Discontinuance of
Immunosuppression To the Editor.\p=m-\Ourexperience at the University of Wisconsin permits me to agree with Dr Najarian's editorial comments on the article by Owens et al concerning the discontinuance of immunosuppression in renal trans-
plant patients (Arch Surg 110:1450\x=req-\ 1451, 1975). We have recently reviewed our immunosuppressive protocol at the University of Wisconsin, after finding that several patients had voluntarily stopped taking the drugs without informing the physician. Eight patients (five living related donor recipients and three cadaver recipients) stopped all immunosuppression against medical advice.
This represents a 4% incidence of major lapses in immunosuppression, and is probably lower than the actual incidence. In addition, several other transplantation patients had their immunosuppressive therapy removed by medical advice due to severe infection or leukopenia. Two of the mixed leukocyte culture
(MLC)-nonidentical living related donor recipients underwent severe rejection following cessation of immunosuppressive therapy; this was ultimately fatal to both. This occurred despite the fact that they both had low incompatibility indices with their do¬ nors. All patients at our institution
who did not resume immunosuppres¬ sion went on to reject their grafts, save
one
MLC-histocompatibility-
identical living related donor recipient who remains, more than 40 months after the transplant, without immuno¬ suppression and with normal renal function. However, the individuals who had their immunosuppression removed by medical advice failed to evidence any rejection, and were returned to immunosuppression after three months. In these patients, the association of infection and a reduc¬ tion or absence of immunosuppression tend to refute the hypothesis that rejection may be triggered by the
onset of infection. It is our belief that
immunosuppres¬ strongly indicated posttrans¬ plantation, but should be instituted at the lowest possible dose compatible with graft maintenance and patient sion is
survival. We favor reinstitution of prednisone as well as azathioprine for a more complete regimen, and have had no detrimental effects related to this. Clinical outcome from immuno¬ suppression cessation seems to depend on the degree of histocompatibility, as best measured by MLC. L. HUSSEY, MD JOHN Madison, Wis In Reply.\p=m-\Weare not advocating the treatment of transplant recipients
immunosuppression. On the we have been impressed by the general readiness with which our recipients initiate rejection: frequently, rejection occurs as we attempt to
without
contrary,
taper the corticosteroid dose,
or
after
therapy had to be stopped for a short time. Unusually (six patients in 203), immunosuppressive drugs were unintentionally stopped for a very long time without rejection. One patient, the only recipient of a cadaver graft, has since rejected his kidney. The rejection was preceded by a viral illness, and was only partially reversible. One patient died of hypoxic brain damage. As of their last clinic visits, four patients are 20, 51, 62, and 90 months posttransplant, respectively, without immunosuppressants or graft rejection. We think it is arguable whether these patients should be taking immunosuppressant drugs or not; either alternative carries risks.
Any decision ought to be carefully individualized, with attention to the presence or absence of previous rejections, the degree of histocompatibil¬ ity, and the risks from drug therapy. For example, one patient developed aseptic necrosis of the femoral heads in the first few days after transplan¬
tation. He gets around well and we are reluctant to restart his corticosteroids for fear the necrosis will progress. He
Downloaded From: http://archsurg.jamanetwork.com/ by a University of Iowa User on 05/30/2015
has been advised to take azathioprine, which he does only sporadically. The other three patients have refused medication, thereby avoiding for us the necessity of any difficult deci¬ sions. Preliminary studies show that se¬ rum from these patients strongly in¬ hibits lymphocyte activation by phytohemagglutinin and concanavalin A. Serum from a control group of trans¬ plant patients lacks similar activity. Patients such as those we reported on deserve our attention, because we may learn something from them that eventually can be used to the advan¬ tage of other patients. We appreciate the comments of Drs Najarían and Hussey, and believe we have no argument in principle with either of them. MILTON L. OWENS, MD Los Angeles Hazards of Heparin
To the
Therapy
Editor.\p=m-\Ariyanand Stansel's on delayed bleed-
recent observation
ing after vascular surgery with the use of heparin sodium (Arch Surg 111:120-121,1976) is not only of considerable practical, clinical significance,
but also tends to confirm a basic theoretical concept, namely, that fibrin deposition is not a static but a dynamic process. The explanation for this concept, which also explains how heparin therapy promotes the "spontaneous" disappearance of thrombi, is simple. Thrombin clotting activity is readily inhibited by heparin; thrombin esterase activity is not.1 Thrombin esterase activates plasminogen. It should be recalled that thrombin and plasminogen are integral components of a clot; in fact, both are firmly bound to fibrin. Treatment with heparin, leaving thrombin esterase activity unaffected, is expected to result in a fibrin-associated localized fibrinolysis in thrombi and in fibrin deposited at the site of a vascular anastomosis. However, it interferes
with the thrombin clotting activity, thus interrupting the formation and deposition of new fibrin. These findings confirm the conclusion that the use of agents with antithrombin activ¬ ity, such as heparin and dextran sulfate, is contraindica ted after vascu¬ lar surgery. HENRY GANS, MD, PhD
New York
1. Gans H, Boulton A: Differences in the effect of antithrombin on thrombin clotting and thrombin esterase activity. Thromb Diath Haemorrh 22:28-31, 1969.
To the Editor.\p=m-\Inresponse to the by Ariyan and Stansel outlining the dangers associated with recent article
delayed bleeding following heparin
sodium administration in three patients with vascular anastomoses, all of the treated individuals received the same dose of heparin during bolus intravenous therapy, and aside from the Lee-White clotting time determined in the second patient, adjustments in dosage according to body
weight, plasma coagulation factors, platelet function, or underlying pathologic problems were not done. Work in our laboratory over the past four
years has indicated that these variables may be important in the calculation of heparin dosage.1.2 We have demonstrated the importance of platelets and platelet red blood cell interactions in the neutralization of intravenously administered heparin in the dog. In addition, unpublished data from our laboratory demonstrate the tremendous fluctuation between incoagulability and hypercoagulability of a variety of tests following bolus heparin injections in the dog. These marked fluctuations were not observed when continuous infusion of heparin was given alone and during partial bypass experi-
ments.1' Changes in coagulability as a result of disease processes, including the postoperative state, sepsis, neo¬ plasms, burns, and other conditions, have been seen by many investiga¬ tors, and, we think, may result in individual differences in the response to a given heparin dose. The impor¬ tance of all of these factors in calculating heparin dosages is not universally accepted; nevertheless, the importance of the route of adminis¬ tration as recently emphasized by Salzman et al' should be mentioned. A sevenfold increase in complications was observed during intermittent heparin administration compared to continuous pump infusion of this anti¬ coagulant. The authors were not able to relate any of the bleeding complica¬ tions to standard coagulation tests and recommended that continuous infusion therapy was much safer than bolus injections, and that the patient's weight could be used as a guide to dosage calculations. Putting aside the bias of this observer regarding the importance of measuring a multitude of factors during heparin therapy, we wonder whether these bleeding problems would have occurred or been as severe if the patients received continuous infusion therapy. Again, we wish to commend the authors for bringing this unusual complication into public focus, and think that continuous infusion of heparin on a weight basis should be employed instead of resort¬ ing to either dextran or other
agents.
JOSEPH
A.
Chicago
CAPRINI, MD
1. Caprini JA, Eckenhoff JB, Ramstack JM, et al: Contact activation of heparinized plasma. Thromb Res 5:379-400, 1974. 2. Zuckerman L, Ramstack JM, Vagher JP, et al: Neutralization of heparin by cellular blood elements. Thromb Res 7:149-159, 1975. 3. Gaylor JDS, Murphy JF, Caprini JA, et al:
Incorrect Incidence. \p=m-\Inthe
Gas transfer and thrombogenesis in an annular membrane oxygenator with active blood mixing. Trans Am Soc Artif Intern Organs 19:516-524, 1973. 4. Salzman EW, Deykin D, Shapiro RM, et al: Management of heparin therapy. N Engl J Med 292:1046-1050, 1975.
In Reply.\p=m-\Theargument regarding the efficacy of continuous vs intermittent intravenous heparin therapy has been continuing for years. A recent controlled prospective trial comparing the two modalities demonstrated that although there were fewer bleeding complications in the group receiving continuous heparin sodium infusion, there were no significant differences in the doses of heparin used daily between those who bled and those who did not bleed in any of the groups.1 Furthermore, the frequency of bleeding was the same in those who had determinations of partial thromboplastin time as in those who had "no laboratory control" of the heparin dosage when intermittent schedule was used. We wish to bring attention to the dangers of the use of heparin soon after major arterial surgery, and propose that it disrupts the dynamic balance between resorption of old thrombus and replacement with new clot until the suture line is sealed with new intima. It is hard to speculate whether the bleeding problems in our patients may have been as severe if they had received continuous infusion therapy. We do not exclude the possibility that this type of heparin therapy may be safer, but propose low molecular weight dextran as another alternative treatment.
STEPHAN ARIYAN, MD H. C. STANSEL, JR, MD New Haven, Conn 1. Salzman EW, Deykin D, Shapiro RM, et al: Management of heparin therapy: Controlled prospective trial. N Engl J Med 292:1046-1050, 1975.
article, "The Modified Bovine Arterial Graft,"
published in the March Archives (111:222-226,1976), the final answer to question 6 gave the incidence of aneurysm in the combined femoropopliteal experience as 2.1%. The correct number is 3.1%.
Downloaded From: http://archsurg.jamanetwork.com/ by a University of Iowa User on 05/30/2015
Immunosuppression To the Editor.\p=m-\Ourexperience at the University of Wisconsin permits me to agree with Dr Najarian's editorial comments on the article by Owens et al concerning the discontinuance of immunosuppression in renal trans-
plant patients (Arch Surg 110:1450\x=req-\ 1451, 1975). We have recently reviewed our immunosuppressive protocol at the University of Wisconsin, after finding that several patients had voluntarily stopped taking the drugs without informing the physician. Eight patients (five living related donor recipients and three cadaver recipients) stopped all immunosuppression against medical advice.
This represents a 4% incidence of major lapses in immunosuppression, and is probably lower than the actual incidence. In addition, several other transplantation patients had their immunosuppressive therapy removed by medical advice due to severe infection or leukopenia. Two of the mixed leukocyte culture
(MLC)-nonidentical living related donor recipients underwent severe rejection following cessation of immunosuppressive therapy; this was ultimately fatal to both. This occurred despite the fact that they both had low incompatibility indices with their do¬ nors. All patients at our institution
who did not resume immunosuppres¬ sion went on to reject their grafts, save
one
MLC-histocompatibility-
identical living related donor recipient who remains, more than 40 months after the transplant, without immuno¬ suppression and with normal renal function. However, the individuals who had their immunosuppression removed by medical advice failed to evidence any rejection, and were returned to immunosuppression after three months. In these patients, the association of infection and a reduc¬ tion or absence of immunosuppression tend to refute the hypothesis that rejection may be triggered by the
onset of infection. It is our belief that
immunosuppres¬ strongly indicated posttrans¬ plantation, but should be instituted at the lowest possible dose compatible with graft maintenance and patient sion is
survival. We favor reinstitution of prednisone as well as azathioprine for a more complete regimen, and have had no detrimental effects related to this. Clinical outcome from immuno¬ suppression cessation seems to depend on the degree of histocompatibility, as best measured by MLC. L. HUSSEY, MD JOHN Madison, Wis In Reply.\p=m-\Weare not advocating the treatment of transplant recipients
immunosuppression. On the we have been impressed by the general readiness with which our recipients initiate rejection: frequently, rejection occurs as we attempt to
without
contrary,
taper the corticosteroid dose,
or
after
therapy had to be stopped for a short time. Unusually (six patients in 203), immunosuppressive drugs were unintentionally stopped for a very long time without rejection. One patient, the only recipient of a cadaver graft, has since rejected his kidney. The rejection was preceded by a viral illness, and was only partially reversible. One patient died of hypoxic brain damage. As of their last clinic visits, four patients are 20, 51, 62, and 90 months posttransplant, respectively, without immunosuppressants or graft rejection. We think it is arguable whether these patients should be taking immunosuppressant drugs or not; either alternative carries risks.
Any decision ought to be carefully individualized, with attention to the presence or absence of previous rejections, the degree of histocompatibil¬ ity, and the risks from drug therapy. For example, one patient developed aseptic necrosis of the femoral heads in the first few days after transplan¬
tation. He gets around well and we are reluctant to restart his corticosteroids for fear the necrosis will progress. He
Downloaded From: http://archsurg.jamanetwork.com/ by a University of Iowa User on 05/30/2015
has been advised to take azathioprine, which he does only sporadically. The other three patients have refused medication, thereby avoiding for us the necessity of any difficult deci¬ sions. Preliminary studies show that se¬ rum from these patients strongly in¬ hibits lymphocyte activation by phytohemagglutinin and concanavalin A. Serum from a control group of trans¬ plant patients lacks similar activity. Patients such as those we reported on deserve our attention, because we may learn something from them that eventually can be used to the advan¬ tage of other patients. We appreciate the comments of Drs Najarían and Hussey, and believe we have no argument in principle with either of them. MILTON L. OWENS, MD Los Angeles Hazards of Heparin
To the
Therapy
Editor.\p=m-\Ariyanand Stansel's on delayed bleed-
recent observation
ing after vascular surgery with the use of heparin sodium (Arch Surg 111:120-121,1976) is not only of considerable practical, clinical significance,
but also tends to confirm a basic theoretical concept, namely, that fibrin deposition is not a static but a dynamic process. The explanation for this concept, which also explains how heparin therapy promotes the "spontaneous" disappearance of thrombi, is simple. Thrombin clotting activity is readily inhibited by heparin; thrombin esterase activity is not.1 Thrombin esterase activates plasminogen. It should be recalled that thrombin and plasminogen are integral components of a clot; in fact, both are firmly bound to fibrin. Treatment with heparin, leaving thrombin esterase activity unaffected, is expected to result in a fibrin-associated localized fibrinolysis in thrombi and in fibrin deposited at the site of a vascular anastomosis. However, it interferes
with the thrombin clotting activity, thus interrupting the formation and deposition of new fibrin. These findings confirm the conclusion that the use of agents with antithrombin activ¬ ity, such as heparin and dextran sulfate, is contraindica ted after vascu¬ lar surgery. HENRY GANS, MD, PhD
New York
1. Gans H, Boulton A: Differences in the effect of antithrombin on thrombin clotting and thrombin esterase activity. Thromb Diath Haemorrh 22:28-31, 1969.
To the Editor.\p=m-\Inresponse to the by Ariyan and Stansel outlining the dangers associated with recent article
delayed bleeding following heparin
sodium administration in three patients with vascular anastomoses, all of the treated individuals received the same dose of heparin during bolus intravenous therapy, and aside from the Lee-White clotting time determined in the second patient, adjustments in dosage according to body
weight, plasma coagulation factors, platelet function, or underlying pathologic problems were not done. Work in our laboratory over the past four
years has indicated that these variables may be important in the calculation of heparin dosage.1.2 We have demonstrated the importance of platelets and platelet red blood cell interactions in the neutralization of intravenously administered heparin in the dog. In addition, unpublished data from our laboratory demonstrate the tremendous fluctuation between incoagulability and hypercoagulability of a variety of tests following bolus heparin injections in the dog. These marked fluctuations were not observed when continuous infusion of heparin was given alone and during partial bypass experi-
ments.1' Changes in coagulability as a result of disease processes, including the postoperative state, sepsis, neo¬ plasms, burns, and other conditions, have been seen by many investiga¬ tors, and, we think, may result in individual differences in the response to a given heparin dose. The impor¬ tance of all of these factors in calculating heparin dosages is not universally accepted; nevertheless, the importance of the route of adminis¬ tration as recently emphasized by Salzman et al' should be mentioned. A sevenfold increase in complications was observed during intermittent heparin administration compared to continuous pump infusion of this anti¬ coagulant. The authors were not able to relate any of the bleeding complica¬ tions to standard coagulation tests and recommended that continuous infusion therapy was much safer than bolus injections, and that the patient's weight could be used as a guide to dosage calculations. Putting aside the bias of this observer regarding the importance of measuring a multitude of factors during heparin therapy, we wonder whether these bleeding problems would have occurred or been as severe if the patients received continuous infusion therapy. Again, we wish to commend the authors for bringing this unusual complication into public focus, and think that continuous infusion of heparin on a weight basis should be employed instead of resort¬ ing to either dextran or other
agents.
JOSEPH
A.
Chicago
CAPRINI, MD
1. Caprini JA, Eckenhoff JB, Ramstack JM, et al: Contact activation of heparinized plasma. Thromb Res 5:379-400, 1974. 2. Zuckerman L, Ramstack JM, Vagher JP, et al: Neutralization of heparin by cellular blood elements. Thromb Res 7:149-159, 1975. 3. Gaylor JDS, Murphy JF, Caprini JA, et al:
Incorrect Incidence. \p=m-\Inthe
Gas transfer and thrombogenesis in an annular membrane oxygenator with active blood mixing. Trans Am Soc Artif Intern Organs 19:516-524, 1973. 4. Salzman EW, Deykin D, Shapiro RM, et al: Management of heparin therapy. N Engl J Med 292:1046-1050, 1975.
In Reply.\p=m-\Theargument regarding the efficacy of continuous vs intermittent intravenous heparin therapy has been continuing for years. A recent controlled prospective trial comparing the two modalities demonstrated that although there were fewer bleeding complications in the group receiving continuous heparin sodium infusion, there were no significant differences in the doses of heparin used daily between those who bled and those who did not bleed in any of the groups.1 Furthermore, the frequency of bleeding was the same in those who had determinations of partial thromboplastin time as in those who had "no laboratory control" of the heparin dosage when intermittent schedule was used. We wish to bring attention to the dangers of the use of heparin soon after major arterial surgery, and propose that it disrupts the dynamic balance between resorption of old thrombus and replacement with new clot until the suture line is sealed with new intima. It is hard to speculate whether the bleeding problems in our patients may have been as severe if they had received continuous infusion therapy. We do not exclude the possibility that this type of heparin therapy may be safer, but propose low molecular weight dextran as another alternative treatment.
STEPHAN ARIYAN, MD H. C. STANSEL, JR, MD New Haven, Conn 1. Salzman EW, Deykin D, Shapiro RM, et al: Management of heparin therapy: Controlled prospective trial. N Engl J Med 292:1046-1050, 1975.
article, "The Modified Bovine Arterial Graft,"
published in the March Archives (111:222-226,1976), the final answer to question 6 gave the incidence of aneurysm in the combined femoropopliteal experience as 2.1%. The correct number is 3.1%.
Downloaded From: http://archsurg.jamanetwork.com/ by a University of Iowa User on 05/30/2015
