Quantitative Disorders Of Platelets

A normal platelet count is 150 to 450 X 109/L. In this range, an individual will have properly functioning platelets that assist in the coagulation process by creating a platelet plug and stimulating the formation of a solid fibrin clot. A decrease in platelet count will cause bleeding from the mucous membranes such as gum bleeding (gingival bleeding), nose bleeding (epistaxis), extensive bruising (ecchymoses), or petechiae (pinpoint hemorrhages). A patient with a platelet count of 60,000 will bleed in surgery and a patient with a platelet count of 30,000 may have petechial bleeding At less than 5000 platelets, there is a risk of bleeding into the central nervous system. Laboratory tests that are helpful in the evaluation of platelet function are the evaluation of the peripheral smear for platelet number and morphology, the bleeding time test (or similar platelet function tests), platelet aggregation by one of several methods, or other methods that assess platelet function and aggregation. Thrombocytopenia or a decreased platelet count is caused by a number of factors. Decreased production of platelets or increased destruction of platelets usually accounts for the pathophysiology of most quantitative defects in platelets. Additionally, sample related conditions or preanalytic variables may lead to falsely decreased platelet counts.

Thrombocytopenia Related to Sample Integrity/Preanalytic Variables

Coagulation samples are drawn into blue top tubes containing sodium citrate. Sodium citrate anticoagulates a specimen by binding calcium in a 1:9 anticoagulant-to-blood ratio. Sample tubes must be at least 90% full and the phlebotomy must be nontraumatic. The blue top tube must be inverted at least three or four times for proper mixing of the anticoagulant. If this does not happen, there is a possibility of small clots being formed on the top of the tube. Platelet satellitism is another condition related to samples that may give a falsely decreased platelet count. First reported in 1963,1 this condition is an in vitro phenomenon in which the patient's platelets rosette around segmented neutrophils, monocytes, and bands. This phenomenon occurs only in EDTA (ethyl-enediaminetetraacetic acid) samples and produces a pseudo-thrombocytopenia unrelated to medication or any other disease state (see Fig. 10.21). If platelet satel-litism is observed on the peripheral smear, the sample should be redrawn in sodium citrate and cycled through the automated hematology counter for a more accurate platelet count.

Thrombocytopenia Related to Decreased Production

Any condition that leads to bone marrow aplasia or a lack of megakaryocytes, the platelet forming cell, will lead to a thrombocytopenia. Most patients with leukemia will exhibit a thrombocytopenia as a result of infiltration of the bone marrow with blast cells. Blasts of any cellular origin crowd out normal bone marrow elements leading to thrombocytopenia. Defects in platelet synthesis can occur in the megaloblastic anemias that show a pancytopenia, a decrease in all cell lines. Cytotoxic agents or chemotherapy usually interferes with the cell cycle, thereby reducing the number of active platelets. Patients undergoing chemotherapy are carefully monitored for platelet count and may need to be given platelet support if the count drops too far below 20.0 X 109/L.

Megakaryocytic function is impaired during the infectious process. Infections with several viral agents such as cytomegalovirus, Epstein-Barr virus, varicella, and rubella and certain bacterial infections may cause a thrombocytopenia. The mechanism at work in viral infections is thought to be megakaryocytic suppression; in bacteria, the mechanism is direct toxicity of circulating platelets.2

Thrombocytopenia Related to Altered Distribution of Platelets

The normal spleen holds one third of the platelet volume. Several hematological conditions may lead to an enlarged spleen as part of their pathological process: the myeloproliferative disorders, extramedullary hema-topoiesis, and hemolytic anemias. As the spleen enlarges, blood pools in this organ withholding platelets from the peripheral circulation. If the organ is removed, then large numbers of platelets may spill into the circulation, causing possible thrombotic complica-tions.3 An additional scenario in which platelet distribution is altered is in massive transfusion. Once the total blood volume (10 units) has been replaced with two or three volume exchanges, the platelet and the coagulation factors become diluted leading to a transient thrombocytopenia.4

Thrombocytopenia Related to the Immune Effect of Specific Drugs or Antibody Formation

Drug-induced immune thrombocytopenia produces a reduced platelet count that can be severe and dangerous. Several drug classifications are particularly relevant and include quinines, NSAIDs (nonsteroidal anti-

inflammatory drugs), sulfonamides, and diuretics.5 The mechanism for thrombocytopenia is 2-fold. On the one hand, ingestion of the drug will cause an antidrug antibody formation that will bind to a glycoprotein on the platelet surface and be removed by the reticuloendothelial system (RES). The second mechanism involves the drug combining with a larger carrier protein to form an antigen that triggers an antibody response and subsequent platelet destruction, potentially in the spleen. The incidence of drug-induced thrombocytopenia is 10 cases per 1 million.5

Additionally, there are two rare conditions in which thrombocytopenia may be quite dramatic. Fortunately, these are rare. The first, posttransfusion purpura (PTP), occurs after transfusion of platelet-containing products in which the recipient has developed an antibody. The antibody is directed against an antigen on the platelet Pl1A, a primary platelet antigen, and therefore when donor platelets are transfused containing this antigen, the platelets are coated and removed by the spleen. The resultant thrombocytopenia is quite long lasting, and treatment is directed toward delaying antibody production. The second condition, neonatal isoimmune throm-bocytopenia, occurs as a result of maternal antibody made against a previous exposure to platelet antigens from an earlier pregnancy. The antibody is usually directed against the Pl1A. Since this antibody can cross the placenta, it can coat the baby's platelets in utero. Infants born to mothers carrying these antibodies will often show a normal platelet count initially but within days they will develop petechiae and skin hemorrhages with decreasingly low platelet counts. Infants are carefully observed and treatment is only begun when there is a risk of central nervous system hemorrhage.2

may be increased in the marrow; however, they are poorly functioning.2 There are two types of ITP: chronic and acute. Patients with acute ITP are usually children between the ages of 2 and 6 who have just recovered from a viral illness.2 The platelet counts may drop precipitously, some as low as 20 X109/L. In this range, the child will usually show bruising, nose bleeding, or petechiae but will not usually show life-threatening hemorrhage. Fortunately, this low platelet count usually resolves in less than 6 weeks as the child fully recovers from the viral illness. Treatment, if necessary, may consist of intravenous immunoglobulin (IvIg or WinRho, anti-D immune globulin), splenectomy, or platelet transfusion.2 Chronic ITP, on the other hand, shows a platelet count between 30 and 60 X 109/L in a much older age range of between 20 and 50 years of age. For these patients, an IgG antibody is produced that coats the platelets, causing them to be sequestered and subsequently destroyed in the spleen. Splenomegaly is a frequent physical symptom. Most patients are treated with prednisone, which suppresses the antibody response, increases the platelet count, and decreases the hemorrhagic episodes. For those who are nonresponsive, anti-CD20, Rituximab, has been shown to provide a sustained platelet response.6 Splenectomy is a therapeutic option, but it must be carefully considered. Recently, immune thrombocy-topenia related to infections has been investigated. Patients infected with HIV, hepatitis C, and Helicobacter pylori show thrombocytopenia at some point during their disease. The precise mechanism, thought to be immune derived, is under study.7 Table 16.1 compares acute and chronic ITP.

Thrombocytopenia Related to Consumption of Platelets

Hematological conditions studied under this category usually include idiopathic thrombocytopenia purpura, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. In these conditions, excessive clots are formed throughout the body, which consume platelets. Each of these conditions is serious and can produce significant life-altering complications.

Idiopathic (Immune) Thrombocytopenic Purpura

Patients with idiopathic (immune) thrombocytopenic purpura (ITP) show a decreased platelet count that is thought to be a result of immune destruction of platelets. In 66% of cases, the antibody is an auto-antibody directed against specific sites on glycoprotein (GP) IIb-IIIa or GP Ib-IX. Additionally, megakaryocytes

Table 16.1

Chronic and Acute

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