Ethylenediaminetetraacetic Acid-Dependent Pseudothrombocytopenia in a Cardiac Surgical Patient

Thrombocytopenia may represent a benign, incidental finding in an asymptomatic patient or a potentially life-threatening disorder. Failure to make this important distinction leads to unnecessary diagnostic tests, delay of surgery, and unwarranted exposure to transfusion-related complications. We report a case of pseudothrombocytopenia secondary to ethylenediaminetetraacetic acid (EDTA)-induced platelet clumping in a cardiac surgical patient. Case Report A 74-yr-old man with a history of gout, hypertension, aortic stenosis, and coronary artery disease was admitted the morning of surgery for coronary artery bypass grafting and aortic valve replacement. Medications included isosorbide 40 mg three times daily, verapamil SR 240 mg daily, aspirin 81 mg daily, allopurinol 100 mg daily, and cyanocobalamin 400 mg daily. The patient denied symptoms of heart failure, recent viral symptoms, bleeding or bruising tendencies, hemoptysis, hematochezia, or melena. On physical examination, the patient's vital signs were normal. Skin examination was unremarkable, and no petechiae were present. Cardiac examination revealed a regular rate with a grade III/VI systolic ejection murmur best heard at the right sternal border without radiation; no gallops were noted. Preoperative right heart catheterization demonstrated an average cardiac output of 4.5 L/min with normal pulmonary vascular resistance. Left heart catheterization demonstrated peak and mean transvalvular aortic gradients of 40 and 28 mm, respectively. The calculated aortic valve area was 1.24 cm2. Coronary angiography revealed three-vessel disease with an 80% occlusion of the left anterior descending coronary artery. Left ventricular systolic function was normal. The electrocardiogram was notable for a normal sinus rhythm with left axis deviation, left ventricular hypertrophy, and nonspecific ST/T-wave changes. Chest radiograph and concentrations of electrolytes, blood urea nitrogen, and creatinine were normal. Activated partial thromboplastin time and prothrombin time were normal. Preoperative laboratory evaluation of venous blood collected into an EDTA-containing vacutainer demonstrated a hemoglobin concentration of 13.0 g/100 mL and a white blood cell count of 9.4/mm3 with a normal differential. The platelet count was reported as 53,000/mm3. A repeat platelet count obtained immediately before surgery using a citrate-containing vacutainer was 186,000/mm3 (Table 1).Table 1: Platelet CountsSurgery was performed without complications. No abnormal bleeding occurred, and no platelets were transfused perioperatively. Postoperative platelet counts from blood specimens collected into EDTA- and citrate-containing vacutainers were 65,000/mm (3) and 118,000/mm3, respectively (Table 1). Discussion The differential diagnosis of thrombocytopenia encompasses a diverse list of potential underlying etiologies (Table 2). However, most cases of thrombocytopenia are within the category of either impaired platelet production or accelerated platelet destruction [1]. Impaired platelet production is usually characterized by reduced megakaryocytes in the marrow and may accompany malignant infiltration, marrow hypoplasia in response to chemical or radiation exposure, or congenital diseases, such as Fanconi's pancytopenia.Table 2: Mechanisms of ThrombocytopeniaThrombocytopenia may also occur secondary to decreased platelet survival. Immunologically mediated destruction occurs in association with a variety of drugs, such as heparin-associated thrombocytopenia, and pathologic conditions, such as idiopathic thrombocytopenic purpura. Increased platelet consumption occurs in settings characterized by increased thrombin/fibrin generation, e.g., disseminated intravascular coagulation. Less common mechanisms of thrombocytopenia include hemodilution and platelet sequestration related to hypersplenism. In most cases, these latter two mechanisms of thrombocytopenia are easily identified by a detailed medical history and physical examination. When a patient has an abnormally low platelet count in the absence of a characteristic medical history, pseudothrombocytopenia should be suspected. Pseudothrombocytopenia refers to the measurement of a spuriously low platelet count despite a normal plasma platelet concentration [2]. Although pseudothrombocytopenia may occur secondary to an inadequate blood collection technique, EDTA-dependent platelet clumping represents the most common underlying etiology [3]. Incubation of platelets with EDTA (a calcium chelator) results in an altered conformation of platelet surface glycoproteins. In susceptible patients, neoantigens exposed after in vitro calcium chelation precipitate binding of immunoglobin G and, less commonly, immunoglobin M or A antibodies, resulting in platelet agglutination [4-7]. Although the diagnosis of EDTA-induced pseudothrombocytopenia is readily apparent on microscopic examination of a blood smear, the inability of electronic cell counters to differentiate platelet aggregates from individual cells leads to spuriously low estimates of the platelet count. Pseudothrombocytopenia occurs most frequently in hospitalized patients; however, there seems to be no correlation between patient age or sex. In addition, no consistent association has been observed between particular pathophysiologic conditions or medications. EDTA-dependent pseudothrombocytopenia occurs in approximately 0.2% of asymptomatic individuals, but the incidence may be as great as 1.9% in hospitalized patients [3,8-10]. Given the widespread use of EDTA-containing vacutainers for blood collection for platelet counts, identification of pseudothrombocytopenia requires an increased index of suspicion after the identification of thrombocytopenia in the absence of a consistent medical history. The patient identified in this report was admitted the morning of surgery, and his thrombocytopenia was attributed to marrow suppression resulting from "two drinks per day." Unrecognized pseudothrombocytopenia may result in needless laboratory testing and unwarranted transfusions. Examination of the peripheral blood smear provides definitive evidence of pseudothrombocytopenia in the form of overt platelet clumping. However, the simultaneous collection of blood into EDTA- and citrate-containing vacutainers provides a simple, rapid means of identifying the presence of EDTA-induced pseudothrombocytopenia in the operative setting.