Bleeding Disorders - LECOM

Bleeding Disorders

Thursday, 19 March 2020

Bleeding disorders include many subtypes but all of these disorders are generally characterized by impaired process of forming blood clots1,2.  Blood clots are formed by a specific interaction of clotting factors and there are 13 clotting factors.  If there is a deficiency of clotting factors or if any the clotting factors are defective the regular process of formation of blood clots can be affected and cause bleeding which can result in mild, moderate or severe bleeding1.  Some of the most common symptoms of bleeding include: bleeding into joints, muscles and soft tissue, excessive bruising, prolonged and heavy menstrual periods, extended bleeding after minor cuts or minor surgeries and others1,2.  Treatment of bleeding disorders depends on the specific type of the bleeding disorders as well as the severity of bleeding1.  Some of the most common types of bleeding disorders include hemophilia A and B, Von Willebrand disease, disseminated intravascular coagulation, acquired and congenital platelets function defects1,2.

The most common congenital bleeding disorder in the United States and worldwide is von Willebrand disease.  The prevalence of von Willebrand disease is 1% to 2%.  Von Willebrand disease is characterized by quantitative and/or qualitative defect of von Willebrand factor.    Von Willebrand factor is involved in both, primary and secondary hemostasis and it helps with platelet adhesion to injured blood vessel sites and platelet aggregation.  Three subtypes of von Willebrand disease developed by the National Institute for Health are types 1, 2 and 3.  Types 1 and 3 are characterized by quantitative defect in von Willebrand factor and type 2 is characterized by functional abnormalities in von Willebrand factor.  Some patients with von Willebrand disease may be asymptomatic and some can experience mucocutaneous bleeding such as epistaxis, gingival bleeding, easy bruising, and others.  Specific laboratory tests for diagnosis of von Willebrand disease include measurement of von Willebrand antigen (vWF:Ag), factor VIII assay, determination of vWF ristocetin cofactor (vWF:RCo) activity, and vWF multimer analysis.  Historically, patients with von Willebrand disease were treated by administration of cryoprecipitate which contains anywhere between 80 to 100 units of von Willebrand factor per unit.  Since, cryoprecipitate is not virally inactivate it is not anymore used as a first-line treatment3.

The current treatment of von Willebrand disease includes local and systemic measures.  Local treatment options for bleeding caused by von Willebrand disease include application of pressure, ice and administration of topical thrombin.  Systemic treatment options are used when local treatment options are not effective and to prevent bleeding episodes with surgeries.  Systemic treatment options include administration of products that contain von Willebrand factor and factor VIII.  For patients with type 1 von Willebrand disease, the first step in systemic treatment is infusion of desmopressin test.  If the patient responds to the administration of desmopressin test, then the full dose of desmopressin is administered.  Patients with von Willebrand disease type I who do not respond to the desmopressin test or patients with type 2 or 3 von Willebrand disease should receive intermediate or high purity virus-inactivated factor VIII concentrates.  These patients should then be monitored for factor VIII level, von Willebrand factor activity and von Willebrand antigen.  Some of these patients may also require transfusion of platelets3.

Hemophilia is a type of bleeding disorder which is characterized by congenital deficiency in plasma coagulation protein.  There are two types of hemophilia: hemophilia A and hemophilia B.  Hemophilia A also called classic hemophilia is characterized by deficiency of coagulation factor VIII.   Hemophilia B which is also called Christmas disease is characterized by deficiency of coagulation factor IX.  Hemophilia A is more common and it constitutes for about 80%-85% of all hemophilia cases and hemophilia B is less common and it constitutes for about 15%-20% of all hemophilia cases.  Both types of hemophilia are recessive X-linked diseases where defective genes are located on chromosome X.  Since males have one X chromosome the disease primarily affects males and females are generally carriers.  About 30% of patients with hemophilia do not have family history for the disease which indicates the probability of a spontaneous mutation.  General clinical presentation of hemophilia includes: ecchymoses, hemarthroses, joint pain, joint swelling and erythema, muscle and intracranial hemorrhage, oral bleeding with dental extractions or trauma, hematuria, and others.  Laboratory testing generally shows prolonged activated partial thromboplastin time (aPPT) and decreased factor VIII with hemophilia A or decreased factor IX with hemophilia B.  Treatment options for hemophilia A include administration of recombinant factor VIII, plasma-derived factor VIII products, desmopressin which is the antidiuretic hormone vasopressin and causes release of factor VIII from endogenous endothelial storage sites.  Antifibrinolytic therapy, which prevents clot lysis, is also used for the treatment of hemophilia A as an adjunctive therapy.  There are currently two antifibrinolytic agents available: aminocaproic acid and tranexamic acid.  Hemophilia B is treated with administration of recombinant or plasma derived factor IX.  Administration of factor VIII for the treatment of hemophilia A and administration of factor IX for the treatment of hemophilia B can be on demand or as prophylaxis.  Administration of factors VIII and IX on demand is used for the treatment of acute bleeding episodes.  Prophylactic administration of factors VIII and IX is used to convert more severe forms of disease to milder forms3.

Vitamin K is one of the agents that is important for formation of clots.  Deficiency in vitamin K can cause bleeding.  Patients can have vitamin K deficiency caused by the administration of an overdose of warfarin.  The bleeding caused by vitamin K deficiency is treated by the administration of vitamin K4.

Bleeding disorders can cause serious complications for patients.  There are currently effective treatment options for the management of different subtypes of bleeding disorders.  However, more therapies are needed.  There are several new treatment strategies that are currently being developed and those include gene therapy and new factor products with improved pharmacokinetic properties.  Hopefully, these therapies will be approved in the near future and will improve overall management of patients with different types of bleeding disorders.

 

References:

  1. What is a Bleeding Disorder? National Hemophilia Foundation. Website: www.hemophilia.org.  Accessed March 10, 2020.
  2. Bleeding Disorders. MedlinePlus. U.S. National Library of Medicine.  U.S. Department of Health and Human Services.   National Institutes of Health.  Website: https://medlineplus.gov/ency/article/001304.htm.  Accessed March 10, 2020.
  3. Trinkman H, Beam D, Hagemann T. Coagulation Disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds.  Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill.  Website: http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=133893594. Accessed March 15, 2020.
  4. Kruse-Jarres R, Singleton T, Leissinger CA. Identification and Basic Management of Bleeding Disorders in Adults. J Am Board Fm Med.  2014;27:549-564.  doi: 10.3122/jabfm.2014.04.130227.
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