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Shouki Bazarbashi,1 Heba Mohamed El Zawahry,2 Tarek Owaidah,3 Mohammad A AlBader,4 Ashraf Warsi,5– 7 Mahmoud Marashi,8,9 Emad Dawoud,10 Hassan Jaafar,11 Sherif M Sholkamy,12 Fady Haddad,13 Alexander T Cohen14 1Section of Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia; 2Department of Medical Oncology, The National Cancer Institute, Cairo University, Cairo, Egypt; 3Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia; 4Hematology Unit, Al Sabah Hospital, South Surra, Kuwait; 5Department of Adult Hematology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs–Western Region, Jeddah, Saudi Arabia; 6College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs–Western Region, Jeddah, Saudi Arabia; 7King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs-Western Region, Jeddah, Saudi Arabia; 8Hematology Department, Dubai Hospital, Dubai, United Arab Emirates; 9Department of Hematology, Mediclinic City Hospital, Dubai, United Arab Emirates; 10Department of Oncology, Tawam Hospital, Al Ain, United Arab Emirates; 11Department of Oncology, Sheikh Khalifa Specialty Hospital, Ras Al-Khaimah, United Arab Emirates; 12Department of Vascular Surgery, Ain Shams University, Cairo, Egypt; 13Vascular and Endovascular Surgery, American University of Beirut Medical Center, Beirut, Lebanon; 14Department of Haematological Medicine, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, King’s College London, London, UKCorrespondence: Shouki Bazarbashi, Section of Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Alfaisal University, 1 Alzahrawi Street, Riyadh, 11211, Saudi Arabia, Tel +966 505443546, Email bazarbashi@gmail.comAbstract: 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.Plain Language Summary: 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, drug–drug 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.Keywords: anticoagulation, apixaban, cancer, vitamin K antagonist, low-molecular-weight heparin

Ahmad A Alharbi,1,2 Abdullah A Alharbi,2,3 Dhafer Salem Bashen,2 Tarek Owaidah4 1Pathology Department, College of Medicine, Majmaah University, Al Majmaah 11952, Riyadh, Kingdom of Saudi Arabia; 2Laboratory Department, Dr. Sulaiman Al-Habib Hospital in Al Takhassusi, Riyadh, Kingdom of Saudi Arabia; 3Pathology Department, College of Medicine, Imam Muhammad Ibn Saud Islamic University, Riyadh, Kingdom of Saudi Arabia; 4Hematology and Transfusion Medicine Department, Alfaisal University, Riyadh, Kingdom of Saudi ArabiaCorrespondence: Tarek Owaidah, Consultant Hematology and Transfusion Medicine, Alfaisal University, P.O.Box 5092, Riyadh, 11533, Kingdom of Saudi Arabia, Tel +966 50 531 2925, Email towaidah@gmail.comBackground: Iron supplementation is administered orally or intravenously to treat iron-deficiency anemia (IDA). Ferric Carboxymaltose (FCM) “Ferinject®” is an intravenous (IV) iron preparation that has emerged as a safe therapeutic option for treating IDA in the past decade.Aim: This study aimed to evaluate safety and efficacy of carboxymaltose in a cohort of patients with IDA not responding to oral therapy.Methods: This 12-month retrospective study included 106 patients with IDA, with-or without bariatric surgery, who received (single or multiple doses) of Carboxymaltose 500mg/10mL. Data points included patients’ demographics, baseline data for Hb, platelet, ferritin, and MCV pre–and at 1, 2, and 3 months following different doses of IV-Carboxymaltose. Changes in Hb, MCV, platelets, and ferritin levels were recorded in response to Carboxymaltose to assess the optimal dose, risk of hyperferritinemia, and hypophosphatemia.Results: At three months (95 days) follow-up, the median change pre-and post-therapy in hemoglobin was from 9.5 to 11.9g/dL (p < 0.01), MCV 73.6– 80.5fL (p < 0.01), and ferritin 5.3– 93.8ng/mL. A significant difference was observed between platelet count of patients who underwent bariatric surgery and those who did not. An optimal ferritin response (> 30ng/mL) was observed in 87.8% of patients who received first dose, and none of the full three doses showed no response. 37% of patients who received two doses developed hyperferritinemia. Serum phosphate levels were assessed in 28 cases, and hypophosphatemia was observed in 25% of these patients.Conclusion: Carboxymaltose is a reliable option for IDA. IV-FCM therapy helps achieve significant improvement in hemoglobin concentration and MCV from the first dose carrying a low reversible risk of hyperferritinemia following multiple doses. An interesting finding of this study is the discovery of a population of IDA patients requiring periodic assessment for iron reinfusion to sustain normal levels, mostly post-bariatric surgery. Changes in serum phosphate levels reported to occur consecutively with FCM treatment should be further studied.Keywords: iron deficiency, anemia, ferrous carboxymaltose, hypophosphatemia

Esra’a Abudouleh,1 Ahmad Alhamshari,2 Ahmed A Al-Qahtani,3,4 Amelita Aguilos,5 Tarek Owaidah5 1Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia; 2College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 3Department of Infection and Immunity, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; 4Department of Microbiology and Immunology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 5Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi ArabiaCorrespondence: Tarek Owaidah, Tel +966 114647272, Email towaidah@kfshrc.edu.saAbstract: Thrombosis and coagulopathy have been found to be the most prevalent complications in patients with COVID-19. Thromboprophylaxis to prevent thromboembolic events is recommended for hospitalized COVID-19 patients. Heparin-induced thrombocytopenia (HIT) is a known complication of heparin use. This study aimed to determine the incidence of HIT among admitted patients with confirmed COVID-19 by PCR. In this study, two different HIT assays, rapid immunoassay (STic Expert HIT, Stago) and H-PF4 specific enzyme-linked immunosorbent assay (Asserachrom® HPIA – IgG), were performed. Of 200 patients with confirmed COVID-19, we identified 49 patients who met the possibility of HIT (low platelet count and high D-Dimer level). Only five (10.2%) had a positive HIT rapid test. However, none of the tested samples tested positive by ELISA. Thrombosis was reported in two of five (40%) patients. Further extensive studies are required to determine the prevalence and clinical significance of a positive HIT test among patients with COVID-19.Keywords: COVID-19, thrombosis, coagulopathy

Mahasen Saleh,1 Amani Alkofide,1 Anfal Alshammari,1 Khawar Siddiqui,1 Tarek Owaidah2,3 1Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, 11533, Kingdom of Saudi Arabia; 2Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Kingdom of Saudi Arabia; 3Department of Pathology, Alfaisal University, Riyadh, 11533, Kingdom of Saudi ArabiaCorrespondence: Tarek Owaidah Email towaidah@kfshrc.edu.saBackground: COVID-19 wreaked havoc on the healthcare system, with more than 36 million cases reported globally. Although the pediatric population makes up a lesser proportion of total COVID-19 patients than adults, the clinical status, age and comorbidities warrant identifying possible prognostic factors associated with disease severity in this group. The current study aimed to explore the incidence of thrombosis, overall outcome, and different hematological and coagulation markers in children with COVID-19.Methods: This is a single-center prospective study of 43 patients (age < 14 years) with confirmed COVID-19 diagnosis recruited from April to August 2020. Data for clinical presentation were collected and analyzed. The samples were tested for different hematological and coagulation markers.Results: Twenty-nine (67.4%) were symptomatic at presentation, with fever being the most common symptom (n = 23, 53.5%), followed by respiratory (n = 5, 11.6%) and gastrointestinal symptoms (n = 3, 7%). Co-morbid conditions were recorded in 26 (60.5%) patients, with malignancy being the commonest (n = 9, 20.9%). In this cohort of patients with age < 14 years, hypertension, respiratory symptoms and ABO group-A were significantly associated with pediatric intensive care unit (PICU) admission during the course of treatment. Patients with elevated FVIII and fibrinogen levels at presentation were more likely to have an extended length of hospital stay (LOS) (P–value =0.036 and 0.032 respectively). No thrombotic event was observed in our cohort. D-dimer values were higher (above 0.5 μg/mL) in 24 (55.8%) patients at admission. We found an association between high D-dimer and PICU admission and LOS.Conclusion: Although we did not observe thrombosis in our cohort, serial measurements of D-dimer and elevated FVIII bear a prognostic value in predicting the need for critical care in children with COVID-19. Further studies with larger sample size can aid in the establishment of prognostic factors for the pediatric COVID-19 population.Keywords: COVID-19, children, hematological and coagulation markers

The article focuses on study that assess the diagnostic value of antiphospholipid syndrome (aPS) antibodies and compare their utility to that of other aPL antibodies. Topics discussed prospective observational study, diagnostic value of aPS versus other aPL antibodies and independent association between aPS and primary APS.

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., (© 2024 The Authors.)

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., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

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., Competing Interests: Declaration of Competing Interest Dr. Le Gal reports financial support, article publishing charges, statistical analysis, and writing assistance were provided by Sanofi, honoraria for lectures and advisory boards from BMS, Inari, Leo Pharma, Pfizer, Sanofi and Stago. Dr. Agnelli reports financial support, statistical analysis, and writing assistance were provided by Sanofi, honoraria for lecture and advisory board contribution from BMS, Pfizer, Daiichi Sankyo and Anthos Therapeutics; reports a relationship with European Journal of Internal Medicine that includes: board membership. Dr. Darius reports financial support, statistical analysis, and writing assistance were provided by Sanofi. Dr. Kahn reports financial support was provided by Sanofi, and reports research grants from the Canadian Institutes of Health Research and consulting honoraria from Alexion for unrelated educational activities. Dr. Owaidah reports honoraria from Sanofi and financial support, statistical analysis, and writing assistance were provided by Sanofi. Dr. Rocha reports financial support, statistical analysis, and writing assistance were provided by Sanofi, and honoraria from the pharmaceutical industry for lectures on anticoagulation; is on speaker’s bureau for Bayer, Boehringer and Pfizer, and is a consultant/advisor for Pfizer and Sanofi. Dr. Zhai reports financial support, statistical analysis, and writing assistance were provided by Sanofi. Dr. Khan is an employee and stockholder of Sanofi and reports financial support was provided by Sanofi. Dr. Djoudi is an employee and stockholder of Sanofi and reports financial support was provided by Sanofi. Dr. Ponomareva is a consultant to Sanofi and reports financial support, statistical analysis, and writing assistance were provided by Sanofi. Dr. Cohen reports financial support, statistical analysis, and writing assistance were provided by Sanofi and fees for serving on adjudication committees for Boehringer Ingelheim and AbbVie; grant support and fees for serving on committees from Bristol Myers Squibb, Daiichi Sankyo, and Pfizer; consulting fees from Janssen, Portola Pharmaceuticals, and Ono Pharmaceuticals; and fees for serving on a steering committee and consulting fees from Bayer., (Copyright © 2023. Published by Elsevier B.V.)

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., Competing Interests: None., (AJBR Copyright © 2023.)

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., Competing Interests: Conflict of interest: None declared., (© 2023 Saudi Heart Association.)

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-O 2 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 O 2 , 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., (© 2023 [The Author/The Authors].)

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.

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., Competing Interests: RS: scientific editor of HemaSphere. Unrestricted grants or consultancy fees from Bayer, CSL Behring, Hemab, NovoNordisk, Octapharma, Sanofi, Sobi, Takeda [all fees to the institution]. VJ-Y: Consultancy: Pfizer, Shire, NovoNordisk, Sobi, Grifols, Roche, CSL Behring; Research funding: Pfizer, Shire, NovoNordisk, Sobi, Octapharma, Roche, Grifols, CSL Behring; Membership on an entity’s board of directors, speaker’s bureau, or its advisory committees: NovoNordisk, Pfizer, Shire, Sobi, Grifols, Roche, CSL Behring. MAE: Consultancy fees from NovoNordisk, BioMarin, CSL Behring, Genentech/Roche, Sanofi, Takeda, Pfizer, Bayer, Hemobiologics/LFB, Kedrion, UniQure. Participated in clinical trials sponsored by: NovoNordisk, UniQure, Takeda, Bayer, Genentech/Roche, OPKO Biologics, CSL Behring. AF: honoraria for lectures from Sanofi, Stago, Bayer, and Pfizer. RK: Research grants: Bayer, CSL Behring, LEO, NovoNordisk. Consultancy and speaker fees from BioMarin, Bayer, Biotest, Chugai, CSL Behring, Daiichi Sankyo, Grifols, NovoNordisk, Octapharma, Pfizer, Roche, Sanofi, SOBI, Takeda. RL: Consultancy fees from Alexion, Astra Zeneca, Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Roche, Sanofi, SOBI, Takeda. FWGL: Unrestricted grants/research funding from CSL Behring, UniQure, Sobi, Takeda; consultancy fees from BioMarin, CSL Behring, Takeda, and uniQure [all fees to the institution], and served as DSMB member for a study sponsored by Roche. MM: Consultancy fees from NovoNordisk, Grifols, Sanofi, Freeline, Biotest. He is the project lead for the European Hemophilia Safety Surveillance (EUHASS) safety reporting scheme which is funded by Bayer, BioMarin, BPL, CSL Behring, Grifols, Kedrion, NovoNordisk, Octapharma, Roche, Sanofi, Sobi, and Takeda. TO: consulting fees from Bayer, Sobi and Novo Nordisk. MS: Unrestricted research funding from Octapharma, Pfizer and Amgen (to institution); honoraria from advisory boards from Amgen, Novartis, Octapharma, Pfizer, and Amgen. AT: grants and personal fees for lectures and consultancy from Bayer, BioMarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda. DW: has received: grant funding from the Stroke Association and British Heart Foundation; speaking honoraria from Bayer; speaking and chairing honoraria from Alexion and NovoNordisk; and consultancy fees from Bayer and NovoNordisk. HBvdW: funding for consultancy from Bayer and TargED, all paid to institution. JW: Research support and honoraria for lectures from: Alnylam, Amgen, Bayer, CSL Behring, LFB, Novartis, Novo Nordisk, Octapharma, Roche, Sanofi, Siemens, Sobi, Swixx Biopharma, Takeda. GC: Unrestricted grants/research funding from CSL Behring, Sobi, Pfizer; speaker/consultancy fees from Bayer, BioMarin, CSL Behring, Grifols, Kedrion, LFB, NovoNordisk, Roche, Sanofi, Takeda, uniQure and Werfen. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

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., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

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.

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., (© 2022 [The Author/The Authors].)

Introduction: Emicizumab is a bispecific monoclonal antibody with the ability to bridge FIXa and FX, mimic FVIII, and restore normal hemostasis in patients with hemophilia A. Moreover, substantial evidence has shown that emicizumab-treated patients do not require monitoring, except before surgery or invasive procedures. However, introducing this novel drug to the market poses some challenges to physicians and clinical laboratories due to its interaction with conventional coagulation tests., Methods: Given the challenges and laboratory interactions posed by this novel drug, there is an unmet clinical need to develop clear recommendations for emicizumab laboratory monitoring to highlight which laboratory tests should be used, which tests should be avoided, and when these tests should be performed. These expert recommendations are essential to prevent inappropriate testing or misleading interpretations and reduce the extra costs of unnecessary monitoring., Results: A consensus meeting was conducted in December 2019, including top experts on hemophilia from Saudi Arabia, to discuss this issue., Conclusion: The experts agreed that, aPTT (activated Partial Thromboplastin Time)-based tests are not suitable for laboratory monitoring patients treated with emicizumab. Only FVIII chromogenic assays based on bovine FIX and FX proteins can be used to measure FVIII levels. They reviewed and recommended the type and time of testing for anti-factor VIII antibodies. Drug levels should be measured using the recommended test only when the anti-drug antibody (ADA) is clinically suspected and after excluding other causes (such as patient non-compliance)., Competing Interests: None., (AJBR Copyright © 2022.)

Background/objective: Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells, characterized by ineffective hematopoiesis, peripheral cytopenias along with hypercellularity of the bone marrow, and marked dysplastic features. Establishing MDS diagnosis is difficult due to nonspecific clinical presentation and imprecise morphological criteria. In anticipation to improve the diagnostic approach in this field, we aimed to characterize the clinical and morphological features of patients presented with cytopenias with a special focus on MDS., Methods: We comprehensively reviewed all medical record of patients who were referred to the hematology laboratory at KFSH-RC, Riyadh, Saudi Arabia, between January 2009 and March 2016 for evaluation of bone marrow aspirates and trephine biopsies due to severe and persistent cytopenia(s) to rule out MDS., Results: A total of 183 patients, 155 adult and 28 pediatric, were identified. In the adult group, MDS was diagnosed in 82 (52.9%) patients, with a male-to-female (M:F) ratio of 1.6:1 and mean age at diagnosis of 50 years. According to the World Health Organization (WHO) 2017 criteria, MDS subtypes were as follows: MDS with single lineage dysplasia (SLD, 5%), MDS with ring sideroblasts and SLD (MDS-RS-SLD 7%), MDS with multilineage dysplasia (MDS-MLD 21%), MDS with deletion of chromosome 5q (MDS del(5q), 2%), MDS unclassifiable (MDS-U7%), hypoplastic MDS (h-MDS 4%), MDS with excess blasts-1 (MDS-EB1, 20%), MDS with excess blasts-2 (MDS-EB2, 28%), and therapy-related MDS (6%). Laboratory and morphological features were described. In both groups, cytogenetic abnormalities were classified according to the Revised International Prognostic Scoring System cytogenetic risk groups. In adults, the dominating cytogenetic abnormalities were monosomy 5 and monosomy 7 seen in 20.7% and 24.4% of patients, respectively. Peripheral cytopenia not due to MDS was diagnosed in 54 (34.8%) patients, with a mean age of 43 years and M:F ratio of 1:1. The cause of these cytopenias were as follows: bone marrow failure (BMF, 22%), peripheral destruction (20%), drug induced (20%), anemia of chronic disease (16%), B12 deficiency (7%), infection (7%), paroxysmal nocturnal hemoglobinuria (4%), idiopathic cytopenia of undetermined significance (2%), and idiopathic dysplasia of undetermined significance (2%). A definite diagnosis of MDS was not possible in 19 patients due to insufficient clinical data. In the pediatric group, MDS was diagnosed in 14/28 (50%) patients, with M:F ratio of 1.8:1 and mean age at diagnosis of 4 years. MDS subtypes (WHO 2017) in 14 patients were as follows: refractory cytopenia of childhood (RCC, 42.8%), MDS-EB1 (42.8%), and MDS-EB2 (14.2%). Laboratory and morphological features were described. The prevalent cytogenetic abnormality was monosomy 7 in six/14 (42.8%) patients. Cytopenias due to other causes were diagnosed in eight/28 patients (28.5%), with a mean age of 6.5 years and M:F ratio of 1.6:1. The causes of non-MDS related cytopenia were: congenital BMF (4 patients), peripheral destruction (2 patients), immune deficiency (1 patient), and viral infection (1 patient). A definite diagnosis of MDS could not be made in six/28 (21.4%) patients., Conclusion: MDS is the cause of cytopenia in a significant number of patients referred for evaluation of cytopenias, appears at younger age, and tends to be more aggressive than that reported in international studies. Anemia, dysplastic neutrophils in the peripheral blood, and dysplastic megakaryocytes in the bone marrow trephine biopsy are the most reliable features in distinguishing MDS from other alternative diagnoses.

Background: Laboratory hematological tests are widely used in clinical practice to assess health and disease conditions. Reference ranges provided by laboratory reports are considered the most authoritative medical tools to assist in the decision-making phase. International standards institutes recommend that reference ranges be established for each region., Objectives: Provide reference values of routine hematological parameters in Saudi adults according to age and gender., Design: Cross-sectional SETTING: Central province of Saudi Arabia., Patients and Methods: Apparently healthy Saudi adults were subjected to laboratory testing of routine hematological parameters (full blood count, hemostatic profile, and serum hematinics), after completing a detailed health medical questionnaire., Main Outcome Measures: Hematological reference values based on the local population., Sample Size and Characteristics: 637 after screening 827 potentially healthy Saudi adults with ages ranging from 15 to 65 years., Results: The reference values of routine hematological parameters for the full population and by gender are presented with 90% CI as the lower and upper limits. Reference ranges mostly differed from universal established ranges shown in textbooks., Conclusion: The reference ranges of routine hematologic parameters for accurate assessment and appropriate management will help improve the routine clinical care of the adult Saudi population., Limitations: Difficulty in assessing health status of participants, who could have subclinical illnesses not reflected in the evaluated blood measurement. Lack of ability to eliminate individuals who might be carriers for haemoglobinopathies. Studies with larger sample sizes from different areas of the country are required to achieve a more accurate representation of the whole Saudi population., Conflict of Interest: None.

Introduction: The relationship between cancers and thromboembolic events is well established. In our study, we aim to determine the burden of thromboembolic events in patients with solid tumors and identify the risk factors related to their development., Materials & Methods: Data on patients with solid tumors and thromboembolism between January 2013 and September 2014 were collected and analyzed., Results: During the study period 174 patients were identified. Of which, 172 (98.9%) had venous thrombus embolism, 137 (79%) were diagnosed with deep vein thromboses, 67 (38.5%) with pulmonary embolism, 84 (48.3%) were symptomatic and 90 (51.7) were incidental at diagnosis. The most common patients and disease characteristics were female sex, high body mass index (BMI), metastatic stage, colorectal and breast primaries, and anti-neoplastic therapy., Conclusion:  Our study confirmed the high burden of thromboembolic events in cancer patients and the relevant factors associated with its development., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Bazarbashi et al.)

Background: Thrombotic events can increase the COVID-19 associated disease mortality. The administration of prophylactic anticoagulants had been shown to decrease the incidence of thrombosis, mortality, and ICU admission rates in COVID-19 patients., Aims: The present study investigates the rate of thrombosis with early anticoagulation prophylaxis, the various risk factors for thrombotic events, and the overall survival rate in hospitalized COVID-19 cases., Methods: In this prospective observational study, 425 patients aged ≥14 years were included in the study who were hospitalized with COVID-19 related symptoms from March to October 2020 at two tertiary care hospitals in the Kingdom of Saudi Arabia. Venous thromboembolism (VTE) score was evaluated, and VTE prophylaxis was administered according to the hospital guidelines. Patients' demographics, comorbidities, disease presentation, and sequential hematological profiles were also recorded. Samples were collected at different time points to determine the hematological profiles., Results: Out of 425 with positive COVID-19 subjects, eight (1.9%) patients developed thrombosis during admission, with pulmonary embolism being the most common type. VTE prophylaxis was administered to 394 (92.7%) patients. These anticoagulants included enoxaparin (86.3%), heparin (12.7%), warfarin (0.8%) and apixaban (0.3%). Comorbid conditions were recorded in 253 (59.5%) patients. ICU admission rate was 28% (n = 119), with a median time to transfer to ICU of 1 day (r: 0-33 days). A trend of high VTE score (5.0) with ICU admission and mortality ( P  = <.001) was observed. The observed mortality rate for our cohort was 5.9% (25 events out of 425); however, for patients admitted in ICU, it was 16% (19 events out of 119 admissions)., Conclusion: We are reporting a low incidence of thrombosis in COVID-19 patients. We have demonstrated that the early administration of prophylactic anticoagulants might reduce the risk of thrombotic events and the associated mortality. We observed a higher VTE score and thrombosis in patients admitted to the ICU.

The advances and development of sequencing techniques and data analysis resulted in a pool of informative genetic data, that can be analyzed for informing decision making in designing national screening, prevention programs, and molecular diagnostic tests. The accumulation of molecular data from different populations widen the scope of utilization of this information. Bleeding disorders are a heterogeneous group of clinically overlapping disorders. We analyzed the targeted sequencing data from ~1285 Saudi individuals in 17 blood and bleeding disorders genes, to determine the frequency of mutations and variants. We used a replication set of ~5000 local exomes to validate pathogenicity and determine allele frequencies. We identified a total of 821 variants, of these 98 were listed in HGMD as disease related variants and 140 were novel variants. The majority of variants were present in VWF, followed by F5, F8, and G6PD genes, while FGG, FGB, and HBA1 had the lowest number of variants. Our analysis generated a priority list of genes, mutations and novel variants. This data will have an impact on informing decisions for screening and prevention programs and in management of vulnerable patients admitted to emergency, surgery, or interventions with bleeding side effects., (© 2021. The Author(s).)

Bernard-Soulier syndrome is a rare autosomal recessive bleeding disorder and has a low incidence. Bernard-Soulier syndrome is caused by the deficiency of glycoprotein GPIb-V-IX complex, a receptor for von Willebrand factor and is characterized by thrombocytopenia, giant platelets and bleeding tendency. We are reporting three members of a same family with variable phenotypic clinical presentation. The index case is a 20-year-old boy who has a frequent presentation with epistaxis, and low platelet counts (25 × 109/l). He had been hospitalized multiple times and received platelet transfusions. His brother and cousin reported bleeding symptoms with less frequent medical intervention. Genetic analysis by next-generation sequencing identified a homozygous GP1BB variant (c.423C>A:p.Cys141Ter), which segregated amongst the family members. The results led us to an improved insight into the disease for this family with variable phenotypic expression, in addition to the identification of a variant for further structural and functional characterization., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The antiphospholipid syndrome (APS) is an autoimmune disease that is characterized by thrombosis and/or pregnancy failure and associated with the presence of all or at least one of three standard antibodies (anti-phospholipid (aPL) antibodies, including lupus anticoagulant (LA), anti-cardiolipin (aCL), and anti-β2-glycoprotein I (anti-β2GPI)). A growing body of evidence recommends adding additional aPL antibodies, such as anti-phosphatidylserine (aPS), anti-prothrombin (aPT), and anti-annexin A5 (aAA5), to conventional laboratory tests (revised Sapporo criteria), especially in seronegative APS cases., Objectives: We aimed to compare the diagnostic value, utility, and performance of these three additional antibodies along with the standard aPL antibodies in cases with confirmed and non-criteria APS (seronegative)., Methods: This was a prospective observational study on 59 patients who presented with clinical features of APS at the hematology, medical, rheumatology, and obstetric clinics. LA was detected by standard coagulation tests, while other aPL, IgG, and IgM antibodies (aCL, aβ2GPI, aPS, aPT, aAA5) were detected with enzyme-linked immunosorbent assay (ELISA)., Results: Anti-PS antibody was more frequent compared to aPT and aAA5 in both confirmed cases (84.6%) and non-criteria (seronegative) (15.4%) APS. As a single test, the aPS antibody was significantly better ( P <0.05) than the aPT and aAA5 antibodies in the detection of APS cases. Seven non-criteria patients were confirmed using additional aPL antibodies. Among these patients, four, two, and one patient was confirmed with aPS, aPT, and aAA5 antibodies, respectively., Conclusion: Our data support the findings of previously published studies and attribute the clinical significance of additional aPL antibodies, particularly aPS, in identifying non-criteria APS cases. In the future, along with conventional aPL antibodies, these additional antibodies should be included as standard laboratory tests in the revised Sapporo criteria., (© 2021 by the Association of Clinical Scientists, Inc.)