Amir Kuperman

Vitamin K-dependent coagulation factors deficiency.

All vitamin K-dependent coagulation factors require normal function of gamma-glutamyl carboxylase and vitamin K epoxide reductase enzyme complex (VKORC1). Heritable dysfunction of gamma-glutamyl carboxylase or of the VKORC1 complex results in the secretion of poorly carboxylated vitamin K-dependent proteins that play a role in coagulation. The following review will summarize the clinical manifestations of vitamin K-dependent coagulation factors deficiency I and II and will provide a detailed explanation about the gene and protein structure, the function of the protein, and an analysis of the previously reported mutations. Laboratory assays used for diagnosis will be discussed, and treatment for various clinical settings will be recommended.

Intraventricular hemorrhage in preterm infants: coagulation perspectives.

It has long been considered that a severe coagulation deficiency in premature newborns could be a major contributing factor in the occurrence of intraventricular hemorrhage (IVH). High-grade IVH has also been shown to coincide with severe derangement of coagulation in extremely low birth weight infants. This review focuses on the relevance of the physiologically developing immature hemostatic system to IVH, and the potential benefit of agents affecting hemostasis for IVH therapy or prevention in preterm infants. The findings of small, open-label interventional studies on the effect of ethamsylate, vitamin K, fresh frozen plasma, recombinant activated factor VII, and prothrombin complex concentrate on the premature coagulation system will be reviewed.

Severe pertussis and hyperleukocytosis: is it time to change for exchange?

Pertussis is an important cause of infant death worldwide and continues to be a public health concern even in countries with high vaccination coverage. Severe (critical) pertussis with hyperleukocytosis is a severe form of the disease with up to 80% mortality rate. Attempts have been reported to reduce the white blood cell burden by exchange transfusion (ET) with conflicting conclusions.

Intraventricular hemorrhage in preterm infants and coagulation--ambivalent perspectives?

Intraventricular hemorrhage (IVH) is a major complication of preterm birth, and large hemorrhages may yield significant future disability. During the last few decades, the survival of preterm infants has increased dramatically. Nevertheless, morbidity is still a major problem especially for very young and extremely low birth weight infants. As both, mortality and incidence of morbidities known to influence outcome, show a weekly decline with increasing gestational age, prematurity and low birth weight have been identified as major risk factors for IVH occurrence. This stems probably from the increased vulnerability of the premature germinal matrix as well as the physiologically impaired hemostasis, demonstrated in neonates. The hypothesis that a severe coagulation deficiency in the premature newborn could be a major contributing factor for IVH has been suggested, and small open label interventional studies targeting the premature coagulation system have been conducted with ethamsylate, vitamin K, fresh frozen plasma, recombinant activated factor VII and prothrombin complex concentrate. Nevertheless, potential venous origin of hemorrhages, which may be related to thrombophilic risk factors, has also been discussed. The following manuscript will focus upon IVH pathogenesis and address potential therapies.

Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT

Keller et al. describe for the first time human LAT deficiency, which causes severe immune dysregulation with autoimmunity, lymphoproliferation, and progressive immunodeficiency.

Genetic analysis and clinical picture of severe congenital neutropenia in Israel.

The relative frequency of mutated genes among patients with severe congenital neutropenia (SCN) may differ between various ethnic groups. To date, few population‐based genetic studies have been reported. This study describes the genetic analysis of 32 Israeli patients with SCN.

Anemia and bleeding in patients receiving anticoagulant therapy for venous thromboembolism

In patients receiving anticoagulant therapy for venous thromboembolism (VTE), the important issue of anemia influence on the risk of bleeding has not been consistently studied. We used the large registry data RIETE (Registro Informatizado Enfermedad Tromboembólica) to compare the rate of major bleeding in patients receiving anticoagulant therapy for VTE according to the presence or absence of anemia at baseline. Patients with or without cancer were separately studied. Until August 2016, 63492 patients had been enrolled. Of these, 21652 (34%) had anemia and 14312 (23%) had cancer. Anemia was found in 57% of the patients with cancer and in 28% without (odds ratio 3.46; 95% CI 3.33–3.60). During the course of anticoagulant therapy, 680 patients with cancer had a major bleeding event (gastrointestinal tract 43%, intracranial 14%, hematoma 12%). Cancer patients with anemia had a higher rate of major bleeding (rate ratio [RR]: 2.52; 95% CI 2.14–2.97) and fatal bleeding (RR 2.73; 95% CI 1.95–3.86) than those without anemia. During the course of anticoagulation, 1133 patients without cancer had major bleeding (gastrointestinal tract 32%, hematoma 24%, intracranial 21%). Patients with anemia had a higher rate of major bleeding (RR 2.84; 95% CI 2.52–2.39) and fatal bleeding (RR 2.76; 95% CI 2.07–3.67) than those without. On a multivariable analysis, anemia independently predicted the risk for major bleeding in patients with and without cancer (hazard ratios: 1.66; 95% CI 1.40–1.96 and 1.95; 95% CI 1.72–2.20, respectively). During anticoagulation for VTE, both cancer- and non-cancer anemic patients had a higher risk for major bleeding than those without anemia. In anemic patients (with or without cancer), the rate of major bleeding during the course of anticoagulant therapy exceeded the rate of VTE recurrences. In patients without anemia the rate of major bleeding was lower than the rate of VTE recurrences.

Primary prophylaxis for children with severe congenital factor VII deficiency — Clinical and laboratory assessment

Severe congenital factor VII (FVII) deficiency is a rare bleeding disorder. Prophylaxis with replacement therapy has been suggested to patients, yet the most beneficial dosing regimens and therapy intervals are still to be defined. Due to the lack of evidence-based data, we hereby present our experience with long-term administration and monitoring primary prophylaxis in children with severe FVII deficiency and an extremely high bleeding risk. Four children with familial FVII deficiency, treated by prophylactic recombinant activated factor VII (rFVIIa), 15-30μg/kg/dose, given 2-3 times weekly since infancy, are discussed. Clinical follow up and monitoring laboratory assays, including thrombin generation, measured at various time points after prophylactic rFVIIa administration are presented. Among our treated patients neither FVII activity nor thrombin generation parameters (both already declined 24h post rFVIIa administration) were able to predict the impact of prophylaxis, and could not be used as surrogate markers in order to assess the most beneficial treatment frequency. However, the long clinical follow-up and comprehensive laboratory assessment performed, have shown that early primary prophylaxis as administered in our cohort was safe and effective.

Targeted next generation sequencing for the diagnosis of patients with rare congenital anemias

Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes.

A Puzzling “Switch” in Blood Type Following Blood Transfusion

Luiza Akria, M.D., Judith Chezar, Ph.D., Simona Zisman-Rozen, Ph.D., Eyal J. Scheinman, Ph.D., Zeev Zonis, M.D., Yoav Hoffmann, M.D., Tzipora Falik-Zaccai, M.D., Limor Kalfon, Ph.D., Michael Weiss, M.D., Andrei Braester, M.D., Celia Suriu, M.D., Masad Barhoum, M.D., Amir Kuperman, M.D., and Ety Shaoul, Ph.D. Blood Bank and Molecular Hematology Laboratory, Pediatric Intensive Care Unit, Cytogenetic Laboratory, Department of Surgery, Hematology, and Pediatrics, Galilee Medical Center, Nahariya; Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel