). PMP levels were determined at baseline in CHC, NAFLD patients, and HV, and at end-of-treatment (EOT) and 24 weeks post-treatment (SVR24) in CHC patients. PMP levels at baseline were higher in CHC than NAFLD patients (P<0.001) and HV (P=0.007). Higher PMPs at baseline were observed in smokers than non-smokers with CHC (P=0.006). Among smokers from all groups, PMPs at baseline were higher in CHC than NAFLD patients (P=0.001) and HV (P=0.024). In CHC patients, PMPs declined from baseline to both EOT (P=0.035) and SVR24 (P=0.006). Only CHC patients with SVR had a significant decline in PMPs from baseline to SVR24 (P=0.018). PMPs at ΕΟΤ and SVR24 in all CHC patients were similar to PMPs in NAFLD patients and HV. CONCLUSIONS: PMP levels are increased in CHC patients, particularly smokers, which further supports the atherosclerotic potential of CHC and suggests a potentially synergistic effect of smoking and CHC on the atherosclerotic process. Since PMP levels in CHC patients with SVR were similar to NAFLD patients and HV, the atherosclerotic potential of CHC seems to be abolished by effective antiviral treatment.

Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.

BACKGROUND AND AIM: The presence of spur-cell anemia (SCA) is due to lipid disturbances of the erythrocyte membrane and may develop in patients with advanced liver cirrhosis. The accurate predicting value of SC for survival has not been clarified. The aim of this study was to evaluate SCA as a prognostic indicator in patients with cirrhosis. METHODS: We prospectively evaluated clinical, laboratory parameters, and survival in patients with cirrhosis, with or without SCA, during the period 2008-2011. Patients who had at admission renal failure, other causes of hemolytic anemia, hepatocellular carcinoma, sepsis, and/or active bleeding, were excluded. One hundred sixteen patients with cirrhosis were included. The presence of SCA (SC rate higher or equal to 5% [≥ 5%]) was diagnosed in 36 (31%) patients. RESULTS: Patients with SCA compared to those without had more advanced liver disease (higher Model for End-Stage Liver Disease [MELD], P < 0.001), higher total bilirubin (P < 0.001), and International Normalized Ratio (P < 0.001). Patients with SCA had worse survival (log rank P < 0.001). Survival of patients with SCA at the first, second, and third month of follow-up was 77%, 45%, and 33%, respectively. In multivariate Cox's regression analysis, the presence of SCA was an independent predictor of mortality (hazard ratio = 3.17 [95% CI 1.55-6.48]). CONCLUSIONS: The presence of spur-cell anemia is not uncommon in cirrhosis and seems to be strongly associated with mortality. SCA can be used in combination with MELD as an additional predictor of early mortality.

Bevacizumab in the treatment of hereditary hemorrhagic telangiectasia.

INTRODUCTION: Hereditary hemorrhagic telangiectasia (HHT) is a rare multisystem vascular disorder characterized by epistaxis, mucocutaneous telangiectases and visceral arteriovenous malformations predisposing to shunting and hemorrhage. Angiogenesis has been implicated in the pathogenesis of HHT and therefore angiogenesis inhibitors appear to be the most promising agents. A literature search was performed to identify all articles reporting bevacizumab , a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). We focused on the HHT pathogenesis, mechanism of action of the drug, its impact on the HHT symptoms and safety profile. AREAS COVERED: Systemic intravenous administration of bevacizumab improves the frequency and intensity of epistaxis, gastrointestinal (GI) bleeding episodes and liver arteriovenous malformations consequences. The safety profile of the systematic administration of the drug appears to be excellent with hypertension as the unique adverse effect reported so far. Its intranasal administration significantly decreases frequency and severity of nosebleeds and blood transfusion requirements. EXPERT OPINION: In the absence of randomized controlled trials in HHT, criteria of selecting patients and formal recommendations for treatment are lacking. For life-threatening epistaxis requiring blood transfusion, topical treatment with bevacizumab may be beneficial. Systemic treatment with bevacizumab is promising in symptomatic patients with organ involvement and life-threatening conditions.

Myelodysplasia and autoimmunity.

PURPOSE OF REVIEW: Primary myelodysplastic syndromes (MDS) are heterogeneous clonal haemopoietic stem-cell disorders clinically presented with a varying degree of peripheral cytopenias and an increased probability of leukemic evolution. The natural history of MDS ranges from more indolent forms of disease spanning years to those rapidly progressing to overt leukemia. A distinct subset of MDS patients manifest overt autoimmune manifestations (AIMs), the pathogenesis and prognostic significance of which remain controversial. This review will briefly highlight aspects of immune-mediated myelosuppression and cytokine-induced cytopenias in MDS and further analyze MDS-associated AIMs clinically and pathogenetically. RECENT FINDINGS: Facts provided by advanced studies suggest that an immune reaction against the evolving clone, operated by macrophages, T, natural killer and other effectors contribute to ineffective and dysplastic MDS hemopoiesis. Despite the fact that several immunologic abnormalities have been described in MDS, the precise pathophysiologic mechanism underlying AIMs remains unclear. SUMMARY: The encouraging biological insights into the autoimmune component of MDS pathophysiology can lead to the development of novel forms of treatment for controlling MDS process. MDS with AIMs constitute an ideal model in the investigation of disordered immune function in preleukemic states.

Development of non-Hodgkin's lymphoma in a patient with primary biliary cirrhosis: A case report and review of the literature.

Patients with autoimmune disorders seem to have an elevated risk of lymphoma, especially non-Hodgkin's lymphoma (NHL). The increased risk has been attributed to the disturbance of immune function found in these patients or to the immunosuppressive therapy used to treat the autoimmune disorders. However, little information exists about the estimated baseline risk for lymphoma in patients with primary biliary cirrhosis (PBC). In this case report, we describe a female patient who developed nodal diffuse large B-cell lymphoma ten years following PBC diagnosis. Twenty five additional case reports (19 NHL and 4 Hodgkin's disease (HD), 2 without data about NHL or Hodgkin's disease) predominantly females were identified in the English literature. B-cell lymphoma was the most common NHL type reported but beyond that no clear predisposition for any specific lymphoma subtype was documented. PBC usually preceded lymphoma diagnosis. Fifteen cases had extranodal localization and the most common site was the liver.

Sarcoid-like granulomatosis in patients treated with anti-TNFα factors. A case report and review of the literature.

This report describes a 56-year-old woman who developed granulomatous lesions consistent with sarcoidosis during adalimumab therapy for rheumatoid arthritis. Cervical and axillary lymphadenopathy developed approximately 21 months after adalimumab administration. Non-caseating epithelioid cell granulomas consistent with sarcoidosis were detected both in an axillary lymph node specimen and in the bone marrow. Diseases showing similar histologic changes, especially tuberculosis, were excluded, and a diagnosis of sarcoidosis was made. Adalimumab was discontinued, and recovery was observed. The current case is, to our knowledge, the first to describe adalimumab-induced non-caseating granulomas in lymph nodes and bone marrow without pulmonary involvement in a patient treated for rheumatoid arthritis.

Pylephlebitis: an overview of non-cirrhotic cases and factors related to outcome.

Pylephlebitis is a condition with significant morbidity and mortality. We review herein 100 relevant case reports published since 1971. Eighty-one patients were reported with acute pylephlebitis, while the remaining patients had chronic pylephlebitis. The most common predisposing infections leading to pylephlebitis were diverticulitis and appendicitis. Cultures from blood or other tissues were positive in 77%. The infection was polymicrobial in half of the patients and the most common isolates were Bacteroides spp, Escherichia coli and Streptococcus spp. Thrombosis was extended to the superior mesenteric vein (SMV), splenic vein, and intrahepatic branches of the portal vein (PV) in 42%, 12%, and 39%, respectively. Antibiotics were administered in all and anticoagulation in 35 cases. Patients who received anticoagulation had a favourable outcome compared to those who received antibiotics alone (complete recanalization 25.7% vs 14.8% (p > 0.05), no recanalization 5.7% vs 22.2% (p < 0.05), and death 5.7% vs 22.2% (p < 0.01)). Cases with complete recanalization had prompt diagnosis and management and two-thirds were recently published. Nineteen patients died; the majority of these (73.7%) died over the period 1971-1990. In conclusion, pylephlebitis remains an entity with high morbidity and mortality, but modern imaging modalities have facilitated an earlier diagnosis and have improved the prognosis. Anticoagulation has a rather beneficial effect on patients with pylephlebitis.

Primary hepatic actinomycosis.

The clinical and imaging findings of primary hepatic actinomycosis are nonspecific and can mimic other diseases. This condition usually needs to be distinguished from other liver-occupying lesions, including malignancy. Review of the English language literature showed 67 cases of hepatic actinomycosis in immunocompetent, predominantly male patients. Infection was usually (75%) cryptogenic. The results of radiologic imaging showed that the lesion involved the right lobe in half of the cases, mimicked a liver tumor in 45%, and was single in two thirds of the cases. Hepatic actinomycosis coexisted with infections by common bacteria in 32% of cases reported. Diagnosis was usually achieved by microscopic examination of surgical or percutaneous specimens in 84.2% and 78.6%, respectively. Antibiotic therapy alone was used for treatment in approximately one half of cases and combined antibiotic treatment with surgical or percutaneous drainage procedure in the other half. The overall mortality rate was 7.6%. In conclusion, primary hepatic actinomycosis is a rare and usually cryptogenic infection. It is more common in men and immunocompetent subjects. It is well responsive to medical or combined medical and interventional treatment.

Peritoneal instillation of taurolidine or polihexanide modulates intestinal microcirculation in experimental endotoxemia.

BACKGROUND AND AIMS: Treatment of peritonitis may include peritoneal lavage/instillation with anti-infective agents like taurolidine or chlorhexidine. MATERIALS AND METHODS: We examined the effects of peritoneal instillation (INST, 5-ml solution) with taurolidine (TAURO) or polihexanide (POLI-LS) on intestinal microcirculation using intravital microscopy (IVM) in experimental endotoxemia (15 mg/kg lipopolysaccharide i.v.; LPS) in the rat (n = 8 each group), their direct effects on local small blood vessels, aortal rings, and myocardial strips in vitro, as well as plasma interleukin levels. RESULTS: It was found that LPS produced hypotension (98.8 +/- 9.5 vs 130.4 +/- 10.5 mmHg; mean arterial pressure [MAP], mean +/- standard deviation [SD]), which was further pronounced after INST of TAURO (78.8 +/- 10.8; P < 0.005) or POLI-LS (78.1 +/- 6.0; P < 0.001). IVM revealed a reduction in temporary adhering leucocytes and an increase in firmly adhering leucocytes after INST with TAURO and POLI-LS. Both agents reduced functional capillary density either in the mucosa (POLI-LS vs sham: 259.7 +/- 54 cm/cm(2) vs 337.1 +/- 35.5) or longitudinal muscular layer in LPS rats (TAURO vs sham: 119.8 +/- 14.8 vs 153.7 +/- 11.0). POLI-LS induced local vasodilatation, whereas TAURO induced small vasoconstriction; in vitro, both agents showed vasodilating properties and did not have any effect on myocardial strip contraction. CONCLUSION: Some of the observed microcirculatory changes could be a result of the direct vascular effects of these agents.