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Excessive Clotting Disorders

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Conditions that Can Cause Excessive Clotting

Acquired Conditions

Acquired conditions are those that are not present at birth but ones that a person develops during their lifetime. They are more commonly the cause of inappropriate clotting than inherited ones. 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.

Some examples of acquired risk factors 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—the development of antiphospholipid antibodies such as the lupus anticoagulant or cardiolipin antibody
  • Cancer or malignancies—cancer may cause hypercoagulable states for a variety of reasons: 1) tumor growth may cause external compression on a blood vessel or, in some cases, actually extend into the vasculature (for example, renal cell cancers extending into the renal veins); 2) treatments for cancer (radiation, chemotherapy) may leave patients more susceptible to hypercoagulation.
  • Trauma 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 build-up of cholesterol-lipid-calcium deposits in the walls of arteries; they make the blood vessel walls less smooth, weaken them, and eventually form plaques that may rupture and lead to abnormal clotting and to strokes and heart attacks.
  • Vasculitis— inflammation of blood vessel walls; it may increase the risk of platelet adhesion and coagulation factor activation. Healed vasculitis may provide sites within the vessels for accelerated 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 drop, clot formation is less well-regulated and the risk of thrombosis increases. Deficiencies of protein C, protein S, or antithrombin may be caused by increased consumption (e.g., overt DIC, severe infection without overt DIC, acute VTE), by decreased synthesis of the active protein (e.g., administration of vitamin K antagonists, severe hepatic synthetic dysfunction), or by loss through the kidney (e.g., loss the antithrombin in nephrotic syndrome, a kidney disorder).
  • 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
  • Paroxysmal nocturnal hemoglobinuria (PNH)— an acquired condition that can cause hemolytic anemia, bone marrow failure, kidney failure, as well as clotting, particularly in abdominal veins (e.g., hepatic, portal, mesenteric, splenic, renal) and cerebral veins
  • Systemic lupus erythematosus, 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 that may predispose someone to excessive clotting, such as 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. Other inherited hypercoagulable disorders, such as protein C deficiency, protein S deficiency, antithrombin deficiency, and abnormal fibrinogen (dysfibrinogenemia), 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.

All of the inherited disorders (except for antithrombin deficiency) may be seen in heterozygous (one gene copy) or homozygous (two gene copies) form. If someone has two mutated gene copies, they tend to have a more severe form of the condition, and if they are 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 40 years of age). The patient may have recurrent thrombosis, a family history of thrombosis, and blood clots in unusual sites (such as cerebral veins, hepatic veins, and renal veins).

Some of the most common inherited factors contributing to thrombophilia 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.

Other less common inherited conditions include:

  • Antithrombin (formerly known as antithrombin III) deficiency or dysfunction -- 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 deficiency or dysfunction -- Protein C helps regulate the speed of the coagulation cascade by degrading activated factors V and VIII.
  • Protein S deficiency or dysfunction -- Protein S is 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.
  • Congenital plasminogen deficiency -- rare factor deficiency; plasminogen is activated to form plasmin. Plasmin helps break apart the clot's crosslinked fibrin net. Most affected people have eye problems, not thrombotic complications.
  • Dysfibrinogenemia -- abnormal fibrinogen; it leads to fibrin that does not break down normally. Patients with dysfibrinogenemia may have bleeding or thrombotic complications. Dysfibrinogenemia can be inherited or acquired.

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