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Benign Hematologic (Blood) DisordersA collaborative project of the Arizona Telemedicine Program, the Arizona Health Sciences Library and the Arizona Cancer Center.
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Inherited Bleeding Disorders: Abnormalities in Fibrin Clot Formation
A. What Causes Abnormalities in Fibrin Clot Formation?
When a wound occurs, several changes take place to minimize blood loss. First, the blood vessel slows the flow of blood past the wound site. Next, platelets collect at the wound site to form a plug. Finally, fibrin clots form scabs to replace these temporary platelet plugs.
Problems with fibrin clot formation can be caused by abnormalities in fibrin itself or by defects in fibrin clotting factors necessary for clot formation. With both of these problems, severe bleeding may result. Deficiencies in coagulation factors include the hemophilias and hereditary von Willebrand’s disease. Dysfibrinogenemia produces a deficiency in fibrin itself.
B. The Hemophilias
The hemophilias are produced by an inherited deficiency in one of the blood’s clotting factors. This may result in severe bleeding.
Hemophilia A. Hemophilia A is a rare disease found in all parts of the world. It is also known as classic hemophilia and is the most common type, affecting factor VIII. The disease varies in severity depending on the genetic defect and the functional level of factor VIII in the bloodstream. Hemophilia A occurs almost exclusively in men. In healthy individuals, levels of factor VIII vary at different times in life, with elevated levels present at birth, during pregnancy, and increasingly with age.
In mild cases of hemophilia A, symptoms usually appear in the first fourteen years of life. In more severe cases, symptoms will appear before the age of one. Symptoms of the disease include: easy bruising, excess bleeding after surgery or injury, blood in the urine and stool, pain and swelling from bleeding into the joints and muscles, and intracranial hemorrhage (bleeding within the skull).
Diagnosis of hemophilia A is made based on family history of the disease, signs of bleeding, and laboratory testing. Family history is not always present in patients with the disease. If left untreated, hemophilia A may result in crippling deformities from bleeding in the muscles and bones, intracranial hemorrhage, internal bleeding, and bleeding after surgery or injury. In addition, cancer-like tumors as well as nerve damage may develop.
Treatment varies depending on the severity of the case. In mild cases, desmopressin (DDAVP) administration will increase factor VIII to acceptable levels. In moderate and severe cases, concentrated factor VIII must be used. If severe bleeding has occurred, red cell transfusions may be necessary.
Treatment complications include development of hepatitis and acquired immunodeficiency syndrome (HIV) from infection from transfusions. While recent techniques have made the danger of hepatitis B and human immunodeficiency virus (HIV) infection extremely small, the human parvovirus B19 may still be transmitted, resulting in profound anemia. In addition, factor VIII inhibitor development occurs in 15 percent of the hemophilia A population. In most cases, this inhibitor inactivates factor VIII. Patients with inhibitors can usually be treated to control bleeding.
Hemophilia B. Hemophilia B is produced by a defect in factor IX activity. It is an inherited trait that is found almost exclusively in men. Symptoms of hemophilia B are the same as those for hemophilia A. Like hemophilia A, it is diagnosed based on family history of the disease (although patients with hemophilia B may not have a family history), signs of bleeding, and laboratory testing. Treatment is also similar to that of hemophilia A, with replacement of factor IX in the form of prothrombin-complex concentrates (PCC), which includes prothrombin, factor VIII, and factor X as well as factor IX.
C. Other Coagulation Factor Deficiencies
Other hereditary bleeding disorders may occur due to deficiencies or defects in other specific clotting factors. They are diagnosed by specific laboratory studies and treated by factor replacement.
Coagulation factors V, VII, X, XI, and XIII. Deficiencies in other factors, such as V, VII, X, XI, and XIII, are rarer than the hemophilias, but produce similar symptoms. Diagnosis depends on detection of bleeding, family history, and laboratory testing. Treatment usually involves blood transfusions, especially replacement of the missing coagulation factor, medications such as desmopressin (DDAVP), and antifibrolytic medications such as e-aminocaproic acid (Amicar), and tranexamic acid (TA).
Hereditary von Willebrand’s Disease. Hereditary von Willebrand’s disease is an inherited bleeding disorder that affects the von Willebrand factor (vWf). vWf is a coagulation factor necessary for platelet function and for fibrin clot formation. In von Willebrand’s disease, there is a defect in the body’s ability to produce vWf. This results in excessive bleeding from the body cavities, such as the nose, the uterus, the bladder, and the rectum.
Most patients with von Willebrand’s disease have a history of the disorder in their family. Diagnosis is made based on patient and family history, physical examination, and laboratory testing. In addition to detecting von Willebrand’s disease, diagnostic testing classifies the disease into types I, II, and III. Type I patients have levels of vWf that are below normal; type II patients have vWf that is unable to perform its function; type III patients are the most serious cases, with virtually no vWf in their bloodstream.
Treatment depends on the type and severity of the disease. In type I patients, desmopressin (DDAVP) administration can be used to raise levels of vWf. However, DDAVP is usually ineffective in types II and III. Instead viral-free vWf concentrate or cryoprecipitate (concentrated blood clotting factors) may be used in treatment. In cases of severe bleeding, transfusions may be necessary. Other treatment may include doses of estrogens such as premarin for some type I women or antifibrolytic agents such as e-aminocaproic acid (Amicar) and transexamic acid. Side effects of treatment include formation of vWf inhibitor (which would destroy vWf in the blood) and reactions against transfusions.
D. Dysfibrinogenemia
Fibrinogen is the molecule that will eventually become fibrin, the major blood clotting protein. Fibrinogen is produced in the liver and bone marrow and released into the blood and eventually becomes fibrin. Dysfibrinogenemia is produced by an inherited problem in fibrinogen production. Abnormal fibrinogen is produced, leading to clotting problems in some individuals. While not all patients have symptoms, some note excessive bleeding after surgery and injury and the tendency to form thrombi (blood clots). Diagnosis is made based on patient and family history, physical examination, and laboratory testing. Transfusions may be necessary to treat serious bleeding. Cryoprecipitates may also be used.
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Updated: October 30, 2000