Rarely, patients with previously-normal hemostasis who develop prolonged PT and/or PTT assays and bleeding will not have either vitamin K deficiency or DIC. These patients will probably have acquired antibodies against a clotting factor, usually factor VIII or factor V [1]. The appropriate evaluation is to first perform mixing studies (see Chap. 5) to determine if an inhibitor (antibody) is present. Next, specific factor assays confirm the affected factor. Thus, for a patient with previously-normal PT and PTT values who develops bleeding with an isolated, prolonged PTT, failure to correct the prolonged PTT with a mixing study, followed by assay of factors VIII, IX, XI would diagnose this patient’s acquired bleeding disorder. Antibodies to factor VIII are the most commonly seen.

For patients who have acquired prolonged PT and PTT values, performing mixing studies with both the PT and PTT assays is indicated, followed by assay of common pathway coagulation proteins—fibrinogen, prothrombin, factor V, and factor X. Of these clotting factors, antibodies to factor V are most commonly seen.

In addition to antibody inhibitors, heparin-like inhibitors may occasionally be seen, causing coagulopathy and bleeding in patients with malignant disease. Heparin-like inhibitors are suspected in bleeding patients who have prolonged PTT values that do not correct with mixing, normal PT values, markedly prolonged thrombin time values, normal reptilase assays, and positive results for heparin using an anti-factor X_a assay.

Abnormal fibrinolysis is an uncommon bleeding disorder in which excessive plasmin is generated. Plasmin is appropriately generated following initiation of coagulation and thrombin formation (secondary fibrinolysis). For example, patients with DIC have secondary fibrinolysis which is appropriate. In contrast, in abnormal or primary fibrinolysis, there is no laboratory evidence for thrombin formation (negative D-dimer). Examples of clinical conditions associated with abnormal fibrinolysis include inherited α₂-antiplasmin deficiency, tumors of the genito-urinary tract, gynecologic tumors, acute promyelocytic leukemia, liver disease, and fibrinolytic drugs [1].