Thrombophilia

The Importance of Clotting

Venous Thromboembolism (VTE): A Common Clotting Problem

Blood Clot Signs and Symptoms

DVT and PE have different symptoms that may sometimes be confused with other less serious health problems. For example, the cramping often characteristic of a DVT in the thigh can be interpreted as a “Charlie horse.” The breathlessness from a PE can be mistaken for allergies or anxiety. Only your doctor can accurately assess the presence or absence of a blood clot, so seek medical attention promptly if you experience any of the following signs or symptoms:

• Swelling of your legs or arms
• Pain or tenderness not caused by an injury
• Skin that is warm to the touch
• Redness or discoloration of the skin
• Difficulty breathing
• Chest or back pain that worsens with a deep breath
• Coughing or coughing up blood
• Faster than normal or irregular heartbeat
• Dizziness or feeling faint

Blood Clot Risks

Thrombophilia: A Hidden Risk for Blood Clots

Currently Recognized Thrombophilias

The following is a brief summary of some of the better-known inherited thrombophilias:

• Factor V Leiden: Named after the city in the Netherlands in which the genetic mutation was first identified, Factor V Leiden is the most common thrombophilia, occurring heterozygous (i.e., one defective gene copy) in approximately 5 percent of the Caucasian population and homozygous (i.e., two defective gene copies) in less than 1 percent. Hispanic Americans and African Americans are affected less often (2% and 1% prevalence, respectively) As with most thrombophilias, it is rare in people of Asian, African or Native American descent.¹⁶Factor V Leiden causes a genetic mutation that generates an abnormal version of factor V. As an instrumental clotting protein, factor V helps generate fibrin, the fibrous material that creates a “net’ to hold a blood clot together. Once a functional blood clot has been completed, factor V is inactivated by another substance called activated protein C – also known as APC. The altered version of factor V is resistant to APC, so its activity continues beyond its period of usefulness. As a result, factor V Leiden can cause an exaggerated clotting response.

  The heterozygous form of factor V Leiden increases the risk for a first DVT 5- to 7-fold (i.e., an additional 5 to 7 people per thousand each year as compared to a 1 in 1,000 risk for the general population). However, the homozygous form increases blood clot risk by as much as 50-fold.¹⁷

• Hereditary Antithrombin Deficiency (HAD): Discovered in the 1950s, antithrombin is a protein that is necessary to prevent blood clots. People whose bodies don’t produce enough antithrombin are much more likely to develop a blood clot.HAD is less common than factor V Leiden. It occurs in  about 0.02 % of the general population, or 1 out of 5000 people in the U.S. There are approximately 66,200 people in the USA that have this mutation. However, this is an estimate. It is the highest risk thrombophilia in terms of causing clots in the affected population. About 50% of people with antithrombin deficiency will have at least one clot by age 50. About six in 10 people with HAD will have recurrent blood clots. The presence of HAD can be established with a blood test. You may be at risk for HAD if you have already had a clot, particularly if the clot did not have an obvious cause or if it was unusual in some way, or if you have a family member with a history of clots. Similar to protein C and protein S deficiency, HAD can be caused by genetic mutations that result in either inadequate production of antithrombin or production of dysfunctional antithrombin. Both types result in deficient antithrombin activity and an increased risk of blood clot formation.

  Blood clots with antithrombin deficiency occur at an average age of 30 and can appear in unusual locations, such as the veins of the brain or gastrointestinal tract, or in multiple veins simultaneously. Approximately 50 percent of people with HAD will experience a blood clot in their lifetime¹⁹ and 40 percent will experience a pulmonary embolism specifically. HAD increases the risk of blood clots by 20 percent compared to the general population.²⁰

  People with HAD are often treated by getting extra antithrombin to compensate for the antithrombin that is missing from the body. Treatment is more common in certain high-risk situations such as surgery, pregnancy and childbirth, or when the person already has a blood clot.

• Factor V Leiden: Named after the city in the Netherlands in which the genetic mutation was first identified, Factor V Leiden is the most common thrombophilia, occurring heterozygous (i.e., one defective gene copy) in approximately 5 percent of the Caucasian population and homozygous (i.e., two defective gene copies) in less than 1 percent. Hispanic Americans and African Americans are affected less often (2% and 1% prevalence, respectively) As with most thrombophilias, it is rare in people of Asian, African or Native American descent.¹⁶

  Factor V Leiden causes a genetic mutation that generates an abnormal version of factor V. As an instrumental clotting protein, factor V helps generate fibrin, the fibrous material that creates a “net’ to hold a blood clot together. Once a functional blood clot has been completed, factor V is inactivated by another substance called activated protein C – also known as APC. The altered version of factor V is resistant to APC, so its activity continues beyond its period of usefulness. As a result, factor V Leiden can cause an exaggerated clotting response.

  The heterozygous form of factor V Leiden increases the risk for a first DVT 5- to 7-fold (i.e., an additional 5 to 7 people per thousand each year as compared to a 1 in 1,000 risk for the general population). However, the homozygous form increases blood clot risk by as much as 50-fold.¹⁷

• Hereditary Antithrombin Deficiency (HAD): Discovered in the 1950s, antithrombin is a protein that is necessary to prevent blood clots. People whose bodies don’t produce enough antithrombin are much more likely to develop a blood clot.

  HAD is less common than Factor V Leiden, affecting between 1 in 500 to 5000 people.¹⁸ This range suggests that approximately 63,000 to 630,000 people in the United States could be affected. However, it is the highest risk thrombophilia in terms of causing clots in the affected population. More than eight out of ten patients with HAD will have at least one clot by age 50. About six in ten people with HAD will have recurrent blood clots. The presence of HAD can be established with a blood test. You may be at risk for HAD if you have already had a clot, particularly if the clot did not have an obvious cause or if it was unusual in some way, or if you have a family member with a history of clots. Similar to protein C and protein S deficiency, HAD can be caused by genetic mutations that result in either inadequate production of antithrombin or production of dysfunctional antithrombin. Both types result in deficient antithrombin activity and an increased risk of blood clot formation.

  Blood clots with antithrombin deficiency occur at an average age of 30 and can appear in unusual locations, such as the veins of the brain or gastrointestinal tract, or in multiple veins simultaneously. Approximately 50 percent of people with HAD will experience a blood clot in their lifetime¹⁹ and 40 percent will experience a pulmonary embolism specifically. HAD increases the risk of blood clots by 20 percent compared to the general population.²⁰

  People with HAD are often treated by getting extra antithrombin to compensate for the antithrombin that is missing from the body. Treatment is more common in certain high-risk situations such as surgery, pregnancy and childbirth, or when the person already has a blood clot.
• Prothrombin G20210A: Discovered in 1996, Prothrombin G20210A is the second-most common thrombophilia, occurring in heterozygous form in 2 percent of the Caucasian population.²¹ Less than 1 in 10,000 have the homozygous form. As with factor V Leiden, Prothrombin G20210A is rare in people of non-European or Middle-Eastern descent. Its name includes the code designating the exact location of the mutation within the DNA molecule. Prothrombin G20210A features a mutation in the gene responsible for production of prothrombin – also known as factor II – a protein like factor V that plays a critical role in the generation of fibrin – again, the material that constitutes the structural meshwork in a blood clot. Individuals with the heterozygous disorder have too much circulating factor II, increasing the odds of VTE by 2 or 3 times the normal blood clot risk.²² Scientists have yet to quantify the risk for the homozygous form.
• Protein C deficiency: First described in the medical literature nearly 40 years ago, protein C deficiency is a relatively uncommon thrombophilia, occurring in less than half of 1 percent of the population or 1 in 200-300 people in its heterozygous form.²³ However, when it does appear, homozygous protein C deficiency is considered a life-threatening illness.²⁴ Unlike factor V- and prothrombin-based thrombophilias, protein C deficiency is correlated with an elevated risk of recurrent blood clots. As a result, it may require more concern in those who have already experienced an initial VTE event. Protein C is instrumental to shutting down the clotting process once repair of a damaged blood vessel is completed. Individuals with a protein C-related mutation produce either too little of the protein or a version that is inactive.
• Protein S deficiency: This protein’s name stems from the city in which the protein was discovered, Seattle. Protein S is known as a co-factor in coagulation. By itself, it cannot produce the chemical reactions necessary to regulate blood clotting. Instead, it enhances the activity of other proteins and enzymes that have direct impact on the process. Individuals with this condition lack enough functional protein S in their circulation. As with other thrombophilias, mutations can occur to one or both gene copies. The milder heterozygous deficiency affects less than a quarter of 1 percent of the population (1 in 500).²⁵ The life-threatening homozygous form is extremely rare, but is usually the culprit in purpura fulminans, an often lethal and systemic clotting disorder in infants.
• Homocystinuria: An inherited disorder, homocystinuria is characterized by the body’s inability to metabolize certain amino acids – particularly homocysteine – that are the building blocks of proteins. This defect leads to chronic elevations of homocysteine that can injure the interior walls of blood vessels and trigger blood clots. Blood clots in the arterial circulation, such as heart attacks or strokes, are more common that blood clots in the veins in people who have very high homocysteine levels in their blood. A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene can elevate homocysteine levels and was once thought to increase the risk of venous thrombosis. However larger studies do not support an association between the most common MTHFR gene variants and the risk of thrombosis. Medical experts no longer suggest testing for MTHFR gene mutation when testing for inherited thrombophilia.

Acquired Thrombophilia

Thrombophilia Testing and Diagnosis

Some Testing Concerns

As with any medical decision, there are also concerns about testing, so screening for thrombophilia is an option that you and your healthcare provider should make together carefully. Should you decide to pursue testing, you should work together with your doctor and a genetic counselor. Together, they can help you understand your results and their implications.

Some considerations and cautions about testing include:

• Testing can be inaccurate. False positives and negatives are possible with these tests, although uncommon when the testing is conducted at the right time. To minimize inaccuracies, your physician will avoid testing you if you have an active blood clot or are taking blood thinning medications, are pregnant or taking estrogen hormonal therapy as these conditions are known to influence test results. Likewise, certain illnesses, like kidney and liver disease, can also affect test results.
• Results typically don’t affect treatment decisions. If you are already being treated for a blood clot, neither a positive nor negative thrombophilia testing result will likely alter your treatment plan. However, in the case of HAD, a prevention strategy is available since AT levels can be increased by the addition of AT factor. In the case of a confirmed thrombophilia diagnosis, your physician will continue your treatment with medications known as blood thinners. (See Section 7 for information about these medicines.) Of course, a negative thrombophilia test would be a relief. However, it’s critical that you don’t assume a false sense of security from the good news. You are still at risk based on your blood clot history. So, continue to take prescribed medication and follow all other medical instructions such a weight reduction as obesity is an important modifiable risk factor. If you are diagnosed with a thrombophilia and haven’t had a blood clot, it is unlikely that you will be given preventive treatment unless you have other significant risk factors. While all thrombophilias increase the risk for blood clots, overall risk remains low. For example, the general odds of experiencing a blood clot are approximately 1 to 2 per 1,000 people. If your thrombophilia increases this chance 5-fold, your risk is still only 1 percent or less. So, your doctor may not want to expose you to the potential side effects of blood thinners — including life-threatening bleeding — if your chance of a clot is low.
• Negative test results don’t mean you aren’t at risk. Sometimes people with extensive family histories test negative for thrombophilia. However, they remain at heightened risk for blood clots because VTE in close family members is a risk factor for a future blood clot. Yet, patients and/or their physicians may wrongly assume that negative test results minimize risk and may forego prudent preventive actions.
• Diagnosis can cause significant anxiety. If patients receive a diagnosis of thrombophilia in absence of other risk factors, it may cause them unnecessary anxiety even though the results may not change their overall risk profile. Unfortunately, many patients may worry excessively, lose sleep and have difficulty concentrating on work or family. In worst-case scenarios, some people pursue unnecessary treatment that exposes them to alternate risks. In most instances, a positive diagnosis is considered secondary to family history or personal experience with VTE. For most patients who have never had a blood clot, thrombophilia status is only considered relevant to prevention strategies when they face particular health events, such as surgery or pregnancy, that are established risk co-factors.
• Testing can be expensive. Some insurance plans won’t cover testing except under clearly defined circumstances that demonstrate medical necessity. Insurers are more likely to pay for tests if you have an abnormal blood clotting history, but not all do. Without coverage, testing – especially genetic screening – can be quite costly. Anyone considering thrombophilia screening should contact their insurance company to understand the criteria for coverage. Likewise, patients should know in advance their own financial obligations including co-pays, deductibles and out-of-pocket percentages. Although your doctor’s office and laboratory may handle much of the paperwork, make sure you are knowledgeable about the requirements.

Genetic Counseling

Blood Clot Treatment and Prevention

Sometimes blood thinners are prescribed strictly for primary clot prevention in people who have multiple risk factors, including a known thrombophilia, a strong family history of VTE, and a current health issue – such as pregnancy, hospitalization or impending surgery or prolonged immobilization – that are correlated with a higher incidence of clotting. Individuals with HAD may also receive additional antithrombin in high risk situations.

Blood thinners are highly effective but may cause side effects, including moderate to severe bleeding and heavier menstrual cycles. Some of these therapies require periodic monitoring to ensure that they’re working consistently.

The following are summaries of the most commonly prescribed blood thinners:

Unfractionated Heparin (UFH)

Unfractionated heparin (UFH) is a fast-acting anticoagulant that suppresses blood clot formation soon after administration.

Due to its rapid onset of action, UFH is normally the emergency treatment of choice for blood clots that are diagnosed in a hospital setting. It is typically given intravenously (IV), so it is not given in the outpatient setting. Shots of unfractionated heparin are prescribed for patient self-administration, but only in rare circumstances.

UFH therapy given through an IV requires strict and frequent monitoring to ensure adequate blood levels. Initial dosing is based on the patient’s weight. UHF needs antithrombin to be effective, so people who have HAD may need to be treated with additional antithrombin in order to achieve therapeutic levels with UHF therapy.

Heparins don’t cross the placenta, so they are considered safe to use in pregnant women, although low-molecular weight heparin (see below) is considered the optimal formulation for various reasons.

Before starting UFH treatment, you should alert your physician if you are taking a pain medication, such as aspirin, ibuprofen, naproxen or any other non-steroidal anti-inflammatory drug (NSAID) as these increase bleeding risks.

Low-Molecular Weight Heparin (LMWH)

Warfarin

People who require intermediate to long-term therapy with blood thinners are often prescribed warfarin (Coumadin), an anticoagulant used successfully since the 1950s.

Warfarin is taken orally, so it is highly suitable for home use and eliminates the need for painful and inconvenient injections or infusions. Its once-daily formulation improves patient compliance, a critical concern for outpatient blood clot management. Although warfarin can cause bleeding characteristic of all blood thinning drugs, its effects are easily reversed in the event of complications.

Warfarin dosing is individualized and not based on weight. Therefore, it requires frequent monitoring by a test called the prothrombin time or PT. The PT measures the time it takes for blood to clot. The PT test is used to make sure the patient is taking the right dose of warfarin. The PT is reported by labs as an International Normalized Ratio or INR. For most patients, the ideal INR range is between 2.0 and 3.0. Readings lower than 2.0 increase the chances for clot formation and results above 3.0 elevate the risk for bleeding.

Warfarin crosses the placenta and thins the blood of the fetus and therefore should not be taken by pregnant women except in very limited circumstances. Warfarin is the best blood thinner for patients with mechanical heart valves so women with heart valves should discuss their management with their cardiologist and obstetrician before becoming pregnant. Warfarin is not found normally in breast milk, so it is suitable for nursing moms.

Many foods interact with warfarin, especially foods high in vitamin K, such as many green leafy vegetables. Alcohol can also affect warfarin levels, so patients who drink should consume no more than 1-2 daily servings.

As with all anticoagulant therapy, NSAIDs such as aspirin and ibuprofen should be avoided when taking warfarin. Notify your doctor if you currently use any of these medications before beginning a warfarin regimen.

Direct-Acting Oral Anticoagulants (DOACs)

Direct-acting oral anticoagulants (DOACs), offer a mix of short- and long-acting agents with good safety profiles and relatively low bleeding risks. The medications have been extensively studied and are considered to be at least as effective as conventional treatments.³¹ Members of this class of compounds include apixaban (Eliquis), betrixaban (BevyxXa), dabigatran (Pradaxa), edoxaban (Savaysa) and rivaroxaban (Xarelto).

DOACs block various proteins that are instrumental to the production of fibrin, an essential component of blood clots. They perform predictably at fixed doses so they do not require routine monitoring.³² DOACs also have fewer medication and food interactions than standard therapies.

There is limited information on DOACs during pregnancy but animal studies suggest they may cause adverse effects, so they should be avoided in pregnant women.³⁴ Likewise, they should be used with caution in people with kidney or liver impairment. In the setting of antiphospholipid syndrome (APS), DOACs are generally not preferred, and the choice of blood thinner needs to be discussed in detail with a specialist familiar with APS.  Dabigatran and the anti Xa inhibitors do have antidotes available, but not all hospital systems carry all products. As a result, the ease of reversibility of blood thinners is part of the decision-making with your health care provider when choosing a medication right for you.

Again, anyone prescribed DOACs should notify their physician if they are taking aspirin or other NSAIDs for pain relief as they increase bleeding risks.

Lifestyle Changes to Reduce the Risk for Blood Clots