Hemostasis is the body's way of stopping injured blood vessels from bleeding. Hemostasis includes clotting of the blood. Too much clotting can block blood vessels that are not bleeding; consequently, the body has control mechanisms to limit clotting and dissolve clots that are no longer needed. An abnormality in any part of this system that controls bleeding can lead to excessive bleeding or excessive clotting, both of which can be dangerous. When clotting is poor, even a slight injury to a blood vessel may lead to major blood loss. When clotting is uncontrolled, small blood vessels in critical places can become clogged with clots. Clogged vessels in the brain can cause strokes; clogged vessels leading to the heart can cause heart attacks; and pieces of clots from veins in the legs, pelvis, or abdomen can travel through the bloodstream to the lungs and block major arteries there (pulmonary embolism).
Hemostasis involves three major processes: narrowing (constriction) of blood vessels, activity of platelets, and activity of blood clotting factors.
An injured blood vessel constricts so that blood flows out more slowly and clotting can start. At the same time, the accumulating pool of blood outside the blood vessel (a hematoma) presses against the vessel, helping prevent further bleeding. As soon as a blood vessel wall is damaged, a series of reactions activates platelets so that they stick to the injured area. The "glue" that holds platelets to the blood vessel wall is von Willebrand factor, a protein produced by the cells of the vessel wall. The proteins collagen and thrombin act at the site of the injury to induce platelets to stick together. As platelets accumulate at the site, they form a mesh that plugs the injury. The platelets change shape from round to spiny, and they release proteins and other substances that entrap more platelets and clotting proteins in the enlarging plug that becomes a blood clot.
Blood Clots: Plugging the Breaks
When an injury causes a blood vessel wall to break, platelets are activated. They change shape from round to spiny, stick to the broken vessel wall and each other, and begin to plug the break. They also interact with other blood proteins to form fibrin. Fibrin strands form a net that entraps more platelets and blood cells, producing a clot that plugs the break.
Blood Clots: Plugging the Breaks(click here to see the video)
Formation of a clot also involves activation of a sequence of blood clotting factors that generate thrombin. Thrombin converts fibrinogen, a blood clotting factor that is normally dissolved in blood, into long strands of fibrin that radiate from the clumped platelets and form a net that entraps more platelets and blood cells. The fibrin strands add bulk to the developing clot and help hold it in place to keep the vessel wall plugged.
The reactions that result in the formation of a blood clot are balanced by other reactions that stop the clotting process and dissolve clots after the blood vessel has healed. Without this control system, minor blood vessel injuries could trigger widespread clotting throughout the body—which actually happens in some diseases.
Hemophilia
Hemophilia is a bleeding disorder caused by a deficiency in one of two blood clotting factors: factor VIII or factor IX.
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Several different gene abnormalities can cause the disorder.
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People bleed unexpectedly or after minor injuries.
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Blood tests are needed for diagnosis.
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Transfusions are given to replace missing clotting factors.
There are two forms of hemophilia. Hemophilia A, which accounts for about 80% of all cases, is a deficiency in clotting factor VIII. Hemophilia B is a deficiency in clotting factor IX. The bleeding patterns and consequences of these two types of hemophilia are similar.
Deficiency of clotting factor XI also causes a hereditary bleeding disorder. About 50% of cases of factor XI deficiency occur among people of Eastern European Jewish ancestry. Factor XI deficiency affects both males and females and may cause bleeding after injury or surgery. Spontaneous bleeding episodes are usually less frequent and milder than in hemophilia A or B.
Hemophilia is caused by several different gene abnormalities. They are sex-linked, which means that the gene abnormalities are inherited through the mother and that nearly everyone with hemophilia is male.
Did You Know...
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Hemophilia can affect both males and females.
Symptoms and Complications
The severity of the symptoms depends on how a particular gene abnormality affects the blood clotting activity of factor VIII or IX. People whose clotting activity is 5 to 25% of normal have very mild hemophilia that may go undiagnosed; however, these people may bleed more than expected after surgery, dental extractions, or a major injury. People whose blood clotting activity is 1 to 5% of normal may have only mild hemophilia. They have few unprovoked bleeding episodes, but surgery or injury may cause uncontrolled and fatal bleeding. When the clotting activity is less than 1% of normal, hemophilia is severe. Serious episodes of bleeding occur and recur for no apparent reason.
In severe hemophilia, the first bleeding episode often occurs during or immediately after delivery. The infant may develop a collection of blood under the scalp (cephalhematoma) or may bleed excessively during circumcision. A bleeding episode generally occurs before 18 months of age and may follow a minor injury. A child who has hemophilia bruises easily. Even an injection into a muscle can cause bleeding that results in a large bruise and hematoma. Recurring bleeding into the joints and muscles can lead to crippling deformities. Bleeding can swell the base of the tongue until it blocks the airway, making breathing difficult. A slight bump on the head can trigger substantial bleeding in the brain or between the brain and the skull, causing brain damage and death.
Diagnosis and Treatment
A doctor may suspect hemophilia in a child (especially a boy) who bleeds without an apparent cause or bleeds more than expected after injury. A blood test can determine whether the boy's clotting is abnormally slow. If it is, further blood tests can confirm the diagnosis of hemophilia and can determine its type and severity.
People who have hemophilia should avoid situations that might provoke bleeding and should avoid drugs (for example, aspirin Some Trade Names
BAYER
) that interfere with the function of platelets. They should be conscientious about dental care so that they will not need to have teeth extracted. If people who have milder forms of hemophilia need to have dental or other surgery, the drugs aminocaproic acid Some Trade Names
AMICAR
or desmopressin Some Trade Names
DDAVPSTIMATE
may be given to improve temporarily the body's ability to control bleeding so that transfusions can be avoided.
Often, treatment involves transfusions to replace the deficient clotting factor. These factors are found normally present in normal the liquid component of blood (plasma). Clotting factors may be obtained from donated blood by concentrating or purifying them from plasma products, or they may be produced using special technological procedures as highly purified recombinant factor concentrates. Recombinant forms of both factor VIII and IX are available; because they are not obtained from human donors, they do not have the risk of infection that is present with factors derived from donated blood. The dose, frequency, and duration of therapy are determined by the site and severity of the bleeding problem. Clotting factors may also be used to prevent bleeding before surgery or at the first sign of bleeding.
Some people with hemophilia develop antibodies to transfused clotting factors, which destroy the factors. As a result, factor replacement therapy becomes less effective. If antibodies are detected in the blood of a person with hemophilia, the dosage of the recombinant factor or plasma concentrates may be increased, or different types of clotting factors or drugs to reduce the antibody levels may be needed.
Henoch-Schönlein Purpura
Henoch-Schönlein purpura (allergic purpura) is a disease in which blood vessels in the skin, joints, digestive tract, or kidneys become inflamed and may leak.
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Henoch-Schönlein purpura results from an autoimmune reaction.
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People have small bluish purple spots on their feet, legs, arms, and buttocks.
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A biopsy of affected skin may be used to confirm the diagnosis.
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Drugs that may be causing the reaction are stopped, and corticosteroids and other drugs are given to reduce the activity of the immune system.
Henoch-Schönlein purpura, an uncommon disease, affects mainly young children, but it can affect older children and adults. The disease is believed to result from an autoimmune reaction, in which the body attacks its own tissues. Usually, Henoch-Schönlein purpura develops after a respiratory tract infection, but it can develop after an immunization or an insect bite or be caused by an allergic reaction to drugs or food. The rate at which the disease develops and its duration vary.
Symptoms and Diagnosis
The disease may begin with the appearance of small, bluish purple spots (purpura)—most often on the feet, legs, arms, and buttocks-as blood leaks from vessels in the skin. Over several days, the purpura may become raised and hard; crops of new purpura may break out for several weeks after the first one appears. Swollen, achy joints are common, usually accompanied by fever. Bleeding in the digestive tract may cause abdominal cramps and pain. Blood in the urine (hematuria) may develop. Most people recover completely within a month, but symptoms may recur several times. Bleeding in the kidneys may cause kidney damage.
The diagnosis is based on the symptoms. Sometimes a sample of affected skin is removed and examined under a microscope (biopsy) to confirm the diagnosis.
Treatment
A drug that may be causing an allergic reaction is discontinued immediately. Corticosteroids (for example, prednisone) may help relieve swelling, joint pain, and abdominal pain, but they do not prevent or reverse kidney damage. Drugs that reduce the activity of the immune system (immunosuppressive drugs), including azathioprine Some Trade Names
IMURAN
or cyclophosphamide Some Trade Names
LYOPHILIZED CYTOXAN
, are sometimes used if kidney damage develops, but it is not known if they are helpful.
Hereditary Hemorrhagic Telangiectasia
Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) is a hereditary disorder in which blood vessels are malformed, making them fragile and prone to bleeding.
Blood vessels under the skin may break and bleed, causing small, red-to-violet discolorations, especially on the face, lips, lining of the mouth and nose, and tips of the fingers and toes. Severe nosebleeds may also occur. Small blood vessels in the digestive and urinary tracts, as well as in the brain and spinal cord, may also be affected, causing bleeding in these sites.
Treatment is aimed at stopping an occurrence of bleeding. Treatment may involve applying pressure, using a topical drug that narrows blood vessels (astringent), or using a laser beam to destroy the leaking blood vessel. Severe bleeding may require more invasive techniques. Bleeding almost always recurs, resulting in iron deficiency anemia; consequently, people with hereditary hemorrhagic telangiectasia need to take iron supplements. Some people may also need to take drugs that inhibit the formation of fibrin.
Thrombocytopenia (ITP, TTP)
Thrombocytopenia is a deficiency of platelets (thrombocytes).
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Thrombocytopenia occurs when the bone marrow makes too few platelets or when too many platelets are destroyed.
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Bleeding in the skin and bruising occur.
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Blood tests are used to make the diagnosis and determine the cause.
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Sometimes platelet transfusions are needed.
The blood usually contains about 140,000 to 440,000 platelets per microliter. Bleeding can occur with relatively minor trauma when the platelet count falls below about 50,000 platelets per microliter of blood. The most serious risk of bleeding, however, generally does not occur until the platelet count falls below 10,000 to 20,000 platelets per microliter. At these very low levels, bleeding may occur without any injury.
Causes
Many diseases can cause thrombocytopenia. Thrombocytopenia can occur when the bone marrow does not produce enough platelets, as happens in leukemia and some anemias. Infection with the human immunodeficiency virus (HIV), the virus that causes AIDS, often results in thrombocytopenia. Platelets can become entrapped in an enlarged spleen, as happens in myelofibrosis and Gaucher's disease, reducing the number of platelets in the bloodstream. Massive blood transfusions can dilute the concentration of platelets in the blood. Finally, the body may use or destroy too many platelets, as occurs in many disorders, three of the most notable being idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome.
Causes of Thrombocytopenia
- Bone marrow does not produce enough platelets
- Leukemia
- Lymphoma
- Aplastic anemia
- Heavy alcohol consumption
- Megaloblastic anemias, including vitamin B12 and folic acid deficiency anemias
- Some bone marrow disorders
- Platelets become entrapped in an enlarged spleen
- Cirrhosis with congestive splenomegaly
- Myelofibrosis
- Gaucher's disease
- Platelets become diluted
- Massive blood replacement or exchange transfusion with stored blood containing too few platelets
- Cardiopulmonary bypass surgery
- Use or destruction of platelets increases
- Idiopathic thrombocytopenic purpura
- HIV infection
- Drugs such as heparin, quinidine, quinine, sulfa-containing antibiotics, some oral drugs for diabetes, gold salts, and rifampin
- Conditions involving disseminated intravascular coagulation within blood vessels, such as can occur with obstetric complications, cancer, blood poisoning (septicemia) from gram-negative bacteria, and traumatic brain damage
- Thrombotic thrombocytopenic purpura
- Hemolytic-uremic syndrome
- Paroxysmal nocturnal hemoglobinuria
Idiopathic thrombocytopenic purpura (ITP): ITP is a disease in which antibodies form and destroy the body's platelets. Why the antibodies form is not known. Although the bone marrow increases platelet production to compensate for the destruction, the supply cannot keep up with the demand.
Thrombotic thrombocytopenic purpura (TTP): TTP is a rare disease in which small blood clots form suddenly throughout the body. The blood clots mean that an abnormally high number of platelets are being used, which leads to a sharp decrease in the number of platelets in the bloodstream.
Hemolytic-uremic syndrome (HUS): HUS is a disorder related to TTP in which the number of platelets suddenly decreases, red blood cells are destroyed, and the kidneys stop functioning. HUS is rare but can occur with certain bacterial infections (particularly intestinal infections with Escherichia coli O157:H7 or some strains of Shigella dysenteriae) and with the use of some drugs (including quinine Some Trade Names
QUALAQUIN
, cyclosporine Some Trade Names
NEORALSANDIMMUNE
, and mitomycin Some Trade Names
MUTAMYCIN
C). The syndrome is most common in infants, young children, and women who are pregnant or have just given birth, although it can occur in older children, adults, and women who are not pregnant.
Symptoms and Complications
Bleeding in the skin may be the first sign of a low platelet count. Many tiny red dots (petechiae) often appear in the skin on the lower legs, and minor injuries may cause small scattered bruises. The gums may bleed, and blood may appear in the stool or urine. Menstrual periods may be unusually heavy. Bleeding may be hard to stop.
Bleeding worsens as the number of platelets decreases. People who have very few platelets may lose large amounts of blood into the digestive tract or may develop life-threatening bleeding in the brain even though they have not been injured.
The rate at which symptoms develop can vary depending on the cause of thrombocytopenia. For example, in TTP and HUS, symptoms develop suddenly. In ITP, symptoms may develop suddenly or gradually and subtly.
Symptoms in TTP and HUS are quite distinct from symptoms of most other forms of thrombocytopenia. In TTP, the small blood clots that develop (using up platelets) cause a wide range of symptoms and complications, some of which can be life threatening. Symptoms that result from clots in the brain may include headache, confusion, seizures, and coma. Symptoms that result from clots elsewhere in the body include abnormal heart rhythms, blood in the urine that accompanies kidney damage, and abdominal pain. The predominant symptoms and complications of HUS are related to blood clots that develop in the kidneys, causing damage that is usually severe and may progress to kidney failure.
Diagnosis
Doctors suspect thrombocytopenia in people who have abnormal bruising and bleeding. They often check the number of platelets routinely in people who have disorders that cause thrombocytopenia. Sometimes they discover thrombocytopenia when blood tests are performed for other reasons in people who have no bruising or bleeding.
Determining the cause of thrombocytopenia is critical to treating the condition. Certain symptoms may help determine the cause. For example, people usually have a fever when thrombocytopenia results from an infection. In contrast, they usually do not have a fever when the cause is ITP, TTP, or HUS. An enlarged spleen, which a doctor may be able to feel during a physical examination, suggests that the spleen is trapping platelets and that thrombocytopenia results from a disorder that causes the spleen to enlarge. HUS is diagnosed when poor kidney function is identified by blood tests that show high levels of urea nitrogen and creatinine.
A sample of blood may be examined under a microscope, or the platelet count may be measured with an electronic counter to determine the severity of thrombocytopenia and provide clues to its cause. A sample of bone marrow removed and examined under a microscope (bone marrow aspiration and biopsy (see Symptoms and Diagnosis of Blood Disorders: Bone Marrow Examination) may be needed to provide information about platelet production.
Treatment
People who have a very low platelet count are often treated in a hospital or advised to stay in bed to avoid accidental injury. When bleeding is severe, platelets may be transfused.
Addressing the underlying cause can often treat the thrombocytopenia. Thrombocytopenia caused by a drug usually is corrected by discontinuing the drug. The effects produced by antibodies that destroy platelets in ITP can be blocked temporarily with a corticosteroid (for example, prednisone) or intravenous immune globulin, allowing the number of platelets to increase. Danazol may have similar effects as prednisone. Drugs that suppress the immune system, including cyclophosphamide Some Trade Names
LYOPHILIZED CYTOXAN
and sometimes azathioprine Some Trade Names
IMURAN
, may reduce the formation of antibodies. Most adults (but not children) with ITP eventually require surgical removal of the spleen (splenectomy) to increase the number of platelets. People with TTP are often treated with plasma transfusions along with plasmapheresis (see Testing Donated Blood for Infections). The two procedures together are called plasma exchange.
Complications that require long-term treatment can result from some causes of thrombocytopenia. For example, the number of platelets usually increases as people recover from the hemolytic-uremic syndromeHUS; however, lifelong dialysis or kidney transplantation may be needed if the kidney failure persists.
Thrombophilia
Thrombophilia is a disorder in which the blood clots easily or excessively.
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Inherited and acquired disorders can increase blood clotting.
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Clots cause legs or arms to swell.
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Blood levels of proteins that control clotting are measured.
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People may need anticoagulants.
Most disorders that cause thrombophilia increase the risk of blood clot formation in veins; a few increase the risk of clot formation in both arteries and veins.
Causes
Some of the disorders that cause thrombophilia are inherited. Many of these result from changes in the amount or function of certain proteins in the blood that control clotting. For example, activated protein C resistance (Factor V Leiden mutation); a specific mutation in the prothrombin gene, (prothrombin 20210 mutation); and a deficiency of protein C, protein S, or antithrombin all cause an increase in the production of fibrin, an important protein involved in clot formation. Hyperhomocysteinemia, an increase in the amount of homocysteine (a type of amino acid) in the blood, may increase the risk of clotting in veins and arteries.
Other disorders that cause thrombophilia are acquired after birth. These disorders include disseminated intravascular coagulation (often associated with cancer), and antiphospholipid antibody (anticardiolipin) syndrome (including the presence of the lupus "anticoagulant"), which increase the risk of clotting because of overactivation of blood clotting factors.
Other factors may increase the risk of clotting along with thrombophilia. Many involve conditions that result in a person not moving around sufficiently, causing blood to pool in the veins. Examples include paralysis, prolonged sitting (especially in confined spaces as in a car or airplane), prolonged bed rest, recent surgery, and heart attack. Heart failure, a condition in which the blood is not pumped sufficiently through the bloodstream, is a risk factor. Conditions that result in increased pressure on veins, including obesity and pregnancy, also increase risk.
Symptoms and Complications
Most of the inherited disorders do not begin to cause an increased risk of clotting until young adulthood, although clots can form at any age. Many people with inherited disorders develop a deep vein clot (deep vein thrombosis) in the legs, which can result in leg swelling. Formation of a deep leg clot may be followed by pulmonary embolism. After several deep vein clots have occurred, more serious swelling and skin discoloration may develop (chronic deep vein insufficiency). Sometimes, clots form in superficial leg veins, causing pain and redness (superficial thrombophlebitis). Less commonly, clots may form in arm veins, abdominal veins, and veins inside the skull. Hyperhomocysteinemia and the antiphospholipid syndrome may result in venous or arterial clots. When clots obstruct blood flow in arteries, tissues lose their blood supply and may be damaged or destroyed.
Diagnosis and Treatment
A person who has had at least two separate instances of a blood clot without an apparent predisposing factor may have an inherited thrombophilia disorder. An inherited disorder may also be suspected if a person with an initial blood clot has a family history of blood clots. A young healthy person who develops an initial clot for no apparent reason may have an inherited disorder.
Blood tests that measure the amount or activity of different proteins that control clotting are used to identify specific inherited disorders ofthat cause thrombophilia. These tests are usually more accurate when performed after a blood clot has been treated.
The inherited disorders that cause thrombophilia are incurable. People who have had two or more clots are especially likely to be advised to take the anticoagulant warfarin Some Trade Names
COUMADIN
for the rest of their lives. When a person has had only one clot, warfarin Some Trade Names
COUMADIN
or heparin to prevent future clots may be used only when the person is at higher risk for clot formation, including during a period of prolonged bed rest.
People with hyperhomocysteinemia may be advised to take vitamin supplements with folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin), which can reduce homocysteine levels. However, it is unclear whether these supplements also reduce clot formation.
Von Willebrand's Disease
Von Willebrand's disease is a hereditary deficiency or abnormality of the blood protein von Willebrand factor, which affects platelet function.
The von Willebrand factor is found in plasma, platelets, and the walls of blood vessels. When the factor is missing or defective, platelets cannot adhere to the vessel wall at the site of an injury. As a result, bleeding does not stop as quickly as it should.
Symptoms and Diagnosis
Often, a person with von Willebrand's disease has a parent who has a history of bleeding problems. Typically, a child bruises easily or bleeds excessively after a cut, tooth extraction, or surgery. A young woman may have increased menstrual bleeding. Bleeding may worsen at times. On the other hand, hormonal changes, stress, pregnancy, inflammation, and infections may stimulate the body to increase production of the von Willebrand factor and temporarily improve the capacity of platelets to stick to the blood vessel wall and stop bleeding.
Laboratory tests typically show that the bleeding time it takes for blood to clot is abnormally long. Bleeding time is the amount of time that elapses before bleeding stops after a small cut is made on the forearm. Bleeding time is the amount of time that elapses before bleeding stops after a small cut is made on the forearm. Doctors may order tests that measure the amount of von Willebrand factor in the blood. Because the von Willebrand factor is the protein that carries an important clotting factor (factor VIII) in the blood, the level of factor VIII in the blood may also be decreased.
Treatment
Many people with von Willebrand's disease never need treatment. If excessive bleeding occurs, a transfusion of concentrated blood clotting factors containing von Willebrand factor may be given. For some mild forms of the disease, drug treatment with desmopressin Some Trade Names
DDAVPSTIMATE
may be given to increase the amount of the von Willebrand factor long enough for surgery or dental procedures to be performed without transfusions.
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