SCREENING AND DIAGNOSIS OF COAGULATION DISORDERS

After clinical assessment, pertinent history, and family history, the clinician often has a good idea concerning the cause of a patient's bl eeding. The most appropriate laboratory tests can then be ordered. Rou tine screening tests include a complete blood cell count, platelet cou nt, and evaluation of a peripheral blood sample, a prothrombin time, a nd an activated partial thromboplastin time. Thrombocytopenia may resu lt from idiopathic thrombocytopenic purpura, disseminated intravascula r coagulation, or, less commonly, acute leukemia, aplastic anemia, thr ombotic thrombocytopenic purpura, or a particular drug that a patient is taking. Again, the patient's history, physical findings, and evalua tion of a well-prepared peripheral blood smear will be helpful in dete rmining the cause of the patient's thrombocytopenia. An isolated prolo ngation of the activated partial thromboplastin time may result from l ow levels of factors VIII, IX, or XI. A slightly prolonged activated p artial 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 ac quired factor VIII inhibitor (autoantibody against factor VIII) or fro m severe (type III) von Willebrand disease. If von Willebrand disease is suspected (because of menorrhagia with or without other mucous memb rane bleeding, a positive family history, and a prolonged activated pa rtial thromboplastin time), more specific laboratory tests for this di sease should be done. These include assays of factor VIII, von Willebr and factor antigen, von Willebrand factor activity (measured by the ri stocetin cofactor assay), and template bleeding time. In von Willebran d disease the defect is in von Willebrand factor. The affected individ ual may have subnormal levels of structurally and functionally normal von Willebrand factor (this is called ''classic'' or type I von Willeb rand disease) or may produce von Willebrand factor that is structurall y and functionally abnormal (von Willebrand disease type 2). Individua ls who inherit a gene for von Willebrand disease from both parents hav e severe (type 3) von Willebrand disease and will have extremely low l evels (<3%) of von Willebrand factor and factor VIII and will have a v ery prolonged bleeding time. In most populations type I disease is the most common form, whereas type 3 is the least commonly encountered fo rm. It should be noted that levels of von Willebrand factor can be inf luenced by the patient's blood type (persons who have blood type AB ha ve 60% to 70% higher levels than do persons who have blood type O) and can be elevated during pregnancy, stress, and hyperthyroidism. The tw o major functions of von Willebrand factor are to serve as a ''bridge' ' between platelets and injury sites in blood vessel walls and to prot ect circulating factor VIII from rapid proteolytic degradation. Thus, if a patient has either too little or functionally abnormal von Willeb rand factor, the bleeding time will be prolonged and factor VIII will be decreased (because it is not being protected by von Willebrand fact or). It should be determined which type of von Willebrand disease a pa rticular patient has because treatment depends on type. Multimeric ana lysis of von Willebrand factor can be done with use of sodium dodecyl sulfate gels, radiolabeled antibody to von Willebrand's factor and aut oradiography. This will allow visualization of the multimeric structur e of von Willebrand factor. In type I disease all bands are present, w hereas in the type 2 variants 2A and 2B no high-molecular-weight multi mers 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. T he drug effects a rapid release of von Willebrand factor from endothel ial cell storage sites. In type I disease the von Willebrand factor re leased is structurally and functionally normal; thus the patient's ble eding can be stopped, the bleeding time wilt be transiently corrected, and factor VIII levels will also increase. In type 3 disease there ar e no endothelial cell stores of von Willebrand factor to be released; thus desmopressin acetate is ineffective. In the type 2 variants desmo pressin acetate will effect release of structurally and functionally a bnormal 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 correc ted and hemostasis will not be improved. if disseminated intravascular coagulation is suspected, prothrombin time, activated partial thrombo plastin time, thrombin time, platelet count, and assays for factors VI II 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 obt ained from a citrated blood sample (blue-topped tube); the D-dimer tes t can be done on citrated, heparinized, or dotted blood. If an acquire d 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 patient's activated part ial 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 e xtremely low, and an inhibitor assay will be positive.