In a clear and informative parallel to anemia, thrombocytopenia can be due either to decreased platelet production or enhanced platelet destruction. The life span of normal platelets in the circulation is about 7 to 9 days. Therefore, if the bone marrow stops producing platelets, it takes nearly a week before severe thrombocytopenia develops. In contrast, an acute immune or consumptive process that suddenly and drastically curtails platelet survival can produce severe thrombocytopenia within hours.
Damage or suppression of pluripotent hematopoietic stem cells may result in not only thrombocytopenia but also anemia and leukopenia (pancytopenia) accompanied by marrow aplasia. Aplastic anemia and other causes of pancytopenia are covered in Chapter 4. Transient thrombocytopenia due to marrow aplasia and decreased platelet production predictably follows certain forms of chemotherapy or radiation therapy for cancer. Other drugs selectively inhibit platelet production. Occasionally, patients with severe alcoholism will present with thrombocytopenia that appears to be due to a toxic effect of ethanol on megakaryocytes. In most cases, the platelets gradually return to baseline levels following cessation of therapy or drinking. Somewhat less often, decreased platelet production is due to a primary bone marrow disorder such as acute leukemia or a myelodysplastic syndrome. Less severe thrombocytopenia can be due to megaloblastic anemia or to invasion of the bone marrow by tumors such as lymphoma or carcinoma.
The administration of thrombopoietin (Tpo) or Tpo-mimetic agents is seldom effective in the treatment of severe thrombocytopenia due to impaired platelet production. This may be due to the fact that endogenous plasma Tpo levels are already markedly elevated in these patients, owing to very low numbers of megakaryocytes in the bone marrow as well as platelets in the periphery. (See Chapter 2 for information on the regulation of platelet production by endogenous Tpo.) Because the platelet life span is usually normal in these patients, platelet transfusions produce a significant and beneficial rise in the platelet count unless or until the patient develops alloimmunization. In contrast, platelet transfusions are much less effective in patients in whom thrombocytopenia is due to enhanced destruction.
As explained in Chapter 1, the spleen in normal individuals contains (sequesters) about a third of the body's platelets. Patients who have splenomegaly due to a wide range of disorders (Chapter 1, Table 1-4) have a higher proportion of their platelets entrapped along with white and red blood cells. A significant reduction in one or more of the peripheral blood counts by splenic sequestration is called hypersplenism.
Patients with hypersplenism generally have platelet counts of 50,000 to 120,000/mm3. Thus, the degree of thrombocytopenia is almost never low enough to pose a risk of hemorrhage. Accordingly, splenectomy is not indicated for correction of the platelet count. However, some patients may have neutropenia that is sufficiently severe to warrant splenectomy.
Severe thrombocytopenia is commonly caused by rapid destruction of platelets, most often due either to immune clearance or to consumption in conditions associated with intravascular thrombosis. In either case, the bone marrow produces increased numbers of platelets that have a short survival in the circulation. Because platelets normally become smaller as they age in vivo, the few platelets that are seen in blood films of patients with thrombocytopenia due to increased destruction tend to be larger than average.
Immunologic recognition followed by destruction of platelets is a relatively common cause of severe thrombocytopenia in individuals of all age groups. Most of these individuals come to medical attention because they develop purpura—hence the designation immune thrombocytopenic purpura (ITP). In children, the peak incidence is about 5 years of age. These previously healthy children typically develop a sudden onset of petechiae or ecchymoses within a few days or weeks following an infectious illness, usually viral. In the majority of these patients, the thrombocytopenia and purpura resolve within 6 months regardless of whether they have received therapy. Adults with ITP have a strikingly different clinical presentation and course. In these patients, the onset is insidious and seldom accompanied by a viral prodrome. The illness is chronic and, when severe, requires meticulous and often complex management. In both children and adults, if ITP is the primary diagnosis, patients normally have no symptoms or physical findings except for purpura. The spleen and lymph nodes are not enlarged. Some women also experience menorrhagia. Gastrointestinal bleeding is much less common. Rarely patients with ITP sustain cerebral hemorrhage.
There is overwhelming circumstantial evidence that in ITP platelets are destroyed by autoantibodies directed against platelet antigens. In early (less regulated) days of clinical research, it was noted that the intravenous administration of plasma from a patient with ITP to a normal volunteer resulted in the development of acute and severe thrombocytopenia and purpura. These studies led to the hypothesis that ITP patients had circulating autoantibodies directed against "public" antigens displayed on the surface of platelets in all individuals. These antibody-coated platelets are rapidly cleared by the interaction of the Fcγ receptor on tissue macrophages with the Fc (constant) portion of the immunoglobulin.
The primary public antigen targeted for immune attack in ITP is GPIIb/IIIa, which, as explained in Chapter 13, undergoes a conformational change during platelet activation and is the site of fibrinogen cross-linking. As shown in Figure 14-2, once the antibody-coated platelet is recognized and engulfed by the macrophage, GPIIb/IIIa as well as other platelet membrane proteins are degraded. These peptide antigens are then coupled with HLA class 2 molecules and displayed on the macrophage cell surface. This antigen-presenting complex interacts with the T-cell receptor on CD4 helper lymphocytes, inducing proliferation and recruitment of antigen-specific B-cell clones, which also proliferate and produce high levels of antibody against not only GPIIb/IIIa but also GPIb/IX and other platelet antigens.
Amplification of the immune response in immune thrombocytopenic purpura. Phagocytosis of antibody-coated platelets by macrophages results in the presentation of platelet peptide neoantigens to CD4 helper T cells, which then trigger proliferation of B-cell clones, producing high levels of antiplatelet antibodies. (Modified with permission from Cines DB and Blanchette VS. Immune thrombocytopenic purpura. New Engl J Med. 2002; 346:995-1008. Copyright © 1972 Massachusetts Medical Society, all rights reserved.)
The rapid destruction of platelets by resident macrophages results in Tpo-mediated stimulation of megakaryocyte production in the bone marrow. Thus, patients with ITP usually have increased numbers of marrow megakaryocytes (Fig. 14-3). Indeed, as a general rule, the level of platelet production parallels the number of megakaryocytes in the bone marrow. In this respect, the pathophysiology of ITP closely parallels that of immune hemolytic anemia (Chapter 11). In both disorders, the enhanced destruction of the blood cell in the peripheral circulation is accompanied by a compensatory hyperplasia of the respective precursors in the bone marrow. However, the plasma levels of the critical cytokines differ in the two disorders. In immune hemolytic anemia, as in nearly all other types of anemia, plasma erythropoietin levels are markedly elevated, in response to hypoxic stress (Chapter 1). In contrast, in ITP, plasma Tpo levels are generally normal or modestly elevated, owing to the clearance of this cytokine by hyperplastic marrow megakaryocytes.
Bone marrow of a patient with immune thrombocytopenic purpura, showing increased numbers of megakaryocytes. Erythroid and myeloid lineages are normal.
Most often, immune thrombocytopenia arises spontaneously in otherwise healthy individuals with no underlying illness. The sudden development of purpura in an asymptomatic patient with normal hemoglobin level, white blood cell count, and differential count is very likely to be ITP. However, even in this setting the possibility of associated disorders should be investigated and ruled out. Immune thrombocytopenia is encountered in a substantial minority of patients with lymphoma and human immunodeficiency virus (HIV) infection, sometimes when these illnesses are at a preclinical stage. In other cases, the association with an underlying condition is obvious, such as immune thrombocytopenia seen in patients with acute mononucleosis, in those who have undergone bone marrow transplantation, and in those with systemic lupus erythematosus. Occasionally, drugs can cause immune-mediated destruction of platelets. The classic example is the antiarrhythmic agent quinidine, a drug that is now seldom used. Much more often the anticoagulant heparin (Chapter 13) is associated with immune thrombocytopenia. The drop in platelet count caused by heparin is generally modest, but affected patients are paradoxically at high risk of developing life-threatening venous and arterial thrombosis (see Chapter 17).
Other than a complete blood count, no other laboratory test is essential in making the diagnosis of ITP. However, it is prudent to check a baseline coagulation profile to rule out disseminated intravascular coagulation and to obtain screening tests for lupus and infection with HIV and Epstein-Barr virus. Unfortunately, no serological test for detecting antibody coating of platelets is nearly as reliable as the Coombs test for detecting antibody-coated red cells. As mentioned earlier, the presence of large platelets in the peripheral blood smear suggests that the thrombocytopenia is due to a decrease in platelet life span. If doubt persists, a bone marrow examination will provide more definitive evidence as to whether the thrombocytopenia is due to impaired production or increased destruction.
As mentioned earlier, most children with ITP remit spontaneously and therefore do not require treatment. In contrast, adult patients require treatment if the thrombocytopenia poses a significant risk of bleeding (platelet count <50,000/mm3). The treatment strategy for ITP closely parallels that of immune hemolytic anemia (Chapter 11). Administration of high doses of corticosteroids reliably results in a boost in the platelet count within the first week, and with continued treatment, the platelet count often reaches normal levels. Steroid therapy appears to suppress both the clearance of the antibody-coated platelets and the production of anti-platelet autoantibodies. Most patients relapse during or following the withdrawal of steroids. Alternative therapy is required in patients who either fail to respond to steroids or require prolonged treatment in order to maintain platelet counts in a safe range (>50,000/mm3). Currently, the recommended second-line therapy is rituximab, a monoclonal antibody directed against the CD20 surface antigen on B lymphocytes. If this treatment is not effective, splenectomy offers a good chance of prolonged remission. It should be noted that this is true even though splenomegaly is not a feature of ITP. Recent clinical trials have shown that Tpo-mimetic drugs are effective in patients with refractory ITP, but it is too early to know whether this treatment will become part of standard care. Patients with extremely low platelet counts and those being prepared for surgery generally respond promptly, albeit transiently, to the intravenous (IV) administration of high doses of immunoglobulin; the mechanism of this response is not known.
Treatment of ITP
DISSEMINATED INTRAVASCULAR COAGULATION
Disseminated intravascular coagulation is a relatively common cause of thrombocytopenia due to enhanced platelet destruction. This often catastrophic complication is encountered in patients with a wide range of severe illnesses including sepsis, obstetrical emergencies, trauma, and cancer. In contrast to ITP, the coagulation profile is markedly abnormal. Rapid platelet consumption is secondary to inappropriate triggering of the coagulation cascade. This topic is covered in detail in Chapter 16.