Background-ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes. Methods and Results-This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg. Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer. In terms of pharmacokinetics, the concentration-time profile of ARC1779 appeared monophasic. The observed concentration and area under the curve were dose proportional. The mean apparent elimination half-life was Ϸ2 hours, and mean residence time was Ϸ3 hours. The mean apparent volumes of distribution (at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from Ϸ10% to Ϸ21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC 90 value of 2.0 g/mL (151 nmol/L) and of platelet function with an EC 90 value of 2.6 g/mL (196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related. Conclusions-This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose-and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.

A retrospective review of HLA antibody testing and transfusion records of 100 cancer patients who required extensive platelet support revealed that 27 of 100 patients exhibited positive HLA antibody tests; only 13 remained positive on repetitive examination, while 88% of aplastic anemia patients so tested were positive. Sixty-five patients with leukemia, 16 with Ewing's sarcoma, and 19 with recurrent undifferentiated lymphoma were studied. Each patient received at least 10 U of platelets (mean of 72). HLA antibodies were detected in 31% (20/65) of the leukemias, 12% (2/16) of the Ewing's, and 26% (5/19) of the lymphoma patients. Fourteen of the 27 patients who developed antibodies became antibody negative again within 2 mo and remained so. There were no significant differences in quantity of platelet transfusions between antibody-negative patients and alloimmunized patients. A smaller group (n = 8) of aplastic anemia patients followed at the NCl exhibited a frequency of alloimmunization of 88% (7/8) after a mean of 44 U of platelets were transfused. Granulocyte transfusions given therapeutically for granulocytopenia and documented infection did not appear to influence HLA antibody formation. These data indicate that significant immunosuppression occurs in intensively treated cancer patients, as measured by their ability to from antibodies to HLA antigens expressed on the surface of transfused platelets.

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The use of histocompatability antigen (HLA)-matched platelets has been advocated for the support of thrombocytopenic cancer patients. We randomized 78 newly diagnosed cancer patients prospectively (before thrombocytopenia) to receive either HLA-matched or mismatched single-donor platelet transfusions. Three hundred forty-one platelet transfusions were given for 80 separate episodes of therapy-induced thrombocytopenia in 33 patients. Forty-five patients receiving intensive chemotherapy did not develop significant (less than 20,000 platelets/mm3) thrombocytopenia and did not receive a platelet transfusion. No marked difference was observed between the matched and mismatched groups in regard to number of total platelet transfusions per patient (median, 3 vs. 5, respectively; P = 0.076), number of platelet transfusions per episode (median, 3.0 vs. 3.5, respectively; P = 0.28), or days between transfusions (median, 2 vs. 2, respectively, P greater than 0.4). Bleeding episodes, although rare, tended to be of increased severity in the mismatched group. Febrile patients receiving mismatched platelets tended to have a lower posttransfusion increment increase than their nonfebrile counterparts (P = 0.068), although a similar trend could not be demonstrated between febrile and nonfebrile patients who received matched platelets (P = 0.22). Patients treated as outpatients had significantly higher posttransfusion increments than when transfused as inpatients when they were given mismatched platelets (P less than 0.0005). Development of antiplatelet antibody did not appear to affect response to platelet transfusions. Only one patient developed sustained high-level antibody titers. In patients where thrombocytopenia was significant, the transfusion of HLA-matched platelets did not appear to offer a significant advantage. However, HLA-matched platelet transfusions tended to be associated with higher posttransfusion increments in febrile patients and a trend toward fewer severe bleeding episodes. A multi-institution trial containing a large number of patients is needed to evaluate trends observed in this study.

Diagnosis-related negligent adverse events are a serious problem in the healthcare industry.