Types and Classifications

Bleeding disorders are a group of disorders that share the inability to form a proper blood clot. Symptoms include large, unexpected bruising after minor injury, sudden painful joint swelling and severe menstrual bleeding. Signs include abnormal bleeding into joints, muscles, and/or soft tissue after injury, surgery, trauma, or menstruation. Sometimes the bleeding is spontaneous, without a known or identifiable cause. Individuals with severe genetic bleeding disorders are typically diagnosed within the first few years of their lives. Improper clotting can be caused by defects in blood components such as platelets and/or clotting proteins, also called clotting factors. The body produces thirteen clotting factors, with many additional components needed for normal hemostasis. If any of them are defective or deficient, blood clotting is affected resulting in a mild, moderate, or severe bleeding disorder, depending on the severity of the hemostatic defect. Some bleeding disorders can occur from conditions such as anemia, collagen disorders (hypermobility spectrum disorders), tissue fragility, cirrhosis of the liver, HIV, leukemia, and vitamin K or vitamin C deficiency. They also can result from certain medications that impair coagulation, including aspirin, heparin, warfarin, and platelet aggregation inhibitors such as Plavix. Other bleeding disorders such as hemophilia, can be inherited or more rarely acquired due to autoimmunity or spontaneous mutation.¹⁴

Some patients can develop an inhibitor.[A1] This is a phenomenon when the immune system recognizes infused factor (either plasma-derived or laboratory derived) as a foreign antigen due to anti-factor antibodies. This is most likely to occur in people with hemophilia A, however it can occur with other bleeding disorders as well. When this occurs, infused factor is no longer effective for restoring hemostasis because it is neutralized in vivo, and other special medications called bypassing agents are needed. An inhibitor also reduces the patient’s own endogenous factor, if they have endogenous factor. In this fashion, a patient with mild hemophilia A (i.e. 8% FVIII) with rare bleeding episodes can develop an inhibitor after a simple procedure when factor is used for hemostasis, and as a result experience more bleeding afterwards and develop a severe hemophilia phenotype and very low factor level (i.e. <1%). Bypassing agents are more difficult to administer than factor due to dosing kinetics, and the risk of bleeding generally is greater for patients with an inhibitor. Hematologists treat inhibitors by inducing immune tolerance with high levels of factor injections or by using novel non-factor therapies.

Acquired Bleeding Disorders

Individuals may develop a bleeding disorder if something, such as a disease or a medicine, causes the body to stop making platelets and/or blood clotting factors or causes these factors to stop working correctly. Problems with blood vessels can also lead to severe bleeding. Although the majority of factor deficiencies are inherited, acquired factor deficiencies can occur. These are autoimmune disorders, and typically present later in adult life, with no prior history of bleeding.

Severe bleeding may develop as consequence of acquired disorders and can include:

• Disseminated intravascular coagulation (DIC) as result of sepsis or cancer

• Severe liver cirrhosis or liver failure

• Vitamin K deficiency

• Von Willebrand disease (vWD) and hemophilia

• Leukemia

• Autoimmune conditions targeting factors or platelets as in acquired hemophilia or idiopathic thrombocytopenic purpura (ITP)

• Pharmacologic agents such as Coumadin

• Spontaneous rupture or injury to hemangiomas and vascular malformations

Inherited Bleeding Disorders

Inherited bleeding disorders include:

• Combined deficiency of the vitamin K–dependent clotting factors (VKCFD), which is caused by a problem with clotting factors II, VII, IX, and X

• Hemophilia A, the most common type of hemophilia, which occurs when an individual is missing or has low levels of clotting factor VIII

• Hemophilia B, which occurs when an individual is missing or have low levels of clotting factor IX

• Hemophilia C, which is rare and occurs when an individual is missing or has low levels of clotting factor XI

• Von Willebrand disease (vWD) is the most common inherited hematologic bleeding disorder. It affects both men and women equally and is caused by quantitative or qualitative defects inthe von Willebrand factor. vWD has multiple types requiring various treatment modifications.

• Hereditary hemorrhagic telangiectasia (HHT), a rare inherited disorder that causes tangles of blood vessels in different parts of the body, which can lead to bleeding.

• Other rare types of inherited bleeding disorders, such as factor I, II, V, V + VIII, VII, X, XI, or XIII deficiencies, which are named after the clotting factor causing the problem¹⁵

• Hereditary disorders of connective tissue or hypermobility spectrum disorders, such as Ehlers-Danlos Syndrome (EDS), in particular hypermobile-EDS, are thought to be the most common inherited bleeding disorders (not of hematologic etiology). These may often escape diagnosis since there is no clear abnormal laboratory test to aid in diagnosis.