Chronic ITP

v Clinical Presentation of Chronic ITP

Definition

Chronic means that the disorder persists unless treated and ITP stands for: I-immune; T-thrombocytopenic; P-purpura. Immune means that the body's immune system is involved in destroying platelets; thrombocytopenia means a low platelet count and purpura is a medical name for bruising.

In chronic ITP, the body's immune system (for reasons that are not known) produces autoantibodies against proteins on the patient's platelets and causes them to be destroyed by the body's white blood cells. A similar clinical pattern may occur with certain drugs (e.g., quinidine, quinine, or sulfa-like drugs, although many drugs have been involved) and may be associated with other diseases such as systemic lupus erythematosus, lymphoproliferative disorders (e.g., non-Hodgkin's lymphoma) or infection (e.g., HIV infection, cytomegalovirus infection or hepatitis). These other causes must be ruled out before the diagnosis of chronic ITP can be made.

Clinical Findings

Patients may have no symptoms and the low platelet count may be noted during routine blood studies. However, most patients see their doctor because they develop a skin rash on their legs (called petechiae, a collection of small pinpoint bruises), excessive bruising or, less commonly, bleeding from the nose, gums or rarely from the gastrointestinal tract (stomach or bowel) or genitourinary tract (blood in the urine). Women may note prolonged or heavy menstrual bleeding. Symptoms may be exagerrated by certain medications which interfere with platelet function (e.g., aspirin, ibuprofen).

Laboratory Findings

The blood count is normal except for a low platelet count (a normal platelet count in our laboratory is 130,000 to 400,000). Occasionally, patients are anemic if significant bleeding has occurred. Bone marrow examination is normal except that the number megakaryocytes (the cells which produce platelets) is often increased since the body is attempting to respond to the destruction of platelets by increasing their production. Autoantibodies against platelets can be detected in most patients. In chronic ITP, all other laboratory tests should be normal (including tests to rule out HIV, hepatitis or cytomegalovirus infection).

Cause and Pathophysiology of Chronic ITP

Chronic ITP is an autoimmune disorder in which normal proteins located on the platelet surface act as antigens and stimulate the immune system to produce autoantibody. This autoantibody then binds to the platelet protein, which signals the body's white blood cells to remove the platelets from the blood stream by phagocytosing (eating) the antibody-sensitized platelets. Why these platelet proteins are recognized as `foreign' by the immune system is not known.

Platelet production. Platelets are produced in the bone marrow by large cells called megakaryocytes. The bone marrow is capable of increasing the production of platelets up to 6 to 8 times normal, if necessary. However, platelet production in many ITP patients is less than would be expected, in view of the ongoing platelet destruction. This suggests that the autoantibody, in some patients, may inhibit platelet production or destroy platelets in the bone marrow before they can be released into the blood.

Platelet survival in the bloodstream. Once released from the bone marrow, platelets normally circulate in the blood for 8-10 days. In patients with chronic ITP, the platelet survival time is shortened due to their destruction by autoantibody and the patient develops a low platelet count (thrombocytopenia). Platelet destruction occurs mainly in the spleen and to some extent in the liver and bone marrow. This is one reason that patients with ITP respond to removal of the spleen.

Antiplatelet autoantibody. Studies in the 1950's showed that transfusion of blood or plasma from a patient with chronic ITP into a normal volunteer subject caused thrombocytopenia. Subsequent studies showed that the substance, in the blood of ITP patients, that destroys platelets is an autoantibody. In most patients, the autoantibody binds to an antigen on one of the protein complexes (a complex is a combination of two or more proteins) on the platelet surface. About 75% of patients have antibodies which bind to either the platelet glycoprotein IIb/IIIa complex (a combination of glycoprotein IIb and glycoprotein IIIa) or the platelet glycoprotein Ib/IX complex (a combination of glycoprotein Ib and glycoprotein IX); in the other 25%, the location of the antigen on the platelet is not known. Since these glycoprotein complexes are also present on the megakaryocyte, the autoantibody in chronic ITP may also affect platelet production.

Sites of antibody production. The spleen is the most important site of antibody production in chronic ITP. This is another reason why splenectomy is a successful treatment in many patients. Autoantibody production may also occur in the bone marrow.

Platelet destruction. Platelet destruction in chronic ITP is due to antibody binding to a platelet autoantigen(s) followed by phagocytosis of the platelets by white blood cells. For platelet destruction to occur, three things must be present: sufficient antigen (platelets), autoantibody and phagocytic cells (white blood cells). The spleen is an optimal location for this. About one third of the circulating platelets are in the spleen at all times and the production of antiplatelet antibody in the spleen subjects these platelets to high antibody concentrations. The antibody-sensitized platelets circulate slowly through the spleen, which is rich in the white blood (phagocytic) cells that destroy them. Removal of the spleen results in the cure of many ITP patients. In patients who have no spleen, the antibody is mostly produced in the bone marrow, and the antibody-sensitized platelets are destroyed in either the bone marrow or liver.

v Evaluation of Antiplatelet Autoantibody

The diagnosis of chronic ITP can be made without measuring antiplatelet antibodies. The measurement of antiplatelet antibody is primarily of research interest, although it may be useful in cases where there is confusion about the diagnosis. Either autoantibody bound to the patient's platelets (platelet-associated autoantibody, the most sensitive test) or autoantibody circulating in the plasma (plasma autoantibody) can be measured.

Specific tests. There are two excellent tests to measure platelet-associated and plasma autoantibody: the immunobead assay and the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay. Both tests measure autoantibody against antigens on specific platelet glycoprotein complexes (a complex is a combination of two or more proteins), usually glycoprotein IIb/IIIa (a combination of platelet glycoprotein IIb and platelet glycoprotein IIIa) and glycoprotein Ib/IX (a combination of platelet glycoprotein Ib and platelet glycoprotein IX). These tests give positive results in about 75% of ITP patients and are not positive in patients with other causes of thrombocytopenia. Unfortunately, these specific tests are done primarily in research laboratories and are unavailable in most clinical laboratories.

Non-specific test. The test used in most clinical laboratories measures platelet-associated IgG. This detects any IgG antibody (both specific antiplatelet antibody and any other IgG antibody associated with the platelet). Although this test gives positive results in about 90% of chronic ITP patients, it may also be falsely positive in patients who have other causes of a low platelet count that are not due to antiplatelet autoantibody. Therefore, this test does not specifically measure antiplatelet antibody and most people in the field do not recommend it.

v Differential Diagnosis and Prognosis of Chronic ITP

Differential diagnosis. The diagnosis of chronic ITP is one of exclusion. Other causes must be ruled out by careful attention to the patient's history and physical examination and by performing indicated tests. A complete blood count is always needed and in many cases a bone marrow examination is recommended. Other tests may be needed, depending on the clinical presentation.

Disorders most commonly confused with chronic ITP

Drugs. Certain drugs cause low platelet counts. The most common are quinine, quinidine, sulfa and sulfa-like drugs and heparin. However, many other drugs have caused thrombocytopenia in occasional patients. If the patient is taking a potentially causitive drug, it should be stopped and the platelet count observed. If a drug is the cause, the platelet count will become normal within 2-3 weeks, although there are occasional exceptions (e.g., thrombocytopenia due to gold therapy in patients with rheumatoid arthritis).

Immune thrombocytopenia associated with other diseases. Thrombocytopenia may be associated with a variety of diseases including: collagen vascular disease (such as systemic lupus erythematosus), lymphoproliferative disorders (such as chronic lymphocytic leukemia or non-Hodgkin's lymphoma), and infections (particularly viral infections such as HIV, cytomegalovirus, hepatitis and mononucleosis). These disorders can be ruled out by careful examination and the appropriate laboratory studies.

Disorders associated with decreased platelet production. A variety of diseases such as aplastic anemia, acute leukemia, etc. can cause thrombocytopenia. These can be easily ruled out by evaluation of the blood count and bone marrow.

Clinical course and prognosis. In some patients, the platelet count recovers spontaneously, usually within the first few weeks. These patients may have another cause of thrombocytopenia such as a viral illness. Other chronic ITP patients (about 5-10%) have stable disease, with a platelet count of 30-100,000, which may persist for months to years and rarely requires treatment. Of patients who need treatment (platelet count consistently less than 25-30,000), approximately 75% are cured of their disease with either corticosteroids (cortisone) or by removal of their spleen (splenectomy). Most of the remaining patients can be controlled and sometimes cured of their disease with other forms of treatment. The mortality rate from chronic ITP is about 4%.

v Standard Treatment of Adult Chronic ITP

Who should treat ITP?

Initial treatment (steroids/splenectomy) in an uncomplicated patient can be managed by a family practitioner or general internist with experience in this area. If the patient is actively bleeding or has failed to respond to intitial treatment with corticosteroids and splenectomy, a hematologist/oncologist should be contacted. In extremely complicated cases, the treating hematologist/oncologist may wish to contact a consultant with a special interest in adult chronic ITP.

Indications for treatment

Treatment is indicated only in patients who are unable to maintain platelet counts consistently over 25-30,000. There are occasional exceptions to this (patients should discuss this with their doctor). Patients whose lifestyle involves a significant risk of injury (e.g., a professional football player) will require higher platelet counts for safety.

General treatment recommendations

Patients with low platelet counts should: (1) avoid aspirin or non-steroidal anti-inflammatory drugs, such as ibuprofen, since these agents may interfere with platelet function and induce bleeding. For mild pain relief, acetominophen (Tylenol) is safe since it does not affect platelet function. (2) avoid situations where significant injury could occur (e.g., football, skiing, sky diving, etc.)

Index of treatment options

n   Emergency treatment