John A. Penner

Reversal of renal allograft rejection with intravenous methylprednisolone “pulse” therapy☆☆☆

Abstract Intravenous administration of large doses of methylprednisolone sodium succinate was demonstrated to modify rejection in both canine and human renal allografts. One dose of intravenous methylprednisolone 30 mg./kg. administered during acute rejection in dogs resulted in an increase in urine volume and osmolality, and a decrease in serum and urine LDH. In two dogs treated with a single dose and in one dog treated with four consecutive daily doses histologic evidence of reversal of rejection with reduction of cellular infiltrate was achieved. Ninety-two percent of rejections encountered in 100 consecutive human recipients of renal allografts were halted or reversed with intravenous methylprednisolone 30 mg./ kg. given every 48–72 hours to a maximum of three or four doses. No significant side effects were observed either in dogs or humans with this therapy. The mean circulating half-life of intravenous methylprednisolone was determined to be 3.48 ± 0.7 hours in dogs. Intermittent intravenous administration of methylprednisolone has the potential advantage of being associated with fewer side effects than frequent oral administration and has been shown to be an effective method for modifying rejection.

Coagulation Defects and Bleeding in Open-Heart Surgery

emorrhagic diathesis associated with extracorporeal circulation has been described by a number of investigators, many of H whom have emphasized the presence of specific coagulation defects [ 1, 6, 10, 1 1, 16-1 81. Unfortunately, information on the clinical significance of these abnormalities with respect to incidence and their effect on hemostasis has been lacking. With the increasing use of extracorporeal circulation in cardiac surgery, there is a demand for a means of evaluating the adequacy of hemostasis. As a consequence, the interpretation of the results of routine coagulation procedures has agsumed greater importance. The following study was undertaken to provide such information and includes a description of 50 patients, 15 with excessive blood loss and 35 with “normal” postoperative blood loss. It was presumed correctly that a distinct separation of the two groups of patients could be made on the basis of the coagulation studies.

AN EX VIVO METHOD FOR THE EVALUATION OF BIOMATERIALS IN CONTACT WITH BLOOD

The use of extracoporeal (ex vivo) shunts for studying thrombus formation was given impetus by a number of studies from J. F. Mustard’s 1aboratory.lS In these studies the essential problems of this method were recognized and the requirements for a reproducible system were delineated. The basic features are: 1) uniform blood flow, 2 ) a chamber that represents preferential region for thrombus formation, and 3 ) access to the thrombus for analysis. Murphy et a1.l tried a number of flow chamber designs and finally settled on the use of a model bifurcation for their studies,2 and other investigators s , have evaluated alternative flow chamber configurations. This type of ex vivo test with recirculation of blood should be distinguished from other ex vivo procedures in which animals are bled through a test chamber.5, In the latter cases chronic shunts are not used, which simplifies the procedure, but the loss of blood usually limits the duration of the experiment to less than one hour. To develop an ex vivo method for the evaluation of the thrombogenicity of materials in contact with blood, a system was devised that exposes a test chamber to a dog’s systemic circulation by means of a chronic arteriovenous shunt. The general aspects of this approach are shown in the flow diagram in FIGURE 1 and the schematic FIGURE 2. Male dogs were selected after screening to ensure that they were normal with respect to weight and blood coagulation values. An arteriovenous shunt was implanted in accepted animals, and after surgery, coagulation factors and other physiological parameters were evaluated periodically to monitor the approach of the dog’s coagulation system toward steady state. After about one week, labeled fibrinogen and platelets were introduced systemically, and after 24-48 hours the chamber containing the test material was introduced into the bypass system. The rate of thrombus formation was determined by monitoring the buildup of radioactive fibrinogen and platelets in the test chamber. Blood flow through the chamber was measured with an electromagnetic or Doppler flow meter and controlled at a constant value. After a predetermined time the chamber was disconnected from the shunt, and any thrombus formed was removed and quantitated in terms of clot weight, moisture, fibrinogen, red cell, and platelet content. These values are used as indices of thrombus formation on a given biomaterial under defined flow conditions.

Hypercoagulation and Thrombosis

As knowledge of blood coagulation has advanced we have begun to examine not only the clinical entities associated with hemorrhage but also a group in which thrombosis represents the major problem. Thrombotic disorders believed to be associated with coagulation are recognized clinically but seldom investigated in the laboratory. The present approach to the problem is based on theoretical and experimental knowledge and a rapidly developing body of clinical information related to the role of platelets and antithrombin III in the initiation and control of thrombosis.

Enzymatic Mechanisms of Red Cell Adaptation to Anemia

It has long been known that many anemic patients adjust to their low hemoglobin levels and tend to have clinical symptoms less severe than might be expected. It is now generally accepted that the increased level of DPG in red blood cells of anemic patients plays a major role in this adjustment through its right- shifting effect on the erythrocyte-oxygen affinity curve. The biochemical mechanisms by which DPG levels are increased in anemia have yet to be satisfactorily demonstrated. It is known that DPG is produced by a two enzyme shunt in the glycolytic pathway (Rapoport and Luebering, 1950). The DPG shunt bypasses an ATP producing enzyme, phosphoglycerate kinase. There are three possible mechanisms by which DPG levels may be elevated: The first, a block in the lower part of the pathway, is trivial in our considerations here because it leads to decreased glycolysis and to hemolytic anemia if the block is severe enough. The second mechanism for elevating DPG levels would be an increase in the DPG shunt activity relative to the phosphoglycerate kinase step. It seems unlikely that this is the predominant mechanism because this implies that there should be a tendency for ATP levels to be low in anemia and this is not the case in most types of anemia.

Fibrinogen Petoskey: identification of a new dysfibrinogenemia characterized by altered release of fibrinopeptide A.

Abstract A new congenital dysfibrinogenemia, designated fibrinogen Petoskey, which was traced through four generations of a Michigan family, was found to exhibit an abnormally slow rate of release of fibrino-peptide A upon treatment with thrombin and batroxobin. Batroxobin only partially hydrolyzed and polymerized the fibrinogen from affected individuals, suggesting that these patients had both normal and abnormal fibrinogen in their circulation and that batroxobin was not capable of releasing fibrinopeptide A from the abnormal fibrinogen. Polymerization of fibrin monomers from fibrinogen Petoskey and plasmin mediated digestion of fibrinogen Petoskey were normal. The Factor XIIIa-catalyzed cross-linking of fibrinogen Petoskey was slightly delayed at low (but not at high) concentrations of thrombin. This delayed cross-linking appeared to be a secondary effect of the lower rate of release of fibrinopeptide A.

Polylysine aggregation of human blood platelets

The importance of looking for molecular factors that might be critical in aggregation phenomenae of blood platelets cannot be denied. Metcalf and Lyman (1) have implied that the conformational state of different samples of poly-L_-lysine (PLL), in normal saline, is different, and that this difference results in different interaction of the PLL samples in their ability to aggregate platelets. We do not agree with these conclusions.

HEPARIN AND OTHER SULFATED POLYANIONS: THEIR INTERACTION WITH THE BLOOD PLATELET*

Heparin is a heterogeneous mixture of partially sulfated polysaccharide chains. Different subfractions of heparin have been found to interact with platelets to different degrees, which do not parallel the anticoagulant activity of the preparation.] There is some suggestion that the low antithrombin I11 atfinity of a subfraction results in more potent platelet interaction. It is, however, extremely difficult to relate function to molecular structure when heterogeneity of molecular species exists. A logical approach is to work with more homogeneous model compounds (sulfated polyanions) in order to understand the molecular features involved in the functions observed and is the basis for the following report.

Coagulation changes in saline-induced abortion

Abstract Coagulation function was prospectively studied in 25 patients undergoing intra-amniotic instillation of hypertonic saline for the purpose of termination of pregnancy. Consistent and statistically significant changes in platelet count, prothrombin time, plasma fibrinogen, and fibrin degradation products were found. The platelet count and fibrinogen level decreased, the prothrombin time increased, and fibrin degradation products became detectable. These findings suggest that disseminated intravascular coagulation is a sequela of saline-induced abortion.

Eastern massasauga rattlesnake bites

The Eastern massasauga rattlesnake is native to many Midwestern states. Although this rattlesnake is smaller in size than many other pit vipers, envenomation can still produce significant morbidity, particularly in children. Children bitten by Eastern massasauga rattle-snakes appear to do well with treatment programs consisting primarily of antivenom and blood component replacement.