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Excessive Clotting Disorders

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Conditions That 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.

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.

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