Pathophysiology of bleeding diathesis in haemophilia-A: A sequential and critical appraisal of non-FVIII related haemostatic dysfunctions and their therapeutic implications

Haemophilia-A is characterized by deficiency of FVIII, but the bleeding diathesis is not a mere reflection low FVIII activity. The pathophysiology of haemophilic bleeding diathesis is a complex interplay between defective procoagulant function and up-regulated fibrinolysis. Moreover, haemophilic bleeding diathesis is frequently compounded by treatment-related and infective complications such as FVIII inhibitors, hepatitis, HIV infection, non-steroidal anti-inflammatory drugs (NSAID) induced gastritis, and infective mucosal injuries such as H pylori gastritis and intestinal and urinary helminthiasis. Hence, pathophysiology of haemophilic bleeding is multi-factorial, encompassing both FVIII and non-FVIII haemostatic defects. Currently available literature on pathophysiologic roles of non-FVIII haemostatic defects in haemophilia is fragmented. This articles is aimed at providing a composite and comprehensive review of the roles of non-FVIII haemostatic defects and their therapeutic implications in haemophilic bleeding diathesis, which will enable a holistic approach towards clinical management of the bleeding diathesis. This is necessary because FVIII therapy alone maybe insufficient in managing complicated haemophilic bleeding unless compounding non-FVIII-related haemostatic dysfunctions and comorbidities are identified, targeted and treated. This will necessitate appropriate use of non-FVIII therapeutic modalities, which may include anti-fibrinolytic agents, FVIII by-passing agents, immune modulation, and anti-microbial agents. Lots of work has been done in the areas of non-FVIII agents and FVIII by-pass therapy in the management of haemophilia, but more research is needed to validate many of these targeted therapeutic techniques. Meanwhile, healthcare personnel must consider the roles of both FVIII and non-FVIII haemostatic defects when evaluating haemophilic bleeding diathesis for the purpose of choosing appropriate and optimal treatment options.Keywords: Haemophilia, Bleeding diathesis, Pathophysiology, Targeted therapy, Non-FVIII therapy, FVIII by-pas

Review: Determinants and modifiers of bleeding phenotypes in haemophilia-A: General and tropical perspectives

Haemophilia-A is an X-linked recessive bleeding disorder characterized by deficiency of FVIII. Although severity of haemophilia is largely determined by the extent to which different mutations abolish FVIII production, the overall phenotypic variations among haemophiliacs is determined by a combination of several other factors, which range from general to tropical factors on the one hand, and from genetic to immunologic and infective factors on the other hand. Determinants and modifiers of haemophilic bleeding phenotypes are important predictors of prognosis. However,  tropical determinants of haemophilic bleeding phenotypes are virtually ignored because majority of haemophilia research originated from developed non-tropical countries. The aim of this paper is to present a balanced review of the haemophilic bleeding phenotypes from general and tropical perspectives. Hence, we present a concisely updated comprehensive review of the  pathophysiologic and clinical significance of general vis-à-vis tropical determinants and modifiers of haemophilic bleeding phenotypes from genetic, immunologic and infective perspectives. Understanding of general phenotypic determinants such as FVIII gene mutations, immunological (inhibitors) and infective (e.g. hepatitis and HIV)  complications, classical thrombophilias (e.g. FV-Leiden) and non-classical thrombophilias (e.g. non-O blood groups) will throw more light into the mechanisms by which some tropical prothrombotic gene mutations (such as sickle b-globin gene) and certain chronic tropical pro-haemorrhagic parasitic infections (such as urinary and gastrointestinal helminthiasis) may modify frequency, intensity and pattern of bleeding among haemophiliacs in the tropics. The clinical significance of iron deficiency within the context of helminthiasis and haemophilia is also reviewed. More research is needed to determine the precise effect of non-classical thrombophilias such as sickling disorders and ABO blood groups on haemophilic bleeding phenotypes. Meanwhile, tropical healthcare workers should incorporate regular screening and treatment for common prohaemorrhagic parasitic diseases and iron deficiency into standard of care for management of haemophilia.Keywords: Haemophilia Bleeding Phenotype Thrombophilia ABO blood  group Sickle cell Helminthiasis Iron deficienc

Efficacy and safety of misoprostol for intrauterine device insertion in women with no previous vaginal delivery: a systematic review and meta-analysis of randomized controlled trials

Introduction: The efficacy of misoprostol use for cervical priming before intrauterine device insertion (IUD) is controversial. This review aims to evaluate the evidence from published randomized controlled trials about the efficacy and safety of misoprostol before IUD insertion for pain relief in women with no previous vaginal delivery. Materials and methods: We searched the following electronic databases: Web of Science, Cochrane CENTRAL, SCOPUS, and PubMed for relevant studies using the following Mesh terms: (misoprostol) AND (intrauterine device OR IUD). The primary outcome was the mean pain score during insertion. Secondary outcomes included the ease of insertion score, the rate of successful IUD insertion, the rate of IUD insertion failure, and the adverse effects. Results: Ten randomized controlled trials (RCTs) (misoprostol: n=698 and placebo: n=689) were pooled in the analysis. The overall Standardized Mean Difference (SMD) of pain score did not favor either of the two groups (SMD= -0.09, 95%CI [-0.50, 0.33], p=0.007). Pooled results were highly heterogeneous (I2=93%, P<0.001). The total MD of the ease of insertion score favored the misoprostol group (MD= -1.36, 95% CI [-2.20, -0.52], p =0.002). The overall risk ratio (RR) of the number of failed insertions showed that misoprostol is associated with less IUD insertion failures compared to placebo (RR=0.55, 95% CI [0.38, 0.81], p=0.002). Finally, the overall risk showed that misoprostol is associated with more shivering, diarrhea and pelvic pain. Conclusions: Misoprostol facilitates IUD insertion in women with no previous vaginal delivery, and is associated with 50% less chance for IUD insertion failure despite inducing mild adverse effect

A cost-efficient dependability management framework for self-aware system-on-chips based on IEEE 1687

A cost-efficient framework for executing life-time dependability procedures is presented in this paper. The proposed framework relies on distributed sensors and actuators (embedded instruments) for self-awareness and adaptation, where the IEEE 1687 standard (iJTAG) is utilized for the dependability communications and the on-chip access of the instruments

Developing a Performance Criteria for Stone Columns to Improve Surface Pavement for Weak Subgrade Conditions

AbstractSoft, saturated, fine grained subgrade soils are distinguished by their low undrianed shear strength and high compressibility. Such soils cover most of the middle and southern parts of Iraq. The effect of using stone column, encased in geogrid and steel mesh to improve pavement's performance is experimentally investigated and evaluated. To compare the experimental and analytical outputs, three dimensions finite element throughout elastic and elasto-plastic models using ABAQUS ver.6.12.3 software are developed to simulate and analyze the relations between the cycling load and deformation of the suggested pavement modes. Based on the results and the limitation of this study it is concluded that, using encased stone columns, is more practical and suitable alternative to improve weak subgrade against permanent deformation as compared with the other simulated pavement modes. The results of ABAQUS program are very close to results of laboratory tests

Rainfall interpolation analysis on river Kaduna catchment for climate change assessment

The Inverse Distance Weighing (IDW) technique for rainfall interpolation considered by researchers as a suitable method for predicting missing rainfall records was used to estimate missing rainfall records in River Kaduna Catchment area from 1979-1990. Distances among respective rainfall stations were used to calculate the weighing factor for stations with missing records and radius of influence of 22.5-201km. The Root Mean Square Error (RMSE) was used to test the accuracy of the assessment and the results were validated using correlation coefficient. From the results of the analysis through optimization of steps of α values and radius of influence, the smaller the optimum parameter value the better the prediction and in most cases the accuracy increases at short optimum search radii, also small amount and long duration rainfall values enhances the prediction potential of the IDW.Keywords: Rainfall data, Inverse Distance Weighing, Interpolation, Optimum parameter