Rare Bleeding Disorders

This issue of Seminars in Thrombosis and Hemostasis is devoted to the topic of rare bleeding disorders (RBDs) caused by coagulation factor defects and deficiencies. The issue begins with an introductory article by the guest editor and some colleagues that primarily looks at the incidence of the separate RBDs as well as some of their features. The remaining articles within this issue have been prepared by experts in the field, each of who were asked to focus on individual or specific cases of RBDs. Specifically, each of the authors were asked to detail, for each RBD, the clinical manifestations, the laboratory assays used in the diagnosis of the specific RBD, the phenotype and genotypic analysis, problems with the laboratory evaluation, prenatal diagnosis (if required), and treatment options, with an additional focus on treatment of women suffering these rare disorders.

The prevalence of RBDs in the general population is low, and homozygous or double heterozygous deficiencies vary from 1:500,000 for factor VII deficiency to 1:2,000,000 for prothrombin and FXIII deficiencies (Table [1]). This low prevalence leads to significant diagnostic challenges, because the likelihood of identifying such disorders is in general low but at the same time certainly not improbable. Thus, although these disorders are generally not foremost in the minds of treating clinicians and testing laboratories, they can occur, and their possibility should always be considered by clinicians and laboratory scientists alike after discounting other more common disorders or in those cases where familial history might otherwise be suggestive. Indeed, it is likely that many of us will actually come across at least one of each of these disorders over the period of our careers.

Table 1 Rare Bleeding Disorders: A Comparative Summary* Rare Bleeding Disorder Afibrinogenemia; Hypofibrinogenemia; Dysfibrinogenemia Prothrombin Deficiency Factor V Deficiency Combined Factor V and Factor VIII Deficiency Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor XIII Deficiency Multiple Vitamin K–Dependent Factor Deficiency Gene(s) responsible Fibrinogen Bβ (FGB) Prothrombin (F2) Factor V (F5) Lectin mannose binding protein (LMAN1 or ERGIC-53) and multiple coagulation factor deficiency 2 (MCFD2) Factor VII (F7) Factor X (F10) Factor XI (F11) Factor XIIIA (F13A) factor XIIIB (F13B) γ-Glutamyl carboxylase (GGCX) and vitamin K epoxide reductase (VKORC1) Fibrinogen Aα (FGA) Fibrinogen γ (FGG) Approximate prevalence of RBDs Afibrinogenemia: 1:1,000,000; hypofibrinogenemia and dysfibrinogenemia more common Aprothrombinemia: incompatible with life. Prothrombin deficiency: 1:2,000,000. 1:1,000.000 1:1,000.000 1:500,000 1:1,000,000 1:1,000,000 1:2,000,000 Not known Frequency among RBDs † (see Ref. 1) 8% to 10% 2% 7% to 9% 3% to 15% 21% to 34% 8% to 10% 23% to 39% 5% to 7% Not known Factor(s) affected (common name[s]/alternate name[s]) Fibrinogen/factor I Prothrombin/factor II Factor V Factor V and Factor VIII Factor VII Factor X Factor XI Factor XIII FII/FVII/FIX/FX Major function(s) of factor(s) Major clotting protein; converts to fibrin On conversion to thrombin promotes fibrin clot formation; displays anticoagulant activities through activation of the thrombomodulin/protein C pathway FVa assembles with FXa on phospholipid membranes, forming a complex that enhances the rate of prothrombin activation. FV also contributes to the anticoagulant pathway by downregulating FVIII activity. The LMAN1-MCFD2 protein complex functions as a cargo receptor that facilitates the transport of FV and FVIII from the ER to the Golgi apparatus FVIIa, complexed with tissue factor, generates a burst of activated FIX and FX ultimately leading to formation of a stable fibrin clot Complexed with FVa, FXa accelerates to 280,000-fold thrombin formation. FXa activates also FV, FVIII, and FVII. FXIa acts by cleaving FIX in the intrinsic blood-coagulation pathway. It also displays antifibrinolytic properties by promoting activation of thrombin activatable fibrinolysis inhibitor. FXIIIa forms fibrin γ-chain dimers, to cross-link its α-chains into high-molecular-weight polymers, and to attach α2 plasmin inhibitor to fibrin α-chains Hepatic γ-glutamyl carboxylase (GGCX) catalyzes the γ-carboxylation of vitamin K–dependent coagulation factors, requiring reduced vitamin K (KH2) as a cofactor. During the γ-carboxylation reaction, KH2 is converted to vitamin K epoxide (KO), which is recycled to KH2 by the vitamin K VKORC1 Site(s) of synthesis Liver Liver Liver and megakaryocytes LMAN1: highest expression in skeletal muscle, kidney, liver, and placenta. Liver Liver Liver and megakaryocytes FXIIIA: cells of bone marrow origin. Liver MCFD2: expressed in multiple tissues. FXIIIB: liver. Approximate biological half-life 2–4 days 70 hours 36 hours FV: 36 hours. FVIII: 10–14 hours. 4–6 hours 40–60 hours 50 hours 9–12 days See corresponding factors FVIII: 10–14 hours. Typical normal reference range ‡ 1.5–3.5 g/L 75% to 113% 70% to 134% FV: 70% to 134%. 62% to 138% 66% to 126% 70% to 130% 53% to 221% See corresponding factors FVIII: 51% to 147%. Main bleeding sites and/or symptoms for severe deficiencies Afibrinogenemia: Common: Common: Common: Common: Common: Most bleeding manifestations are injury-related. Common: - Intracranial (at birth) Common: - Hematomas - Epistaxis - Easy bruising - Easy bruising - Epistaxis Women are prone to excessive bleeding during menstruation. - Umbilical cord bleeding - Umbilical stump - Umbilical cord bleeding - Bruising - Menorrhagia - Epistaxis - Epistaxis - Menorrhagia - Bruising - Hemarthrosis Less Common: - Hemarthrosis - Oral cavity - Gum bleeding - Gum bleeding - Hemarthrosis - Subcutaneous hematoma - Retroperitoneal soft tissue - Skin - After tooth extraction Less common: - After surgery - Menorrhagia - Hematomas - Mouth - GI - GI Less common: - Hematomas - After dental extraction - After surgery - Posttrauma - Gum bleeding - Easy bruising - Genitourinary tract - CNS - Hemarthrosis - Postcircumcision Less common: - After surgery - Intracranial - Mucocutaneous - CNS - GI - Posttrauma - Hemarthrosis Less common: Less common: - After surgery. - Menorrhagia - Menorrhagia - Hematoma - GI - Wound healing Children may show skeletal abnormalities. - Postpartum - Hematuria - Umbilical cord bleeding - Hemarthrosis - CNS - Hematuria - Epistaxis - GI - CNS - After surgery Risk of thrombosis Afibrinogenemia: reported. In the inherited dysprothrombinemia caused by a G20210A mutation and linked to slightly increased levels of circulating prothrombin, there is a significantly higher risk to develop thromboembolic diseases — — Thrombotic episodes and particularly deep vein thrombosis have been reported in 3–4% of patients (FVII-deficient patients seem to be not protected for venous and arterial thrombosis) — Cases of myocardial infarction and venous thrombosis have been reported (idiopathic or after FXI infusion) — Although protein S and protein C levels are low in VKCFD, there are no reports of venous or arterial thrombosis. Dysfibrinogenemia: reported. Treatment: Replacement therapy - FFP - FFP - FFP FV: see FV column. - FFP - FFP - FFP - FFP Oral or parenteral vitamin K. In patients who responded poorly to vitamin K and require surgical procedures or have acute bleeding, factor replacement is necessary with prothrombin complex. - Cryoprecipitate - PCC - Platelet transfusions (suggested in cases of severe bleeding not controlled with FFP or in case of inhibitor development) FVIII: - FVII plasma derived concentrate - PCC - FXI plasma derived concentrate - PCC - Fibrinogen plasma derived concentrate - FFP - Recombinant FVIIa - Recombinant FVIIa (few cases reported) - FXIII plasma derived concentrate - Recombinant human fibrinogen (rhFIB) has recently being developed and has received orphan drug designation from the U.S. FDA - FVIII plasma derived concentrate - Recombinant FXIII (under study) - Recombinant FVIII Treatment: Non-transfusional therapy (minor surgery, not severe bleeding, menorrhagia) - Estrogen-progestin preparations - Antifibrinolytics - Antifibrinolytic - Antifibrinolytics - Antifibrinolytics - Antifibrinolytics - Antifibrinolytics - Antifibrinolytics - Estrogen-progestin preparations - Levonorgestrel intrauterine - Levonorgestrel intrauterine - Estrogen-Progestin preparations - Estrogen-progestin preparations - Estrogen-progestin preparations - Surgical treatments (menorrhagia) - Desmopressin - Levonorgestrel intrauterine - Estrogen-Progestin preparations CNS, central nervous system; GI, gastrointestinal; ER, endoplasmic reticulum; FFP, fresh-frozen plasma; PCC, prothrombin complex concentrate; RBD, rare bleeding disorder. This table provides a comparative synopsis of some important features of each of the distinct RBDs. The inheritance pattern for all these RBDs is autosomal recessive. Due to the lack of definitive data, this table does not provide information on typical ranges for defining deficiency severity and on the minimum level of factors necessary for effective hemostasis. Large data collections of patients affected with different RBDs is required to draw definitive conclusions regarding these issues. Data collected by World Federation of Hemophilia (WFH; www.wfh.org) and International Rare Bleeding Disorders Database (www.rbdd.org). Ranges are approximate guides and will vary from laboratory to laboratory.

At the same time, the rarity of these disorders means that definitive information is lacking about presenting symptoms, the levels of specific factor(s) required for supporting normal hemostasis, and also for surgical hemostasis, as are specific guidelines on their diagnosis and treatment. That the appropriate diagnosis, monitoring, and treatment of affected individuals will be compromised by this paucity of knowledge and the limited understanding among general care centers was the main driving force behind the preparation of this issue of Seminars in Thrombosis and Hemostasis.

We expect that readers of this journal will find this issue to be not only of considerable interest but also a valuable long-term future reference source for both clinical and laboratory practice. In addition, a summary of some of the major observations for the RBDs is provided in Table [1].

We thank all the contributors to this issue for their thoughtfully considered articles, and we also thank Roberta Palla, Marzia Menegatti, and Pier Mannuccio Mannucci for their valuable assistance in the preparation of this issue. We are grateful also to Giuseppe Lippi for undertaking an additional review of the content of each article prior to publication.

REFERENCE

• 1 Peyvandi F, Palla R, Menegatti M, Mannucci P M. Rare bleeding disorders: general aspects of clinical features, diagnosis, and management.  Semin Thromb Hemost. 2009;  35 xx