Bleeding disorders consist of a group of conditions where blood cannot clot properly. The body maintains blood in a fluid state in normal vessels by a complex process called Hemostasis. It generates a quick response at the site of vascular injury. This process requires a coordinated function of the vascular endothelium, platelets, and clotting factors. In the clotting process platelets, a type of blood cell, stick together and form a plug at the site of an injured blood vessel. Clotting factors in the blood then interact to form a fibrin clot, essentially a gel plug. It prevents blood from escaping the blood vessel and allows healing to occur at the site of the injury. The dysfunctional activity of any of the numerous components of the body’s hemostatic response can lead to fatal events. A basic understanding of normal endothelial, platelet, and coagulation pathway function is necessary to understand the variety of ways hemostasis can go awry (1). While too much clotting can lead to conditions such as heart attacks and strokes, the inability to form clots can be very dangerous as well, as it can result in excessive bleeding. March is a Bleeding Disorders Awareness Month, where communities raise awareness of the group of rare bleeding disorders. It’s an opportunity to learn more about bleeding disorders that can often be misdiagnosed. This special month aims to bring together people with all inherited (conditions that run in families) bleeding disorders to raise awareness of these rare conditions and their potential health problems.
The vascular lining secretes antiplatelet, anticoagulant, and fibrinolytic substances to maintain liquid blood flow. It is composed of endothelial cells supported by a basement membrane, connective tissue, and smooth muscle. During an injury, the endothelium takes on procoagulant properties important for proper clot formation. Endothelial cells when damaged release von Willebrand factor (VWF), which allows platelet binding, synthesize tissue factor, which activates the coagulation cascade and bind activated coagulation factors IXa and Xa, which increase the activity of the coagulation cascade. VWF in particular complexes with factor VIII in the plasma, serving as its carrier and stabilizing the protein. The half-life of factor VIII decreases from 12 hours to 2.4 hours in the plasma if VWF levels are decreased or absent. Dysfunction of the endothelial lining is often acquired or infectious like cutaneous drug reactions, scurvy, and meningococcemia. Congenital causes of endothelial abnormality include connective tissue disorders like Ehlers-Danlos syndrome and hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Hemorrhagic telangiectasia is an autosomal dominant disorder characterized by tortuous thin-walled vessels that predispose to bleeding, particularly of the mucous membranes. These disorders of the vasculature rarely cause life-threatening bleeding with the exception of some cases of hereditary telangiectasias.
Platelets are thin membrane-bound discs that contain granules filled with procoagulant factors and surface receptors that assist in clot formation and aggregation. The exposed endothelial extracellular matrix of damaged endothelium when encounter platelets initiate a chain of reaction. First one is adhesion in which a strong bridge is formed by VWF, which bridges between the platelet’s receptors and the exposed endothelial extracellular matrix (ECM) collagen. This bonding helps platelets to withstand the shear forces of circulating blood, particularly in the microcirculation. Adhesion is followed by secretion where the granules within platelets are released after binding to VWF. The released factors include chemotaxins for platelet aggregation and cofactors for the intrinsic clotting pathway. Adenosine diphosphate (ADP) and thromboxane A2 (TxA2) are two of the most important substances in attracting more platelets and creating the platelet plug. An intrinsic clotting cascade gets activated and tissue factor released from the endothelium activates the extrinsic pathway. With these factors prothrombin gets converted to thrombin, hardening the platelet plug into an irreversibly fused mass. In the final step, fibrinogen gets activated to fibrin (by thrombin), which cements the plug in place and completes the hemostatic cascade. Thrombin and fibrin get attracted in catalytic fashion and platelet receptors get activated. Disorders of platelet function can occur at any of the 3 steps to cemented platelet plug formation. Platelet disorders are the most common cause of bleeding disorder and are usually acquired rather than inherited.
The coagulation cascade is a series of events where prothrombin converts to thrombin. Thrombin converts the soluble protein fibrinogen to the insoluble fibrin, cementing and stabilizing the adherent platelet plug. Each reaction in the coagulation cascade requires an enzyme (the activated coagulation factor from the prior reaction), a substrate (the proenzyme form of the coagulation factor next in line to be activated), and a cofactor. Calcium is one of the key elements stored in platelet granules and required to hold the enzymatic machinery together. The coagulation pathway typically remains localized to surfaces (ie, damaged epithelium) where all the necessary enzymatic components can be found. The coagulation pathway is traditionally divided into extrinsic and intrinsic pathways, but in reality, the pathways overlap and interact. The extrinsic pathway tissue factor VIIa complex activates factor IX in the intrinsic pathway. The extrinsic pathway initiates the coagulation cascade, generating thrombin, which then serves as a catalyst for the intrinsic pathway, which in turn creates more thrombin. Along with any step of the coagulation cascade dysfunctional or deficient coagulation factors can be found.
Clinical symptoms of bleeding disorders may significantly differ among patients, however, the severe disorders tend to present early at the neonatal period. Adult population often carry a diagnosis of either hemophilia A, hemophilia B, or von Willebrand disease (VWD). VWD affects both the platelet aggregation and coagulation pathways (2). It is the most common inherited bleeding disorder in America caused by clotting proteins. Von Willebrand disease can affect males as well as females. Hemophilia is the most frequent congenital rare inherited and most well understood the bleeding disorder. It affects mostly males. Hemophilias are X-linked recessive traits with variable levels of severity across the affected population. The most severe form of hemophilia A is associated with a missense mutation causing the destruction of the synthetic capacity. Some mutations cause problems with the function of the coagulation factors even if the measured levels of proenzyme are within the normal range. Similar genetic mutations and phenotypic expressions can be found within the spectrum of those affected by hemophilia B. Most rare bleeding disorders are inherited as autosomal recessive (AR). Heterozygous carriers may have varying degrees of corresponding factor deficiency. Intracranial hemorrhage (ICH) is by far the most devastating and often fatal event that occurs in patients with rare blood diseases (RBD). The diagnosis of ICH is often delayed due to the vague symptoms of ICH. Most congenital RBD are monogenic diseases and even a small increase in factor activity levels can profoundly improve the disease phenotype. RBD in women leads to menorrhagia, bleeding ovarian cysts or corpus luteum, post-partum hemorrhage or other obstetric complications. Recurrent miscarriages also occur due to the deficiency of FXIII and FI factors which play important role in placental implantation and pregnancy maintenance.
The main stray of bleeding disorder management is the substitution/replacement of the deficient factor. Various bleeding disorders yield impaired thrombin generation (TG), which may be corrected by proper replacement therapy. The countries with high resources use specific factor concentrate (3), mostly plasma-derived (PD) to treat RBD. Recombinant products are also available for FVII and FXIII deficiency. Some RBD is treated with fresh frozen plasma (FFP), cryoprecipitate or combinations of prothrombin complex concentrate (PCC), containing the absent coagulation factor, when a specific concentrate is not available. FFP is still the standard of care for bleeding patients with factor V deficiency. Adjuvant therapies are also available for less severe mucosal tract hemorrhage or heavy menstrual bleeding. Gene therapy has achieved great progress in hemophilia B in comparison to hemophilia A. Recently gene therapy using AAVFVII zymogen transgene approach in an animal model of FVII deficiency has shown initial efficacy and safety. New treatments include non-replacement therapies and inhibition of inhibitors of the coagulation cascade.
Homeostasis control is recommended for bleeding disorders which mainly include replacement of the missing coagulation factors (unless the presence of inhibitors renders it impossible). In the growing era of genetic knowledge identification of the causative mutation of a bleeding disorder is becoming the definitive diagnostic method. Early diagnosis is important as it may allow for pregnancy termination or proceeding towards intervention and therapy. Future gene therapy may be promising and disruptive, non-replacement alternatives may be interesting for the treatment and prophylaxis of patients with bleeding disorders.
- Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance and regulation. Biochemistry 1991;30(43):10363–70.
- The National Heart, Lung, and Blood Institute. The evaluation and management of Von Willebrand disease. Bethesda (MD): National Heart, Lung, and Blood Institute, National Institutes of Health; 2007. Available at: www.nhlbi.nih.gov/ guidelines/vwd. Accessed February 5, 2014.
- Lillicrap D, Poon MC, Walker I, et al. Efficacy and safety of the Factor VIII/von Willebrand Factor concentrate, haemate-P/humate-P: ristocetin cofactor unit dosing in patients with von Willebrand disease. Thromb Haemost 2002;87:224.