Thrombophilias

What Is It?
Thrombophilias are a group of inherited or acquired disorders that increase a person's risk of developing thrombosis (abnormal "blood clotting") in the veins or arteries.

The human body is equipped with a sophisticated and wellbalanced blood coagulation (or clotting) system, in which platelets (the "clotting" blood cells) and multiple coagulation proteins mingle in order to avoid both excessive bleeding and excessive clotting. Thrombus (blood clot) formation is a good thing after injuries to blood vessels, regardless of whether the injury results from an accidental cut, major trauma, a broken bone, or surgery. If blood clotting did not occur, you would experience unstoppable (and even life threatening) bleeding. This normal blood clot formation should be localized to the area where blood vessel injury occurred and should stop as soon as the leak of blood from the vessels is contained and/or the vessel injury is healed or repaired. In the presence of thrombophilias, the well-balanced coagulation system has a predisposition toward thrombosis, which is also referred to as "hypercoagulability" or a "hypercoagulable state."

Thrombophilias can be inherited (hereditary), acquired (not inherited), or both. Inherited thrombophilias are abnormalities of the genes that are responsible for making the coagulation proteins (known as genetic mutations). Acquired thrombophilias are due to increased levels of certain clotting substances in the blood or special proteins called antibodies which may also lead to clotting. The most common inherited thrombophilias are Factor V Leiden (a symptom-free condition that increases the risk of deep vein thrombosis) and the Prothrombin gene mutations, as well as the uncommon but well-known deficiencies of Protein C, Protein S, or Antithrombin. Individuals who are born with an inherited thrombophilia are also referred to as "carriers" of that particular genetic mutation. The most common acquired thrombophilias are commonly encountered during surgery, injury, or medical conditions including congestive heart failure and certain respiratory conditions, and these are called antiphospholipid antibodies (APLA). These represent a family of several different individual antibodies which may, as a group or independently, lead both to blood clotting events and also to recurrent miscarriages. Some thrombophilias can both have a genetic predisposition and be acquired. Research studies have estimated that nearly 10% of the world population has an underlying thrombophilia, the most common being the Factor V Leiden and the Prothrombin gene mutations.

Both inherited and acquired thrombophilias appear to "tilt" the well-balanced coagulation system towards clotting (thrombosis). Such an imbalance in the coagulation system results in a greater risk of clotting events, such as deep venous thrombosis (DVT) or pulmonary embolism (PE). Fortunately, not all people with thrombophilia will have a blood clot in their lifetime, whereas unfortunately many patients who do experience blood clots (such as DVT or PE) may not have any detectable thrombophilia at all.

Symptoms
Thrombophilias cause no specific symptoms other than those related to blood clotting events. The most common clotting events related to thrombophilias are acute DVT (a blood clot within large veins) and acute PE (pieces of blood clots which form in the veins of the body, then dislodge and travel to the arteries of the heart and lungs), as well as recurrent clots of the superficial veins of the arms and legs. While most research studies suggest that inherited thrombophilias increase the risk of vein clots only (i.e., DVT and PE), some acquired thrombophilias are also believed to cause arterial clotting events, such as acute strokes, acute limb ischemia (sudden loss of blood flow to the legs or arms), and even acute myocardial infarction (heart attack).

A review of the most common symptoms related to DVT, PE, and stroke and limb ischemia can be found on the VDF Web site at www.vdf.org.

Risk Factors
It has been estimated that 50% to 70% of the DVT and PE events that occur in patients with an underlying inherited thrombophilia are triggered by other risk factors. High-risk situations include, orthopedic or other major surgery, bed rest during hospitalization for a medical problem, immobilization in a plaster cast for a broken leg, use of birth control pills or hormone replacement therapy, cancer, obesity, very long airline flights, and obesity.

Diagnosis
The diagnosis of thrombophilia is made by blood tests; specific blood tests for each known thrombophilia are available.

Testing should only be offered only to patients for whom the results will have an impact on their care. Thrombophilia testing in individuals without any personal history or family history of DVT/ or PE is not appropriate.

While there are no formal guidelines as to who should be tested, suggested candidates for testing include:

• Young (age <45 years) patients with "idiopathic" or "unprovoked" DVT/PE
• Patients who have had more than one DVT and/or PE
• Patients who have suffered from blood clots in unusual locations, such as the veins of the abdomen or brain, when there is no triggering event
• Patients with DVT/PE and a strong family history of the same
• Women with multiple miscarriages with no clear explanation

Even in the circumstances listed above, specific thrombophilia testing should not be viewed as "mandatory," and an in-depth evaluation and discussion with a knowledgeable physician are of utmost importance prior to determining the goals of testing. And even if testing is deemed indicated or appropriate, not all thrombophilias may need to be screened.

The timing of thrombophilia testing is as important as the decision to proceed with testing or not. Testing should be avoided during hospitalization, during periods of severe illness, as well as during pregnancy, because of the potential for false-positive results. The use of certain medications, such as blood thinners and birth control pills or hormone replacement pills or patches may also lead to false-positive results.

Treatment
There is no specific treatment for most thrombophilias, except for treatment with anticoagulants ("blood thinners") if there has been a clotting event. Anticoagulants that are used to treat blood clots include heparin, low-molecular-weight heparin, fondaparinux, and warfarin (or Coumadin¨). The length of anticoagulation treatment depends upon the type of blood clot and the nature of the thrombophilia and is decided by the patient's physician after reviewing all of the clinical information. If a person without any history of DVT or PE is found to have a thrombophilia, use of blood thinners is rarely recommended.

In some cases, a patient with thrombophilia may be referred to see a physician who specializes in blood clotting disorders such as a hematologist, internist, medical geneticist, or a vascular medicine specialist.

About the Author: Marcelo P. Villa-Forte Gomes, M.D. is Director of Vascular Medicine Fellowship Program for the Department of Cardiovascular Medicine Heart and Vascular Institute, Cleveland Clinic, in Cleveland, OH.