Cause and Pathophysiology of Chronic ITP
**Note! If you have trouble understanding this section, refer to the section on Definition of General Terms.
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 and specific cytotoxic T lymphocytes. Why these platelet proteins are recognized as 'foreign' by the immune system is not known.
Platelet production in the bone marrow and survival in the bloodstream.
Platelets are produced in the bone marrow by large cells called megakaryocytes. These cells are stimulated to multiply and produce platelets primarily by a substance called thrombopoietin. Once platelets are released from the bone marrow, they normally circulate in the blood for 8-10 days. In patients with chronic ITP, platelet survival in the blood is reduced due to their destruction (sometimes as short as a few hours) 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.
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. The majority 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 patients, 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. The spleen is the most important site of antibody production in chronic ITP, although autoantibody is also produced in the bone marrow.
Cytotoxic thymic-dependent (T) lymphocytes.
These specialized white blood cells are produced in the bone marrow and then mature in the thymus gland. They have receptors on their surface that are programmed to bind to a specific antigen that, in the case of ITP, is on the surface of platelets and probably megakaryocytes. Cytotoxic T lymphocytes may circulate in the blood but are primarily localized in the spleen and lymph nodes.
Causes of thrombocytopenia in ITP.
Platelet destruction. Platelet destruction in chronic ITP is due to either: (1) antibody binding to a platelet autoantigen(s) followed by phagocytosis of the platelets by white blood cells (neutrophils or monocytes) or (2) binding of cytotoxic T lymphocytes to platelets followed by release of toxins causing platelet death. For platelet destruction by antibody to occur, three things must be present: sufficient antigen (platelets), autoantibody and phagocytic 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 phagocytic cells that destroy them. Concurrently, cytotoxic T lymphocytes are reacting with antigens on platelets, adding to the destruction of platelets. Removal of the spleen results in the cure of many ITP patients. In patients who have no spleen, the antibody is produced mostly in the bone marrow, and the antibody-sensitized platelets are destroyed in either the bone marrow or liver.
Suppression of platelet production. The bone marrow is capable of increasing the production of platelets up to 6 to 8 times normal, if necessary. However, platelet production in most ITP patients is less than would be expected, in view of the ongoing platelet destruction. This suggests that, in some patients, the autoantibody and probably the cytotoxic T lymphocytes may also damage megakaryocytes and inhibit platelet production. There is experimental evidence to show that autoantibody can suppress platelet production; studies have not been done, thus far, to evaluate the role of cytotoxic T lymphocytes.
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