Publications by authors named "Tarek Owaidah"

43 Publications

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

Brain 2021 Mar 25. Epub 2021 Mar 25.

Department of Genetics, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, 11211, Kingdom of Saudi Arabia.

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.
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http://dx.doi.org/10.1093/brain/awaa459DOI Listing
March 2021

Screening hemostatic defects in Saudi University students with unexplained menorrhagia: a diagnosis, which could be missed.

Blood Coagul Fibrinolysis 2021 Mar 19. Epub 2021 Mar 19.

Department of Clinical Pathology/Hematology, Faculty of Medicine, Fayoum University, Egypt College of Medicine, Princess Nourah bint Abdulrahman University College of Medicine, Alfaisal University Department of Pathology, King Faisal Specialist hospital and Research Center, Riyadh, Saudi Arabia.

Bleeding disorders are a common cause of unexplained menorrhagia in adolescents. However, there is lack of information provided on Arab girls. To estimate the prevalence of coagulation factor deficiencies and platelet dysfunction among Saudi university students with unexplained menorrhagia. In this cross sectional study, 463 adolescent girls surveyed for having heavy menses for further evaluation of underlying bleeding tendencies using screening standardized questionnaire. Only 109 girls out of the total 463 girls reported menorrhagia and were included in the evaluation. All girls with menorrhagia were evaluated by Pictorial blood assessment chart (PBAC) for precise evaluation of menstrual blood loss (PBAC score >100), had underwent pelvic ultrasonography and screening of hemostatic abnormalities (complete blood count, PFA-100, PT, aPTT, vWF:RCo, vWF:Ag, coagulation factors assay). On the basis of the score of PBAC more than 100, 25.6% (28/109) of adolescent women (age ranged: 17-25 years old) had confirmed menorrhagia. In 30.8% of them, an ultimate diagnosis of bleeding tendency or hemostatic abnormality was detected [five cases of probable von Willebrand disease (vWD) or low level of vWF:Ag and/or vWF:RCo, two cases of probable platelet dysfunction, and one case of factorV (FV) deficiency]. Anemia was found in 39.28% (11/28) of them; however, only 4 (36%) had received iron supplements. Our study demonstrated that hemostatic defects are not uncommon in Saudi adolescent women presenting with menorrhagia but mostly unrecognized and untreated. It is probably advisable to screen women with menorrhagia for these defects.
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http://dx.doi.org/10.1097/MBC.0000000000001033DOI Listing
March 2021

A homozygous loss-of-function mutation in GP1BB causing variable clinical phenotypes in a family with Bernard-Soulier syndrome.

Blood Coagul Fibrinolysis 2021 Mar 1. Epub 2021 Mar 1.

Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre College of Medicine, Alfaisal University Department of Pathology and Laboratory Medicine, Centre of Excellence Thrombosis and Homeostasis, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

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.
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http://dx.doi.org/10.1097/MBC.0000000000001027DOI Listing
March 2021

Prevalence of Coagulation Factors Deficiency among Young Adults in Saudi Arabia: A National Survey.

TH Open 2020 Oct 23;4(4):e457-e462. Epub 2020 Dec 23.

Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Alfaisal University, Riyadh, Saudi Arabia.

 Inherited bleeding disorders vary in prevalence due to genetic disparity and ethnicity. Little is known about the prevalence of coagulation factor deficiency and bleeding disorders in middle-eastern population.  Young Saudi adults with at least one positive bleeding symptom reported in semi-structured validated condensed MCMDM-1vWD questionnaire were tested for complete blood count, routine and special coagulation tests, serum ferritin level, and capillary zone electrophoresis. After initial testing, those with prolonged prothrombin time (PT) or activated prothrombin time (APTT) had further testing to evaluate coagulation factors level. Platelet function was tested through platelet function analyzer (PFA)-100, and multiplate aggregometer (MEA) on patients suspected of having platelet disorders.  Six-hundred-forty patients (male = 347, 54.2%) were included. A possible platelet function defect was diagnosed in three patients with one matching Glanzmann's thrombasthenia trait pattern, and one that of Bernard-Soulier trait pattern. One patient was diagnosed with von Willebrand disease. Deficiencies in coagulation factor levels were revealed as F-VIII in 14 (7.4%), F-IX in 15 (7.6%), F-II in two (3.3%), F-V in 17 (26.1%), FVII in two (3.1%), and F-X in one (1.8%) of study subjects; low vWF activity (<50%) was found in 14 (8%). Abnormal values were found for various laboratory tests with prolongation of platelet function analyzer-epinephrine (PFA-EPI) in 11%, PFA-ADP or arachidonic acid in 15.2%, PT in 35.9%, and APTT in 63.7%. Five-hundred-seventy-six patients (90%) had normal results in the coagulation factor assays and were categorized as patients with bleeding of unknown cause (BUC). A diagnosis of a bleeding disorder was more frequently made in men than in women (38 vs. 26). Iron deficiency anemia was found in 18 (25%) females positively associated with F-IX deficiency ( -value 0.000). Male gender (73.3%,  = 0.007) was independently associated with the diagnosis of coagulation factor deficiency.  The current study reports a higher prevalence of coagulation factors deficiency in Saudi population than reported in the western population.
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http://dx.doi.org/10.1055/s-0040-1721500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758154PMC
October 2020

Spectrum of myelodysplastic syndrome in patients evaluated for cytopenia(s). A Report from a Reference Centre in Saudi Arabia.

Hematol Oncol Stem Cell Ther 2020 Nov 18. Epub 2020 Nov 18.

Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.hemonc.2020.11.001DOI Listing
November 2020

Assessing the Performance of Extended Half-Life Coagulation Factor VIII, FC Fusion Protein by Using Chromogenic and One-Stage Assays in Saudi Hemophilia A Patients.

Adv Hematol 2020 9;2020:8768074. Epub 2020 Sep 9.

Pediatric Hematology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Background: The one-stage assay is the most common method to measure factor VIII activity (FVIII : C) in hemophilia A patients. The chromogenic assay is another two-stage test involving purified coagulation factors followed by factor Xa-specific chromogenic substrate.

Aim: This study aimed to assess the discrepancy and correlation between the chromogenic and one-stage assays in measuring FVIII : C levels in hemophilia patients receiving Extended Half-Life Elocta® as a recombinant extended half-life coagulation factor.

Methods: We performed a study comparing the measurements of FVIII : C levels by the chromogenic versus the one-stage assays at different drug levels. Data of FVIII : C levels, dosage, and the time interval from administration to measurement were retrieved from the hospital records. The correlation, mean differences, and discrepancy between the two assays were calculated. The linear regression analysis was used to predict the time interval till reaching 1% FVIII : C.

Results: Fourteen patients with 56 samples were included in the study. Of them, 13 patients were receiving Elocta® as a prophylactic, while one was receiving Elocta® on demand. One-third of these samples showed a discrepancy between the chromogenic and one-stage assays. The two assays were well correlated. Mean differences were significant at the individual and the time interval level. The time since the last Elocta® injection could significantly predict FVIII : C levels ( = 0.366, < 0.001).

Conclusion: Our findings suggested a significant difference between both methods; the FVIII : C levels measured by the one-stage assay were less than those estimated by the chromogenic assay. However, the measurements of FVIII levels by the two assays were well correlated but discrepant in one-third of the samples. The levels of FVIII : C reach 1% after 5.4 days since the last Elocta® administration.
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http://dx.doi.org/10.1155/2020/8768074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499282PMC
September 2020

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

Ann Pharmacother 2021 May 22;55(5):592-604. Epub 2020 Sep 22.

King Faisal Specialist Hospital & Research Center, Riyadh, Kingdom of Saudi Arabia.

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.
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http://dx.doi.org/10.1177/1060028020960409DOI Listing
May 2021

Isotretinoin is active in the initial management of acute pro-myelocytic leukemia.

Leuk Res Rep 2020 7;14:100220. Epub 2020 Aug 7.

Department of pathology and Laboratory medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Pro-myelocytic acute leukemia (APL) is characterized by the proliferation of cells blocked at promyelocytic stage and ATRA is the choice of initial treatment because of the APL sensitivity to this compound. In this case study we report a 28-year-old man who presented to the Emergency Department with epistaxis, petechial rash, and fever. Laboratory tests revealed the presence of high white blood cell count with 60% blasts and evidence of coagulopathy. The diagnosis was confirmed later as APL. Because of the delayed transfer to the reference center and unavailability of ATRA initial treatment, the patient received isotretinoin, a related compound. The treatment was successfully implemented in the initial management of acute pro-myelocytic leukemia as patient condition improved. isotretinoin could be used as an alternative therapy for ATRA whenever the latter is not available. further research is needed to establish the appropriate doses and to assess the potential risk of differentiation syndromes.
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http://dx.doi.org/10.1016/j.lrr.2020.100220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426566PMC
August 2020

Outreach and diagnosis: Saudi Arabia's experience.

Authors:
Tarek Owaidah

Haemophilia 2020 Apr;26 Suppl 3:6-8

Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia.

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.
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http://dx.doi.org/10.1111/hae.13890DOI Listing
April 2020

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

Med Princ Pract 2020 5;29(4):371-381. Epub 2019 Nov 5.

Department of Medicine, Division of Gastroenterology/Hepatology, Tawam Hospital, Al Ain, United Arab Emirates.

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.
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http://dx.doi.org/10.1159/000503707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445696PMC
November 2019

Machine learning applications in the diagnosis of leukemia: Current trends and future directions.

Int J Lab Hematol 2019 Dec 9;41(6):717-725. Epub 2019 Sep 9.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Machine learning (ML) offers opportunities to advance pathological diagnosis, especially with increasing trends in digitalizing microscopic images. Diagnosing leukemia is time-consuming and challenging in many areas globally and there is a growing trend in utilizing ML techniques for its diagnosis. In this review, we aimed to describe the literature of ML utilization in the diagnosis of the four common types of leukemia: acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myelogenous leukemia (CML). Using a strict selection criterion, utilizing MeSH terminology and Boolean logic, an electronic search of MEDLINE and IEEE Xplore Digital Library was performed. The electronic search was complemented by handsearching of references of related studies and the top results of Google Scholar. The full texts of 58 articles were reviewed, out of which, 22 studies were included. The number of studies discussing ALL, AML, CLL, and CML was 12, 8, 3, and 1, respectively. No studies were prospectively applying algorithms in real-world scenarios. Majority of studies had small and homogenous samples and used supervised learning for classification tasks. 91% of the studies were performed after 2010, and 74% of the included studies applied ML algorithms to microscopic diagnosis of leukemia. The included studies illustrated the need to develop the field of ML research, including the transformation from solely designing algorithms to practically applying them clinically.
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http://dx.doi.org/10.1111/ijlh.13089DOI Listing
December 2019

First description of the molecular and clinical characterization of hereditary factor V deficiency in Saudi Arabia: report of four novel mutations.

Blood Coagul Fibrinolysis 2019 07;30(5):224-232

Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre and Center of Excellence in Thrombosis and Hemostasis, Riyadh, Saudi Arabia.

Coagulation factor V plays a significant role in the blood coagulation cascade as part of the prothrombinase complex. Factor V deficiency (FVD) is a rare autosomal recessive bleeding disorder with a variable phenotypic expression which varies from being asymptomatic-to-severe bleeding episodes. The aim of this study was to perform molecular and clinical characterization of FVD in patients originating from Saudi Arabia. Eleven patients (two males and nine females) with confirmed FVD were recruited in the study with ages ranging between 5 and 53 years. A next-generation sequencing-based hematology panel encompassing 393 known genes was used. A total of six sequence variations in F5 gene were identified, including four missense mutations (p.Pro189Leu, p.Trp2004Arg, p.Met2148Thr, p. Arg2202Cys), a deletion (p.Arg872Lysfs*12) and a splicing variant (c.1118+5G>T). Four variants were identified for the first time in this study. Three patients were homozygous for their respective mutations and seven patients were heterozygous. We were not able to identify a pathogenic variant in one patient of the cohort. In-silico and three-dimensional structural analyses were performed to predict the possible impact and functional consequences of the identified variants. To our knowledge, this is the first study addressing factor V mutations in patients with Arab ancestry. Results have helped in providing a definitive diagnosis to the patients and carrier detection in extended family members. Overall, the hematology panel assay was an efficient platform, demonstrating a formidable approach for the molecular diagnosis of other suspected bleeding disorders.
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http://dx.doi.org/10.1097/MBC.0000000000000828DOI Listing
July 2019

Identification of six novel factor viii gene variants using next generation sequencing and molecular dynamics simulation.

Acta Biochim Pol 2019 Feb;66(1):23-31

1Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; 2Science and Technology Unit, Umm Al Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia.

Hemophilia A is an X-linked recessive hemorrhagic disorder caused by variants in the F8 gene. To identify known and novel causative variants in hemophilia A, we have carried out genetic analysis among Saudi patients. Twenty-one patients, who were negative for inv-1/inv-22, were selected for analysis by next generation sequencing, thereafter confirmed by Sanger sequencing. In addition, the functionality and structural changes in the variant proteins were assessed using Molecular dynamics (MD) simulation and compared with wild-type and native proteins. In the samples we analyzed, we found 10 variants in 12 individuals; among them, five were novel and five were previously reported. The novel variants were located at positions: c.6130_6131insC, c.5815G>C, c.5493C>G, c.3734_3740delinsATTTCT and c.3744A>T. With the exception of one variant which was silent, the MD simulation revealed that the observed variants were causing severe structural changes when compared to the native protein and resulted in a loss of the protein's function. The MD analysis is in line with clinical data of patients who had <1% Factor VIII levels (severe hemophilia) with episodic bleeding, and were on more than one treatment. Moreover, some patients presented with chronic joint disability. These results will enrich the spectrum of variants and enlarge the factor VIII protein's database in the Saudi Arabian population.
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http://dx.doi.org/10.18388/abp.2018_2339DOI Listing
February 2019

Molecular yield of targeted sequencing for Glanzmann thrombasthenia patients.

NPJ Genom Med 2019 14;4. Epub 2019 Feb 14.

2Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder. Around 490 mutations in and genes were reported. We aimed to use targeted next-generation sequencing (NGS) to identify variants in patients with GT. We screened 72 individuals (including unaffected family members) using a panel of 393 genes (SHGP heme panel). Validation was done by Sanger sequencing and pathogenicity was predicted using multiple tools. In 83.5% of our cohort, 17 mutations were identified in and (including 6 that were not previously reported). In addition to variants in the two known genes, we found variants in , and . The SHGP heme panel can be used as a high-throughput molecular diagnostic assay to screen for mutations and variants in GT cases and carriers. Our findings expand the molecular landscape of GT and emphasize the robustness and usefulness of this panel.
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http://dx.doi.org/10.1038/s41525-019-0079-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375963PMC
February 2019

Implementation of total laboratory automation at a tertiary care hospital in Saudi Arabia: effect on turnaround time and cost efficiency.

Ann Saudi Med 2018 Sep-Oct;38(5):352-357

Dr. Tarek Owaidah, MBC 10, Department of Pathology and Laboratory Medicine,, King Faisal Specialist Hospital and Research Center,, PO Box 3354, Riyadh 11211, Saudi Arabia, T: +966505312925, ORCID: http://orcid. org/0000-0002-9399-300X.

Background: Total laboratory automation (TLA) is a relatively new way of improving the management of high volume clinical laboratories. TLA may reduce staff, reduce operating costs, decrease testing time and provide enhanced process control.

Objectives: Establish a cost efficient TLA that is less labor intensive, improves productivity and reduces turnaround time (TAT).

Design: Implementation of TLA for random glucose and troponin-T as sentinel tests to compare change in TAT.

Setting: Tertiary hospital with high volume of laboratory tests.

Methods: Routine patient samples for random glucose and troponin-T were used to capture TAT. Information on staff grades and schedules before and after implementing the TLA, and cost of contracts to deliver the service were collected.

Main Outcome Measures: TAT, cost efficiency, and reduction in labor.

Results: The consolidation of contracts resulted in a reduction of 28.8 million SAR in direct costs. Staffing cost was reduced by 1.14 million SAR with less senior staff required; there were reductions in staff at both senior and junior level. The overall TAT for all tests was reduced by 32% in 2016 (after TLA implementation) compared to 2012 (before TLA implementation). The median TAT for random glucose tests was reduced by 21% (to 55.7 minutes in 2016 from 70.1 minutes in 2012). Evidence of test optimization by exploring the impact of stat tests, auto-dilutions and reruns on the overall TAT of the TLA is shown by comparing troponin T TATs after reclassifying stat tests (in 2016) to routine (in 2017). At the 75th percentile, there was a 27% reduction in TAT when comparing August 2016 to March 2017 with a 19% reduction in median TAT.

Conclusion: By moving from stat to routine assays, the TAT was reduced, which is counter-intuitive. The use of stat assays slowed down the performance of the TLA. A careful review of the mix of assays should be conducted to maximize performance and to ensure that the system delivers what is required.

Limitations: Room for improvement by systematically analyzing and reviewing the impact of making minor changes that could have significant impact on TAT.

Conflict Of Interest: None.
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http://dx.doi.org/10.5144/0256-4947.2018.352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180219PMC
January 2019

Prevalence of Bleeding Symptoms among Adolescents and Young Adults in the Capital City of Saudi Arabia.

Adv Hematol 2018 2;2018:1858241. Epub 2018 May 2.

Center of Excellence in Thrombosis and Hemostasis, King Saud University, Riyadh, Saudi Arabia.

Background: Bleeding disorders vary in prevalence. While some are rare, some can be common in both sexes. Most bleeding disorders manifest as chronic bleeding tendencies or as an increase in bleeding during surgical procedures or trauma. The consequences of bleeding can be as simple as iron deficiency or catastrophic, resulting in severe morbidity and mortality. Bleeding disorders typically affect both sexes except hemophilia A and B, which mainly affects males.

Method: We conducted a questionnaire-based survey among adolescents and young adults (1901 [49%] boys, 1980 [51%] girls) in Riyadh city regarding bleeding symptoms. Of these, 1849 (47.6%) responded "Yes/Positive" for at least one question about the bleeding symptoms.

Results: The most common bleeding symptom was epistaxis (19.7% of the sample population) detected in Phase I of the study. A tandem survey was conducted among 525 adolescents who had responded "Yes/Positive" to any one of the questions inquiring about bleeding symptoms.

Conclusion: In this study, we report for the first time the prevalence of bleeding symptoms in a representative sample of Saudi adolescents and young adults.
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http://dx.doi.org/10.1155/2018/1858241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954960PMC
May 2018

Plasma cell myeloma with Auer rode like inclusions.

Hematol Oncol Stem Cell Ther 2018 Jun 17;11(2):112-113. Epub 2018 Apr 17.

King Faisal Specialist Hospital & RC, Saudi Arabia. Electronic address:

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http://dx.doi.org/10.1016/j.hemonc.2018.03.007DOI Listing
June 2018

Influence of ABO blood group on von Willebrand factor tests in healthy Saudi blood donors.

Blood Coagul Fibrinolysis 2018 Mar;29(2):211-215

Department of Pathology and Laboratory Medicine, King Faisal Special Hospital & RC.

: Von Willebrand disease is a common bleeding disorder. The wide variation in von Willebrand factor (VWF) levels between and within normal individuals highlights the clinical challenge of defining its cutoff value. Although studies on the influence of ethnicity on ABO phenotypes and the levels of VWF have been carried out on different ethnicities, there is a lack of such data among Arab population. We aimed to evaluate the correlation of ABO phenotypes with all the parameters of the minimal test panel of VWF including VWF antigen, VWF activity using the ristocetin cofactor and the collagen binding activity assays, and factor VIII coagulant activity (VWF:Ag, VWF:RCo, VWF:CB and FVIII:C) tested in a normal Arab population, and to estimate ABO-specific normal reference range. Blood samples were collected from 87 healthy donors in Riyadh to determine levels of factor VIII and VWF panel between the various ABO phenotypes. The highest mean values of factor VIII : C (128 U/dl), VWF : Ag (125 U/dl), VWF : RCo (109 U/dl) and VWF : CB (91 U/dl) were observed with type AB and the lowest mean values of factor VIII : C (81 U/dl), VWF : Ag (85 U/dl), VWF : RCo (73 U/dl) and VWF : CB (70 U/dl) corresponded to type O. ABO phenotypes significantly influence plasma levels of VWF parameters in Arab nations as seen with other ethnicity. Hence, ABO-specific normal ranges of the minimal test panel of VWF and factor VIII : C are essential for the appropriate prediction of mild von Willebrand disease. Further study including a larger categorized sample size is required to generalize the test panel on the Arab population.
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http://dx.doi.org/10.1097/MBC.0000000000000709DOI Listing
March 2018

Molecular Analysis of Factor VIII and Factor IX Genes in Hemophilia Patients: Identification of Novel Mutations and Molecular Dynamics Studies.

J Clin Med Res 2017 Apr 21;9(4):317-331. Epub 2017 Feb 21.

Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.

Background: Hemophilias A and B are X-linked bleeding disorders caused by mutations in the factor VIII and factor IX genes, respectively. Our objective was to identify the spectrum of mutations of the factor VIII and factor IX genes in Saudi Arabian population and determine the genotype and phenotype correlations by molecular dynamics (MD) simulation.

Methods: For genotyping, blood samples from Saudi Arabian patients were collected, and the genomic DNA was amplified, and then sequenced by Sanger method. For molecular simulations, we have used softwares such as CHARMM (Chemistry at Harvard Macromolecular Mechanics; http://www.charmm-gui.org) and GROMACS. In addition, the secondary structure was determined based on the solvent accessibility for the confirmation of the protein stability at the site of mutation.

Results: Six mutations (three novel and three known) were identified in factor VIII gene, and six mutations (one novel and five known) were identified in factor IX gene. The factor VIII novel mutations identified were c.99G>T, p. (W33C) in exon 1, c.2138 DelA, p. (N713Tfs*9) in eon14, also a novel mutation at splicing acceptor site of exon 23 c.6430 - 1G>A. In factor IX, we found a novel mutation c.855G>C, p. (E285D) in exon 8. These novel mutations were not reported in any factor VIII or factor IX databases previously. The deleterious effects of these novel mutations were confirmed by PolyPhen2 and SIFT programs.

Conclusion: The protein functional and structural studies and the models built in this work would be appropriate for predicting the effects of deleterious amino acid substitutions causing these genetic disorders. These findings are useful for genetic counseling in the case of consanguineous marriages which is more common in the Saudi Arabia.
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http://dx.doi.org/10.14740/jocmr2876wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330775PMC
April 2017

A case of T-cell lymphoproliferative disorder associated with hypereosinophilia with excellent response to mycophenolate mofetil.

Hematol Oncol Stem Cell Ther 2018 Dec 1;11(4):241-244. Epub 2017 Feb 1.

King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Hypereosinophilic syndrome (HES) is a group of rare blood disorders characterized by a persistent elevation of blood eosinophil count ⩾1.5×10/L and clinical manifestations attributable to eosinophilia or tissue hypereosinophilia. Lymphocytic variant of HES (HES-L) is a known subtype according to World Health Organization classification. It is well documented in the literature that patients with HES-L are predisposed to develop T-cell lymphoma. We report a case of T-cell lymphoproliferation associated with hypereosinophilia, which has been successfully treated with mycophenolate mofetil, with resolution of skin lesions and normalization of eosinophil count and immunoglobulin E level. We believe this is a clinically relevant case since this is a rare disease with little known knowledge on its best treatment modality.
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http://dx.doi.org/10.1016/j.hemonc.2016.11.001DOI Listing
December 2018

The prevalence of factor VIII and IX inhibitors among Saudi patients with hemophilia: Results from the Saudi national hemophilia screening program.

Medicine (Baltimore) 2017 Jan;96(2):e5456

aDepartment of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center bCenter of Excellence in Thrombosis and Hemostasis, King Saud University cOncology Center dDepartment of Pediatric Hematology, King Faisal Specialist Hospital and Research Center eDepartment of Pediatric Hematology, Ministry of Health, Riyadh fDepartment of Pediatric Hematology, Ministry of Health, Medina gDepartment of Pediatric Hematology, Military Hospital hDepartment of Pediatric Hematology, Security Force Hospital iDepartment of Pediatric Hematology, National Guard Hospital jDepartment of Oncology, Security Forces Hospital, Riyadh, Saudi Arabia.

Hemophilia A and B are X-linked diseases that predominantly affect male patients. Patients can develop coagulation factor inhibitors, which exponentially increases the treatment cost. However, the prevalence of factor VIII and IX inhibitors in Saudi Arabia is unclear.This study aimed to determine the Saudi prevalence of factor VIII and IX inhibitors.This 4-year, 7-center, cross-sectional study evaluated the Saudi prevalences of hemophilia A and B. We collected the patients' clinical data, evaluated their disease, and tested for factor inhibitors.We included 202 patients with hemophilia (median age at diagnosis: 0.13 years, range: birth-34.8 years). The patients included 198 male patients (98%), 148 patients with hemophilia A (73.3%), and 54 patients with hemophilia B (26.7%). The patients exhibited severe factor VIII activity (<1%; 121 patients; 5.2%), moderate activity (1-5%; 7 patients; 4.9%), and mild activity (14 patients; 9.9%). Among the patients with care-related data, most patients were treated for episodic bleeding (76.8%) or received prophylaxis (22.6%); 1 patient received both treatments. Among the patients with source-related data, the factor replacements were derived from plasma (48.4%), recombinant concentrates (22.9%), both sources (14.6%), or fresh frozen plasma (14.1%). Factor VIII inhibitors were observed in 43 (29.3%) of the 147 patients, and only 1 of the 54 patients developed factor IX inhibitors. Most patients who developed inhibitors had severe hemophilia (40/44; 90.9%), and inhibitors were also common among patients who received recombinant products (14/43; 32.6%).The Saudi prevalence of factor inhibitors was similar to those among other ethnic populations.
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http://dx.doi.org/10.1097/MD.0000000000005456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266150PMC
January 2017

Protein signatures as potential surrogate biomarkers for stratification and prediction of treatment response in chronic myeloid leukemia patients.

Int J Oncol 2016 Sep 7;49(3):913-33. Epub 2016 Jul 7.

Adult Hematology/HSCT Section, Oncology Center, King Faisal Specialist Hospital and Research Centre, (KFSH&RC), Riyadh, 11211 Saudi Arabia.

There is unmet need for prediction of treatment response for chronic myeloid leukemia (CML) patients. The present study aims to identify disease-specific/disease-associated protein biomarkers detectable in bone marrow and peripheral blood for objective prediction of individual's best treatment options and prognostic monitoring of CML patients. Bone marrow plasma (BMP) and peripheral blood plasma (PBP) samples from newly-diagnosed chronic-phase CML patients were subjected to expression-proteomics using quantitative two-dimensional gel electrophoresis (2-DE) and label-free liquid chromatography tandem mass spectrometry (LC-MS/MS). Analysis of 2-DE protein fingerprints preceding therapy commencement accurately predicts 13 individuals that achieved major molecular response (MMR) at 6 months from 12 subjects without MMR (No-MMR). Results were independently validated using LC-MS/MS analysis of BMP and PBP from patients that have more than 24 months followed-up. One hundred and sixty-four and 138 proteins with significant differential expression profiles were identified from PBP and BMP, respectively and only 54 proteins overlap between the two datasets. The protein panels also discriminates accurately patients that stay on imatinib treatment from patients ultimately needing alternative treatment. Among the identified proteins are TYRO3, a member of TAM family of receptor tyrosine kinases (RTKs), the S100A8, and MYC and all of which have been implicated in CML. Our findings indicate analyses of a panel of protein signatures is capable of objective prediction of molecular response and therapy choice for CML patients at diagnosis as 'personalized-medicine-model'.
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http://dx.doi.org/10.3892/ijo.2016.3618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948960PMC
September 2016

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

N Engl J Med 2016 May;374(21):2054-64

From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico (F.P., P.M.M., E.S., M.E.M.), and Department of Pathophysiology and Transplantation, Università degli Studi di Milano (F.P., P.M.M., I.G.), Milan, Clinica Medica II, Azienda Ospedaliera di Padova, Centro Emofilia, Padua (E.Z.), and Ematologia, Unità Operativa Diagnostica Speciale e Terapia delle Malattie dell'Emostasi e della Trombosi, Università Sapienza, Policlinico Umberto I, Rome (M.G.M.) - all in Italy; the Pediatric Hematology Department, Cairo University Pediatric Hospital (A.E.-B.), and Department of Pediatrics, Faculty of Medicine, Ain Shams University (M.E.), Cairo; Jehangir Clinical Development Center, Department of Hematology, Jehangir Hospital Premises (V.R.), and Sahyadri Speciality Hospital (S.A.), Pune, Jagadguru Jayadeva Murugarajendra Medical College, Davangere (S.H.), Center for Blood Disorders, Chennai (R.V.), Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai (M.V.M.); St. John's Medical College Hospital, Bangalore (C.R.), All India Institute of Medical Sciences, Department of Hematology (T.S.), and Pediatric Hematology Oncology and Bone Marrow Transplantation, Institute for Child Health, Sir Ganga Ram Hospital (A.S.), New Delhi, Melaka-Manipal Medical College, Manipal University, Manipal (D.M.N.), and Kerala Institute of Medical Science, Trivandrum (M.T.) - all in India; the Congenital Pediatric Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran (P.E.), and Hematology Research Center, Shiraz University of Medical Sciences, Shiraz (M.K.) - both in Iran; Children's Hospital Los Angeles, Los Angeles (G.Y.), and City of Hope National Medical Center, Duarte (N.P.E.) - both in California; Hospital de Especialidades Unidad Médica de Alta Especialidad, Instituto Mexicano del Seguro Social, Monterrey (A.C.S.G.), an

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.).
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http://dx.doi.org/10.1056/NEJMoa1516437DOI Listing
May 2016

Home treatment of haemarthrosis with recombinant activated factor VII in patients with haemophilia A or B and inhibitors: experience from developing countries.

Blood Coagul Fibrinolysis 2017 Mar;28(2):145-151

aService d'Hématologie, Hopital Isaad Hassani, CHU Beni-Messous, Alger, Algeria bCollege of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia cSheikh Khalifa Medical City, Abu Dhabi, UAE dNovo Nordisk Healthcare AG, Zurich Oerlikon, Switzerland eDepartment of Child Health, Sultan Qaboos University Hospital, Muscat, Oman fService of Medicine, Cheikh Zaid Hospital, Rabat, Morocco gDepartment of Haematology, Public Hospital of Mascara, Mascara hDepartment of Haematology, University Hospital of Annaba, Annaba iDepartment of Hematology, University Hospital of Sétif, Sétif jDepartment of Haematology, University Hospital Tlemcen, Tlemcen, Algeria kKing Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia lNovo Nordisk Canada Inc., Mississauga, ON, Canada mHaematology Department, University Hospital of Constantine, Constantine nUniversity Hospital Oran, Bd. Dr Benzerjeb, Oran, Algeria.

Home therapy for uncomplicated mild/moderate bleeding can decrease healthcare burden, promote self-esteem, reduce complications, and provide near-normal quality of life. To evaluate recombinant activated factor VII (rFVIIa) as home therapy for joint bleeds in Algeria, Morocco, Oman, Saudi Arabia, and United Arab Emirates. Twenty-seven patients aged more than 2 years with congenital haemophilia and inhibitors were monitored for up to 8 months after a first haemarthrosis episode treated with rFVIIa. Assessments were made by patients/caregivers with a standardized diary. The main measures included home-managed bleeds, haemostasis, and pain relief within 9 h after first injection. Additional analyses included convenience, time to pain resolution, and doses given within 48 h. Of 132 bleeds, 84 (63.6%) were managed at home. Of these, successful haemostasis (partial or complete) was achieved at 9 h in 87.8%, with pain relief for 84.0%. For all treatment settings, successful haemostasis at 9 h was achieved for 86.3% of bleeds, with pain relief achieved for 74.8% of bleeds. Higher initial dosing was associated with fewer injections. Median time to complete haemostasis was 48 h (spontaneous bleeds) and 24 h (traumatic bleeds). Median time to complete pain relief was 24 h for both bleed types. Satisfaction with treatment was high. No safety concerns were reported. Results from this observational study agree with previous data on the safety and efficacy of home treatment with rFVIIa and will help to increase awareness and aggregate experience, fostering confidence in home management of haemophilia patients with inhibitors in developing countries.
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http://dx.doi.org/10.1097/MBC.0000000000000564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312720PMC
March 2017

Prophylaxis and treatment of venous thromboembolism in patients with cancer: the Saudi clinical practice guideline.

Ann Saudi Med 2015 Mar-Apr;35(2):95-106

Background And Objectives: Venous thromboembolism (VTE) is commonly encountered in the daily clinical practice. Cancer is an important VTE risk factor. Proper thromboprophylaxis is key to prevent VTE in patients with cancer, and proper treatment is essential to reduce VTE complications and adverse events associated with the therapy.

Design And Settings: As a result of an initiative of the Ministry of Health of Saudi Arabia, an expert panel led by the Saudi Association for Venous Thrombo-Embolism (a subsidiary of the Saudi Thoracic Society) and the Saudi Scientific Hematology Society with the methodological support of the McMaster University working group produced this clinical practice guideline to assist health care providers in evidence-based clinical decision-making for VTE prophylaxis and treatment in patients with cancer.

Methods: Six questions related to thromboprophylaxis and antithrombotic therapy were identified and the corresponding recommendations were made following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach.

Results: Question 1. Should heparin versus no heparin be used in outpatients with cancer who have no other therapeutic or prophylactic indication for anticoagulation?

Recommendation: For outpatients with cancer, the Saudi Expert Panel suggests against routine thromboprophylaxis with heparin (weak recommendation; moderate quality evidence).Question 2. Should oral anticoagulation versus no oral anticoagulation be used in outpatients with cancer who have no other therapeutic or prophylactic indication for anticoagulation?

Recommendation: For outpatients with cancer, the Saudi Expert Panel recommends against thromboprophylaxis with oral anticoagulation (strong recommendation; moderate quality evidence).Question 3. Should parenteral anticoagulation versus no anticoagulation be used in patients with cancer and central venous catheters?

Recommendation: For outpatients with cancer and central venous catheters, the Saudi Expert Panel suggests thromboprophylaxis with parenteral anticoagulation (weak recommendation; moderate quality evidence).Question 4. Should oral anticoagulation versus no anticoagulation be used in patients with cancer and central venous catheters?

Recommendation: For outpatients with cancer and central venous catheters, the Saudi Expert Panel suggests against thromboprophylaxis with oral anticoagulation (weak recommendation; low quality evidence).Question 5. Should low-molecular-weight heparin versus unfractionated heparin be used in patients with cancer being initiated on treatment for venous thromboembolism?

Recommendation: In patients with cancer being initiated on treatment for venous thromboembolism, the Saudi Expert Panel suggests low-molecular-weight heparin over intravenous unfractionated heparin (weak; very low quality evidence).Question 6. Should heparin versus oral anticoagulation be used in patients with cancer requiring long-term treatment of VTE?

Recommendation: In patients with metastatic cancer requiring long-term treatment of VTE, the Saudi Expert Panel recommends low-molecular-weight heparin (LMWH) over vitamin K antagonists (VKAs) (strong recommendation; moderate quality evidence). In patients with non-metastatic cancer requiring long-term treatment of venous thromboembolism, the Saudi Expert Panel suggests LMWH over VKA (weak recommendation; moderate quality evidence).
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http://dx.doi.org/10.5144/0256-4947.2015.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074132PMC
June 2016

The Saudi Clinical Practice Guideline for the treatment of venous thromboembolism. Outpatient versus inpatient management.

Saudi Med J 2015 Aug;36(8):1004-10

College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, Jeddah, Kingdom of Saudi Arabia. E-mail.

Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is commonly encountered in daily clinical practice. After diagnosis, its management frequently carries significant challenges to the clinical practitioner. Treatment of VTE with the inappropriate modality and/or in the inappropriate setting may lead to serious complications and have life-threatening consequences. As a result of an initiative of the Ministry of Health of the Kingdom of Saudi Arabia, an expert panel led by the Saudi Association for Venous Thrombo-Embolism (a subsidiary of the Saudi Thoracic Society) and the Saudi Scientific Hematology Society with the methodological support of the McMaster University Guideline working group, this clinical practice guideline was produced to assist health care providers in VTE management. Two questions were identified and were related to the inpatient versus outpatient treatment of acute DVT, and the early versus standard discharge from hospital for patients with acute PE. The corresponding recommendations were made following the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.
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http://dx.doi.org/10.15537/smj.2015.8.12024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549580PMC
August 2015

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.

Thromb J 2014 28;12(1):28. Epub 2014 Nov 28.

Department of Critical Care Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

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.
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http://dx.doi.org/10.1186/s12959-014-0028-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272774PMC
December 2014

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

Crit Care Med 2012 Apr;40(4):1229-36

King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.

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.
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http://dx.doi.org/10.1097/CCM.0b013e3182387befDOI Listing
April 2012

Postmarital follow-up survey on high risk patients subjected to premarital screening program in Saudi Arabia.

Prenat Diagn 2010 May;30(5):478-81

Department of Genetic, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.

Background: Haemoglobinopathies are the most inherited disorders worldwide including Saudi Arabia which can be preventable with application of screening programmers. Ministry of Health in Saudi Arabia had initiated premarital screening program (PMS) in all country regions.

Methods: The aim of this study was to explore the impact of the PMS program and genetic counseling on couples at risk for thalassaemia and sickle cell anima in an area of the country with high hemoglobinopathy prevalence. A total of 129 candidates identified by PMS to be at risk were included.

Results: Out of this cohort, 98% proceeded with marriage. Culture pressure was the main reason in more than 48%. Over a period of 4 years, these marriages resulted in 15 diseased children. Although most of the candidates did not receive genetic counseling yet, the concept of genetic counseling was liked by most of them.

Conclusion: This study showed some early benefits of the PMS in prevention of the targeted diseases and the program helped in early detection of the disease in their offspring.
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http://dx.doi.org/10.1002/pd.2507DOI Listing
May 2010

Megakaryocytic blast crisis at presentation in a pediatric patient with chronic myeloid leukemia.

Hematol Oncol Stem Cell Ther 2010 ;3(1):42-6

Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Patients with chronic myeloid leukemia (CML) infrequently present in blast crisis (BC). While most BC are of myeloid origin, megakaryocytic BC is rare, especially at the time of CML diagnosis. We describe the first pediatric patient presenting with megakaryocytic leukemia and having BCR-ABL1 translocation as the single chromosomal abnormality. Clinical features were more suggestive of CML in megakaryocytic blast crisis than Philadelphia chromosome positive de novo AML. The patient was treated with AML-directed chemotherapy and imatinib mesylate followed by umbilical cord blood stem cell transplantation. The patient was in complete molecular response 16 months after stem cell transplantation.
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http://dx.doi.org/10.1016/s1658-3876(10)50056-6DOI Listing
February 2012