Thrombopoietin-receptor agonists for adult patients with immune thrombocytopenia: a narrative review and an approach for managing patients fasting intermittently.

Introduction: Thrombopoietin-receptor agonist (TPO-RAs) currently represent the state of art for treating immune thrombocytopenia. Their different molecular structures contribute to the difference in their pharmacodynamics and pharmacokinetics. This narrative review aims to provide an overview of the current TPO-RAs approved for primary immune thrombocytopenia (romiplostim, eltrombopag, avatrombopag) and the effect of intermittent fasting in adult patients receiving TPO-RAs. Areas covered: Literature was searched with no limits on date or language, using various combinations of keywords. Data on the pharmacokinetics, pharmacodynamics, efficacy, and safety of TPO-RAs and the effect of intermittent fasting were summarized. Expert opinion: Switching between TPO-RAs is a useful strategy to tackle some associated limitations. Romiplostim and avatrombopag have an advantage over eltrombopag as they do not require any dietary restrictions. In cases where romiplostim and avatrombopag are unavailable, patients should be educated on the appropriate administration, possible interactions, and dietary restrictions before initiating eltrombopag.

The Challenges in Diagnosis and Management of Acquired Thrombotic Thrombocytopenic Purpura: Consensus Report from Three Gulf Countries.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare hematological emergency characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, and multiorgan failure due to autoimmune-mediated deficiency in ADAMTS-13 activity. Currently, plasma exchange, with or without steroids, is the frontline option for the management of aTTP. The treatment should be started promptly once the disorder is clinically suspected. Besides, immunomodulators were studied in patients with aTTP to achieve stable remission and reduce the risk of relapse in patients with suboptimal response to plasma exchange; however, clinical trials showed equivocal results. Published data on early diagnosis, referral, and treatment patterns of aTTP patients in the member nations of the Arabian Gulf Cooperation Council (GCC) are still lacking. Therefore, the present consensus report aimed to present an overview of aTTP situation in GCC by bringing together a panel of experts from three GCC nations, to share their views on current trends and practices regarding aTTP. The experts discussed challenges including the lack of reliable data regarding the incidence of aTTP in GCC and delayed results of ADAMTS-13 activity testing. Limited patient access to tertiary centers and low level of awareness about the aTTP clinical spectrum among general practitioners are other challenges. The experts agreed that there is a need for national and regional consensus regarding the diagnosis and treatment of aTTP in the Gulf region.

Anemia or other comorbidities? using machine learning to reveal deeper insights into the drivers of acute coronary syndromes in hospital admitted patients.

Acute coronary syndromes (ACS) are a leading cause of deaths worldwide, yet the diagnosis and treatment of this group of diseases represent a significant challenge for clinicians. The epidemiology of ACS is extremely complex and the relationship between ACS and patient risk factors is typically non-linear and highly variable across patient lifespan. Here, we aim to uncover deeper insights into the factors that shape ACS outcomes in hospitals across four Arabian Gulf countries. Further, because anemia is one of the most observed comorbidities, we explored its role in the prognosis of most prevalent ACS in-hospital outcomes (mortality, heart failure, and bleeding) in the region. We used a robust multi-algorithm interpretable machine learning (ML) pipeline, and 20 relevant risk factors to fit predictive models to 4,044 patients presenting with ACS between 2012 and 2013. We found that in-hospital heart failure followed by anemia was the most important predictor of mortality. However, anemia was the first most important predictor for both in-hospital heart failure, and bleeding. For all in-hospital outcome, anemia had remarkably non-linear relationships with both ACS outcomes and patients' baseline characteristics. With minimal statistical assumptions, our ML models had reasonable predictive performance (AUCs > 0.75) and substantially outperformed commonly used statistical and risk stratification methods. Moreover, our pipeline was able to elucidate ACS risk of individual patients based on their unique risk factors. Fully interpretable ML approaches are rarely used in clinical settings, particularly in the Middle East, but have the potential to improve clinicians' prognostic efforts and guide policymakers in reducing the health and economic burdens of ACS worldwide.

Challenges in the Management of Sickle Cell Disease During SARS-CoV-2 Pandemic.

The management of sickle cell disease (SCD) and its complications in the COVID-19 era is very challenging. The recurrent sickling process in SCD causes tissue hypoxemia and micro-infarcts, resulting in end organ damage. Since the outbreak of SARS-CoV-2 pandemic, little data has been published about SCD concerning clinical presentation with COVID-19 and management. Hydroxyurea has been the cornerstone of management in children and adults with SCD, with evidence of its effect on controlling end organ damage. There are several anti-sickling drugs that have been approved recently that might have an additive value toward the management of SCD and its complications. The role of simple and exchange transfusions is well established and should always be considered in the management of various complications. The value of convalescent plasma has been demonstrated in small case series, but large randomized controlled studies are still awaited. Immunomodulatory agents may play a role in reducing the damaging effects of cytokines storm that contributes to the morbidity and mortality in advanced cases. Prophylactic anticoagulation should be considered in every management protocol because SCD and COVID-19 are thrombogenic conditions. Management proposals of different presentations of patients with SCD and COVID-19 are outlined.

Consensus Statement by an Expert Panel on the Diagnosis and Management of Iron Deficiency Anemia in the Gulf Cooperation Council Countries.

BACKGROUND: Iron deficiency (ID) and ID anemia (IDA) are common in the member states of the Gulf Cooperation Council (GCC). The unique genetic and lifestyle factors of the patient population in the region have necessitated the development of recommendations to help educate health-care professionals on appropriate diagnosis and management of ID/IDA. METHODS: A panel of regional experts, including gastroenterologists and hematologists with expertise in the treatment of IDA, was convened to develop regional practice recommendations for ID/IDA. After reviewing the regional and international literature, the expert panel developed consensus recommendations for screening, diagnosis, and treatment of patients with IDA in the GCC region. RESULTS: The recommendations proposed were customized to the patient population keeping in view the increasingly recognized burden of coeliac disease, high fertility and obesity rates, high prevalence of alpha- and beta-thalassemia traits, and poor tolerance and low treatment compliance with oral iron therapy. CONCLUSIONS: This consensus statement proposes recommendations for screening, diagnosis, and treatment of IDA in the GCC region.

White blood cell subpopulation changes and prevalence of neutropenia among Arab diabetic patients attending Dasman Diabetes Institute in Kuwait.

BACKGROUND: The effects of diabetes mellitus on the differential white blood cell count are not widely studied in the Arab populations. The objective of this cross-sectional, retrospective study is to assess the influence of chronic diabetes mellitus on white blood cell counts, absolute neutrophil (ANC) and lymphocyte counts (ALC) as well as the prevalence of benign ethnic neutropenia among Arabs attending the Dasman Diabetes Institute (DDI) in Kuwait. METHODS AND FINDINGS: 1,580 out of 5,200 patients registered in the DDI database qualified for our study. Age, gender, HbA1c and creatinine levels, estimated glomerular filtration rate as well as average WBC, ANC and ALC levels, presence of diabetes-associated complications and anti-diabetic medications were analyzed. Our results showed the mean value of the WBC was 7.6 ± 1.93 x 109/L (95% CI: 2.95-17.15). The mean ANC was 4.3 x 109/L (95% CI: 0.97-10.40) and mean ALC was 2.5 x 109/L (95% CI: 0.29-10.80). Neutropenia (ANC: <1.5 x 109/L) was detected in fifteen patients (0.94%). Six patients (0.4%) fulfilled the definition of lymphopenia (ALC < 1 x109/L). Patients with an HbA1c ≥ 7% and those taking at least 3 anti-diabetic medications showed higher values for ANC and ALC. Patients with diabetes-associated neuropathy or nephropathy displayed higher mean ANC values. Our study was limited by overrepresentation of patients over 50 years old compared to those under 50 as well as selection bias given its retrospective nature. CONCLUSIONS: Our study showed that patients with poorly controlled diabetes displayed higher ANC and ALC levels. In addition, patients with DM-associated complications showed higher ANC levels. This finding would suggest that DM exerts a pro-inflammatory influence on differential WBC counts. Our study also showed that the prevalence of benign ethnic neutropenia was lower than previously reported in other studies.

Anemia in diabetes: Experience of a single treatment center in Kuwait.

AIMS: Diabetes mellitus is the most common metabolic disorder in Kuwait. Anemia is a known outcome of diabetes and its related complications. This study examined the prevalence of anemia in diabetic subjects in Kuwait as well as any association between the presence of anemia with Hemoglobin A1c and diabetes complications. METHODS: The study subjects were diabetic patients with complete records and two or more visits at Dasman Diabetes Institute. Patient's data included demographics, complications, medications and laboratory results. Descriptive statistics were applied using SPSS. RESULTS: Of 1580 included diabetic patients; the prevalence of anemia was 28.5% (95% CI: 26.3, 30.8). Diabetic females had a higher rate of anemia compared to males (35.8% vs. 21.3% respectively, p<0.001). There was no association between diabetes control (HbA1c) and anemia in both genders (p=0.887). Patients with elevated serum creatinine and microalbuminuria were more likely to be anemic (p<0.001). Diabetic patients with anemia had higher presence of peripheral neuropathy and diabetic foot (p<0.001). CONCLUSION: This study shows high prevalence of anemia in diabetic patients, particularly in those with diabetic complications. These results should prompt treatment centers to include anemia investigation and management within their diabetes treatment protocols to reduce morbidity in diabetes.

Venous Thromboembolism Risk and Adequacy of Prophylaxis in High Risk Pregnancy in the Arabian Gulf.

OBJECTIVES: To estimate the prevalence of venous thromboembolism (VTE) risk factors in pregnancy and the proportion of pregnancies at risk of VTE that received the recommended prophylaxis according to the American College of Chest Physicians (ACCP) 2012 published guidelines in antenatal clinics in the Arabian Gulf. METHODS: The evaluation of venous thromboembolism (EVE)-Risk project was a non-interventional, cross-sectional, multi-centre, multi-national study of all eligible pregnant women (≥17 years) screened during antenatal clinics from 7 centres in the Arabian Gulf countries (United Arab Emirates, Kuwait, Bahrain, Qatar and Oman). Pregnant women were recruited during a 3-month period between September and December 2012. RESULTS: Of 4,131 screened pregnant women, 32% (n=1,337) had ≥1 risk factors for VTE. Common VTE risk factors included obesity (76%), multiparity (33%), recurrent miscarriages (9.1%), varicose veins (6.9%), thrombophilia (2.6%), immobilization (2.0%), sickle cell disease (2.8%) and previous VTE (1.6%). Only 8.3% (n=111) of the high risk patients were on the recommended VTE prophylaxis. Enoxaparin was used in 80% (n=89) of the cases followed by tinzaparin (4%; n=4). Antiplatelet agents were prescribed in 11% (n=149) of pregnant women. Of those on anticoagulants (n=111), 59% (n=66) were also co-prescribed antiplatelet agents. Side effects (mainly local bruising at the injection site) were reported in 12% (n=13) of the cases. CONCLUSION: A large proportion of pregnant women in the Arabian Gulf countries have ≥1 VTE risk factor with even a smaller fraction on prophylaxis. VTE risk assessment must be adopted to identify those at risk who would need VTE prophylaxis.

Smoking, von Willebrand factor and ADAMTS-13 in healthy males.

While von Willebrand factor (vWF) has been reported to be elevated in smokers, there are no reports on the effects of smoking on its cleaving protease ADAMTS-13, particularly in subjects of Arab ethnicity. This study was conducted to determine the effects of smoking on vWF and ADAMTS-13 antigen and activity levels in Arab males. Venous blood samples from 80 smoking (at rest) and 80 non-smoking healthy males were collected after asking subjects to fast and refrain from smoking for 8 hours. Similar sampling was done for 40 smokers (acute smokers), who were asked to smoke one cigarette immediately before blood collection. Plasma was used to measure ADAMTS-13 antigen and activity levels, as well as vWF antigen and collagen binding activity levels using commercial ELISA kits. Compared to non-smokers, ADAMTS-13 and vWF activities were significantly lower in smokers at rest (p < 0.05). Acute smokers had significantly higher levels of vWF activity and ADAMTS-13 antigen and activity levels (p < 0.01), compared to smokers at rest. Our results suggest that high vWF activity is accompanied by an increase in ADAMTS-13 activity as a natural physiological mechanism to degrade the elevated vWF molecules. If not followed by a subsequent smoke, the activities of both proteins subside. It is possible that the repeated increase in vWF and constant degradation by ADAMTS-13 results in lower overall levels of both proteins in smokers (at rest) compared to nonsmokers who do not experience a similar (repeated) injury to the endothelium.

Assessment of venous thromboembolism risk and adequacy of prophylaxis in selected acute care medical centres in Arabian Gulf States: results from the ENDORSE study.

OBJECTIVES: To assess the prevalence of venous thromboembolism (VTE) risk in acutely ill surgical and medical patients in selected acute care centres in the Arabian Gulf States, and to determine the proportion of at-risk patients who received effective prophylaxis in accordance with 2004 American College of Chest Physicians (ACCP) guidelines. MATERIALS AND METHODS: Eight hospitals from 3 countries (Kuwait, Kingdom of Saudi Arabia, and United Arab Emirates) contributed to the global ENDORSE (Epidemiological International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study. Medical records were reviewed for all the in-patients aged ≥40 years admitted to medical wards, and in patients aged ≥18 admitted to surgical wards. The VTE risk and recommended prophylaxis were assessed according to the 2004 ACCP guidelines. RESULTS: Of 1,291 evaluable patients, 801 were considered at risk of VTE; 391 (48.8%) surgical patients and 410 (51.2%) medical patients. Of the 801 patients, 322 (40.2%) received ACCP-recommended VTE prophylaxis; 159 (40.7%) of surgical patients and 163 (39.8%) of medical patients. CONCLUSIONS: The data showed that VTE prophylaxis was underutilized in high-risk hospitalized patients. We recommend that active measures should be implemented in acute care centres in these Arabian Gulf countries to ensure identification of patients at risk of VTE and institute the appropriate prophylaxis.

Heparin anticoagulation responsiveness in a coronary care unit: a prospective observational study.

The aim of this study is to assess the practice of heparin administration in real-life situations. This study was conducted at the coronary care unit (CCU) in one of the busiest hospitals in Kuwait; with special attention to the rate of heparin resistance, potential factor that may predict resistance or responsiveness and heparin related complications. A prospective observational study was conducted in Farwania hospital over a 4-month period; this study included 146 patients admitted to the CCU. Patients were treated with UFH according to a standard normogram. Several variables were collected and analyzed, including demographic data, initial diagnosis, activated partial thromboplastin time (APTT) on admission and at 6, 24, and 48 h after UFH administration, and any complications that occurred. A significant number of patients had subtherapeutic APTT at 6, 24, and 48 h (41.1%, 42.3%, and 46.7%, respectively). There were four factors that predicted heparin resistance, including race, gender, admitting diagnosis (unstable angina vs. acute myocardial infarction), and an APTT ratio of less than one on admission. There was no significant difference in the rate of development of complications among different groups. Heparin resistance is a common phenomenon especially in the first period of heparin therapy. Special attention should be given to some groups like females, patients admitted with unstable angina, and those with APTT below the normal range. Evidence based protocols for heparin administration and monitoring must be adopted to prevent the risk of under or over anticoagulation.

Rituximab in the treatment of idiopathic thrombocytopenic purpura (ITP).

The objective of this study was to evaluate the efficacy and safety of rituximab in the treatment of patients with idiopathic thrombocytopenic purpura (ITP). A prospective study was performed at Mubarak Al-Kabeer University Hospital involving the use of rituximab in 14 patients who had previously been treated with steroids, steroid sparing drugs, and splenectomy. Several variables have been collected and analyzed including age, gender, treatment received prior to rituximab, co-morbid condition, platelet count before treatment, response to treatment, duration of response, relapses, response to re-treatment, and adverse effects. Of the 14 treated patients, complete remission was achieved in 11 patients, partial remission in two patients, and no response in one patient. Median duration of responses were 12.5 months, ranging from 2 to 19 months. Four patients had at least one relapse. Responses were seen in splenectomized and non-splenectomized patients. This study is the first attempt to evaluate the efficacy and safety of rituximab in the treatment of ITP in the Middle East area. Our findings support the result of other case reports, case series, and pilot studies; however, a randomized control trial is needed to confirm the results of our study.

Use of recombinant activated factor VII to arrest uncontrolled bleeding: a case series.

A retrospective analysis is described to assess the effects of using recombinant activated factor VII to control bleeding in a series of patients who had failed to respond to conventional hemostatic measures. In all, 18 patients (aged 16-65 years) with a range of conditions resulting in bleeding refractory to conventional methods of control were treated with recombinant activated factor VII (60-120 Amicrog/kg; 1-4 doses). The effects of recombinant activated factor VII on bleeding were noted together with the patients' transfusion requirements and hematological parameters. Administration of recombinant activated factor VII successfully stopped bleeding in 17 of the 18 patients. Therapy with recombinant activated factor VII significantly decreased transfusion requirements for packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate compared with pretreatment values along with significant improvement in hemostasis. In various serious bleeding situations, treatment with recombinant activated factor VII may effectively arrest bleeding, which has remained refractory to conventional methods of control.