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Types of Clotting Disorders

Factor V Leiden
Antiphospholipid Syndrome
Thrombophilia
Heparin Induced Thrombocytopenia
Protein S Deficiency
Protein C Deficiency
Prothombin Gene Mutation

Factor V Leiden (Activated Protein C Resistance)

Factor V (five) Leiden (lye–den) is the name of a common genetic disorder that causes an increased risk of excessive blood clotting, known as thrombosis.

Factor V is one of the blood clotting factors or proteins produced by the liver. Normally, it circulates in the blood stream as an inactive substance. When it becomes activated, it contributes to the formation of a blood clot and is then switched off again by another clotting factor that helps to limit clotting to the area of injury, protein C.

In the case of factor V Leiden, there is a small abnormality in the factor V structure, causing it to be more resistant than normal to inactivation by protein C. This leads to more active factor V for a longer period of time and may result in excessive clotting. This abnormality is due to a single “substitution” in the gene for factor V. The affected gene may be passed through a family from a parent to children and is called the factor V Leiden mutation. The disorder is also known as “resistance to activated protein C.” The factor V Leiden mutation was discovered in 1993, and has since been found to be a very common cause of thrombosis in the Caucasian population. It is rare in African–Americans, Hispanics and Asians.
Thrombosis can occur in arteries and veins. Arteries are tough, elasticized blood vessels that carry blood away from the heart and deliver oxygen to the body. Thrombosis in an artery causes stroke, heart attack or damage to limbs or other organs, depending on the area of the arterial circulation affected. Other common contributing causes of arterial thrombosis are cigarette smoking, high blood pressure, high cholesterol and diabetes.
Veins are thinner, collapsible blood vessels that carry blood back from the tissues to the heart. It is estimated that from 500,000 – 2 million Americans experience a venous blood clot in their legs every year. These blood clots are often associated with surgery, pregnancy, birth control pills or other external factors.

Medical researchers estimate that 3 to 5 out of every 100 white Americans has one copy of the factor V Leiden mutation. Having one copy of this is referred to as being heterozygous. This means that these people have inherited the factor V Leiden gene from one parent and a normal gene from the other parent. The factor V Leiden gene is “dominant,” which means that it is not suppressed by the normal gene, although the normal gene does dilute its effect.

One person in 1,000 is homozygous for the mutation, which means that person has inherited the abnormal gene from both parents. Homozygous–affected individuals are much more likely to experience an episode of thrombosis than someone who is heterozygous. A person heterozygous for the mutation is 10 times more likely to develop a venous (vein–involved) blood clot than an unaffected person. Factor V Leiden probably increases the risk of arterial clots as well, but has a much stronger connection with venous blood clots, especially in the veins of the legs. Most blood clots in a heterozygous individual occur in association with some external cause. In women, the most common causes are pregnancy, birth control pills and hormone replacement after menopause. This is because the balance of coagulation is tipped towards clotting during pregnancy. Hormonal replacement and birth control pills mimic the same situation. In one study from Europe, 60% olots during pregnancy turned out to have factor V Leiden. The risk of blood clots is actually highest during the 6 to 8 weeks after the birth of a baby. In men with factor V Leiden, blood clots may occur after surgery or an injury, especially an injury to the legs. Not everyone with factor V Leiden will develop a blood clot. Therefore, for some people with factor V Leiden there is no history of blood clotting in their parents, even if one of their parents has the gene.
A person who has inherited the gene from both parents (homozygous) has no normal factor V gene and is 40 times more likely than an unaffected person to develop a blood clot. Also, homozygous individuals can develop blood clots for no apparent external reason, which is called spontaneous thrombosis.

Symptoms
The symptoms of factor V Leiden include but are not limited to deep vein thrombosis (DVT) often in the lower extremities, pulmonary embolism, superficial thrombophlebitis, and recurrent pregnancy loss. Anyone with these symptoms should have an evaluation for the possibility of an underlying abnormality such as actor V Leiden. Following is an overview of these symptoms.

Deep vein thrombosis (DVT)
DVT is a condition in which blood clots form in the deep blood vessels, usually in the legs and groin. These blood clots can block the normal flow of blood returning from the legs to the heart. The main symptoms of DVT include pain and swelling. The pain may be sharp and sudden in onset or develop more gradually. The pain may be dull and throbbing. There may or may not be some swelling, redness and warmth over the area of the clot. Some people with a DVT may not have any symptoms.

Pulmonary embolism (PE)
PE occurs when a piece or all of a blood clot breaks off and is carried by the bloodstream to the lung. This clot will block the blood vessel in the lung. The size of the clot and the site of the obstruction of blood flow in the vessel will determine the size and severity of the pulmonary embolus. The symptoms of a PE may include difficulty breathing, rapid breathing, fast heartbeat and chest pain – especially when inhaling. Some patients only notice a dull ache in their chest and have fatigue or a feeling of anxiety. A few patients have no symptoms.
Superficial thrombophlebitis:
Superficial thrombophlebitis occurs when blood clots form in veins closer to the surface of the skin and is associated with inflammation. These clots may cause pain and irritation, and may also partially block blood flow in affected veins. Symptoms include: a hard, red vein which is often visible and commonly occurs in the legs or arms; the area may be warm and tender; the surrounding tissue may become itchy and swollen; there may be a throbbing or burning sensation beneath the skin’s surface; an associated fever is possible; and there may be difficulty sleeping as the pain worsens.

Pregnancy loss
There is an increased risk of pregnancy loss in those who are either homozygous or heterozygous for the factor V Leiden mutation. Homozygous individuals have a greater risk for fetal loss and stillbirth than those who are heterozygous for this abnormality. One reason this may occur is excessive and abnormal clotting in the small blood vessels of the placenta. Also, there may be a greater risk of miscarriage if the baby and the mother are affected with the factor V Leiden mutation.

Treatment of Blood Clots
Once a patient is diagnosed with a blood clot, medications – anticoagulants – will be used to decrease the ability of the blood to clot. These anticoagulants may include:

• Unfractionated (regular) heparin
• Low molecular weight heparin (LMWH)
• Coumadin®

Unfractionated heparin (UH) is usually administered in the hospital as an intravenous drug (directly into the vein). UH works though its interaction with a naturally occurring clotting factor, antithrombin III, that is important in limiting the propagation or growth of a clot. UH does not dissolve the blood clot, but it prevents further clot formation while the body’s natural mechanisms dissolve the clot. UH is usually used during the earliest phase of treatment. It requires frequent monitoring with blood tests as often as every 4 to 6 hours to ensure the correct effect is achieved. After the acute phase has passed, many patients may be changed over to low molecular weight heparin or Coumadin for their continued anticoagulation treatment.
Low molecular weight heparin (LMWH), which includes drugs such as Lovenox¨ and Innohep¨, is used for both the treatment and prevention of blood clots. LMWH is used commonly during pregnancy for the prevention of thrombotic complications. It may also be used for the initial treatment of blood clots and while a patient is being started on an oral anticoagulant such as Coumadin. LMWH is given by an injection under the skin much the same way diabetics take insulin. One or two injections per day may be prescribed. Laboratory monitoring of blood levels is not always required.

Coumadin (also known as warfarin) is usually administered by mouth in tablet form. It decreases blood clotting by blocking the effects of the vitamin K pathway in the liver. (Green leafy vegetables contain vitamin K.) This pathway is important in the production of some clotting factors that are able to help form a clot. Interference in this pathway will lead to a decreased amount of clotting factors able to form a clot, leading to anticoagulation or thinning of the blood. Each person may require a different dose of Coumadin, so frequent monitoring initially may be required to ensure that the Coumadin dose is safe and effective. A person being started on Coumadin will need to take some form of heparin for a period of time until the effect of the Coumadin has been proven to be consistently in the desired range. Please note that Coumadin should not be used during pregnancy.

After a deep vein thrombosis, a person will often be treated with an anticoagulant such as Coumadin for approximately 6 months. The total duration of treatment for a blood clot will depend on the cause and severity of the clot, identified underlying risk factors such as factor V Leiden, and will need to be decided on an individual basis.

Concluding Remark
Factor V Leiden is a lifelong disorder. However, not all affected individuals require lifelong anticoagulation therapy. For more information on factor V Leiden, please consult with your medical care provider.

Antiphospholipid Syndrome

What is Antiphospholipid Syndrome?
Antiphospholipid Syndrome is a disorder in which the blood clotting system begins to form blood clots in the veins or arteries without obvious reason.  The symptoms of Antiphospholipid Syndrome include blood clots (thromboses) in leg or arm veins and/or arteries; blood clots which travel to the lungs (pulmonary emboli); sudden loss of vision; occasional episodes of numbness, tingling, or weakness in the face or limbs; stroke; seizures; and recurrent miscarriages. All of these symptoms are the result of blood clots occurring in small to medium sized blood vessels. Most people affected with this disorder have only one or two of any of these symptoms. They are however at risk for developing Additional symptoms if not treated appropriately or monitored by a physician knowledgeable about the disorder.

What causes the blood to clot too easily in Antiphospholipid Syndrome?
It is not really known why people with this disorder have a tendency to clot more easily. Antibodies are proteins produced by the body's immune system to identify and remove foreign proteins, bacteria and viruses. In a person with antiphospholipid syndrome, antibodies are present in blood which appears to react with cell membranes, causing the cells to behave as if they have been irritated or stimulated. This disturbs the normally well controlled clotting system. For example, an antibody may interact with a platelet, causing the platelet to release its cellular contents and form a clot. Antibodies also may attach to cells that line blood vessels. This will cause the normally non-reactive surface to appear reactive to passing blood and a clot will form. In both instances, the antibodies are binding to sites on these cells normally occupied by factors in the blood. When these factors can no longer bind to the cells because their sites are occupied by the antibodies, the blood begins to clot more easily.

What causes these antibodies to be formed?
Unfortunately it is not known why these antibodies occur. Sometimes an antibody is made against ones own body or self which can cause damage to tissues or organs. This is termed an "autoimmune" disease. Common autoimmune disorders include systemic lupus erythematosus (SLE), certain types of thyroid disease, rheumatoid arthritis and vasculitis. Patients taking certain medications such as Dilantin, Phenothiazines, or Hydralazine may develop Antiphospholipid Syndrome. Frequently the antiphospholipid antibody will disappear once the medication has been stopped. Antiphospholipid antibodies also may appear for a short time during a viral infection and may disappear soon after the viral infection is completely resolved. Most often, however, antiphospholipid antibodies are found at the time a patient has developed a blood clot and none of the previously mentioned causes can be found.

How is tire diagnosis of Antiphospholipid Syndrome made?
There is no one test that can make the diagnosis of antiphospholipid syndrome. Generally, a series of blood tests which look for abnormal blood clotting and antibodies are performed. The Lupus Anticoagulant is a test designed to look for abnormal clotting. The name Lupus Anticoagulant is a misnomer since patients who test positive for a lupus anticoagulant generally have a tendency to clot more easily. The presence of two abnormal test results combined with clinical symptoms make the diagnosis of Antiphospholipid Syndrome.

How is Antiphospholipid Syndrome treated?
Treatment of Antiphospholipid Syndrome is generally tailored for each patient depending on their degree of symptoms. Patients who have had blood clots in the veins or arteries will generally need to receive anti-clotting drugs such as coumadin or heparin. If clotting is severe, aspirin or a nonsteroidal anti-inflammatory drug may be prescribed in addition to the coumadin or heparin. If the patient also has an associated autoimmune disorder, other drugs that suppress the immune system such as prednisone or cytoxan may be required. The length of anticoagulation therapy is highly dependent on the severity of the disorder and the type of blood clotting. In general, a minimum of six months of anticoagulation therapy is needed and some patients require treatment indefinitely.

Are there any clinical conditions where antiphospholipid syndrome requires specialized care?
Yes, during pregnancy. Any woman with antiphospholipid syndrome considering pregnancy is advised to seek high risk pregnancy advice and to consult a hematologist with knowledge in bleeding disorders prior to becoming pregnant. Patients with a history of recurrent spontaneous abortions may be placed on intravenous (IV) or subcutaneous heparin or oral aspirin during their pregnancy in order to prevent miscarriage due to clotting of the placental blood vessels.

Thrombophilia

What is Thrombophilia?
Thrombophilia is the potential to develop dangerous blood clotting in the veins or arteries. Several types of conditions have been identified which may lead to dangerous clots. These conditions may be present at birth (congenital or inherited) or may occur as a result of another condition (acquired).
What is a clot?
The blood clotting system is activated when a blood vessel is injured. Platelets circulating nearby respond first by sticking to the injured area and recruiting more platelets to the site. This aggregation- of platelets forms a temporary plug that protects the vessel wall from further bleeding. At the same time, additional proteins are activated in a specific order that lead to the formation of a tissue glue known as fibrin. Fibrin is laid down at the site of the platelet plug, making it secure. Eventually, sear tissue forms completing the healing of the injured vessel.

What keeps blood from clotting?
The clotting process is so efficient that our blood has built in a system to regulate the process. Our plasma contains many proteins that either inhibit the formation of a clot or act to dissolve a clot through the breakdown of fibrin. This balance between clot formation and clot breakdown is normally very efficient. This allows blood clots to form appropriately in response to injury and to breakdown after they have served their purpose.
What acquired conditions can lead to dangerous clots?
There are many acquired conditions which increase the risk for dangerous clot formation (Table I). Some cannot be avoided such as increasing age, recovering from major surgery, or a period of immobilization as a necessary treatment for another medical condition. Pregnancy and surgical immobilization are periods of increased risk for clot formation. In other cases, lifestyle changes can reduce risks such as those associated with smoking and obesity. The use of oral contraceptives is also a risk factor for women. These risk factors are cumulative. For instance, an elderly individual who smokes and has a lower leg fracture requiring immobilization would have a very high chance of developing a dangerous clot in the lower leg.

Why are some clots dangerous?
Under certain circumstances the balance between clot formation and breakdown is disturbed and an unregulated clot forms within our veins or arteries. Sometimes these unregulated clots can become so large that they obstruct the blood flow through that vessel. This can interfere with the blood supply to vital tissues or lead to a backup or pooling of blood behind the clot. This can cause pain and swelling of the tissue in the area and can lead to permanent tissue damage. Clots can grow very fast and can break apart sending small pieces of the clot (known as emboli) through the blood stream. These emboli can then become lodged in smaller vessels throughout remote areas of the body. An emboli lodging within vessels of the lung is known as a pulmonary embolus. An emboli lodging in brain vessels can cause a stroke. Both can be life-threatening.

How common are dangerous clots?
Thankfully dangerous clots are unusual. Unfortunately we do not have any accurate estimates of the true incidence of abnormal clotting in the general population. Less than 5 individuals in 100 will develop a dangerous clot over the course of their lifetime.
Do all individuals with thrombophilia develop dangerous clots?
M Presence of the inherited predisposition alone seems to be only a small risk for certain families. However, for these individuals, the presence of an additional acquired risk factor (Table 1) poses a significant risk for dangerous clot formation. Studies have determined that approximately 20% ous clots have the genetic mutation Factor V Leiden. At least another 10% obuted to the other inherited mutations outlined in Table 11.

Table 11. Inherited Risk Factors For Thrombosis
If acquired conditions are common, why do dangerous clots occur in some individuals and not others?
In recent years several inherited risk factors have been identified (Table 11). In most cases an inherited deficiency of one of the critical plasma proteins predisposes the individual to the formation of a dangerous clot. In addition, genetic mutations in other plasma proteins leads to their unregulated activity and clotting can occur unchecked. The presence of these genetic predispositions in certain families has been termed thrombophilia to emphasize their special risk for thromboembolism or clotting.
Have all the inherited disorders been defined?
No. It is likely that intensive research efforts in families with a history of thrombophilia will lead to the identification of additional genetic risk factors. It is important that patients with thrombophilia be followed by Comprehensive Treatment Centers. This way as new genetic mutations are defined, families can be appropriately screened.

University of Michigan
Comprehensive CANCER CENTER
Hemophilia and Co2gulation Disorders Program Phone: (734) 936-6393
Email: umhtca_umich.edu
Funded in part by a grant sponsored by CASCADE Hemophilia Consortium April 19, 1999

Heparin Induced Thrombocytopenia (HIT)

HIT may occur in 1%-3 receiving heparin for a week or more. HIT is most often encountered in the following populations:

  Those with cardiovascular disease and interventions
  Orthopedic surgery patients
  Medically compromised patients

However, HIT may occur in any population. HIT results when a patient receives heparin (a blood thinner) and antibodies then form that cause damage to the lining of blood vessels as well as to platelets. When this happens, the platelets aggregate or clump together. This causes consumption of platelets, resulting in a fall in the patient’s platelet count. This damage to the blood vessel lining and clumping of the platelets can lead to development of blood clots despite the presence of heparin. It is unclear why some patients on heparin develop this problem.
The fall in platelet count with HIT usually develops 5 to 7 days following the start of heparin for the first time. However, HIT may occur within 1–3 days in patients who have been previously exposed to heparin or sensitized in the recent past (usually within 3 months). Once heparin is stopped, the platelet count should begin to recover in 2–5 days. However, despite the discontinuation of the heparin, the patient may be at continued high risk of thrombosis for the next 30 days, and alternate anticoagulation may be required dependent on the patient’s clinical circumstances. There are several medications specifically indicated and licensed for treating HIT such as Refludan®, Argatroban® and Danaparoid®. The use of low molecular weight heparin (LMWH) as an alternative anticoagulant after the diagnosis of HIT is established is not recommended.
The diagnosis of suspected HIT should be made based upon a clinical assessment made by a medical care provider experienced with this problem, in conjunction with a variety of specialized laboratory tests. One commonly used test is a HIT assay. If HIT is confirmed, all heparin must be stopped. This includes the removal of heparin-coated catheters and the discontinuation of all heparin flushes of catheters. 

Protein S Deficiency

Protein S is made in a variety of places in the body:  the lining of the blood vessels, liver, platelets, testes, kidneys, and brain.  The normal function of Protein S is to downregulate the clotting cascade (to turn off the clotting system once it has been turned on).  Thus, protein S deficiency can lead to excessive blood clotting, as the body doesn’t have enough of the “off switch” to tell the body to stop clotting.

Causes
Protein S deficiency is usually inherited.  Over 100 different mutations in the protein S gene have been identified.  Many persons with protein S deficiency will experience a thromboembolic event (blood clot) by age 40.  Arterial thrombosis occurs more frequently in persons with protein S deficiency than in other thrombophilias.  This is usually in association with other risk factors for arterial thrombosis, such as smoking, obesity, and diabetes.

Diagnosis
Diagnosis of protein S deficiency is done by testing the levels of the two forms of protein S in the bloodstream.  Total protein S antigen and free protein S antigen (unbound to a protein carrier).  To determine if there is a deficiency in protein S, a total protein S antigen, a free protein S antigen and a protein S activity need to be measured.  The protein S antigen tells you how much protein S levels that is in the blood.  But more importantly, the protein S activity level tells you if it is working properly.  Lab values may be falsely low if blood samples are drawn while patients are on Coumadin (warfarin) or in the setting of an acute thromboembolic event, pregnancy, hormone replacement therapy, birth control pills, and certain disease states. 

Treatment
Treatment is the same for patients with protein S deficiency as for other patients who have experienced a thromboembolic event.  Heparin or low molecular weight heparin is commonly prescribed immediately after a thrombotic event followed by Coumadin (warfarin) for long term use.  Patients with known protein S deficiency should be given heparin or low molecular weight heparin during initiation of Coumadin (warfarin) therapy to prevent possible Coumadin-induced skin necrosis. 

For further information on protein S deficiency, visit the National Alliance for Thrombosis and Thrombophilia website at www.nattinfo.org

Protein C Deficiency

Protein C is made in the liver.  The normal function of Protein C is to down regulate the clotting cascade (to turn off the clotting system once it has been turned on).  Thus, protein C deficiency can lead to excessive blood clotting, as the body doesn’t have enough of the “off switch” to tell it to stop clotting.

Causes
Protein C deficiency is usually inherited.  Over half of those individuals with protein C deficiency will experience a thromboembolic event (blood clot) by age 45.  The risk of a blood clot is higher in those individuals who have another compounding risk factor for thrombosis, such as one of the other inherited thrombophilias (Factor V Leiden, protein S deficiency, or antithrombin III deficiency) or have other risk factors, such as pregnancy, oral contraceptive use, elevated homocysteine or factor VIII levels.

Diagnosis
Diagnosis of protein C deficiency is done by testing the levels of protein C in the bloodstream.  In type I protein C deficiency there are decreased levels of protein C antigen and activity.  This is due to decreased production of protein C.  In type II protein C deficiency, there are decreased levels of protein C activity, but the protein levels are not decreased to the same extent.  In this scenario, the body produces a protein that is able to be measured; but does not function properly.  Lab values may be falsely low if blood samples are drawn while patients are on Coumadin (warfarin) or in the setting of an acute thromboembolic event, due to accelerated consumption of protein C.  Acquired protein C deficiency occur in settings such as with liver disease, malignancy, infection or acute respiratory distress syndrome. 

Treatment

Treatment is the same for patients with protein C deficiency as for other patients who have experienced a thromboembolic event.  Heparin or low molecular weight heparin is commonly prescribed immediately during a criticall event followed by Coumadin (warfarin) for long term use.  Protein C is further decreased during the first few days of Coumadin (warfarin) therapy. All patients with known protein C deficiency should be given heparin or low molecular weight heparin during initiation of Coumadin (warfarin) therapy.

For further information on protein C deficiency, visit the National Alliance for Thrombosis and Thrombophilia website at www.nattinfo.org

Prothrombin Gene Mutation

Prothrombin gene mutation, also called factor II mutation, is a genetic mutation that results in an increased risk of blood clotting.  It has been estimated to be found in up to 2-3% op; The prothrombin gene mutation was discovered in 1996.

The prothrombin gene mutation is associated with elevated levels of prothombin in the blood circulation.  This increased concentration of prothrombin could promote increased thrombin generation, which increases the risk for the development of blood clots.  Prothrombin gene mutation is associated with blood clots in unusual sites such as the veins of the brain or in the abdomen.  It is also associated with heart attacks, strokes and recurrent pregnancy loss or stillbirth.

Causes
Prothrombin gene mutation is inherited.  Each individual has 2 copies of the gene to code for the production of prothrombin.  If an individual inherits one gene that is defective and causes an increase in production of prothrombin, that person is said to be heterozygous for the gene mutation.  The prothrombin gene mutation is “dominant,” which means that it is not suppressed by the normal gene.  It is extremely rare for an individual to inherit abnormal prothrombin genes from both parents.  These rare persons are said to be homozygous for the prothrombin gene mutation.  The risk for thrombosis is much greater in an individual that is homozygous than heterozygous. 

Diagnosis
Diagnosis of prothrombin gene mutation is done by a special blood test to determine whether someone has the gene.  If positive, this test will determine whether they are heterozygous or homozygous for the disorder. 

Treatment
Treatment is the same for patients with prothrombin gene mutation as for other patients who have experienced a thromboembolic event.  Heparin or low molecular weight heparin is commonly prescribed immediately during a critical event followed by Coumadin (warfarin) for long term use.

The length of treatment with Coumadin is determined on an individual basis and will take into consideration if there were other factors which contributed to the formation of a blood clot, as well as if a person has a history of previous blood clots.  Persons with prothrombin gene mutation will not necessarily need to be on life long anticoagulation.  However, to prevent a thrombotic episode during a time of increased risk, they will be given anticoagulants for a short time period.  These decisions are made on an individual basis with your healthcare provider.