Consensus-Based Expert Recommendations on the Management of Hemophilia A in the Gulf Region.

BACKGROUND: Hemophilia A presents a significant health challenge in the Gulf region, where it has an especially high prevalence. There are several unmet needs associated with the management of hemophilia A in the region. The aim of this manuscript was to contextualize unmet management needs, provide recommendations to optimize care, and specify requirements for the establishment of gene therapy centers in the region. SUMMARY: An expert panel was assembled comprising ten clinical hematologists from Kuwait, Oman, Saudi Arabia, and the UAE. The Delphi methodology was used to obtain a consensus on statements relating to several aspects of hemophilia A. A consensus was reached for all statements by means of an online, anonymized voting system. The consensus statements pertain to screening and diagnosis, treatment approaches, and requirements for the implementation of gene therapy. KEY MESSAGES: There are significant challenges that hinder the optimal management of hemophilia A in the Gulf region. The consensus statements presented provide specific recommendations to improve diagnostic and treatment approaches, promote multidisciplinary care, and optimize regional data generation and reporting. These statements also delineate the requirements for the establishment of gene therapy centers for hemophilia A in the region.

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

Performance Assessment of a Multifaceted Unfractionated Heparin Dosing Protocol in Adult Patients on Extracorporeal Membrane Oxygenator.

BACKGROUND: The use of extracorporeal membrane oxygenator (ECMO) support devices are associated with complications, including bleeding and thrombosis. Unfractionated heparin (UFH) is the gold standard anticoagulant in ECMO patients. Clinically, UFH is monitored through activated clotting time (ACT), activated partial thromboplastin time (aPTT), and anti-factor Xa assay. It is unknown which assay best predicts anticoagulation effects in adults. OBJECTIVE: To assess the correlation of UFH dosing and monitoring using an established protocol. METHODS: A pilot, prospective cohort, historically controlled study was conducted at a tertiary care hospital. Patients ≥18 years-old who received ECMO on the multifaceted anticoagulation protocol were included and compared with those on the conventional method of anticoagulation. The primary end point was to assess the correlation between UFH dose and different monitoring methods throughout 72 hours using the new protocol guided by ACT and anti-factor Xa assay. RESULTS: In each arm, 20 patients were enrolled. The study revealed that anti-factor Xa assay had the largest number of "strong" correlations 11/20 (55%), followed by both aPTT and aPTT ratio 10/20 (50%), and, finally, ACT 2/20 (10%). Concordance between anti-factor Xa assay and the other monitoring parameters in the prospective arm was generally low: 31% with aPTT ratio, 26% with ACT, and 23% with aPTT. CONCLUSION AND RELEVANCE: The adaption of a multifaceted anticoagulation protocol using anti-factor Xa assay may provide a better prediction of heparin dosing in adults ECMO patients compared with the conventional ACT-based protocol. Further studies are needed to assess the safety and different monitoring modalities.

Outreach and diagnosis: Saudi Arabia's experience.

The World Federation of Hemophilia (WFH) is an international nonprofit organization dedicated to improving and sustaining the lives of individuals with haemophilia. According to the World Federation of Hemophilia (WFH) annual global survey, haemophilia A has a prevalence of 105 per million males and 28 per million males of haemophilia B in a global population of 6 billion. The annual global survey reported 295 000 individuals with haemophilia, von Willebrand disease and other bleeding disorders in 113 countries. WFH estimated approximately 70% of patients with haemophilia under diagnosed globally. The variability of occurrence of these disorders in different ethnicities, lack of awareness and diagnostic facilities/expertise led to the prevalence of other bleeding disorders being much more underestimated. The main reason for the gap between detected (reported) and estimated numbers of patients with bleeding disorders includes the lack of laboratory facilities and trained personnel required to establish an accurate diagnosis for bleeding disorders.

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.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Evaluation of the usefulness of a D dimer test in combination with clinical pretest probability score in the prediction and exclusion of Venous Thromboembolism by medical residents.

INTRODUCTION: Venous thromboembolism (VTE) requires urgent diagnosis and treatment to avoid related complications. Clinical presentations of VTE are nonspecific and require definitive confirmation by imaging techniques. A clinical pretest probability (PTP) score system helps predict VTE and reduces the need for costly imaging studies. d-dimer (DD) assay has been used to screen patients for VTE and has shown to be specific for VTE. The combined use of PTP and DD assay may improve exclusion of VTE and safely avoid imaging studies. MATERIALS AND METHODS: We prospectively used the Wells PTP score and a DD test to evaluate 230 consecutive patients who presented with VTE symptoms. The receiver operating characteristic curve was used to identify a new DD cutoff value, which was applied to VTE diagnosis and compared with the upper limit of locally established reference range for prediction of thrombosis alone and in combination with the clinical PTP score. RESULTS: We evaluated 118 patients with VTE symptoms fulfilling the inclusion criteria, 64 (54.2%) with clinically suspected deep vein thrombosis (DVT) and 54 (45.8%) with symptoms of pulmonary embolism (PE). The PTP was low in 28 (43.8%) and moderate/high in 36 (56.25%) of the suspected DVT patients, and low in 29 (53.7%) and moderate/high in 25 (46.3%) of the suspected PE patients. Eighteen cases were confirmed by imaging studies: 9 DVT and 9 PE. The agreement between confirmed cases and PTP was significant with PE but not DVT. The negative predictive value for both DVT and PE with current DD cutoff value of <250 µg/L DDU was 100%, whereas with the calculated cutoff the NPV was 88%. CONCLUSIONS: We confirm that PTP score is valuable tool for medical residents to improve the detection accuracy of VTE, especially for PE. The DD cutoff value of 250 µg/L FEU is ideal for excluding most cases of low PTP; however, the calculated cutoff was less specific for the exclusion of VTE.

Saudi expert consensus on acquired hemophilia A diagnosis and management.

Objectives: Acquired hemophilia affects approximately one in 1 million people. Timely diagnosis is key to appropriate disease management and the prevention of life-threatening complications. Patients with this condition may initially be seen by inexperienced physicians and remain underdiagnosed for several years. This consensus statement is aimed at providing guidelines for all practitioners in the Kingdom of Saudi Arabia (KSA) to diagnose and manage acquired hemophilia A. Methods: This consensus statement reflects the opinions drafted by a group of hematology specialists, who used an explicit systematic process to identify areas of agreement and disagreement. Results: This consensus statement provides a guide for all practitioners in the KSA regarding the diagnosis of clinical presentation, relevance, characteristics of bleeding symptoms, and case management; it additionally provides guidance for non-specialists. All management aspects, including diagnosis and treatment modalities, are discussed. Conclusions: Patients with acquired hemophilia may initially be seen by physicians who lack appropriate expertise in diagnosing and managing this condition. This consensus statement from the premier experts on the disease in the KSA provides details for diagnosing and managing acquired hemophilia.

Event rates and risk factors for venous thromboembolism and major bleeding in a population of hospitalized adult patients with acute medical illness receiving enoxaparin thromboprophylaxis.

BACKGROUND: We aimed to describe the event rates and risk-factors for symptomatic venous thromboembolism (VTE) and major bleeding in a population of hospitalized acutely ill medical patients. METHODS: Patients ≥40 years old and hospitalized for acute medical illness who initiated enoxaparin prophylaxis were selected from the US Optum research database. Rates of symptomatic VTE and major bleeding at 90-days were estimated via the Kaplan-Meier (KM) method. Risk factors were identified via the Cox proportional hazards model. RESULTS: A total of 123,022 patients met the selection criteria. The KM rates of VTE and major bleeding at 90-days were 3.5 % and 2.2 %, respectively. Among subgroups, the risk of VTE varied from 3.0 % in patients with ischemic stroke to 6.9 % in patients with a cancer-related hospitalization, and the risk of major bleeding varied from 1.9 % in patients with inflammatory conditions to 3.6 % in patients with ischemic stroke. Key risk factors for VTE were prior VTE (HR=4.15, 95 % confidence interval [CI] 3.80-4.53), cancer-related hospitalization (HR=2.35, 95 % CI 2.10-2.64), and thrombophilia (HR=1.64, 95 % CI 1.29-2.08). Key risk factors for major bleeding were history of major bleeding (HR=2.17, 95 % CI 1.72-2.74), history of non-major bleeding (HR=2.46, 95 % CI 2.24-2.70), and hospitalization for ischemic stroke (2.42, 95 % CI 2.11-2.78). CONCLUSION: There is substantial heterogeneity in the event rates for VTE and major bleeding in acute medically ill patients. History of VTE and cancer related hospitalization represent profiles with a high risk of VTE, where continued VTE prophylaxis may be warranted.

The Role of Direct Oral Anticoagulants in the Treatment of Cancer-Associated Venous Thromboembolism: Review by Middle East and North African Experts.

Venous thromboembolism is a leading cause of morbidity and mortality in patients with active cancer who require anticoagulation treatment. Choice of anticoagulant is based on careful balancing of the risks and benefits of available classes of treatment: vitamin K antagonists, low-molecular-weight heparin (LMWH), and direct oral anticoagulants (DOACs). Results from randomized controlled trials have shown the consistent efficacy of DOACs versus LMWH in the treatment of cancer-associated venous thromboembolism (VTE). However, increased major gastrointestinal bleeding was observed for edoxaban and rivaroxaban, but not apixaban, compared with LMWH dalteparin. Most guidelines recommend DOACs for the treatment of cancer-associated VTE in patients without gastrointestinal or genitourinary cancer, and with considerations for renal impairment and drug-drug interactions. These updates represent a major paradigm shift for clinicians in the Middle East and North Africa. The decision to prescribe a DOAC for a patient with cancer is not always straightforward, particularly in challenging subgroups of patients with an increased risk of bleeding. In patients with gastrointestinal malignancies who are at high risk of major gastrointestinal bleeds, apixaban may be the preferred DOAC; however, caution should be exercised if patients have upper or unresected lower gastrointestinal tumors. In patients with gastrointestinal malignancies and upper or unresected lower gastrointestinal tumors, LMWH may be preferred. Vitamin K antagonists should be used only when DOACs and LMWH are unavailable or unsuitable. In this review, we discuss the overall evidence for DOACs in the treatment of cancer-associated VTE and provide treatment suggestions for challenging subgroups of patients with cancer associated VTE.

Patients with cancer are at risk of blood clots forming in their veins, which can cause illness and death. To prevent such blood clots, most patients with cancer need anticoagulant therapy. There are three types of anticoagulants available for the treatment of cancer-associated blood clots in a vein, namely, vitamin K antagonists, low-molecular-weight heparin (LMWH), and direct oral anticoagulants (DOACs). Drug trials have shown that DOACs are more effective than LMWH; however, DOACs can have a greater risk of causing major gastrointestinal bleeding. Among DOACs, edoxaban and rivaroxaban are drugs associated with higher rates of gastrointestinal bleeding. Recently updated guidelines for doctors recommend that DOACs be used as the first treatment for patients with cancer at risk of blood clot formation in a vein. For doctors in the Middle East and North Africa, this new approach differs from existing practices. Notably, choosing a treatment also depends on the type of cancer, because gastrointestinal cancers and cancers of the genitals and urinary system have an especially high risk of gastrointestinal bleeding. The choice also depends on the presence of kidney problems, drug­drug interactions, and access to the drugs. Apixaban may be the preferred DOAC in patients with gastrointestinal cancer, but this drug should be used with care in patients with upper or unresected lower gastrointestinal tumors. For patients with upper or unresected lower gastrointestinal tumors, treatment with LMWH may be preferred. Vitamin K antagonists should be used only when DOACs and LMWH are unavailable or unsuitable.

The Saudi Consensus for the Management of Cancer-Associated Thromboembolism: A Modified Delphi-Based Study.

Background Cancer is a well-known risk factor of preventable thromboembolic disease. This study aims to provide guidance on the prevention and management of cancer-associated thrombosis (CT) that tailors prophylactic and therapeutic options for medical and surgical oncology patients presenting to health care settings in Saudi Arabia. Methods The present consensus was developed in concordance with the modified Delphi-based approach, which incorporates a face-to-face meeting between two voting rounds to gain experts' feedback on the proposed statements. All experts were either oncologists, hematologists, or hemato-oncologist with an active clinical and research profile in hemato-oncology. Results The experts highlighted that the comparatively high incidence of inherited thrombophilia among the Saudi population may account for a higher CT burden in the Kingdom than in other parts of the world. However, due to the lack of literature that assesses CT in Saudi Arabia, primary venous thromboembolism prophylaxis should be tailored according to a valid risk assessment of cancer patients and should be implemented in routine practice. For hospitalized medical oncology patients, the experts agreed that prophylaxis with low-molecular-weight heparin (LMWH) should be offered, regardless of the presence of acute illness. For ambulatory medical oncology patients, LMWH or direct oral anticoagulants (DOACs) prophylaxis should be offered for high-risk patients. Concerning surgical patients, they agreed that all oncology patients undergoing surgery should be offered thromboprophylaxis. In terms of secondary prophylaxis, the experts recommended continuing a prophylactic dose of anticoagulant (LMWH or DOAC), for an appropriate period depending on the cancer type and stage. Finally, they also provided a set of statements on management of CT in Saudi Arabia. Conclusion The present modified Delphi-based study combined the best available evidence and clinical experience with the current health care policies and settings in Saudi Arabia to build a consensus statement on the epidemiology, prevention, and management of CT.

Prognostic markers in patients with COVID-19 requiring intensive care support.

Objectives: Several hematological and immunological markers, particularly neutrophil count, predict the severity of COVID-19. This study aimed at assessing hematological and coagulation parameters at different time points, to predict the complications or outcomes of patients with COVID-19 admitted to the intensive care unit (ICU). Methods: We conducted a prospective observational multicenter study in ICU departments. A total of 118 patients with COVID-19 admitted to the ICU were included. Clinical data and blood samples from routine hematology and coagulation tests were collected at admission, and on days 3, 7, and 14. The main outcome measures were high-flow-O2 requirement, thrombosis, and 30-day mortality. Results: The venous thromboembolism score increased from a mean of 5.10 ± 2 on day 0 to 6.40 ± 2.80 on day 14 (P = 0.0002). The disseminated intravascular coagulation (DIC) score significantly correlated with thrombosis (P = 0.031). A total of 41.20% of patients in the ICU had a DIC score ≥4, and 11.40% had a score <4. Mortality was negatively associated with patients on high-flow O2, 9 patients (10.80%) (P = 0.040), and positively associated with patients receiving ventilation, 16 patients (27.50%) (P < 0.001). An increase in white blood cell count (subdistribution hazard ratio (SHR): 0.91; 95% CI: 0.80-1) and neutrophil count (SHR: 1; 95% CI: 1.01-1.05) was associated with greater disease severity and D-dimer level (SHR: 1.60; 95% CI: 1.10-2.5). Conclusion: The venous thromboembolism score was significantly higher for patients who died than those who recovered. Furthermore, mechanical ventilation was associated with high mortality, whereas the risk of thrombosis and ICU admission correlated with high D-dimer values and DIC scores. Therefore, D-dimer levels and DIC scores are prognostic markers that may predict disease severity in patients with COVID-19.

Clinical and laboratory presentation of von Willebrand disease: Experience from a single center in Saudi Arabia.

Objectives: This study was aimed at assessing the clinical presentations and laboratory findings among patients diagnosed with vWD at a Saudi tertiary care unit. Methods: This retrospective study included 189 patients with vWD who were followed up in our unit over 4 years. Clinical and laboratory data were collected and analyzed in SPSS. Results: The median age of the study cohort was 30 years (range 11 months-56 years). The cohort had a female preponderance, with 32.30% males and 66.70% females. Bleeding from different sites was observed, mostly from the joints and muscles (23.90%), followed by the mucus membranes (14.60%), genitourinary areas (7.70%), ecchymoses (2.80%), and gastrointestinal areas (2.80%). A total of 48% of participants presented with more than one type of bleeding. A total of 105 (58.01%) participants had type 1; 29 (16.02%) had type 2; and 47 (25.96%) had type 3 vWD. Blood tests indicated the following mean value: hemoglobin, 116 ± 25.60 gm/L; ferritin, 75.80 ± 166.80 µg/L (median 28.5); vWAg, 0.40 ± 0.27IU/ml; and vWD:RCo, 0.32 ± 0.20IU/dL. The partial thromboplastin time was prolonged in 49.20% and normal in 50.80% of participants. Platelet function analysis values were prolonged in 92.90% and normal in 7.10% of participants. Comparative analysis of the O-type and non-O blood type showed that blood type O was significantly correlated with factor VIII (p-value = 0.013), vWF:RCo (p-value = 0.004), and vWF:Ag (p-value = 0.019). Conclusion: Joint and muscle bleeds were the most common clinical presentations in our cohort. Although type 1 vWD was most prevalent in our cohort, we observed a comparatively higher prevalence of type 3, possibly because of ethnic differences or referral bias. We found a significant difference between O and non-O blood type regarding FVIII and vWF:Ag, and observed a more pronounced difference for vWD activity measuresd by vWF:RCo with blood type O being the systematic factor.

Position Statement on In-hospital/Clinic Point-of-care Coagulation Testing for Anticoagulation Monitoring in Saudi Arabia.

Objectives: Hospital overload is a persistent occurrence in daily practice. Interventions such as point-of-care testing (POCT) are needed to alleviate the pressure faced by healthcare providers and administrators. Methods: An invited panel of experts from Saudi Arabia was formed under the auspices of the Saudi Heart Association in order to discuss local treatment gaps in the management of patients receiving anticoagulation therapy. This was done in a series of meetings, which resulted in the development of official recommendations for the implementation of POCT for anticoagulation monitoring in the country. Recommendations were based on a comprehensive literature review and international guidelines taking into consideration local clinical practice, clinical gaps, and treatment/testing availabilities. Results: Vitamin K antagonist (VKA)-based anticoagulation therapy requires routine monitoring. POCT is a promising model of care for the monitoring of International Normalized Ratio (INR) in patients receiving oral anticoagulation in terms efficacy, safety and convenience. The availability of POC INR testing should not replace the use of standard laboratory anticoagulation monitoring. However, there are several indications for implementing POCTINR monitoring that was agreed upon by the expert panel. POCT for anticoagulation monitoring should primarily be used in the warfarin (or other VKA) monitoring clinic in order to ensure treatment efficiency, cost-effectiveness of care, patient satisfaction, and quality of life improvement. The expert panel detailed the requirements for the establishment of a warfarin (or other VKA) monitoring clinic in terms of organization, safety, quality control, and other logistic and technical considerations. The limitations of POCT should be recognized and recommendations on best practices should be strictly followed. Core laboratory confirmation should be sought for patients with higher INR results (>4.7) on POCT. Proper training, quality control, and regulatory oversight are also critical for preserving the accuracy and reliability of POCT results. Conclusions: POCT enables more rapid clinical decision-making in the process of diagnosis (rule-in or rule-out), treatment choice and monitoring, and prognosis, as well as operational decision-making and resource utilization. POCT thus can fulfill an important role in clinical practice, particularly for patients receiving VKAs.

Performance Assessment of Anti-Xa Assay-Based Heparin Dosing Protocol in Pediatric Patients on Extracorporeal Membrane Oxygenation.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in the postoperative cardiac critical care setting is evolving. Anticoagulation monitoring is among the most challenging aspects of pediatrics. However, there is no consensus on the optimal dosing and monitoring of unfractionated heparin in this setting. To address this, we developed an anti-Xa assay-based protocol derived from the best available clinical and anecdotal evidence of ECMO use and assessed its effectiveness in achieving the anti-Xa assay therapeutic target. METHODS: This prospective single-arm study was conducted in the pediatric carcardiac-surgery intensive care unit of a large tertiary hospital. We used two different anti-Xa assay intensity levels based on the patients' bleeding status. RESULTS: The median patient age was 7 (interquartile range [IQR]: 5-11.25) months, and the median weight was 5.7 (IQR: 3.8-13.82) kg. The median ECMO duration was 6 (IQR: 4.5-7.5) days. The bleeding protocol was used for most patients. Seventy percent achieved the anti-Xa assay therapeutic target during the study period (median: 75.5 h, IQR: 60.5-117.5 h). Hemorrhagic complications were reported in 40% of the patients, and thrombotic complications were reported in 25%. The median length of stay was 37 (IQR: 22-43) days, with a survival-to-discharge rate of 75%. CONCLUSIONS: Despite a failure to achieve the anti-Xa assay target within the first ECMO days, most patients achieved the target by the median ECMO duration. Moreover, using two different anti-Xa assay levels reduced thrombotic complications.

Genotype Hemophilia Screening Program Identified 2 Novel Variants Including a Novel Variant (c.5816-2A > G) Causing a Pathogenic Variant of the Factor 8 Gene.

Establishing a national screening program for hemophilia patients is highly encouraged by the World Health Organization and the World Federation of Hemophilia. Hence, this study aimed to analyze the variant spectrum of F8 and F9 genes in Arab hemophilia patients. Molecular genetic and sequencing studies were performed on a cohort of 135 Saudi hemophilia patients. Out of all screened hemophilia patients (97 hemophilia A and 39 hemophilia B), 15 (11.1%) were positive for inversion 22 and 4 (3%) for inversion 1. Out of a total of 32 (23.7%) substitution/deletion mutations, 2 novel variants were identified: a novel splice acceptor site missense mutation (c.5816-2A > G) causing a pathogenic variant of the F8 gene and another splicing site point mutation in intron/exon 23 (g.164496G > A). The frequent F8 variants were (c.409A > C, p.T137P) in exon 4, (c.760A > G) in exon 6, and (c.1835G > C, p.R612P) in exon 12, while the frequent F9 variants were (c.580A > G) in exon 6 and (c.880C > T) in exon 8. These study data will enrich the spectrum of the genetic databases in the Arab population that could be applied in the future for national genetic counseling.

A retrospective analysis of the frequency of heparin-induced thrombocytopenia in the intensive care unit at a tertiary care center in Riyadh, Saudi Arabia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an extremely serious and potentially fatal condition that can develop in patients taking heparin-based medications, such as unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). The incidence and risk factors for HIT in critically ill patients, however, are not well defined. METHODS: We retrospectively collected data on HIT test results, route of heparin administration, age, sex, heparin type (UFH or LMWH), and date of illness from patients admitted to the intensive care unit (ICU) and regular nursing floor (non-ICU) at our hospital between January 2011 and December 2014. We screened patients for HIT using the 4T score and confirmed the diagnosis through laboratory testing (direct enzyme immunoassay immunoglobulin G [IgG] or a platelet-activating antibody). RESULTS: We screened a total of 946 patients, 56 (5.9%) of whom were positive for HIT. Among 776 patients receiving UFH and 180 receiving LMWH, 2.8 and 6.6% developed HIT, respectively (P = 0.051). We then classified our patients into two groups: ICU, and non-ICU. In the non-ICU group (n = 317), 4 (2.7%) patients receiving LMWH and 25 (5.1%) receiving UFH were positive for HIT (P = 0.221). In the ICU group (n = 639), 1 (3.1%) patient receiving LMWH and 26 (9.1%) receiving UFH were positive for HIT (P = 0.249). The ICU group, therefore, had a higher cumulative incidence rate of HIT than the non-ICU group (8.5 vs. 4.5%). CONCLUSION: HIT was more common in ICU patients than non-ICU patients and in more patients receiving UFH than LMWH, although the differences were not statistically significant. Early diagnosis and appropriate treatment are essential to prevent adverse outcomes in patients with HIT.

Changes in the Fibrinolytic System of Patients Infected with Severe Acute Respiratory Syndrome Coronavirus 2.

INTRODUCTION: In this study, coagulation and fibrinolysis parameters and their association with disease severity were investigated in coronavirus disease (COVID-19) patients. MATERIALS AND METHODS: COVID-19 patients (n = 446) admitted to our institute between 21 February 2021 and 17 March 2022, were recruited. Clinical data and staging were collected from all patients. Blood samples were collected and analyzed for several parameters of fibrinolysis and coagulation, including alpha-2-antiplasmin(α2AP) and plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), D-dimer, and fibrinogen levels. RESULTS: The TAFI, fibrinogen, and tPA levels were significantly higher in participants who died compared to that of patients who recovered (p < 0.001). However, PAI-1, tPA, and TAFI were significantly higher in patients admitted to the ICU than those of the healthy controls (p < 0.001 for PAI-1 and tPA; p = 0.0331 for TAFI). Our results showed that stage C and D COVID-19 patients had significantly higher levels of PAI-1 (p = 0.003). Furthermore, stage D COVID-19 patients had significantly higher tPA and TAFI values (p = 0.003). CONCLUSIONS: Hypofibrinolysis was the most prevalent condition among patients with severe COVID-19. In this study, several coagulation markers were elevated, making them suitable prognostic markers for hypofibrinolysis.

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance.

Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are <20 IU/dL, but specific recommendations in patients with very low levels according to the different clinical situations are lacking and mainly based on the anecdotal series. For PWH with baseline clotting factor levels >20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH.

Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon.

OBJECTIVE: Excessive activation of coagulation, which can culminate in overt disseminated intravascular coagulation, is a prominent feature of heat stroke. However, neither the mechanism that initiates the coagulation activation nor its pathogenic role is known. We examined whether the tissue factor/factor VIIa complex initiates the coagulation activation in heat stroke and, if so, whether upstream inhibition of coagulation activation through its neutralization may minimize cellular injury and organ dysfunction. We also examined whether coagulation inhibition influences heat stroke-induced fibrinolytic and inflammatory responses. DESIGN: Randomized controlled study. SETTING: Comparative Medicine Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. SUBJECTS: Baboons (Papio Hamadryas). INTERVENTIONS: Twelve anesthetized baboons assigned randomly to recombinant nematode anticoagulant protein c2, a powerful inhibitor of tissue factor/factor VIIa-dependent coagulation (n = 6), or a control group (n = 6) were heat-stressed in a prewarmed neonatal incubator at 44-47°C until systolic blood pressure fell <90 mm Hg, signaling the onset of severe heat stroke. Recombinant nematode anticoagulant protein c2 was administered as a single intravenous dose of 30 µg/kg body weight at onset of heat stroke. The control group received an equivalent volume of sterile saline intravenously. MEASUREMENTS AND MAIN RESULTS: Heat stroke was associated with coagulation activation and fibrin formation as evidenced by the increased plasma thrombin-antithrombin complexes, endogenous thrombin potential, and D-dimer levels. Recombinant nematode anticoagulant protein c2 induced significant inhibition of thrombin generation and fibrin formation. Inhibition of coagulation in recombinant nematode anticoagulant protein c2-treated animals did not influence either fibrinolysis (assessed by tissue plasminogen activator, plasmin-α2-antiplasmin complexes, and plasminogen activator inhibitor) or the release of pro- and anti-inflammatory cytokines. No difference in markers of cell injury and organ dysfunction was observed between recombinant nematode anticoagulant protein c2-treated and control groups. CONCLUSIONS: Tissue factor/factor VIIa-dependent pathway initiates coagulation activation in induced-heat stroke in the baboon without an effect on fibrinolysis and inflammation. The findings suggest also that coagulation activation is not a prerequisite of cell injury and organ dysfunction.