Also Known As
Hypercoagulable Disorders
Thrombophilia
Hypercoagulable States
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This article waslast modified on November 13, 2018.
What is an excessive clotting disorder?

An excessive clotting disorder, also known as a hypercoagulable disorder or thrombophilia, is the tendency of some people to develop blood clots in parts of the body, such as the deep veins in the legs (called venous thromboembolism or DVT) or the arteries of the heart (arterial thrombosis). Pieces of clots may also break off and block an artery in another part of the body, such as the lungs (pulmonary embolism or PE).The tendency to develop a clot may arise because of some underlying condition that develops during a person's lifetime (acquired) or may be due to certain genes passed from parent to child (inherited).

In the U.S., as many as 900,000 people are affected by venous thromboembolism (VTE) annually and about 100,000 people die each year from blood clots. Many people who develop a clot experience long-term health issues, according to the Centers for Disease Control and Prevention (CDC).

Clotting is a normal response to blood vessel or tissue injury. When there is an injury and bleeding occurs, the body stops this blood loss through a complex clotting process called hemostasis. During hemostasis, the injured blood vessel constricts to reduce blood flow, platelets adhere to the injury site and clump together to form a loose platelet plug, and the coagulation cascade is initiated. During the cascade process, the body sequentially activates coagulation factors, proteins that produce a net of fibrin threads that weave through the platelet plug and stabilize the resulting blood clot. This clot functions as a barrier to further blood loss, one that stays in place until the injury has healed, and eventually the clot is broken down by the body.

Usually, the body activates the clotting process, regulates its speed and volume with feedback mechanisms, and after the site has healed, breaks down the clot and removes it in a process called fibrinolysis. When something goes wrong with blood clot formation or breakdown, excessive blood clot formation may occur.

  • Activation problems: Some conditions cause activation of the clotting process when there is no injury and no need for a clot to form. For example, anything that interrupts the smooth blood vessel walls, essential for unimpeded blood flow, may increase risk of clot formation.
  • Regulation problems: Clot formation is carefully regulated by the body. Even as a clot forms to stop bleeding at the site of an injury, the body begins to activate proteins that will slow clot production, much like the brakes in a car. If clot production is not regulated well, excessive clotting may result.
  • Clot breakdown problems: After an injury is healed, proteins are activated that break down and remove the clot (fibrinolysis). Dysfunction or deficiency in the breakdown proteins can cause excessive clotting.

The tendency to develop a clot may arise because of some underlying condition that develops during a person's lifetime (acquired) or may be due to certain genes passed from parent to child (inherited). Acquired conditions are far more commonly the cause of clots than inherited disorders. When someone has experienced a blood clot in a vein or artery (thrombotic episode), a physical examination and thorough patient history may reveal one or more contributing factors that led to inappropriate blood clot formation.

Accordion Title
About Excessive Clotting Disorders
  • Complications: Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Heart Attack and Stroke

    Excessive clotting or thrombophilia can lead to the presence of a blood clot in a vein or artery that can potentially block the flow of blood and cause serious, life-threatening complications. Blood clots are referred to as thrombi (singular, thrombus) when they form in a blood vessel. When thrombi break off, travel through the blood and block another blood vessel in another part of the body, they are called emboli (singular, embolus) or thromboemboli.

    • Blood clots most commonly form in the deep veins of the lower legs (deep venous thrombosis, or DVT). They may grow very large and block blood flow in the legs, causing pain, swelling, and tissue damage.
    • While clots most commonly form in the veins of the legs, they may also form in other areas as well; for example, clots in coronary arteries are the cause of most heart attacks.
    • Clots may also form on the lining of the heart or its valves, particularly when the heart is beating irregularly (atrial fibrillation) or when the valves are damaged by a disease or an abnormal condition.
    • Clots also may form in large arteries as a result of narrowing and damage from atherosclerosis.
    • Pieces of clots may also break off and cause an embolus that blocks an artery in another organ, such as:
      • The brain, where they can cause ischemic strokes.
      • The lungs, called pulmonary embolism or PE, where they can cause chest pain and shortness of breath.
      • The kidneys, where they can cause kidney damage.
         

    There are a number of conditions, diseases and factors that can contribute to a person's risk of developing a clot. A person can have more than one factor or condition that increases their risk, and the resulting risk can be cumulative. For example, a person who has an inherited risk due to the presence of Factor V Leiden mutation will likely be at greater risk if they smoke or use oral contraceptives.

  • Acquired Conditions and Risk Factors

    Some examples of underlying conditions or acquired risk factors for blood clots include:

    • Venous stasis—also known as "coach-class" syndrome, describes any situation that immobilizes someone for long periods of time, such as cramped seating during long distance travel or prolonged bed rest with an illness or hospitalization. Immobility may lead to slow or restricted blood flow (venous stasis) and an increased risk of developing a blood clot, especially in the deep veins of the legs (DVT).
    • Antiphospholipid syndrome—an autoimmune disorder in which a person develops antiphospholipid antibodies such as the lupus anticoagulant or cardiolipin antibody
    • Cancer or malignancies—cancer may cause excessive clotting for a variety of reasons: 1) tumor growth may cause external compression on a blood vessel or, in some cases, actually extend into blood vessels (for example, renal cell cancers extending into the renal veins); 2) tumor may produce substances that can initiate and/or promote clotting (e.g., a type of leukemia known as acute promyelocytic leukemia can cause DIC); 3) treatments for cancer (radiation, chemotherapy) may leave patients more susceptible to excessive clotting.
    • Trauma such as fractures or surgery—damage to blood vessels and prolonged immobilization can lead to blood clots.
    • Presence of a catheter in a central vein—disruption in the flow of blood can cause blood clots to form.
    • Pregnancy or recently giving birth (postpartum)—pregnant women have high levels of platelets and clotting factors and so are at increased risk for clots.
    • Use of certain drugs such as:
      • Hormone replacement therapy
      • Oral contraceptives
      • Tamoxifen
      • Heparin (which can cause heparin-induced thrombocytopenia, HIT)
    • Atherosclerosis—the buildup of cholesterol,lipids, and calcium deposits in the walls of arteries; the deposits make the blood vessel walls less smooth, weaken them, and eventually form plaques that may rupture and lead to clots and to strokes and heart attacks.
    • Vasculitis—inflammation of blood vessel walls may increase risk of a clot forming. Vasculitis that has healed may provide sites within blood vessels that promote formation of plaque (atherosclerosis).
    • An acquired deficiency of one or more of the proteins that regulate clot formation, such as protein C, protein S, or antithrombin. When the level of these proteins drops, clot formation is less well-regulated and the risk of a clot increases. 
    • Disseminated intravascular coagulation (DIC)—a life-threatening, acute, acquired condition that causes tiny clots throughout the body; it uses up coagulation factors at an accelerated rate, leading to both bleeding and clotting.
    • Bone marrow disorders such as myeloproliferative neoplasms (MPNs)
    • Paroxysmal nocturnal hemoglobinuria (PNH)—an acquired condition that can cause hemolytic anemia, bone marrow failure, kidney failure, as well as clotting, particularly in veins in the abdomen (e.g., hepatic, portal, mesenteric, splenic, renal) and in the brain (cerebral veins)
    • Lupus, an autoimmune disorder
    • Elevated levels of homocysteine—can be caused by a deficiency of vitamin B12
    • Heart Failure— may cause slowing of blood flow (stasis)
    • Obesity—this condition can contribute to atherosclerosis, which in turn can lead to excessive clotting.
    • Rapid, uneven heartbeat (atrial fibrillation)—this condition can cause blood to pool in a chamber of the heart, which can increase the risk of the blood clotting.
    • Blood vessel wall abnormalities (usually combined with a clotting abnormality)

     

  • Inherited Conditions

    Certain inherited gene mutations may predispose someone to forming blood clots.

    Some of the most common inherited factors contributing to blood clots include:

    • Factor V Leiden mutation (Activated protein C resistance)—a mutation in the gene that makes the factor V protein; Factor V is activated normally, but it is resistant to degradation by activated protein C, which regulates the clotting process.
    • Prothrombin 20210 mutation (factor II mutation)—a mutation that results in an increased amount of prothrombin (factor II) in the circulation, which is associated with an increased risk for venous blood clots
    • MTHFR mutation—a mutation in this gene may predispose someone to high levels of homocysteine, which can increase the risk of excessive clotting.


    Factor V Leiden or the prothrombin G20210A mutation are relatively common in the population, but it is thought that they add only a slight increase in the risk of actually developing a problem with clotting.

    Some inherited conditions are relatively rare and are usually due to genetic mutations that lead to a deficiency or dysfunction in the coagulation protein that the gene produces. Examples include:

    • Antithrombin (formerly known as antithrombin III)—this is a factor that helps decrease the activity of the clotting process by inhibiting factors Xa, IXa, XIa, and thrombin. Inherited deficiency of antithrombin can lead to a clot formation.
    • Protein C—helps regulate the speed of the coagulation cascade by degrading activated factors V and VIII
    • Protein S—a cofactor with protein C
    • Elevated factor VIII levels—persistently elevated factor VIII levels that are not associated with inflammation or other acquired conditions but are associated with an increased thrombotic risk
    • Dysfibrinogenemia—abnormal fibrinogen leads to fibrin that does not break down normally. Patients with dysfibrinogenemia may have bleeding or clotting complications. Dysfibrinogenemia can be inherited or acquired.


    In all of these inherited disorders (except for antithrombin deficiency), people may inherit one mutated gene copy and one normal gene copy (heterozygous) or two mutated gene copies (homozygous). If someone has two mutated gene copies, the person tends to have a more severe form of the condition, and if the person is heterozygous in more than one condition, the risk of clotting tends to be additive (and sometimes the risk is multiplied). With inherited hypercoagulable disorders, the first thrombotic episode may be seen at a relatively young age (less than 50 years of age). The patient may have recurrent thrombosis, a family history of thrombosis, and blood clots in unusual sites, such as veins of the brain, liver or kidneys.

  • Signs and Symptoms

    The first indication that someone may have a clotting disorder may be the presence of a blood clot somewhere in the body that is blocking the flow of blood through a blood vessel (thrombotic episode). The signs and symptoms that may develop depend on the location of the clot. For example, when a blood clot is present in the deep vein of a leg (DVT), one of the most common complications, signs and symptoms may include:

    • Leg pain or tenderness, usually in one leg
    • Leg swelling, edema
    • Discoloration of the leg


    If a clot is blocking a blood vessel in a lung (pulmonary embolism), signs and symptoms may include:

    • Sudden shortness of breath, difficulty breathing
    • Chest pain or discomfort that may worsen with a deep breath or coughing
    • Coughing up blood
    • Rapid or irregular heartbeat
    • Anxiety
    • Lightheadedness or feeling faint


    If the clot occurs elsewhere in the body, it may cause symptoms associated with, for example, a heart attack or stroke.

    A healthcare practitioner will investigate the underlying cause of the thrombotic episode and will try to determine the person's risk of recurrent blood clots. The healthcare practitioner may do an extensive workup to find a cause if someone has repeated thrombotic episodes and/or if the affected person is young (less than 50 years old) and/or if the clot occurs in an unusual site in the body.

  • Tests

    Initial testing is usually performed to determine if a person has or has had a blood clot (thrombotic episode) and, if so, to help determine the person's risk of a repeat thrombotic episode. Although it may be fairly simple to identify that a person has a clot, identification of the underlying cause may take more time and effort. This is because several of the diagnostic tests that need to be done are affected by an existing or recent blood clot and by any blood-thinning (anticoagulant) therapy that is given.

    Often, the healthcare practitioner may have to order a few tests and treat the person's existing blood clot first. Several weeks or months later, when the person is able to come off of anticoagulant therapy, the the healthcare practitioner can order other tests to finish the evaluation of the cause of the clotting. Follow-up testing is important in helping to determine a person's risk of developing recurrent blood clots.

    The table below lists some of the tests in alphabetical order. For detailed information about each test, click on the name of the test to go to the specific article.

    Not all of the tests listed in the table are needed for each person with excessive clotting disorders. If somebody has been diagnosed as having a blood clot in a vein (venous thrombosis), the first step is to rule out obvious acquired causes, such as major surgery (e.g., orthopedic), trauma, immobilization, congestive heart failure, cancer, myeloproliferative neoplasms, or nephrotic syndrome.

    Routine laboratory tests include:


    As to other tests, the following general guide is used to determine what tests should be performed based on patient age and personal and family history.

    • If a person has a first episode of venous thrombosis at an age younger than 50, or has a history of recurrent clotting episodes, or has a parent, sibling or child (first-degree relative) with documented thromboembolism at age younger than 50, then a test panel is often performed, including factor V Leiden mutation and prothrombin gene G20210A mutation, antiphospholipid antibodies (including lupus anticoagulant work-up), homocysteine, protein C, protein S and antithrombin. If results of these tests are not revealing, additional tests may be needed to rule out rare causes of clotting disorders.
    • If a person has a first episode of venous thrombosis at an age older than 50 without known acquired risk factors and there is no personal or family history of recurrent episodes, then a limited test panel is often performed, including factor V Leiden mutation and prothrombin gene G20210A mutation, antiphospholipid antibodies (including lupus anticoagulant) and homocysteine.


    The medical and family histories plus laboratory testing may reveal that a person has more than one factor or condition that increases their risk of excessive clotting, and the resulting risk can be cumulative. For example, a person whose laboratory tests indicates the presence of Factor V Leiden mutation will likely be at greater risk if they also are bed-ridden or hospitalized for some time (prolonged immobilization).

    Tests for Excessive Clotting

    Test Description Ordered When/To Abnormal Results May Indicate
    Anticardiolipin antibodies
    (Includes cardiolipin antibody, beta-2 glycoprotein antibody, and lupus anticoagulant)
    Detects the presence of one or more of these antibodies To evaluate recurrent blood clots and/or miscarriages Antiphospholipid syndrome
    Antithrombin Activity Measures the activity of antithrombin To evaluate someone for recurrent blood clots; to detect acquired or inherited deficiency Low activity may increase risk of clots.
    Antithrombin Antigen Measures quantity of antithrombin When results from the test for activity are consistently low Decreased production or increased use of factor; may increase thrombotic risk.
    D-dimer Detects or measures the level of a specific type of fibrin degradation product Used to detect and evaluate for the presence of a blood clot  If elevated, indicates recent clotting activity; may be due to condition such as a thromboembolism or DIC (disseminated intravascular coagulation).
    Factor V Leiden mutation (may include activated protein C resistance testing) Identifies a genetic mutation that results in formation of an activated Factor V that resists degradation by activated protein C When an inherited risk factor is suspected as a cause of a blood clot The presence of the mutation increases the risk of thrombosis.
    Fibrinogen Tests measure the function and the amount of fibrinogen As part of an evaluation for a clotting disorder  If low, may indicate decreased production or increased use; may be elevated with inflammation; it is an acute phase reactant.
    Flow cytometry Presence of certain surface proteins on blood red cells and white cells When paroxysmal nocturnal hemoglobinuria (PNH) is suspected Increased risk of venous thrombosis (abdominal and cerebral veins)
    Homocysteine Measures the level in blood To determine a cause of recurrent blood clots If elevated, increased cardiac risk and risk of thrombosis.
    Lupus Anticoagulant (LA)
    (Panel of tests may include LA-sensitive PTT, Dilute Russell Viper Venom Test (DRVVT), and/or Platelet Neutralization Procedure (PNP))
    Panel of tests used to check for Lupus anticoagulant To evaluate someone with recurrent blood clots and/or miscarriages; when results of the PTT are prolonged When PTT or LA sensitive PTT and DRVVT are prolonged, it suggests LA, usually confirmed with additional testing; if present, increased risk of thrombosis.
    Methylenetetrahydrofolate Reductase (MTHFR) Identifies genetic mutation Used when the homocysteine level is elevated with no clear acquired etiology Presence of the mutation confers an increased risk for developing elevated homocysteine levels.
    Protein C Activity Function of protein C To evaluate someone for recurrent blood clots; may be acquired or inherited deficiency or dysfunction Protein C helps regulate blood clot formation by degrading activated Factors V and VIII. If activity is low, there is an increased risk of thrombosis.
    Protein C Antigen Quantity of protein C Tested when protein C activity is low. If decreased, may be due to inherited or acquired condition; increased risk of thrombosis.
    Protein S Activity Function of protein S As part of an evaluation of recurrent blood clots; may be acquired or inherited deficiency or dysfunction  Protein S is a cofactor that helps protein C regulate clot formation. Low activity may increase risk of excess clotting.
    Protein S Antigen (free and total) Quantity of total and free protein S Tested when protein S activity is low. Only free protein S is available to assist protein C; total protein S includes free protein S and inactive bound protein S. If low, increases risk of clotting.
    Prothrombin 20210 mutation Detects inherited genetic mutation When a person has recurrent blood clots and an inherited risk factor is suspected If present, increases risk of thrombosis.
    PTT (Partial Thromboplastin Time) Measures the time it takes for a clot to form in a blood sample after reagents are added As part of an initial workup; screens for lupus anticoagulant; also used to monitor anticoagulant therapy A prolonged PTT suggests need for further tests; may indicate nonspecific inhibitor (such as lupus anticoagulant).

    Non-Laboratory Tests

    One or more of the following imaging studies may be used to detect the presence of a blood clot and/or examine blood vessels:

    • Ultrasound
    • CT scan (e.g., CT angiography)
    • MRI


    For additional details on imaging procedures used to examine blood vessels, visit RadiologyInfo.org's web article on Blood Clots.

  • Treatment

    Depending on the cause, a few things may be done to lower the risks of developing recurrent blood clots. Measures may include avoiding the use of oral contraceptives if you have other inherited or acquired risk factors and avoiding situations that cause prolonged sitting or confinement to bed.

    Regardless of the cause, the treatment for the presence of a blood clot (acute thrombosis) is often fairly standard. It usually consists of short-term treatment with the anticoagulant heparin (or, more commonly, low-molecular weight heparin), followed by an overlap of treatment with heparin and oral warfarin (COUMADIN®), another anticoagulant, followed by several months or longer of warfarin therapy. During this treatment regimen, laboratory tests are used to monitor the effectiveness of therapy:

    • Unfractionated (standard) heparin is monitored using the PTT or occasionally heparin anti-Xa assay.
    • Low molecular weight heparin (LMWH) is monitored with the heparin anti-Xa test if monitoring is needed.
    • Warfarin therapy is monitored with the PT/international normalized ratio (INR) or occasionally factor X activity assay.

    After several months of warfarin, a healthcare practitioner will evaluate the risk of clot recurrence. The healthcare provider must weigh the risk of recurrent clotting against the very real risk of bleeding episodes with continued anticoagulation. If someone is at a high risk of recurrent clotting, anticoagulant therapy may be continued indefinitely. If a person is at a lower risk, the anticoagulant will most likely be discontinued, but the person will need to be vigilant, going back to the healthcare provider promptly if thrombotic symptoms return.

    Those who are on continued anticoagulant therapy will have to plan ahead, with the help of their healthcare provider, when they require medical procedures and surgeries. These usually involve taking the person off of their anticoagulant for a short period of time prior to their surgery. However, current recommendations suggest that warfarin does not need to be held for dental procedures.

    Following surgery, most people, including those with no known clotting disorders, will receive a course of preventative anticoagulation therapy. This is especially true after procedures such as knee replacement surgery that may increase a person's risk of clotting, either because of the nature of the surgery itself or because of immobilization and an extended recovery after the surgery.

    Women who are pregnant and have a blood clot will usually receive subcutaneous anticoagulation with low-molecular weight heparin. People who have antithrombin deficiencies may benefit from antithrombin factor replacement when they cannot take anticoagulant therapy (for example, around the time of surgery). Protein C concentrates can be used to temporarily replenish protein C deficiencies, and aspirin therapy (which affects platelet function) may be useful in some instances.

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