Introduction:Preoperative coagulation screening tests in pediatric patients was once routine clinical practice globally and still used as standard practice in some countries before surgical procedures to assess of perioperative bleeding risk.Objective:The study aimed to evaluate unselected routine preoperative coagulation testing in children undergoing elective or invasive surgery to predict abnormal perioperative bleeding. The study also aimed to provide a rational approach of determining bleeding and family history of coagulation disorders as a predictive risk for bleeding.Methods:This retrospective study conducted between 2014 and 2015 (1 year) on normal healthy children aged under 15 years admitted to the hospitals for elective mild to intermediate surgery or invasive procedures. We reviewed and collected the details of the clinical history, previous surgery, trauma, family history, detail of anti-thrombotic medication and coagulation tests performed (prothrombin time (PT), the activated partial prothrombin time (APTT), and international normalized ratio (INR)) at the time of admission.Results:Among 2078 cases, 1940 cases had normal coagulation tests (93.4%), 77 cases had abnormal coagulation results (3.7%), and 61 patients underwent surgery without preoperative coagulation screening (2.9%). In 15 of 77 patients, coagulation tests were normal on repeat testing. A total of 52 were confirmed to have abnormal screening testing. Among these 52 cases, 45 had normal factors assay; where seven patients had abnormal factors assay. Postoperative bleeding occurred only in three cases (0.14%), two cases due to surgical procedures with normal preoperative testing and one due to hemophilia A which was detected postoperatively as no preoperative testing was performed.Conclusions:Routine coagulation screening before surgery or invasive procedures to predict perioperative bleeding in unselected patients is not recommended. Our study emphasizes that selective preoperative testing is more appropriate. Selective criteria for consideration of the latter includes physical examination, type of surgery, family and bleeding history, and concomitant use of antiplatelet and anti-thrombotic therapy.

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome that is characterized by strong activation of the immune system from hyperinflammatory cytokines. Symptoms of HLH patients include fever, hepatosplenomegaly, cytopenia, and hyperferritinemia. Inherited HLH is classified as primary, whereas secondary HLH (sHLH) occurs when acquired from non-inherited reasons that include severe infection, immune deficiency syndrome, autoimmune disorder, neoplasm, and metabolic disorder. Wolman’s disease (WD) is a rare and fatal infantile metabolic disorder caused by lysosomal acid lipase deficiency, that exhibits similar clinical signs and symptoms as HLH. This paper reports the case of an infant diagnosed with WD and who presented with sHLH. Case presentation A 4-month-old infant presenting with hepatosplenomegaly, failure to thrive, and other abnormalities. WD diagnosis was confirmed by the presence of the LIPA gene homozygous deletion c.(428 + 1_967-1)_(*1_?)del. The infant also met the HLH-2004 diagnostic criteria. Conclusions Metabolic disorder such as WD should be investigated in infants fulfilling the HLH criteria to diagnose the underlying condition. More studies are needed to understand the link between WD and sHLH and to identify appropriate therapies.

Hemorrhage in a patient with factor VIII inhibitor is associated with increased morbidity and mortality. Treatment with factor IX complex concentrates or recombinant factor VIIa (rVIIa) may not control bleeding and may induce thrombosis. In this study, continuous infusion of a monoclonal antibody-purified factor VIII [correction of factor VII] concentrate (Monoclate-P) was used successfully in two hemophilic patients with factor VIII alloantibodies and one nonhemophilic patient with a factor VIII autoantibody. In two patients, hemorrhage was life-threatening, and, in one, bleeding did not stop with repeated infusions of activated factor IX complex concentrates. The patients' ages ranged from 4 to 15 years, and the inhibitor levels from 6 to 300 Bethesda units/ml. Clinical hemostasis was excellent, and in vivo recovery of infused factor VIII was achieved. When an excess of monoclonal factor VIII was added to the inhibitor plasma in vitro, a stable level of residual factor VIII activity was noted after an initial rapid loss. This second-order reaction occurs in plasmas of patients with type I factor VIII inhibitors. In one patient, we showed that the saturation dose of the factor VIII inhibitor predicted in vivo recovery of factor VIII:C. These data emphasize the importance of characterizing the kinetic reactions of the factor VIII inhibitor. Furthermore, we confirm previous reports that continuous infusion of monoclonal factor VIII is a safe and effective treatment of patients with factor VIII inhibitors in whom hemorrhage is either life-threatening or refractory to standard treatment.

We report here a quite rare case of severe homozygous protein C deficiency. The index case is a 9-month-old Saudi boy who was born after an uneventful pregnancy at 39 weeks. The diagnosis of epidermoloysis bullosa and the appearance of scrotal haematoma raised the diagnosis of thrombosis due to protein C deficiency. The clinical presentation and extremely low level of protein C activity (< 0.01 U/ml) in the index case suggested a severe case of protein C deficiency. The father is 28 years old and the mother is 25 years old and are consanguineous. Neither had a personal or family history of thrombosis. Genomic DNA was extracted from peripheral blood of the patient and both parents, exons of protein C were amplified by polymerase chain reaction and sequenced. Sequencing revealed the presence of a novel CCTG duplicate nucleotide (effective insertion) after nucleotide 8826 in exon 9 of the protein C gene. This insertion is found in the homozygous state in the patient and in the heterozygous state in both parents. It results in a frame-shift mutation, which introduces a stop-codon, thereby generating a prematurely truncated protein. These molecular findings agree with the presence of quantitative protein C deficiency in the index case.

Congenital protein C deficiency is an inherited coagulation disorder associated with an elevated risk of venous thromboembolism. A Saudi Arabian male from a consanguineous family was admitted to neonatal intensive care unit in his first days of life because of transient tachypnea and hematuria. Laboratory investigations determined low platelet and protein C deficiency. Direct sequencing of PROC gene and RNA analysis were performed. Analysis of factor V Leiden (G1691A) and factor II (G20210A) mutations was also done. Novel homozygous splice site mutation c.796+3A>T was detected in the index case and segregation was confirmed in the family. RNA analysis revealed the pathogenicity of the mutation by skipping exon 8 of PROC gene and changing the donor splice site of the exon. Detection of the molecular cause of protein C deficiency reduces life threatening and facilitates inductive carrier testing, prenatal and preimplantation genetic diagnosis for families.

Familial Hodgkin Lymphoma (HL) accounts for 4.5% of HL. Both genetic susceptibility and shared environmental factors can play a role. The usual presentation of HL is cervical lymphadenopathy/ mediastinal mass. Subdiaphragmatic presentation is rare and hepatosplenomegaly is associated with advanced HL. Adenosine deaminase 2 (ADA2) act as an outside extracellular growth factor for integrity of endothelial cells and in the development of certain immune cells. Deficiency of ADA2 (DADA2) is a recently described inborn error of immunity caused by biallelic mutations in adenosine deaminase 2 (ADA2) gene (formerly known as CECR1). It is an auto-inflammatory disorder with a spectrum of vascular, inflammatory, hematological and immunodeficiency phenotypes. The condition is inherited in an autosomal recessive pattern.The association of DADA2 with lymphoproliferation such asT-LGL like condition and ALPS like disease have been reported, however, HL has not previously been reported in DADA2. Herein we describe two siblings with DADA2 who presented with Hodgkin Lymphoma. The first patient is the third child of Saudi first degree related parents. He is known to have bronchial asthma on bronchodilators. At the age of 5 years, he was referred from primary care clinic for investigation of hepatosplenomegaly. He was otherwise well with growth along the fifth centile. His complete blood count (CBC) showed mild lymphopenia, other lab results including liver function tests were within normal. Few months later, he developed non-tender mobile cervical lymph nodes enlargement. Viral serology including EBV was negative based on PCR testing. Lymph node biopsy revealed the diagnosis of HL, mixed cellularity type, EBV negative (Figure 1). Whole exome analysis sequencing identified a homozygous variant in ADA2 gene c.1447_1451del. This variant has been confirmed by Sanger sequencing. Plasma assay of ADA2 enzyme activity revealed undetectable levels compatible with ADA2 deficiency. The patient started on prednisone 2 mg/kg/day, which showed good response in the form of being off blood support and regression of splenomegaly. Few months later, the course was complicated by recurrent infections. The patient remained stable for three years on small dose of prednisone, monthly IVIG due to hypogammaglobulinemia. Recently, etanercept was started to control disease progression. Nine months after the diagnosis of first patient, his younger brother who is known to have mild bronchial asthma on bronchodilators presented at the age of five years with hepatosplenomegaly and generalized lymphadenopathy. Lymph node biopsy revealed the diagnosis of classical HL, lymphocyte-rich subtype. Similar to his sibling, whole exome analysis identified the same mutation (a homozygous variant in ADA2 gene c.1447_1451del). This variant has been confirmed by Sanger sequencing and plasma level of ADA2 enzyme activity was undetectable. After the diagnosis of DADA2, screening for serum immunoglobulin levels showed hypogammaglobulinemia. The patient continues to be off treatment. Both patients were treated with chemotherapy with or without radiotherapy showing good response and they remained in remission at respectively and months after cessation of chemotherapy. This study is important for several reasons. First, this is the first report of HL in the context of DADA2. This again widens the clinical spectrum of DADA2. Interestingly, the boys presented two different forms of HL at the cellular level with no evidence of viral infection. The reported siblings presented with subdiaphragmatic diseases, which is uncommon in HL but in line with the sites of lymphoproliferation in DADA2. In addition, the age of presentation in the two siblings is uncommon in HL (less than 10 years). Second, we report an novel mutation in ADA2 gene. It creates a shift in the reading frame starting at codon Ser483. The new reading frame ends in a stop codon 4 positions downstream. This description and the description of the HL occurrence further expands the spectrum of DADA2. Our data, call for judicious exclusion of ADA2 deficiency in the HL patient with an aberrant course and additional symptoms / signs. In summary, we report familial HL in two patients with a novel deleterious mutation in ADA2 gene. This expands the spectrum of this disease to include cancer and should alert the hemato-oncologist to the possibility of DADA2 as an underlying diagnosis in HL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Antiphospholipid syndrome (APS) is a multisystem autoimmune disorder that can affect children and adults alike, with a similar spectrum of thrombotic events, predominately deep vein thrombosis and stroke. It is characterized by recurrent arterial or venous thrombosis and recurrent fetal loss with the presence of antiphospholipid antibodies (aPL) like antibodies to beta-2-glycoprotein I (B-2-GPI) and anticardiolipin (aCL). The disease could be classified into primary APS in the absence of an underlying disease or secondary APS occurring secondary to autoimmune diseases, infections, malignancies, and sometimes medication use. In the absence of clinical manifestations of APS, transient non-thrombogenic antiphospholipid antibodies are seen more commonly in children, predominantly after childhood infections. Cases with clinical manifestations of APS associated with different types of infections have been reported in the literature to keep track of potential triggering causes and take measures to prevent or treat the disease manifestations. This case documents the case of hepatitis-A as a triggering viral infection, causing secondary APS in a child.

We report here a quite rare case of severe homozygous protein C deficiency. The index case is a 9-month-old Saudi boy who was born after an uneventful pregnancy at 39 weeks. The diagnosis of epidermoloysis bullosa and the appearance of scrotal haematoma raised the diagnosis of thrombosis due to protein C deficiency. The clinical presentation and extremely low level of protein C activity (< 0.01 U/ml) in the index case suggested a severe case of protein C deficiency. The father is 28 years old and the mother is 25 years old and are consanguineous. Neither had a personal or family history of thrombosis. Genomic DNA was extracted from peripheral blood of the patient and both parents, exons of protein C were amplified by polymerase chain reaction and sequenced. Sequencing revealed the presence of a novel CCTG duplicate nucleotide (effective insertion) after nucleotide 8826 in exon 9 of the protein C gene. This insertion is found in the homozygous state in the patient and in the heterozygous state in both parents. It results in a frame-shift mutation, which introduces a stop-codon, thereby generating a prematurely truncated protein. These molecular findings agree with the presence of quantitative protein C deficiency in the index case.