Challenges in diagnosis and management of acquired factor V inhibitors

Inhibitors to factor V is a rare phenomenon with varied clinical presentation ranging from asymptomatic states to life-threatening bleeds. They are known to be associated with exposure to bovine thrombin, drugs, autoimmune diseases and malignancies. Establishing the diagnosis of FV inhibitors is challenging and the presence of lupus-like properties of the inhibitor can further complicate the diagnosis. Here we document an unusual case of an asymptomatic elderly female posted for pacemaker implantation and incidentally, the laboratory workup revealed a disproportionately abnormal coagulation screen. The intricacies in the diagnosis and management are discussed along with a brief review of the literature. An awareness of the diverse manifestations of this underrecognized disorder and difficulties in management is essential for medical practitioners, particularly in patients with idiopathic severe bleeding diathesis.

Comparison between the different new anti-coagulants for non-valvular atrial fibrillation: network meta-analysis

Atrial fibrillation is associated with high risk of ischaemic stroke which is considered a major fatal complication in atrial fibrillation. That’s why, anticoagulants were used to prevent this major complication. However, anticoagulants themselves are associated with their own complications. A systematic search of Embase, Medline and Google scholar were conducted. The included papers were extracted for outcomes related to the complications of each drugs. A Bayesian network meta-analysis based on Markov chain Monte Carlo simulation (MCMC) with 10000 burn-in iterations and 50000 inference iterations. We found eighteen papers that fit our inclusion criteria. Apixaban had the least risk of major bleeding compared to Warfarin [HR = 0.536, 95% (0.448, 0.652)] and the least risk of gastrointestinal hemorrhage. For stroke risk, the Rivaroxaban had the least risk compared to Warfarin [HR = 1.05, 95% (0.98, 1.14)]. For intracranial hemorrhage, dabigatran had the least risk of intracranial haemorrhage compared to Warfarin [HR = 0.46, 95% CrI (0.36, 0.61)]. For the thromboembolism risk, other non-vitamin k antagonist had the least risk of intracranial haemorrhage compared to Warfarin [HR = 0.523, 95% (0.095, 2.85)]. There were no conclusive results about the best anticoagulant drugs for non-valvular atrial fibrillation. Apixaban was the least among them to be associated with major bleeding, while rivaroxaban was ranked the first with least stroke complications. Furthermore, dabigatran was associated with less risk of intracranial haemorrhage compared to other anticoagulants.

Dental management of patients on anti-thrombotic agents

The number of geriatric patients seeking dental service is ever-rising because of increased life expectancy, also with problem of increased chronic medical conditions. One of them are patients on anti-thrombotic medication. Bleeding complication after minor oral surgery by anti-thrombotic agents is of concerns to dentists on dental management of these patients. Risk and benefit of the anti-thrombotic agents must be weighed before initiating dental procedures, which should be established as a treatment guideline. Purpose of the paper is to optimize the management of the dental patients on anti-thrombotic medication via standardization of treatment protocol of such a patient.

Clinical characteristics and treatments of anti-coagulant rodenticide poisoning in children lacking of poisoning history / 中国小儿急救医学

Objective To summarize the clinical characteristics,diagnosis and treatments of 50 chil-dren with no history of anti-coagulation rodenticide poisoning.Methods Fifty children lacking of poisoning history were admitted to our hospital from Feb 2011 to Dec 2015,who were due to hemorrhage and finally di-agnosed as rodenticide poisoning.The clinical manifestation,characteristics of blood coagulation dysfunction, toxicology screening results and treatments of 50 cases were retrospectively analyzed.Results All 50 cases were from rural area,and denied the history of taking rodenticide by mistake.The time from the onset to ad-mission to the hospital was from 1 d to 120 d,with an average of 11.66 d.Major clinical manifestations in-cluded:34 cases(68%)of skin ecchymosis,26 cases(52%)of epistaxis,10 cases(20%)of bleeding gums and 4 cases(8%)of hematoma at the injection site,with PT 20 to over 200 s and APTT 31 to over 200 s (maximal detection value).The children were diagnosed as rodenticide poisoning when one of brodifacoum, bromadiolone,and diphacinone-sodium or combination of brodifacoum and bromadiolone were detected from their blood specimens,with an concentration of 5 to 3 270 μg/L.The diagnosed children were intravenous dripped with specific antagonist vitamin K1 and the critically ill children were added fresh frozen plasma.All children recovered from hemorrhage within 24 hours after treatment.The level of PT,APTT was close to nor-mal after 3 to 7 days of treatment,and the using of vitamin K1 was accumulated about 30 to 70 mg.The chil-dren were given maintenance treatment of vitamin K1 for three months after discharge until the condition was stable.Conclusion Commonly used rodenticide has the characteristics of fat soluble, easy to accumulate, long incubation period,and long treatment period and so on.Children with no bleeding performance have the clinical tendency of acute bleeding,prolonged PT and APTT should be considered the possibility of rodenti-cide poisoning.Blood or urine samples should be screened for toxicology as soon as possible,and meanwhile children should be given antagonist treatment with special antidote vitamin K1 until the coagulation function is stable in normal range to avoid recurrence of the illness.

Promising Therapeutics against Ebola Virus Disease.

Ebola Virus Disease (EVD) has become a major threat to global peace and security. Since 1976, when Ebola virus was discovered, over 20 outbreaks have been reported. Most of these outbreaks occurred in rural areas of East and Central Africa. But the current 2014 outbreak, which started in Guinea in March 2014, spread to Liberia, Sierra Leone, Nigeria, Senegal and Mali, and traveled beyond Africa into Europe and US. Thus far, there have been no approved therapeutics and preventive vaccines and hence response is limited to supportive care, barrier nursing, and management of patient complications. Spurred by the global threat, research has identified promising drug candidates against the disease. This review presents the current status of promising drug candidates against EVD. The current development status of the experimental drugs ZMapp, TKM-Ebola, Favipiravir (T-705 or Avigan), AVI 6002, BCX 4430 and Brincidofovir (CMX-001) is given. In the absence of licensed drugs, these first generation anti-Ebola virus experimental drugs, which are currently in phase 1 clinical trial, were administered to a limited number of healthcare workers during the current EVD outbreak.

In vitro study of inhibitory effect of Ulinastatin against serine protease activity / 中国生化药物杂志

Objective To study inhibitory effect of serine protease activity by Ulinastatin in vitro .Methods Different chromogenic peptides were designed and synthesized.Highly sensitive fluorescence detection was performed to optimize the concentration of each serine proteases and their chromogenic substrates.Multi-point method was used for the calculation of half maximal inhibitory concentration of Ulinastatin .ResuIts Ulinastain could inhibit Polymorphonuclear leukocyte elastase ( PMNE ) and plasmin with IC50 lower than 100 U/mL.For factor Xa, and Kallikrein, the IC50 of Ulinastatin was higher than 1000U/mL.No thrombin IC50 could be calculated at the present experiments.ConcIusion Similar to Ulinastatin injection from Japan, domestic Ulinastatin shows the strongest inhibitory effects on PMNE among those serine proteases.As important references, this study gives reliable data for dose range of domestic Ulinastatin in anti-inflammation, coagulation/anti-coagulation and anti-shock therapy.

Pharmacogenetic typing for oral anti-coagulant response among factor V Leiden mutation carriers.

Context: Factor V Leiden mutation is the most common inherited predisposition for hypercoagulability and thereby a common genetic cause for initiation of oral anti-coagulation therapy. There is a dearth of knowledge of coumarin response profile in such thrombophilic population. Aims: The current pilot study aims to estimate coumarin sensitivity in an Indian cohort with an inherited thrombophilia risk factor (Factor V Leiden mutation carriers) based on the observed frequency of CYP2C9 *2, *3 and VKORC1-1639G >A genotype combinations. Settings and Design: A retrospective study carried out in a tertiary health care center in India. Materials and Methods: Carriers of FVL mutation were genotyped for CYP2C9 (*2, *3) and VKORC1 (-1639G >A) variants by PCR-RFLP technique. Statistical Analysis Used: Chi-square test to analyze difference in expected and observed genotype frequency. Results: Sixty-one (n = 61) unrelated carriers of FVL mutation were observed in the 13 years study period. The allele frequency of CYP2C9 *2, CYP2C9 *3, and VKORC1-1639A in this cohort was 0.06, 0.11, and 0.16, respectively. Six (9.7%) individuals had two of the three variant alleles (heterozygous or homozygous), and 28 (45.9%) were heterozygous for at least one polymorphism. Conclusions: Pre-prescription genotyping for coumarin drugs, if introduced in Indians with inherited thrombophilia (in whom oral anti-coagulant therapy may be necessary), is likely to identify 9.7% (hypersensitive) subjects in whom the optimum anti-coagulation may be achieved with reduced dosages, 44.3% (normal sensitivity) who may require higher dose and also 55.6% (hyper and moderate sensitivity) subjects who are likely to experience bleeding episodes.

Anticardiolipin Antibody (ACA) and Lupus Anticoagulant (LA): Association with Vascular Access Occlusion in Hemodialysis (HD) Patients / 대한내과학회지

OBJECTIVES: Anticardiolipin antibody (ACA) and lupus anticoagulant (LA) are acquired antiphospholipid antibodies (APAs), which are regarded as important risk factors far vascular thrombosis and recurrent fetal loss. Although the clinical relevance of APAs in dialysis patients is uncertain, recent studies have suggested that APAs are involved in bioincompatibility and thrombogenic complications in hemadialysis (HD) patients. METHOD: We performed a cross sectional study of ACA and LA in 50 stable HD patients and their 68 vascular accesses (52 native arteriovenous fistulae and 16 synthetic arterovenous grafts), with the analysis of factors associated with the presence of APAs and the retrospective evaluation of vascular access occlusion (VAO). LA was assessed by platelet neutralization method whereas IgG-ACA was measured by a solid phase ELISA. Values higher than 23GPLU/ml (IgG phospholipid units) were considered to be positive for IgG-ACA and positive values for LA was more than 8 seconds in prolongation of the clotting time with human platelet lysate. Vascular access survival was assessed by Kaplan- Meier method, RESULTS: The mean age of the subject (M:F 21:29) was 46 years and the mean duration of hemodialysis was 49 months. The frequency of VAO in entire subjects was 0.45+/-0.98 episodes/patient year. The median value of IgG-ACA was 16.0 GPLU/ml with a distribution from 2.7 to 46.1GPLU/ ml. The median titer of I.A was 4.5 (3.1-45.6) seconds. Fourteen patients (28%) were found to have at least one episode of VAO. In spite of comparable clinical and biochemical data according to the presence of VAO, the titers of IgG-ACA (13.6+/-7.7 vs, 20.3+/-8.7GPLIJ/ml, P<0.05) and LA (4.5+/-2.9 vs. 11.7 +/-12.6sec, P<0.05) were significantly higher in VAO group. Six out of 50 patients(12%) had an increased titer of IgG-ACA and LA was found in 11 patients(22%). No patients were positive for ACA and LA simultaneously. There was no significant difference in sex, etiology of ESRD, diabetic status, the dosage of heparin during HD or the amount of erythropoietin administered according to the presence of APAs. We could not find any significant correlation between the titer of APAs and age, duration of dialysis, blood pressure, platelet count and biochemical parameters. In the patients with positive ACA, the frequency of VAO was 1.05+/-0.12 episodes/patient year, which was significantly higher than patients without ACA (0.33+/-0.17 episodes/ patient year, P<0.05). In the patients with the presence of LA(1.06+/-0.43 vs. 0.12+/-0.06 episodes/ patients year, P<0.01). The median vascular access survival time in IgG-ACA positive patients (32.7 months) was significantly decreased compared to 66.8 months in IgG-ACA negative group. CONCLUSION: Our data suggest that the presence of APAs (ACA and/or LA) affects the event-free vascular access survival in HD patients. Therefore the evaluation of APAs status have to be included in the diagnostic strategies for the patients with recurrent VAO. Further studies are necessary to explore the pharmacologic intervention method to decrease APAs and prevent VAO in HD patients.

Laser Thermal Angioplasty by the Contact Method for Arteriosclerosis Obliterans of the Lower Limbs / 日本心臓血管外科学会雑誌

Laser thermal angioplasty with a metal hot tip probe was performed on 34 cases of arteriosclerosis obliterans of the lower limbs, instead of conventional balloon angioplasty. Initial angiographic and clinical success was achieved in 48 of 53 (90.5%) arterial lesions. The initial success rates were 91.6%, 87.8% and 100% for lesions of the iliac, femoral and popliteal arteries respectively. The initial success rate was 66.6% in occlusive lesions, and was 100% in stenotic lesions. Five of seven (71.4%) occlusions less than 10cm length, and five of eight (62.5%) occlusions longer than 10cm were successfuly treated. Higher laser energy was necessary for ablation in occlusive lesions than in stenotic lesions. The ankle pressure index improved postoperatively in both occlusive and stenotic lesions. Satisfactory long term patency was achieved in 27 of 35 successfully treated lesions (77.1%). These results suggest that laser thermal angioplasty is effective for the treatment of arteriosclerotic disease in the lower limbs.