J.S. Finlayson

Hypotension Associated with Prekallikrein Activator (Hageman-Factor Fragments) in Plasma Protein Fraction

Thirteen lots of plasma protein fraction made by one manufacturer were implicated in 23 recent reports of hypotension in surgical patients. Four of these patients required resuscitation after rapid administration of the product in the postoperative period. All implicated lots had prekallikrein-activator activity but low levels of bradykinin and kallikrein. The prekallikrein activator was identified as Hageman-factor fragments by molecular weight (35,000 as estimated by gel chromatography), isoelectric point (4.2 to 4.4), and inhibition by antibody to Hageman factor. These data suggest that Hageman-factor fragments are potent hypotensive agents, presumably because they trigger the generation of bradykinin in recipients. Prekallikrein-activator activity, usually at levels lower than those in the initial 13 implicated lots, was frequently detected in plasma protein fraction made by other manufactures. Several of these lots were associated with additional reports of hypotension. Prekallikrein-activator activity rarely occurred in albumin.

Immunoglobulin G dimer: An idiotype-anti-idiotype complex

Immunoglobulin G (IgG) prepared from pooled human plasma contains variable amounts (up to 40%) of IgG dimer whereas IgG isolated from the plasma of a single individual is essentially monomeric. The amount of dimer increases with the number of donors contributing to the plasma pool from which the IgG is prepared. Dimerization is reversed by increasing the temp or decreasing the pH. Two intact antibody-combining sites (paratopes) are required for optimal dimer formation; the Fc region is unnecessary. These findings strongly suggest that IgG dimer consists of idiotype-anti-idiotype pairs formed between molecules of IgG from different individuals, and that a mechanism exists for suppressing idiotype-anti-idiotype formation in vivo.

Fibrin sealant: summary of a conference on characteristics and clinical uses

The 2‐day conference clearly outlined the formulations of products that are being developed or are commercially available in Europe. The major difference between products in the United States and those in Europe is that US manufacturers are preparing fibrin sealant that does not contain aprotinin, epsilon amino caproic acid, or any other type of antifibrinolytic agent, whereas antifibrinolytic agents are included in all such preparations used in Europe. The conference provided no clear consensus that such agents are essential to the efficacy of the product. Although many investigators believe in the clinical benefit of fibrin sealant, most of the studies to demonstrate efficacy have not been performed in a well‐controlled fashion. However, fibrin sealant, if found in a controlled trial to have clinical efficacy, could be approved by the FDA for a narrow indication. Opportunities remain for greater exploration of different forms of the product, not only as a hemostatic agent, but as an adjunct to wound healing and as a matrix for delivery of drugs and proteins with other biologic activities.

Frozen platelets and platelet substitutes in transfusion medicine

uring the past few years, efforts to improve platelet storage by cryopreservation and to develop platelet substitutes have been undertaken in multiple academic and commercial settings. A major goal for the researchers and regulators who work with these products is to establish methods for the assessment of hemostatic function in vitro, in animal models, and in clinical trials. To understand how platelet products can be developed for field medicine and to facilitate research in this area, the Combat Casualty Care Programs of the Naval Research and Development Command and the Medical Research and Materiel Command of the United States Army sponsored a conference called “Frozen Platelets and Platelet Products in Transfusion Medicine” on March 7 and 8, 1996, at the Uniformed Services University of the Health Sciences in Bethesda, MD. Co-organizers and participants were the Center for Biologics Evaluation and Research, the Food and Drug Administration (FDA), and the Blood Resources Program of the National Heart, Lung, and Blood Institute, National Institutes of Health.

Considerations of pool size in the manufacture of plasma derivatives

Background: The pooling of human plasma from many donors for the purpose of manufacturing therapeutic proteins increases the risk of exposing recipients of these proteins to pathogens that may contaminate 1 or a few units included in the pool.

The effect on the safety of intravenous immunoglobulin of testing plasma for antibody to hepatitis C

Background: The safety of intravenous immunoglobulin (IGIV), manufactured from units testing negative for antibody to hepatitis C virus (anti‐HCV), was investigated.

Further information on the fibrin sealant conference

To the Editor: The report’ entitled “Fibrin sealant: summary of a conference on characteristics and clinical uses,” by Alving et al. (TRANSFUSION 1995;35:783-90) represents a substantial contribution to an understanding of the clinical importance of this class of hemostatic agents. In summarizing my remarks, at the conference held in Bethesda, MD, in December 1994, however, the authors did not include my comments on an unpublished intent-to-treat analysis that I performed after the publication of a report2 of our randomized clinical trial of fibrin sealant (Tisseel, Immuno AG, Vienna, Austria) in patients undergoing resternotomy or repeat operation after cardiac operations. In the reported study, the primary efficacy endpoint was local hemostasis within 5 minutes. The success rate for the primary endpoint was 92.6 percent for fibrin sealant and 12.4 percent for the control (p<0.001). Fibrin sealant also controlled 82.0 percent of bleeding episodes in patients in the control group in whom conventional therapy initially failed.’ At the conference, I described an intent-to-treat analysis of these data that also showed a significant difference for the primary endpoint of hemostasis within 5 minutes (p = 0.007), mortality (p = 0.029), and hospital stay (p = 0.003). Differences in 12-hour drainage volume and blood units transfused were significant in control and test groups (p = 0.002 and p <0.005, respectively). In other studies, which were historically controlled, fibrin sealant has been useful in spleen salvage (n = 41), liver surgery (n = 145), and compassionate use for reoperative cardiac surgery (n = 2922). (A meta-analysis of the three United States studies combined has also shown a significant reduction in mortality (p<0.01 8) in patients treated with fibrin sealant, as compared to mortality in control patients who received conventional surgical management.) There has been no documented adverse reaction or transmission of viral infections in any of these studies. SIDNEY LEVITSKY, M. David W. and David Cheever Professor of Surgery Harvard Medical School and Chief; Cardiothoracic Surgery New England Deaconess Hospital Boston, MA 02215

Immunoglobulin Safety Related to Testing for Antibody to Hepatitis C Virus

A study was performed to determine whether the safety of intravenous immunoglobulin (IGIV) would be compromised if units of plasma reactive for antibody to hepatitis C (anti-c100-3) were withheld from pools from which IGIV is manufactured. Initially, two chimpanzees were infused with 25 ml/kg of unprocessed, pooled plasma from 2887 donors nonreactive for anti-c100-3. These animals became infected with hepatitis C virus (HCV). Subsequently three chimpanzees were each infused with 1000 mg/kg of IGIV manufactured from the same pooled plasma units. These three animals did not show any evidence of infection with HCV 15 months after inoculation. Two of these animals were then challenged with human non-A, non-B infectious plasma; both showed evidence of HCV infection.