Coagulation disorders (coagulopathies) are disruptions in the body's ability to control blood clotting, an essential function of the body designed to prevent blood loss. The most commonly known coagulation disorder is hemophilia , a condition in which a critical component of blood coagulation is missing, causing individuals to bleed for long periods of time before clotting occurs. There are numerous other coagulation disorders stemming from a variety of causes.
Coagulation, or clotting, is a complex process (called the coagulation cascade) that involves 12 coagulation factors (designated by Roman numerals as factors I through XII) found in blood plasma and several other blood components. The factors include prothrombin, thrombin, and fibrin. Each has a precise role in coagulation. Besides the factors, which are all proteins, plasma (the fluid component of the blood) carries a number of other proteins that regulate bleeding. Platelets, tiny colorless cells in the blood, initiate contraction of damaged blood vessels so that less blood is lost. They also help plug damaged blood vessels and work with other constituents in plasma to accelerate blood clotting. A deficiency in clotting factors or a disorder that affects platelet production or one of the many steps in the entire process can disrupt clotting and severely complicate blood loss from injury, childbirth , surgery, and specific diseases or conditions in which bleeding can occur.
Coagulation disorders arise from different causes and involve different complications. Some common coagulation disorders are:
- Hemophilia or hemophilia A (factor VIII deficiency) is an inherited coagulation disorder, affecting about 20,000 Americans. This genetic disorder is carried by females but most often affects male offspring. It is characterized by spontaneous musculoskeletal bleeding. Christmas disease or hemophilia B (factor IX deficiency) is less common than hemophilia A with similar symptoms. Factor IX is produced in the liver and is dependent on interaction with vitamin K in order to function properly. Deficiency in the vitamin can affect the clotting factor's performance as well as deficiency in the factor itself.
- Disseminated intravascular coagulation, also known as consumption coagulopathy, is not a disease in itself but a clinical emergency that occurs as a result of other diseases and conditions. This condition accelerates clotting, which ironically can result in hemorrhage when the clotting factors are exhausted.
- Thrombocytopenia, the most common cause of coagulation disorder, is characterized by reduced numbers of circulating platelets in the blood. This disease also includes idiopathic thrombocytopenia.
- Von Willebrand's disease, a hereditary disorder with prolonged bleeding time, is due to a clotting factor deficiency and impaired platelet function. It is the most common inherited coagulation disorder.
- Hypoprothrombinemia is a congenital deficiency of clotting factors that can lead to hemorrhage.
- Other coagulation disorders include factor XI deficiency (hemophilia C), and factor VII deficiency. Hemophilia C afflicts one in 100,000 people and is the second most common bleeding disorder among women. Factor VII is also called serum prothrombin conversion accelerator (SPCA) deficiency. One in 500,000 people may be afflicted with this disorder that is often diagnosed in newborns because of bleeding into the brain as a result of traumatic delivery.
Hemophilia, or hemophilia A (factor VIII deficiency) affects about 20,000 Americans and one out of every 5000 males worldwide; Christmas disease, or hemophilia B, is less common than hemophilia A. Von Willebrand's disease affects both males and females and is often diagnosed in children. Thrombocytopenia is the most common coagulation disorder. Factor XI deficiency, or hemophilia C, afflicts one in 100,000 people and is the second most common bleeding disorder among women; it occurs more frequently among certain ethnic groups, with an incidence of about one in 10,000 among Ashkenazi Jews. A deficiency of factor VII, also called serum prothrombin conversion accelerator (SPCA) deficiency, affects one in 500,000 people and is often diagnosed in newborns.
Causes and symptoms
Some coagulation disorders present symptoms such as severe bruising. Others show no apparent symptoms but carry the threat of severe internal bleeding.
Because of its hereditary nature, hemophilia A may be suspected before symptoms occur. Some signs of hemophilia A are numerous large, deep bruises and painful, swollen joints caused by internal bleeding. Individuals with hemophilia do not bleed faster, just longer. A person with mild hemophilia may first discover the disorder with prolonged bleeding following a surgical procedure or injury. If there is bleeding into the neck, head, or digestive tract, or bleeding from an injury, emergency measures may be required. Bleeding can be spontaneous, occurring with no obvious trauma.
Mild and severe hemophilia A are inherited through a complex genetic system that passes a recessive gene on the female chromosome. Women usually do not show signs of hemophilia but are carriers of the disease. Each male child of the carrier has a 50 percent chance of having hemophilia, and each female child has a 50 percent chance of passing the gene on.
Christmas disease, or hemophilia B, is also hereditary but less common than hemophilia A. The severity of Christmas disease varies from mild to severe, although mild cases are more common. The severity depends on the degree of deficiency of factor IX. Hemophilia B symptoms are similar to those of hemophilia A, including numerous, large, and deep bruises and prolonged bleeding. The more dangerous symptoms are those that represent possible internal bleeding, such as swelling of joints or bleeding into internal organs upon trauma. Hemophilia most often occurs in families with a known history of the disease, but occasionally, new cases occur in families with no apparent history.
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) occurs when the malfunction of clotting factors causes platelets to form clots in small blood vessels throughout the body. This action leads to depletion of clotting factors and platelets, which are then not available at a site of injury where clotting is needed. When DIC occurs, the individual bleeds abnormally even though there is no history of coagulation abnormality. Symptoms may include minute spots of hemorrhage on the skin, and purple patches or hematomas caused by bleeding under the skin. Bleeding may occur at a surgical site or intravenous injection (IV) sites. Related symptoms include vomiting ; seizures; shortness of breath; severe pain in the back, muscles, abdomen, or chest; and, if prolonged or uncorrected, shock and coma or death.
Not inherited and not a disease, DIC results from vascular complications during pregnancy or delivery, surgery, overwhelming infections, acute leukemia, metastatic cancer , extensive burns , liver disease, pancreatitis, trauma, snakebites, and other causes. As of 2004 it was not precisely understood why or how these various disorders lead to uncontrolled intravascular coagulation. What the underlying causes of DIC have in common is a dysfunction that involves proteins, platelets, or other clotting factors and processes. For example, uterine tissue can enter the mother's circulation during prolonged labor, introducing foreign proteins into the blood, or the venom of some exotic snakes can activate one of the clotting factors. Severe head trauma can expose blood to brain tissue. Regardless of the specific cause of DIC, the results are a malfunction of thrombin (an enzyme) and prothrombin (a glycoprotein), which activate the fibrinolytic system, releasing clotting factors in the blood. DIC can alternate from hemorrhage to thrombosis, and both can exist, which further complicates diagnosis and treatment.
Thrombocytopenia may be acquired or congenital (existing at birth). It represents a defective or decreased production of platelets. Symptoms include sudden onset of small bruises or spots of hemorrhage on the skin or bleeding into mucous membranes (such as nosebleeds). The disorder may also be evident as blood in vomit or stools, bleeding during surgery, or heavy menstrual flow. Some patients show none of these symptoms but complain of fatigue and general weakness. There are several causes of thrombocytopenia, which is more commonly acquired as a result of another disorder. Common underlying disorders include leukemia, drug toxicity, or aplastic anemia, all of which lead to decreased or defective production of platelets in the bone marrow. Other diseases may destroy platelets outside the marrow. These include severe infection, disseminated intravascular coagulation, and cirrhosis of the liver. The idiopathic form most commonly occurs in children and is most likely the result of production of antibodies that cause destruction of platelets in the spleen and to a lesser extent the liver.
Von Willebrand's disease is caused by a defect in the von Willebrand clotting factor, often accompanied by a deficiency of factor VIII as well. It is a hereditary disorder that affects both males and females. In rare cases, it may be acquired. Symptoms include easy bruising, bleeding in small cuts that stops and starts, abnormal bleeding after surgery, and abnormally heavy menstrual bleeding. Nosebleeds and blood in the stool with a black, tarlike appearance are also signs of von Willebrand's disease.
Hypoprothrombinemia is an inherited or acquired deficiency in prothrombin, or factor II, a glycoprotein formed and stored in the liver. Prothrombin, under the right conditions, is converted to thrombin, which activates fibrin and begins the process of coagulation. Some individuals may show no symptoms, and others may suffer severe hemorrhaging. Easy bruising, profuse nosebleeds, postpartum hemorrhage, excessively prolonged or heavy menstrual bleeding, and postsurgical hemorrhage may also result. Acquired hypoprothrombinemia usually arises from a vitamin K deficiency caused by liver disease, newborn hemorrhagic disease, or other causes.
Other coagulation disorders
Factor XI deficiency, or hemophilia C, is a bleeding disorder that occurs among certain ethnic groups. Nearly 50 percent of individuals with this disorder experience no symptoms, but others may notice blood in their urine, nosebleeds, or bruising. Some factor XI deficiencies may result in bleeding long after an injury, and some women experience prolonged bleeding after childbirth. A deficiency of factor VII may cause varying levels of bleeding severity in those affected. Women may experience heavy menstrual bleeding, bleeding from the gums or nose, bleeding deep within the skin, and episodes of bleeding into the stomach, intestines, and urinary tract. Bleeding into the joints is rare but may also occur in some individuals.
When to call the doctor
Coagulation disorders are usually discovered when an injury or surgery initiates bleeding and the bleeding does not stop. Any signs of prolonged bleeding, even from a small cut, should be reported to a physician or emergency service. Bleeding under the skin (hematoma), which looks like a severe bruise, should also be reported and medical care sought. The sooner bleeding is controlled the better. A diagnostic work up is indicated to reveal any coagulopathy that exists, whether inherited or acquired.
Diagnostic blood tests are performed in the clinical laboratory, including assays of the specific clotting factors, to help detect various coagulation disorders. Measured parameters are compared with known normal values to detect deficiencies or defects. Additionally, a choice of hundreds of diagnostic tests can be ordered by the physician to identify causative conditions, deficiencies, or diseases underlying the coagulopathy. Physicians also complete a medical history and physical examination. If acquired coagulation disorders are suspected, information such as prior or current diseases and medications are important to help determine the cause of the blood disorder. Each possible coagulopathy has specific criteria for diagnosis, including the following:
- Hemophilia A is diagnosed with laboratory tests that can detect the presence of clotting factor VIII, factor IX, and others, as well as the presence or absence of clotting factor inhibitors. Christmas disease involves an investigation of bleeding and clotting times, as well as determining factor IX deficiency. Other tests may include prothrombin time and thromboplastic generation. Gene carriers for both forms of hemophilia can be detected through DNA studies in conjunction with results from factor VIII assays.
- As of 2004 there was no one test or group of tests that can reliably diagnose DIC because it is a clinical event that occurs without warning, arising from another event such as surgery, childbirth, snakebite, and certain disease conditions. Diagnosis usually requires a number of laboratory tests that measure concentrations of platelets and fibrinogen in the blood along with measuring prothrombin time. Other supportive data include measuring levels of factors V and VIII, fibrinogen, hemoglobin, and platelets, any of which may be diminished or entirely depleted. Serial tests may also be recommended, because a single coagulation parameter measured at any one moment may not reveal the rapidly progressive intravascular process.
- Tests for thrombocytopenia include coagulation tests that may reveal a decreased platelet count and prolonged bleeding time. Other coagulation factors may be measured. If these tests indicate that platelet destruction is causing the disorder, the physician may order a bone marrow biopsy.
- Von Willebrand's disease is diagnosed by ordering laboratory tests that reveal a prolonged bleeding time, absent or reduced levels of factor VIII, and a normal platelet count. Other tests are likely be done to confirm a diagnosis.
- Hypothrombinemia is diagnosed based on family history and the use of tests that measure vitamin K deficiency, deficiency of prothrombin, and measurements of clotting factors V, VII, IX, and X.
- Factor XI deficiency is determined by measuring the specific coagulation factor as well as other coagulation tests including prothrombin time and clotting time. It is diagnosed most often after injury-related bleeding.
In mild coagulopathies, treatment may involve the use of drugs that stimulate the release of deficient clotting factors. In severe cases, bleeding may only stop if the clotting factor that is missing is replaced through infusion of human blood components containing concentrated amounts of specific clotting factors. These may be prepared in the form of fresh frozen plasma or cryoprecipitate. Cryoprecipitate was invented in 1965 to replace the need for whole plasma transfusions, which introduced more volume than needed and carried the threat of exposure to hepatitis or AIDs. More sensitive testing methods have virtually eliminated this risk. Commercial preparations of freeze-dried clotting factors have also made it possible for people to infuse themselves as directed by their physicians. This aspect of self-care made life easier for those with coagulation problems; in every other respect as of 2004, bleeding or coagulation disorders should not be self-managed. Comprehensive care addresses children's needs by providing various types of counseling to help deal with the psychosocial aspects of diseases such as von Willebrand's and hemophilia.
With mild bleeding episodes in persons afflicted with hemophilia A, infusions of a drug called desmopressin (DDAVP) may be administered. Severe bleeding episodes require transfusions of human blood clotting factors. Hemophiliacs are encouraged to receive physical therapy to help damaged joints and to exercise through non-contact sports such as swimming, bicycle riding, or walking, to avoid injury that may lead to bleeding.
Christmas disease is treated similarly to hemophilia A, with a mix of synthetic products and human blood products to provide coagulation factors as needed. Superficial wounds can be cleaned and bandaged. When hemophiliac children are to receive immunizations, parents should inform medical personnel in advance so that bleeding problems can be avoided. These children should probably not receive intramuscular injections.
When disseminated intravascular coagulation occurs, progression can be rapid, and treatment is complicated by the large variety of possible underlying causes. If at all possible, the physician first treats the underlying disorder. If the patient is not already bleeding, this supportive treatment may correct DIC. However, if bleeding is already occurring, a combination of transfused blood, platelets, fresh frozen plasma, or other blood products may be needed. Heparin, an anticoagulant, has been controversial in treating DIC, but it is often used as a last resort to stop hemorrhage. However, heparin has not proven useful in treating patients with DIC resulting from heat stroke, exotic snakebites, trauma, incompatible transfusions, and acute problems resulting from obstetrical complications.
Secondary acquired thrombocytopenia is best alleviated by treating the underlying cause or disorder. The specific treatment may depend on the underlying cause. Sometimes, corticosteroids or immune globulin may be given to improve platelet production.
Von Willebrand's disease is treated by several methods to reduce bleeding time and to replace factor VIII, which then replaces the von Willebrand factor. This may include infusion of cryoprecipitate or fresh frozen plasma. Desmopressin may also help raise levels of the von Willebrand factor.
Hypoprothrombinemia may be treated with concentrates of prothrombin. Vitamin K may also be given to stimulate coagulation, and in bleeding episodes, fresh plasma products may be transfused.
Factor XI (hemophilia C) deficiency is most often treated with plasma, since there are no commercially available concentrates of factor XI in the United States. Factor VII deficiency may be treated with prothrombin complex concentrates; as of 2004 factor VII is not licensed in the United States.
The prognosis for individuals with mild forms of coagulation disorders is normally good. Many people can lead normal lives and achieve normal life expectancy. Without treatment of bleeding episodes, severe muscle and joint pain and eventually permanent damage can occur. Any incident that causes blood to collect in the head, neck, or digestive system can be very serious and requires immediate attention. DIC is an emergency situation that can be severe enough to cause stroke, coma, and death. The prognosis depends on early intervention and treatment of the underlying condition. Hemorrhage from a coagulation disorder, particularly into the brain or digestive track, can prove fatal.
Inherited disorders cannot be prevented; they must be managed when detected. Acquired bleeding disorders are caused by a variety of conditions, some related to other diseases. There is no single prevention method although treatment of the underlying disorder or disease may prevent episodes of bleeding and subsequent coagulation problems. Episodes of bleeding can be prevented by avoiding injury. People who have hemophilia A or B and other bleeding disorders are advised to avoid activities and contact sports that can cause severe injury.
Knowledge that a child has an inherited or acquired coagulation disorder that may lead to potentially dangerous bleeding episodes is of great concern to parents. Effective management of coagulation disorders by physicians can help the child to lead a relatively normal life with some cautions about avoiding injury. Counseling is available to help children handle the psychosocial aspects of living with a coagulation disorder.
Clotting factors —Substances in the blood, also known as coagulation factors, that act in sequence to stop bleeding by triggering the formation of a clot. Each clotting factor is designated with a Roman numeral I through XIII.
Coagulopathy —A disorder in which blood is either too slow or too quick to coagulate (clot).
Enzyme —A protein that catalyzes a biochemical reaction without changing its own structure or function.
Hemorrhage —Severe, massive bleeding that is difficult to control. The bleeding may be internal or external.
Heparin —An organic acid that occurs naturally in the body and prevents blood clots. Heparin is also made synthetically and can be given as an anticoagulant treatment.
Idiopathic —Refers to a disease or condition of unknown origin.
Metastatic —The term used to describe a secondary cancer, or one that has spread from one area of the body to another.
Thrombosis —The formation of a blood clot in a vein or artery that may obstruct local blood flow or may dislodge, travel downstream, and obstruct blood flow at a remote location. The clot or thrombus may lead to infarction, or death of tissue, due to a blocked blood supply.
See also Hemophilia .
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Berntorp, Erik, et al. Textbook on Hemophilia. Oxford, UK: Blackwell Publishing, 2005.
Kroll, Michael H. Manual of Coagulation Disorders. Oxford, UK: Blackwell Publishing, 2001
McDougald, Monroe. Hemophilia Care in the New Millennium. Secaucus, NJ: Kluwer Academic Publishers, 2001.
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National Heart, Lung, and Blood Institute. PO Box 30105, Bethesda, MD 20824-0105. Web site: http://www.nhlbi.nih.gov.
National Hemophilia Foundation. 116 West 32nd St., 11th Floor, New York, NY 10001. Web site: http://www.hemophilia.org.
L. Lee Culvert Teresa Norris, RN