Thrombocytopenia is a platelet count below the lower normal limit of 150,000 cells^L and has two major causes, reduced platelet production and accelerated platelet removal. Bleeding does not generally occur until the platelet count falls below 20,000 cells^L or the patient is an older adult, has coexistent diseases such as liver dysfunction or a connective tissue disorder, or is taking a drug that impairs platelet function.
Clinical signs of thrombocytopenia include the appearance of petechiae, small spots of pinpoint (millimeters) bleeding in the skin and subcutaneous tissue in which red blood cells leak from small capillaries or venules. Petechiae occur most frequently at sites in the lower extremities, around the mouth, or where there is constrictive clothing causing pressure on small vessels. Mucosal bleeding, recurrent nosebleeds, small bruises, and excessive menstrual bleeding are likely to be associated with von Willebrand's disease or discrete platelet disorders. If the clinical picture involves deep tissue bleeding into muscles or joints, a clotting factor disorder such as hemophilia is more likely.
Aspirin plays a key role in impairing platelet function and is used prophylactically in small doses to prevent coronary insufficiency syndromes and strokes. The investigation and treatment of thrombocytopenia are significantly affected by whether it is a solitary phenomenon or is associated with other cytopenias. Confirmation of a low platelet count should be done by repeating the CBC, because low platelet numbers can result from clumping caused by inappropriate anticoagulation of the blood sample or cold agglutinins. MPV can provide additional diagnostic information; low values suggest poor production and very old platelets, and high values suggest rapid production of new platelets. Bone marrow aspiration with biopsy may be important in the diagnosis of thrombocytopenia when the cause is unclear, because it may indicate aplasia, hypopla-sia, drug toxicity, or bone marrow infiltration with leuke-mic cells or fibrosis.
Box 39-6 divides the causes of thrombocytopenia into production defects and accelerated platelet removal mechanisms. Platelets may not be produced in adequate numbers or may have dysfunctional characteristics if the marrow has been damaged by radiation or chemotherapeutic drugs or has been infiltrated by cancer or fibrous tissue. Drugs such as gold, sulfa products, thiazides, and ethanol can inhibit platelet production, and certain infections (e.g., HIV, rubella) or vaccines may cause deficits in production. Drug etiologies are more frequently related to drugs started within the previous 1 to 2 months. Deficiencies of vitamins (e.g., B12, folic acid) may render the development of platelets ineffective.
Box 39-6 Classification of Thrombocytopenic Disorders
Platelet production defect
Pancytopenia, aplasia: Radiation, cancer drugs Marrow infiltration: Fibrosis, cancer
Impaired platelet production: Infections (rubella, HIV) drugs; gold, sulfa compounds, alcohol
Impaired platelet development: Folate, vitamin B12 deficiencies, alcohol Accelerated platelet removal
Immune destruction: Autoantibodies—idiopathic thrombocytopenic purpura, systemic lupus erythematosus; infections (HIV, sepsis, mono-nucleosis); drugs
Nonimmune destruction: Disseminated intravascular coagulation, vasculitis, thrombotic thrombocytopenic purpura, HELLP syndrome* Hypersplenism: Various causes
*Hemolysis (microangiopathic), elevated liver enzymes, and low platelets.
The most common phenomenon in accelerated platelet removal is immune destruction. Antibodies produced by the body may facilitate the enhanced removal of platelets from the circulation. Diseases involving immune platelet destruction include idiopathic thrombocytopenic purpura, systemic lupus erythematosus (SLE), drug-induced thrombocytopenia, infectious mononucleosis, HIV/AIDS, malaria, and even posttransfusion purpura. Diseases involving no immunologic mechanism, but in which platelets are removed from the circulation more rapidly than normal, include disseminated intravascular coagulation (DIC), preeclampsia, vasculitis, thrombotic thrombocytopenic purpura, and gram-negative septicemia. Also, a significantly enlarged spleen represents an increased platelet pool, thus lowering the platelet count.
Removal of drugs that could be causing production problems and replacement of vitamins (B12 and folic acid) are probably the easiest remedies to address platelet production defects. Recombinant thrombopoietin is in development, but has not yet been approved for clinical use. Platelet counts greater than 50,000 cells^L are generally safe for interven-tional procedures, except major surgery or epidural anesthesia. Childbirth and tooth extractions may occur safely with stable platelet levels (30,000-50,000) and no evidence of bleeding.
Accelerated Platelet Removal Caused by Immune Destruction
Formerly seen most often in young women, idiopathic thrombocytopenic purpura (ITP) is now seen more often in HIV-positive men. Associated illnesses or causes may include infectious mononucleosis, Graves' disease, thyroiditis, and other viral illnesses. ITP has an insidious onset, with the only physical finding being petechiae in the lower extremities. There may be some gingival bleeding with brushing or flossing of the teeth; splenomegaly is uncommon. ITP is characterized as an autoimmune disorder in which IgG antibodies are formed against the patient's own platelets. These antibodies attach to platelets, causing them to be identified as abnormal. The platelets are then removed by the RES, most often in the spleen. The bone marrow responds to the rapid destruction of platelets by increasing production, resulting in functionally large platelets, which accounts for the low incidence of bleeding in this disorder. The laboratory evaluation reveals a higher-than-normal MPV and the presence of few platelets on a peripheral blood smear (Bain, 2005); however, the platelets present are large and well granulated. If schistocytes or helmet cells are seen, this suggests a mechanical hemolytic process as well. The bone marrow reveals a plethora of megakaryocytes, whereas other test results for autoimmune diseases should be negative. Other, similar presentations might include a falsely low platelet count resulting from the anticoagulant used in the blood sampling (e.g., pseudothrombocytopenia caused by clumping), cold agglu-tinins, gestational thrombocytopenia, and myelodysplastic syndrome.
Treatment of ITP varies with the degree of bleeding, whether the patient is pregnant, CNS involvement, and to some extent, the patient's age. The goal is to prevent serious bleeding. The American Society of Hematology has made the following evidence-based recommendations for the management of ITP (George et al., 1996):
1. Patients with platelet counts above 50,000 cells^L do not require treatment routinely.
2. Treatment is indicated in patients with platelet counts of 20,000 to 30,000 and in patients with platelets below 50,000 with significant mucosal bleeding or risk factors for bleeding.
3. Patients with platelets below 20,000 need not be hospitalized if they are asymptomatic or if they have only mild purpura.
Patients in the second category who have mucosal bleeding with a platelet count between 20,000 and 30,000 cells^L are often treated with prednisone, 60 to 100 mg/day, to reduce the amount of antiplatelet antibodies produced by lymphocytes in the marrow and spleen. When the platelet count rises after 2 to 3 weeks of therapy, the prednisone can be tapered over another 3 to 4 weeks. Long-term complete response occurs in probably 15% to 20% of patients. If the platelet counts remain below 30,000 after 6 to 8 weeks of therapy, or if the platelet count begins to fall after the steroids have been tapered, splenectomy should be considered. If splenectomy is planned, steroid therapy should be resumed to boost the platelet count to a more acceptable level. The lymphoid system in the spleen can respond best to immunizations, such as pneumococcal, Haemophilus influenzae, or meningococcal vaccine, which should be administered 1 to 2 weeks before surgery. If steroids do not raise the platelet level to an acceptable presurgical level, IVIG at 0.4 to 1.0 mg/kg may also be administered before surgery but will take 1 to 3 days to increase platelet counts to safe levels. CNS bleeding is a medical emergency in which hospitalization, large doses of prednisone, and IVIG are used as concomitant therapeutic measures.
Patients who go into remission and later relapse or fail to respond to these measures are considered to have refractory ITP. If the platelet count is above 30,000, the best course of action is to consider it an incomplete response and manage the patient conservatively, without further therapy. If therapy is indicated in these refractory cases, the physician can consider agents such as azathioprine or cyclophosphamide, plus prednisone. Referral of these patients to a hematologist is often necessary.
Immune-mediated thrombocytopenia may occur in patients with SLE or lymphoma; treatment is similar to that of ITP in other patients. If the ITP is associated with a hemolytic anemia, the clinical picture is that of Evans' syndrome. Treatment is similar to that for ITP without autoimmune hemolytic anemia. Patients with aggressively treated HIV may develop antibodies to the platelet GP-IIb/IIIa, causing thrombocytopenia; if platelet count is below 10,000, prednisone or splenectomy (or both) can be used. Patients treated with GP-IIb/ IIIa antagonists may develop thrombocytopenia. Removal of the antagonist is usually effective. For platelet counts less than 10,000, one platelet transfusion is usually effective in restoring platelets to safe levels.
Approximately 5% of all pregnant women have a platelet count as low as 70,000 cells^L. If the platelet count drops lower, preeclampsia should be ruled out before making a diagnosis of ITP. Splenectomy carries significant risks of miscarriage, which can be reduced by administering cortico-steroids or IVIG.
Multiparous women receiving a blood or platelet transfusion may have posttransfusion thrombocytopenia at a level of 10,000 cells^L or lower. This is apparently the result of having previously been sensitized to blood and platelet antigens that induced an antibody not only to the foreign platelets in the transfusion, but also to endogenous platelets. This occurs 2 to 10 days after the transfusion and may last for as long as 4 weeks. Platelet transfusions are not effective. Therapeutic use of IVIG and sometimes high doses of corticoste-roids are more likely to be effective.
Specific drugs can elicit immune-mediated platelet destruction that mimics ITP, including cocaine, gold, heparin, quinidine, and platelet glycoprotein antagonists (e.g., abcix-imab [ReoPro]). Removal of the offending drug is usually sufficient, along with time to allow the situation to resolve. A few cases of thrombocytopenia have occurred in patients taking a combination of naproxen and acetaminophen; their metabolism caused an immune reaction involving normal platelets, leading to their enhanced destruction.
A common theme in nonimmune platelet destruction is blood vessel wall injury, resulting in thrombin and platelet activation, with ensuing consumption of platelets and a reduction in the platelet count. Heparin-induced thrombo-cytopenia may result from heparin flushes used in settings where large, vascular access lines are needed.
Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome
One of the more serious entities in this category is thrombotic thrombocytopenic purpura (TTP) and the adult hemolytic uremic syndrome (HUS). These disorders may be stimulated by similar agents or factors, but their pathophysiology differ. In both, damage to the endothelium of small vessels triggers platelet deposition in small arterioles and capillaries, resulting in a thrombotic microangiopathy. TTP is characterized by five major clinical features: (1) microangiopathic hemolytic anemia with a high lactate dehydrogenase (LDH) level, (2) severe thrombocytopenia, (3) fever, (4) CNS symptoms and signs, and (5) renal compromise.
The physician should suspect TTP or HUS in the patient with thrombocytopenia and microangiopathic hemolytic anemia alone, with no other apparent cause. The blood smear in both disorders will show reduced platelets, helmet cells, and schistocytes, indicative of the microangiopathic hemolytic process. If assayed, bone marrow will reveal increased numbers of megakaryocytes. Renal disease will be more severe in HUS, whereas CNS symptoms may be more prominent in TTP. Not all patients have all five features on presentation. Differentiation must be made from other disorders such as Evans' syndrome, SLE, and leukemia. Hemolysis, leukocytosis, and a negative direct Coombs test are hallmarks of TTP and HUS. The absence of abnormal coagulation results essentially eliminates DIC. Causes of these syndromes may range from pregnancy to bone marrow transplantation, drugs, cancer, and in children, infection with Escherichia coli O157:H7. Treatment of this E. coli infection with antibiotics does not help and may make the disease worse. Various drugs may also cause TTP and HUS, such as cancer chemotherapeutic drugs, immunosuppressive agents such as cyclosporine, antiplatelet drugs such as ticlop-idine, oral contraceptives, and quinine.
A number of theories exist concerning the cause of these syndromes. Damage to the endothelial surface of small arteries may stimulate extensive platelet aggregation, thereby plugging up small vessels. Some investigators have found that there are abnormally large von Willebrand factor multimers in the circulation, suggesting that there is a deficiency in the enzyme (ADAMTS-13) that cleaves this blood-clotting factor. These large proteins then bind to platelets and cause plugging of small arterioles and capillaries.
A large, randomized clinical trial in Canada found that plasma exchange transfusions at 1.5 to 2 times the total body plasma volume were significantly more effective than simple plasma transfusions (Rock et al., 1991). This therapy must use a higher volume during the first 3 days and a lower volume over the next 4 to 5 days, for a minimum of 7 days. Other therapies, such as aspirin and steroids, have not been studied in randomized clinical trials. Splenectomy has been used occasionally, but only by experts seeing larger numbers of cases than normally seen in a family medicine setting.
The HELLP syndrome—hemolysis (microangiopathic), elevated liver enzymes, and low platelets (<100,000^L)—can occur in pregnant women between the 23rd and 39 th weeks of gestation. This is a form of preeclampsia in which the patients are extremely ill. Treatment is delivery of the infant. The lowest platelet counts occur several days after delivery, although in some cases, thrombocytopenia does not present until after delivery. If a clinical picture of TTP emerges, plasma exchange should be strongly considered.
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