Abstract :
After clinical assessment, pertinent history, and family history, the clinician often has a good idea concerning the cause of a patientʹs bleeding. The most appropriate laboratory tests can then be ordered. Routine screening tests include a complete blood cell count, platelet count, and evaluation of a peripheral blood sample, a prothrombin time, and an activated partial thromboplastin time. Thrombocytopenia may result from idiopathic thrombocytopenic purpura, disseminated intravascular coagulation, or, less commonly, acute leukemia, aplastic anemia, thrombotic thrombocytopenic purpura, or a particular drug that a patient is taking. Again, the patientʹs history, physical findings, and evaluation of a well-prepared peripheral blood smear will be helpful in determining the cause of the patientʹs thrombocytopenia. An isolated prolongation of the activated partial thromboplastin time may result from low levels of factors VIII, IX, or XI. A slightly prolonged activated partial thromboplastin time and a moderate decrease in factor VIII may reflect von Willebrand disease or the “carrier” state for hemophilia A. In women a greatly prolonged activated partial thromboplastin time and very low levels of factor VIII (<3%) most often result from an acquired factor VII inhibitor (autoantibody against factor VIII) or from severe (type III) von Willebrand disease. If von Willebrand disease is suspected (because of menorrhagia with or without other mucous membrane bleeding, a positive family history, and a prolonged activated partial thromboplastin time), more specific laboratory tests for this disease should be done. These include assays of factor VIII, von Willebrand factor antigen, von Willebrand factor activity (measured by the ristocetin cofactor assay), and template bleeding time. In von Willebrand disease the defect is in von Willebrand factor. The affected individual may have subnormal levels of structurally and functionally normal von Willebrand factor (this is called “classic” or type I von Willebrand disease) or may produce von Willebrand factor that is structurally and functionally abnormal (von Willebrand disease type 2). Individuals who inherit a gene for von Willebrand disease from both parents have severe (type 3) von Willebrand disease and will have extremely low levels (<3%) of von Willebrand factor and factor VIII and will have a very prolonged bleeding time. In most populations type I disease is the most common form, whereas type 3 is the least commonly encountered form. It should be noted that levels of von Willebrand factor can be influenced by the patientʹs blood type (persons who have blood type AB have 60% to 70% higher levels than do persons who have blood type O) and can be elevated during pregnancy, stress, and hyperthyroidism. The two major functions of von Willebrand factor are to serve as a “bridge” between platelets and injury sites in blood vessel walls and to protect circulating factor VIII from rapid proteolytic degradation. Thus, if a patient has either too little or functionally abnormal von Willebrand factor, the bleeding time will be prolonged and factor VIII will be decreased (because it is not being protected by von Willebrand factor). It should be determined which type of von Willebrand disease a particular patient has because treatment depends on type. Multimeric analysis of von Willebrand factor can be done with use of sodium dodecyl sulfate gels, radiolabeled antibody to von Willebrandʹs factor, and autoradiography. This will allow visualization of the multimeric structure of von Willebrand factor. In type I disease all bands are present, whereas in the type 2 variants 2A and 2B no high-molecular-weight multimers are seen. Desmopressin acetate (which is available in parenteral form for intravenous use and in a highly concentrated intranasal spray formulation) is the treatment of choice for classic type I disease. The drug effects a rapid release of von Willebrand factor from endothelial cell storage sites. In type I disease the von Willebrand factor released is structurally and functionally normal; thus the patientʹs bleeding can be stopped, the bleeding time will be transiently corrected, and factor VIII levels will also increase. In type 3 disease there are no endothelial cell stores of von Willebrand factor to be released; thus desmopressin acetate is ineffective. In the type 2 variants desmopressin acetate will effect release of structurally and functionally abnormal von Willebrand factor from the endothelial cell storage sites. Because the hemostatically important high-molecular-weight multimers of von Willebrand factor are lacking, bleeding time will not be corrected and hemostasis will not be improved. If disseminated intravascular coagulation is suspected, prothrombin time, activated partial thromboplastin time, thrombin time, platelet count, and assays for factors VIII and V, fibrinogen, and D-dimer should be obtained. The latter test is particularly useful because a positive D-dimer test indicates that fibrin has formed intravascularly. (Plasmin then cleaves D-dimers from the polymerized fibrin.) Most coagulation tests are run on plasma obtained from a citrated blood sample (blue-topped tube); the D-dimer test can be done on citrated, heparinized, or clotted blood. If an acquired factor VIII inhibitor is suspected (because of the sudden appearance of large ecchymoses and hematomas, for example, in a peripartum woman whose platelet count is normal), look at the patientʹs activated partial thromboplastin time and prothrombin time. If an acquired inhibitor (autoantibody against factor VIII) is present, the activated partial thromboplastin time will be prolonged, the factor VIII level will be extremely low, and an inhibitor assay will be positive.
