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 ::  Abstract
 ::  Introduction
 ::  Material And Method
 ::  Results
 ::  Discussion
 ::  Conclusion
 ::  Acknowledgements
 ::  References
 ::  Article Tables

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Year : 1979  |  Volume : 25  |  Issue : 2  |  Page : 70-74

Heparin rebound : A cause of bleeding following open heart surgery

Department of Cardio-vascular and Thoracic Surgery, Seth G. S. Medical College and K.E.M. Hospital, Bombay-400 012, India

Correspondence Address:
S V Purandare
Department of Cardio-vascular and Thoracic Surgery, Seth G. S. Medical College and K.E.M. Hospital, Bombay-400 012
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Source of Support: None, Conflict of Interest: None

PMID: 501673

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 :: Abstract 

Fifty patients undergoing open-heart surgery were studied. Twelve patients showed heparin rebound phenomenon in the post­perfusion period and was one of the important factors responsible for bleeding after open-heart surgery. The clotting time came back to normal in all the cases after administration of extra pro­tamine.

How to cite this article:
Purandare S V, Parulkar G B, Panday S R, Bhattacharya S, Bhatt MM. Heparin rebound : A cause of bleeding following open heart surgery. J Postgrad Med 1979;25:70-4

How to cite this URL:
Purandare S V, Parulkar G B, Panday S R, Bhattacharya S, Bhatt MM. Heparin rebound : A cause of bleeding following open heart surgery. J Postgrad Med [serial online] 1979 [cited 2023 Jun 6];25:70-4. Available from:

 :: Introduction Top

The introduction of extracorporeal cir­culation for open intra-cardiac operations faced a number of difficulties in the early years of its development. The foremost was the maintenance of blood in a fluid state during its extracorporeal circulation. An attempt was made by the early workers to maintain the fluidity of blood by using the defibrinating tech­nique for obtaining incoagulable blood. But the danger of using this blood is ap­parent. The first real breakthrough came with the discovery of heparin by McLean. [12] Further work was carried out by Howell and Jolt (as quoted by Jorpes, 1964 [10] ). Protamine and polybrene per­mitted neutralization of heparin.

This paper deals with our experience of the role heparin plays in postperfusion bleeding.

 :: Material And Method Top

Fifty patients of either sex undergoing open intracardiac operations were stu­died. The age varied from 8 to 40 years. Heparin in a dose of 3 mg/kg. was ad­ministered to the patient before cannula­tion. Five mg% of heparin was added to the priming solution. Half the initial dose of heparin was administered in case the bypass was more than one hour. The heparin level was maintained bet­ween 3 and 5 mg% during perfusion. The heparin was neutralized at the end of by­pass with a calculated dose of protamine sulphate. [17] The heparin-protamine titra­tion was performed after 15 minutes of administration of protamine. A dispos­able bubble oxygenator was used during the entire period of study.

 :: Results Top

[Table 1] summarizes the patients who showed heparin rebound. [Table 2] gives the level of circulating heparin and the amount of additional protamine required in the patients who showed heparin re­bound.

 :: Discussion Top

Excessive bleeding in the postperfusion period is not uncommon. The relative importance attributed to inadequate neu­tralization of heparin, thrombocytopenia, alteration of some blood clotting factors and fibrinolysis has varied in different studies. [4],[18],[19]

The phenomenon of "heparin rebound" has been considered to be the most com­mon cause of bleeding in the postbypass period. The phenomenon is best defined as the reappearance of hypocoagulability of blood after adequate neutralization of heparin has been accomplished. Heparin is an indispensable anticoagulant in car­diopulmonary bypass procedures employ­ing extracorporeal apparatus. The chelat­ing agents such as ethylene diamine tetra­acetic acid (EDTA) and citrate are un­suitable, since the degree of hypocalcemia required to prevent coagulation is incom­patible with myocardial activity. [5] An inadequate neutralization results in pro­longed time for closure of the incision, increased post-operative blood loss, in­creased morbidity and perhaps mortality.

Heparin rebound was observed in 12 patients during the course of the present study [Table 1]. It was detected as early as two hours after perfusion or as late as 18 hours post-operatively, after complete neutralization of heparin by protamine sulphate had been obtained. In all the instances the clotting time returned to normal on administration of a titrated dose of protamine. The amount of addi­tional protamine required was 30-80 mg. A number of workers [9],[11],[14],[16] confirmed the presence of heparin rebound iii their patients and found no evidence of excess protamine interfering with blood clot­ting as suggested by Andersen and his coworkers. [3] Wright et al [24] in their study of heparin levels during and after hypo­thermic perfusion reported the presence of the rebound phenomenon in 5 out of 45 cases, although in only one instance it was considered likely to be of any signi­ficance. A point which needs to be em­phasized is that unlike heparin which has both antithrombin and antithromboplastin activities, protamine sulphate being only antithromboplastic shows a considerably weaker anticoagulant effect. [22]

A number of reasons have been attri­buted to the reappearance of heparin in the circulation. It may be either due to reabsorption of heparin into the blood stream from extravascular depots in which it was stored during perfusion [6] or it may be due to the faster degradation of protamine. [1] Protamine is known to combine with plasma proteins, especially fibrinogen. Thus a competition for prota­mine between plasma proteins and hepa­rin may arise as suggested by Rothnie and Kinmonth [19] The action of complex acidic phospholipid of blood may play a role in changing the equilibrium between heparin and protamine. [2] An alternative explanation is simply that the administer­ed dose of protamine was not in fact suf­ficient and therefore no true heparin re­bound phenomenon occurs. [17]

However efficiently designed an arti­ficial heart-lung machine may be, the cir­culation it provides cannot be compared with that provided by the heart. As a result, blood gets sequestered in the poorly perfused areas. Tanaka and his co-workers [23] in studies in dogs reported that the heparinized blood gets sequester­ed in the different parts of the body with­in three to five minutes of the start of perfusion. The most likely organs where the blood gets trapped are the spleen, liver and splanchnic bed . [8],[20] Large volumes of blood can also be pooled in the skin or the muscles. [13] After the per­fusion is discontinued, some time elapses before the patient achieves hemodyna­mic equilibrium. It is during this period that the organs in which the blood is sequestered release it, thus bringing along with it unneutralized heparin.

Sharp and Eggleton [21] suggested that the dose of protamine be given on the basis of the initial dose given rather than on the titrated residual heparin at the end of perfusion. This would take care of the heparin in the extravascular fluid which returns to the circulation. We at this institute, give protamine on the basis of the total heparin (initial dose) admini­stered. On an average, the amount of protamine required to neutralise the heparin works out to two and half times the amount of heparin given.

In an earlier study, Pardanani et al [15] have reported an interesting observation that by using protamine hydrochloride the incidence of heparin rebound and as­sociated postperfusion bleeding is greatly reduced when compared to the group re­ceiving protamine sulphate. Furthermore, a large amount of protamine is required in the protamine sulphate group as com­pared to protamine hydrochloride group in the post-operative period to control the rebound phenomenon. It has been sug­gested that protamine hydrochloride is a more stable salt compared to protamine sulphate. [7] We routinely use protamine sulphate to neutralize the effect of ­heparin in patients undergoing open-heart surgery.

 :: Conclusion Top

Though an occasional patient bleeds excessively in the postperfusion period, as a result of alteration in the clotting factors, heparin rebound phenomenon is a major factor in postbypass bleeding. A prompt recognition of this effect by the heparin-protamine titration and imme­diate treatment with additional doses of protamine helps in avoiding excessive blood loss and minimizes blood transfu­sions.

 :: Acknowledgements Top

We take this opportunity to thank Dr. C. K. Deshpande, M.D., F.R.C. Path. (Lond.), Dean, K.E.M. Hospital and Seth G. S. Medical College, Bombay, for per­mitting us to report the hospital material.

 :: References Top

1.Allen, J. G.: "Extracorporeal Circula­tion", C. C. Thomas, Springfield, 1958.  Back to cited text no. 1    
2.Amatuzio, D. S., Grande, F., Wada, S, and Hay, L. J.: A natural occurring lipid that neutralizes heparin activity in blood, J. Lab. Clin. Med., 56: 277-280, 1960.  Back to cited text no. 2    
3.Andersen, M. N., Mandelow, M. and Alfano, G. A.: Experimental studies of heparin protamine activity with special reference to protamine inhibition of clotting. Surgery, 46: 1060-1068, 1959.  Back to cited text no. 3    
4.Bentall, H. H. and Allwork, S. P.: Fib­rinolysis and bleeding in open-heart sur­gery. Lancet, 1: 4-8, 1968.  Back to cited text no. 4    
5.Bunker, J. P., Stetson, J. B,, Coe, R. C., Grillo, H. C. and Murphy, J.: Citric acid intoxication. J. Amer. Med. Assoc., 157: i.61.-1367, 1955.  Back to cited text no. 5    
6.Clowes, G. H. A. Jr.: Extracorporeal maintenance of circulation and respiration. Physiol. Rev., 40: 826-897, 1960.  Back to cited text no. 6    
7.Frick, P. G. and Brogli, H.: The mechan­ism of heparin rebound after extracorpo­real circulation for open cardiac surgery. Surgery, 59: 721-726, 1966.  Back to cited text no. 7    
8.Giannelli, S., Mahajan, D. R., Navarre, J. R. and Pratt, G. H.: Studies of blood volume changes during cardiopulmonary bypass in dogs. Ann. Surg., 152: 190-196, 1960.  Back to cited text no. 8    
9.Hyun, B. H., Pence, R. E., Davila, J. C., Butcher, J. and Custer, R. P.: Heparin rebound phenomenon in extracorporeal circulation. Surg. Gynec. Obstet., 115: 1.91-198, 1962.  Back to cited text no. 9    
10.Jorpes, J. E.: The early history of hepa­rin, Ann. N.Y. Acad. Sci., 115: 392-398, 1964  Back to cited text no. 10    
11.Keats, A. S., Cooley, D. A. and Telford, J.: Relative antiheparin potency of poly­brene and protamine in patients under­going extracorporeal circulation. J. Thorac. Cardiovas. Surg., 38: 362-3M, 1959.  Back to cited text no. 11    
12.McLean, J.: The thromboplastin action of heparin. Amer. J. Physiol., 41: 250-257, 1916.  Back to cited text no. 12    
13.Neville, W. E., Kameya, S., Mustafa, O., Bloor, B. and Cloves, G. H. A.: Pro­found hypothermia and complete circula­tion interruption. Experimental, clinical and physiological observations. Arch. Surg., 82: 1.08-119, 1961.  Back to cited text no. 13    
14.Pardanani, D. S., Roy, C. and Sen, P. K.: Heparin Rebound. A clinical study in cases of open-heart surgery under car­diolpulmonary bypass, J. Postgrad. Med., lti: 26-32, 1970.  Back to cited text no. 14    
15.Pardanani, D, S. Roy, C. and Sen, P. K.: Comparative study of protamine hydro­chloride and protamine sulphate for neu­tralization of circulating heparin after cardiopulmonary bypass for open heart surgery. Ind. J. Surg., 34: 148-151, 1972.  Back to cited text no. 15    
16.Peden, J. C. Jr. and McFarland, J. A.: Use of the plasma thrombin time to assess the adequacy of i:c vivo neutralization of heparin: Comparative studies following operations employing extracorporeal cir­culation. Blood, 14: 1230-1236, 1959.  Back to cited text no. 16    
17.Perkins, H. A., Osborn, J. J. and Gerbode, F.: The management of abnor­mal bleeding following extracorporeal circulation. Ann. Int. Med., 51: 658-667, 1959.  Back to cited text no. 17    
18.Porter, J. M. and Silver, 0.: Alterations in fibrinolysis and coagulation associated with cardiopulmonary bypass. J. Thorac. Cardiovasc. Surgery, 56: 869-878, 1968.  Back to cited text no. 18    
19.Rothnie, N. G. and Kinmonth, J. B.: Bleeding after perfusion for open-heart surgery. Importance of unneutralized heparin and its proper correction. Brit. Med. J. 1: 73-78, 1960.  Back to cited text no. 19    
20.Rowen, H., Viles, P. and Ankeney, J. L.: The effect of total body perfusion upon cardiac output and vascular resistance. J. Thorac. Cardiovasc. Surg., 40: 529-535. 1960.  Back to cited text no. 20    
21.Sharp, A. and Eggleton, M. J.: Haemato­logy and the extracorporeal circulation. J. Clin. Path., 16: 551-557, 1963.  Back to cited text no. 21    
22.Soloway, H. B . , Cornett, B. M., Dona - hoo, J. V. and Cox, S. P.: Differentiation of bleeding diatheses which occur follow­ing protamine correction of heparin anti­coagulation. Amer. J. Clin. Path., 60: 188-191, 1973.  Back to cited text no. 22    
23.Tanaka, T . , Hayashi, H . , Chiba, C . , Osawa, M., Shimizu, T., Iwamato, J., Hashimoto, A., Matsumura, C. and Saka­kibara, S.: Extracorporeal circulation in dogs. Significant variation in the size of the spleen in response to various flow rates. J. Amer. Med. Assoc., 179: 708­716, 1962.  Back to cited text no. 23    
24.Wright, J. S., Osborn, J. J., Perkins, H. A. and Gerbode, F.: Heparin levels during and after hypothermic perfusion. J. Cardiovasc. Surg., 5: 244-250. 1964.  Back to cited text no. 24    


  [Table 1], [Table 2]


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