Enhancer-gene rewiring in the pathogenesis of Quebec platelet disorder.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78-kb tandem duplication of PLAU. How this duplication causes megakaryocyte-specific PLAU overexpression is unknown. To investigate the mechanism that causes QPD, we used epigenomic profiling, comparative genomics, and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes from participants with QPD and unaffected controls. QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD). Our results support a unique disease mechanism whereby the reorganization of sub-TAD genome architecture results in a dramatic, cell-type-specific blood disorder phenotype.

Inherited disorders of the fibrinolytic pathway.

Deficiencies or excessive activation of the fibrinolytic system can result in severe, lifelong bleeding disorders. The most severe clinical phenotype is caused by α2-Antiplasmin (α2-AP) deficiency which results in excess fibrinolysis due to the inability to inhibit plasmin. Another bleeding disorder due to a defect in the fibrinolytic pathway results from Plasminogen activator inhibitor-1 (PAI-1) deficiency causing enhanced fibrinolysis due to the decreased inhibition of plasminogen activators resulting in increased conversion of plasminogen to plasmin. Both these disorders are rare and have an autosomal recessive pattern of inheritance. They can remain undetected as routine coagulation and platelet function tests are normal. A unique gain-of-function defect in fibrinolysis causes the Quebec platelet disorder (QPD) which is characterized by profibrinolytic platelets containing increased urokinase-type plasminogen activator (uPA) in the α-granules. A high index of suspicion based on clinical phenotype along with the availability of specialized hemostasis testing is required for timely and accurate diagnosis. Antifibrinolytic agents, such as tranexamic acid or ε-aminocaproic acid, are the mainstays of treatment which inhibit fibrinolysis by preventing the binding of plasminogen to fibrin and thereby stabilizing the fibrin clot. The purpose of this review is to summarize the pathogenesis, clinical phenotype, approaches to diagnosis and treatment for these three major disorders of fibrinolysis.

Factor V Deficiency in Korean Patients: Clinical and Laboratory Features, Treatment, and Outcome.

Due to rarity of factor V (FV) deficiency, there have been only a few case reports in Korea. We retrospectively analysed the clinical-laboratory features of FV deficiency in 10 Korean patients. Between January 1987 and December 2013, 10 case reports published in a Korean journal or proceedings of Korea Society on Thrombosis and Hemostasis were reviewed. Severity is defined as mild (> 5% of factor activity), moderate (1%-5%), and severe (< 1%). The median age at diagnosis, six males and four females, was 26 years (range, 1 month-73 years). Six of 10 patients were classified as moderate, three as mild, and one as severe disease. Eight patients were diagnosed as inherited FV deficiency. The most frequent symptoms were mucosal tract bleedings (40%) such as epistaxis, and menorrhagia in female. Hemarthroses and postoperative bleeding occurred in one and four patients, respectively. Life-threatening bleeding episodes occurred in the peritoneal cavity (n = 2), central nerve system (n = 1), and retroperitoneal space (n = 1). No lethal haemorrhages happened to patients with mild disease. The majority of bleeding episodes were controlled with local measures and fresh-frozen plasma replacement. Two acquired FV deficient-patients showing life-threatening haemorrhages received the immunosuppressive therapy, but one of them died from postoperative bleeding complications. Despite the small sample size of this study due to rarity of the disease, we found that Korean patients with FV deficiency had similar clinical manifestations and treatment outcomes shown in previous studies.

Congenital factor V deficiency: comparison of the severity of clinical presentations among patients with rare bleeding disorders.

BACKGROUND: Factor V deficiency (FVD) is a rare bleeding disorder (RBD) mostly present in regions with a high rate of consanguinity. FVD after FXIII deficiency is the next more prevalent RBD in Sistan and Baluchistan (S&B) in southeastern Iran. The aim of this study was to evaluate the clinical manifestations and severity of bleeding diathesis in patients with FVD. METHODS: This descriptive study was conducted on 23 patients with FVD in S&B province. FVD was diagnosed by clinical findings and routine laboratory tests. Bleeding diatheses were classified into three grades (I-III) depending on the severity of symptoms. The severity of bleeding episodes in our patients was compared with other RBDs. RESULT: Based on residual plasma FV activity, 6 (26%), 16 (69.5%) and 1 (4.5%) patients had mild, moderate and severe factor deficiency, respectively. 24% of the patients had grade III life-threatening bleeding episodes which in comparison with FVII deficiency (17.4%) and FI deficiency (21%) had a higher incidence, and in comparison with FX deficiency (41.7%) and FXIII deficiency (63.1) had a lower incidence. Grade II and grade I bleeding diathesis were observed in 56.2 and 16.7% of the patients, respectively. CONCLUSION: FVD is the second most common type of RBD in S&B province and grade II bleeding episodes were the major bleeding presentation and observed in more than half of the patients.

The COPII pathway and hematologic disease.

Multiple diseases, hematologic and nonhematologic, result from defects in the early secretory pathway. Congenital dyserythropoietic anemia type II (CDAII) and combined deficiency of coagulation factors V and VIII (F5F8D) are the 2 known hematologic diseases that result from defects in the endoplasmic reticulum (ER)-to-Golgi transport system. CDAII is caused by mutations in the SEC23B gene, which encodes a core component of the coat protein complex II (COPII). F5F8D results from mutations in either LMAN1 (lectin mannose-binding protein 1) or MCFD2 (multiple coagulation factor deficiency protein 2), which encode the ER cargo receptor complex LMAN1-MCFD2. These diseases and their molecular pathogenesis are the focus of this review.

Testing for inherited thrombophilias in arterial stroke: can it cause more harm than good?

BACKGROUND AND PURPOSE: Despite a paucity of evidence supporting a true association of ischemic stroke and the inherited thrombophilias, it is common practice for many neurologists to order these tests as part of the work-up of ischemic stroke, especially in young patients. Treatment with oral anticoagulation is often used in patients with positive results for the inherited thrombophilias. METHODS: We reviewed the literature focusing on case-control studies of the 5 most commonly inherited disorders of coagulation: protein C deficiency, protein S deficiency, antithrombin deficiency, and the factor V Leiden and prothrombin gene mutations in patients with stroke. We also analyzed the available data on stroke patients with inherited thrombophilia and patent foramen ovale. RESULTS: Multiple case-control studies have not convincingly shown an association of the inherited thrombophilias with ischemic stroke, even in young patients and patients with patent foramen ovale. CONCLUSIONS: If there is an association between the inherited thrombophilias and arterial stroke, then it is a weak one, likely enhanced by other prothrombotic risk factors. The consequences of ordering these tests and attributing causality to an arterial event can result in significant costs to the health care system and pose a potential risk to patients, because this may lead to inappropriate use of long-term oral anticoagulants, exposing patients to harm without a clearly defined benefit.

Phenotype Report on Patients with Congenital Factor V Deficiency in Southern Iran: Recent Ten Years' Experience.

This study aimed to investigate clinical symptoms in patients with congenital factor V (FV) deficiency and the relationship between phenotype and factor activity level. Thirteen patients with congenital FV deficiency were investigated and the factor activity level and first clinical presentations were studied for each patient. The most common first signs and symptoms were post-surgery, post-partum, post-circumcision, and post-traumatic bleeding (30.76%), followed by easy bruising in 23.10% of the patients. The median age at the onset of clinical signs was 18 (range: 1-53) years. Patients were categorized into two groups of major and minor bleeding based on their first clinical bleeding symptoms. There was not a significant difference between the two groups with regard to factor activity level, age at diagnosis, prothrombin time, partial thromboplastin time, and international normalized ratio (p>0.05). There is a discrepancy between plasma FV activity level and the severity of clinical presentations.

Quebec platelet disorder.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with a unique gain-of-function defect in fibrinolysis. In the past 5 years, there have been important advances in the understanding of the pathogenesis of QPD, including its genetic cause, which is a copy number variation mutation of PLAU, the gene for urokinase plasminogen activator (uPA). QPD is the first bleeding disorder identified to be caused by a PLAU mutation and it is also the first bleeding disorder recognized to result from a gene copy number mutation. The molecular defect of QPD leads to marked overexpression of uPA during megakaryopoiesis, producing profibrinolytic platelets that contain active forms of uPA in their α-granules. This article summarizes expert opinions on the features of QPD and recent advances in the understanding of its pathogenesis and genetic cause.

Factor V New Brunswick: Ala221Val associated with FV deficiency reproduced in vitro and functionally characterized.

Factor V (FV) deficiency, also known as parahemophilia, is a rare bleeding disorder. Herein we investigate the first reported missense mutation associated with FV deficiency, Ala221Val, assigned as FV New Brunswick. To elucidate the molecular pathology associated with the Ala221Val substitution, the mutation was recreated in a recombinant system together with 3 FV mutants (Ala221Gly, Glu275Gln, and Cys220Ala/Cys301Ala) designed to help explain the Ala221Val phenotype. The expression pattern was analyzed by pulse-chase experiments and an FV-specific enzyme-linked immunosorbent assay (ELISA), the results suggesting the Ala221Val mutation not to interfere with the synthesis or secretion. The functional properties of the recombinant FV New Brunswick were evaluated in both plasma clotting and purified systems. The Ala221Val mutation did not affect the factor Xa (FXa) cofactor function; nor did it interfere with the activated protein C (APC)-mediated down-regulation of activated FV (FVa) activity. However, FV New Brunswick demonstrated reduced stability at 37 degrees C due to an increased rate of dissociation of light and heavy chains of FVa. In conclusion, this in vitro study of FV New Brunswick suggests the Ala221Val mutation not to impair synthesis and expression of procoagulant activity, indicating overall proper folding of the mutant molecule. Rather, the Ala221Val substitution appears to interfere with the stability of the activated FVa mutant, the reduced stability possibly explaining the deficiency symptoms associated with the mutation.

Manejo anestésico en el déficit de factor V de la coagulación / Anesthetic management of coagulation factor V deficiency

El déficit del factor V o enfermedad de Owren en un raro trastorno congénito de herencia autonómica recesiva. La clínica hemorrágica que presentan los pacientes, está en función de los niveles plasmáticos de factor V. La conducta anestésica a seguir será similar a la utilizada en pacientes con otros tipos de coagulopatías. Por un lado, es conveniente iniciar un protocolo de administración de plasma, en aquellos déficits en los que no se disponga de concentrados purificados. Por otro lado, es importante un control estricto de los parámetros hemostáticos, con el fin de prevenir el riego hemorrágico en el postoperatorio inmediato. En los primeros días del postoperatorio, se continuará la administración de plasma y fármacos antifibrinólicos como el ácido tranexámico. Se presenta el caso de un paciente varón, intervenido de cirugía oncológica de colon, homocigoto para el déficit de factor V. En el presente trabajo se revisan los principales puntos de la actuación anestésica en este tipo de pacientes (AU)

Factor V deficiency, or Owren's disease, is a rare inherited recessive autonomic disorder that is congenital. The bleeding in patients with this disease depends on plasma levels of factor V. Anesthetic management is similar to that used for patients with other coagulation disorders. On the one hand, it is useful to initiate infusion of plasma if purified concentrates are not available. On the other hand, it is important to monitor hemostasis carefully so that bleeding during postoperative recovery can be prevented. Plasma and antifibrinolytic drugs such as tranexamic acid should continue to be administered in the first few days after surgery. We report the case of a man with homozygotic factor V deficiency who underwent surgery for colon cancer. This article reviews the main aspects of anesthetic management of this coagulation disorder (AU)