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Heparin Rebound: An In-Depth Review

Published:December 23, 2022DOI:https://doi.org/10.1053/j.jvca.2022.12.019
      The common conception of “heparin rebound” invokes heparin returning to circulation in the postoperative period after apparently adequate intraoperative reversal with protamine. This is believed to portend increased postoperative bleeding and provides the rationale for administering additional empiric doses of protamine in response to prolonged coagulation tests and/or bleeding. However, the relevant literature of the last 60+ years provides only a weak level of evidence that “rebounded” heparin itself is a significant etiology of postoperative bleeding after cardiac surgery with cardiopulmonary bypass. Notably, many of the most frequently cited heparin rebound investigators ultimately concluded that although exceedingly low levels of heparin activity could be detected by anti-Xa assay in some (but not all) patients postoperatively, there was no correlation with actual bleeding. An understanding of the literature requires a careful reading of the details because the investigators lacked standardized definitions for “heparin rebound” and “adequate reversal” while studying the phenomenon with significantly different experimental methodologies and laboratory tests. This review was undertaken to provide a modern understanding of the “heparin rebound” phenomenon to encourage an evidence-based approach to postoperative bleeding. Literature searches were conducted via PubMed using the following MeSH terms: heparin rebound, heparin reversal, protamine, platelet factor 4, and polybrene. Relevant English language articles were reviewed, with subsequent references obtained from the internal citations. Perspective is provided for both those who use HepCon-guided management and those who do not, as are practical recommendations for the modern era based on the published data and conclusions of the various investigators.

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      References

        • Kolff WJ
        • Effler DB
        • Groves LK
        • et al.
        Disposable membrane oxygenator (heart-lung machine) and its use in experimental surgery.
        Cleve Clin Q. 1956; 23: 69-97
        • Hyun BH
        • Pence RE
        • Davila JC.
        Heparin rebound phenomenon in extracorporeal circulation.
        Surg Gyn Obstet. 1962; 124: 191-198
        • Kaul TK
        • Crow MJ
        • Rajah SM
        • et al.
        Heparin administration during extracorporeal circulation.
        J Thorac Cardiovasc Surg. 1979; 78: 95-102
        • Teoh KHT
        • Young E
        • Blackall MH
        • et al.
        Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery?.
        J Thorac Cardiovasc Surg. 2004; 128: 211-219
        • Meesters MI
        • Veerhoek D
        • de Lange F
        • et al.
        Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial.
        Thromb Haemost. 2016; 116: 251-261
        • Gravlee GP
        • Rogers AT
        • Dudas LM
        • et al.
        Heparin management protocol for cardiopulmonary bypass influences postoperative heparin rebound but not bleeding.
        Anesthesiology. 1992; 76: 393-401
        • Subramaniam P
        • Skillington P
        • Tatoulis J.
        Heparin-rebound in the early postoperative phase following cardiopulmonary bypass.
        Aust N Z J Surg. 1995; 65: 331-333
        • Gollub S.
        Heparin rebound in open heart surgery.
        Surg Gynecol Obstet. 1967; 124: 337-346
        • Ellison N
        • Beatty CP
        • Blake DR
        • et al.
        Heparin rebound. Studies in patients and volunteers.
        J Thorac Cardiovasc Surg. 1974; 67: 723-729
        • Mammen EF
        • Koets MH
        • Washington BC
        • et al.
        Hemostasis changes during cardiopulmonary bypass surgery.
        Semin Thromb Hemost. 1985; 11: 281-292
        • Bachmann F
        • McKenna R
        • Cole ER
        • et al.
        The hemostatic mechanism after open-heart surgery. I. Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal circulation.
        J Thorac Cardiovasc Surg. 1975; 70: 76-85
        • Kuitunen AH
        • Salmenperä MT
        • Heinonen J
        • et al.
        Heparin rebound: A comparative study of protamine chloride and protamine sulfate in patients undergoing coronary artery bypass surgery.
        J Cardiothorac Vasc Anesth. 1991; 5: 221-226
        • Pifarre R
        • Sullivan HJ
        • Montoya A
        • et al.
        Management of blood loss and heparin rebound following cardiopulmonary bypass.
        Semin Thromb Hemost. 1989; 15: 173-177
        • Pifarré R
        • Babka R
        • Sullivan HJ
        • et al.
        Management of postoperative heparin rebound following cardiopulmonary bypass.
        J Thorac Cardiovasc Surg. 1981; 81: 378-381
        • Stormorken H.
        Reactivity of stored plasma to thrombin, with reference to the fibrinogen conversion accelerator and heparinoid activity.
        Br J Haematol. 1957; 3: 299-310
        • Ferguson JH.
        The action of heparin, serum albumin (crystalline), and salmine on blood-clotting mechanisms (in vitro).
        Am J Physiol. 1940; 130: 759-770
        • Godal HC.
        The interaction of protamine with human fibrinogen and the significance of this interaction for the coagulation of fibrinogen.
        Scand J Clin Laboratory Invest. 1960; 12: 433-445
        • Portmann AF
        • Holden WD.
        Protamine (salmine) sulphate, heparin, and blood coagulation.
        J Clin Invest. 1949; 28: 1451-1458
        • Shanberge JN
        • Murato M
        • Quattrociocchi-Longe T
        • et al.
        Heparin-protamine complexes in the production of heparin rebound and other complications of extracorporeal bypass procedures.
        Am J Clin Pathol. 1987; 87: 210-217
        • Esposito RA
        • Culliford AT
        • Colvin SB
        • et al.
        The role of activated clotting time in heparin administration and neutralization for cardiopulmonary bypass.
        J Thorac Cardiovasc Surg. 1982; 85: 174-185
        • Ichikawa J
        • Kodaka M
        • Nishiyama K.
        Reappearance of circulating heparin in whole blood heparin concentration-based management does not correlate with postoperative bleeding after cardiac surgery.
        J Cardiothorac Vasc Anesth. 2014; 28: 1003-1007
        • Gundry SR
        • Drongowski RA
        • Klein MD
        • et al.
        Postoperative bleeding in cardiovascular surgery. Does heparin rebound really exist?.
        Am Surg. 1989; 55: 162-165
        • Taneja R
        • Marwaha G
        • Sinha P
        • et al.
        Elevated activated partial thromboplastin time does not correlate with heparin rebound following cardiac surgery.
        Can J Anaesth. 2009; 56: 489-496
        • Martin P
        • Horkay F
        • Gupta NK
        • et al.
        Heparin rebound phenomenon–much ado about nothing?.
        Blood Coagul Fibrinolysis. 1992; 3: 187-191
        • Galeone A
        • Rotunno C
        • Guida P
        • et al.
        Monitoring incomplete heparin reversal and heparin rebound after cardiac surgery.
        J Cardiothorac Vasc Anesth. 2013; 27: 853-858
        • Murray DJ
        • Brosnahan WJ
        • Pennell B
        • et al.
        Heparin detection by the activated coagulation time: A comparison of the sensitivity of coagulation tests and heparin assays.
        J Cardiothorac Vasc Anesth. 1997; 11: 24-28
        • Gravlee GP
        • Arora S
        • Lavender SW
        • et al.
        Predictive value of blood clotting tests in cardiac surgical patients.
        Ann Thorac Surg. 1994; 58: 216-221
        • Spiess BD
        • Tuman KJ
        • McCarthy RJ
        • et al.
        Thromboelastography as an indicator of post-cardiopulmonary bypass coagulopathies.
        J Clin Monit. 1987; 3: 25-30
        • Olson JD
        • Arkin CF
        • Brandt JT.
        College of American Pathologists Conference XXXI on laboratoryoratory monitoring of anticoagulant therapy: Laboratoryoratory monitoring of unfractionated heparin therapy.
        ArchPathol Laboratory Med. 1998; 122: 782-798
        • Dauchot PJ
        • Berzina-Meottus L
        • Rabnovitch A
        • et al.
        Activated coagulation and activated partial thromboplastin times in assessment and reversal of heparin-induced anticoagulation for cardiopulmonary bypass.
        Anesth Analg. 1983; 62: 710-719
        • Gravlee G
        • Goldsmith J
        • Low J
        • et al.
        Heparin sensitivity comparison of the ACT, SCT and aPTT.
        Anesthesiology. 1989; 71: A4
        • Gravlee GP
        • Case LD
        • Angert KC
        • et al.
        Variability of the activated coagulation time.
        Anesth Analg. 1988; 67: 469-472
        • Mochizuki T
        • Olson PJ
        • Szlam F
        • et al.
        Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass.
        Anesth Analg. 1998; 87: 781-785
        • Shore-Lesserson L
        • Baker RA
        • Ferraris V
        • et al.
        STS/SCA/AmSECT Clinical Practice Guidelines: Anticoagulation during cardiopulmonary bypass.
        J Extra Corpor Technol. 2018; 50: 5-18
        • Karigowda L
        • Deshpande K
        • Jones S
        • et al.
        The accuracy of a point of care measurement of activated partial thromboplastin time in intensive care patients.
        Pathology. 2019; 51: 628-633
        • Ferring M
        • Reber G
        • de Moerloose P
        • et al.
        Point of care and central laboratoryoratory determinations of the aPTT are not interchangeable in surgical intensive care patients.
        Can J Anaesth. 2001; 48: 1155-1160
        • Baker WS
        • Albright KJ
        • Berman M
        • et al.
        POCT PT INR - Is it adequate for patient care? A comparison of the Roche Coaguchek XS vs. Stago Star vs. Siemens BCS in patients routinely seen in an anticoagulation clinic.
        Clin Chim Acta. 2017; 472: 139-145
        • Baker WS
        • Albright KJ
        • Spratt H
        • et al.
        Data documenting the performance of the PT/INR line correction method for reconciling INR discrepancies between central laboratoryoratory coagulation analyzers using different thromboplastins during the evaluation of a portable Coagulometer.
        Data Brief. 2017; 16: 312-320
        • Donaldson M
        • Sullivan J
        • Norbeck A.
        Comparison of international normalized ratios provided by 2 point-of-care devices and laboratoryoratory-based venipuncture in a pharmacist-managed anticoagulation clinic.
        Am J Health Syst Pharm. 2010; 67: 1616-1622
        • Newall F.
        Anti factor Xa (anti-Xa) assay.
        Methods Mol Biol. 2013; 992: 265-272
        • Centeno EH
        • Militello M
        • Gomes MP.
        Anti-Xa assays: What is their role today in antithrombotic therapy?.
        Cleve Clinic J Med. 2019; 86: 417-425
        • Olson JD
        • Arkin CF
        • Brandt JT
        • et al.
        College of American Pathologists Conference XXXI on laboratoryoratory monitoring of anticoagulant therapy: Laboratoryoratory monitoring of unfractionated heparin therapy.
        Arch Pathol Laboratory Med. 1998; 122: 782-798
        • Hirsh J
        • Warkentin TE
        • Shaughnessy SG
        • et al.
        Heparin and low molecular weight heparin; mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety.
        Chest. 2001; 119: 64s-94s
        • Vandiver JW
        • Vondracek TG.
        Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin.
        Pharmacotherapy. 2012; 32: 546-558
        • Kovacs MJ
        • Keeney M
        • MacKinnon K
        • et al.
        Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin.
        Clin Laboratory Haematol. 1999; 21: 55-60
        • Kitchen S
        • Theaker J
        • Preston FE
        Monitoring unfractionated heparin therapy: Relationship between 8 anti-Xa assays and a protamine titration assay.
        Blood Coagul. Fibrinolysis. 2000; 11: 137-144
        • Teoh KH
        • Young E
        • Bradley CA
        • et al.
        Heparin binding proteins. Contribution to heparin rebound after cardiopulmonary bypass.
        Circulation. 1993; 88: II420-II425
        • Miyashita T
        • Nakajima T
        • Hayashi Y
        • et al.
        Hemostatic effects of low-dose protamine following cardiopulmonary bypass.
        Am J Hematol. 2000; 64: 112-115
        • Mittermayr M
        • Velik-Salchner C
        • Stalzer B
        • et al.
        Detection of protamine and heparin after termination of cardiopulmonary bypass by thrombelastometry (ROTEM): Results of a pilot study.
        Anesth Analg. 2009; 108: 743-750
        • Despotis GJ
        • Summerfield AL
        • Joist JH
        • et al.
        Comparison of activated coagulation time and whole blood heparin measurements with laboratoryoratory plasma anti-Xa heparin concentration in patients having cardiac operations.
        J Thorac Cardiovasc Surg. 1994; 108: 1076-1082
        • Raymond PD
        • Ray MJ
        • Callen SN
        • et al.
        Heparin monitoring during cardiac surgery. Part 1: Validation of whole-blood heparin concentration and activated clotting time.
        Perfusion. 2003; 18: 269-276
        • Hardy JF
        • Bélisle S
        • Robitaille D
        • et al.
        Measurement of heparin concentration in whole blood with the Hepcon/HMS device does not agree with laboratoryoratory determination of plasma heparin concentration using a chromogenic substrate for activated factor X.
        J Thorac Cardiovasc Surg. 1996; 112: 154-161
        • Wand S
        • Heise D
        • Hillmann N
        • et al.
        Is there a “blind spot” in point-of-care testing for residual heparin after cardiopulmonary bypass? A prospective, observational cohort study.
        Clin Appl Thromb Hemost. 2020; 26: 1-6
        • Despotis GJ
        • Joist JH
        • Goodnough LT
        • et al.
        Whole blood heparin concentration measurements by automated protamine titration agree with plasma anti-Xa measurements.
        J Thorac Cardiovasc Surg. 1997; 113: 611-613
        • Nicolau-Raducu R
        • Occhipinti E
        • Marshall T
        • et al.
        Thromboprophylaxis with heparin during orthotopic liver transplantation: Comparison of Hepcon HMS plus and anti-xa assays for low-range heparin.
        J Cardiothorac Vasc Anesth. 2017; 31: 575-581
        • Rabenstein DL.
        Heparin and heparan sulfate: Structure and function.
        Nat Prod Rep. 2002; 19: 312-331
        • Porter P
        • Porter MC
        • Shanberge JN.
        Interaction of heparin with the plasma proteins in relation to its antithrombin activity.
        Biochemistry. 1967; 6: 1854-1863
        • Hagedorn HC.
        On the Protamine-Splitting Properties of Blood-Serum.
        Skandinavisches Archiv Für Physiologie. 1938; 80: 156-164
        • Blass J
        • Verriest C
        • Vicaigne MB
        • et al.
        ["In vitro" protaminase activity of human plasma and serum and the human carboxypeptidase N (author's transl)].
        Pathologie-biologie. 1980; 28: 527-534
        • Kitani T
        • Nagarajan SC
        • Shanberge JN.
        Effect of protamine on heparin-antithrombin III complexes. In vivo studies.
        Thromb Res. 1980; 17: 375-382
        • Shanberge JN
        • Gruhl M
        • Kitani T
        • et al.
        Fractionated tritium-laboratoryelled heparin studied in vitro and in vivo.
        Thromb Res. 1978; 13: 767-783
        • Matsuo T
        • Shanberge JN
        • Matsuo O.
        Effect of protamine sulfate on antithrombin III activity.
        Clin Chim Acta. 1983; 131: 233-238
        • Rosenberg RD
        • Damus PS
        The purification and mechanism of action of human antithrombin-heparin cofactor.
        J Biol Chern. 1973; 248: 6490-6505
        • Shanberge JN
        • Quattrociocchi-Longe TM
        • Martens MH.
        Interrelationship of protamine and platelet factor 4 in the neutralization of heparin.
        Thromb Res. 1978; 46: 89-100
        • Shanberge JN
        • Quatrociocchi-Longe TM.
        Influence of platelet factor 4 on the neutralization of heparin by protamine.
        Ann NY Acad Sci. 1989; 556: 354-365
        • Savidge GF
        • Kesteven PJ
        • SF Al-Hasani
        • et al.
        Rapid quantitation of plasma heparin and antithrombin III levels for cardiopulmonary bypass monitoring, using fluorometric substrate assays.
        Thromb Haemost. 1983; 50: 745-748
        • Carr ME
        • Carr SL.
        At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet effects.
        Thromb Res. 1994; 75: 617-630
        • Barstad RM
        • Stephens RW
        • Hamers MJ
        • et al.
        Protamine sulphate inhibits platelet membrane glycoprotein Ib-von Willebrand factor activity.
        Thromb Haemost. 2000; 83: 334-337
        • Khan NU
        • Wayne CK
        • Barker J
        • et al.
        The effects of protamine overdose on coagulation parameters as measured by the thrombelastograph.
        Eur J Anaesthesiol. 2010; 27: 624-627
        • Levy JH
        • Tanaka KA.
        Anticoagulation and reversal paradigms: Is too much of a good thing bad?.
        Anesth Analg. 2009; 108: 692-694
        • Vonk ABA
        • Veerhoek D
        • van dem Brom CE
        • et al.
        Individualized heparin and protamine management improves rotational thromboelastometric parameters and postoperative hemostasis in valve surgery.
        J Cardiothorac Vasc Anesth. 2014; 28: 235-241
        • Storck J
        • Höllger N
        • Zimmermann RE.
        The influence of heparin and protamine sulfate on platelet ADP and platelet factor 4 release and the expression of glycoprotein IIb/IIIa.
        Haemostasis. 1994; 24: 358-363
        • Jaques LB.
        A study of the toxicity of the protamine, salmine.
        Br J Pharmacol Chemother. 1949; 4: 135-144
        • Lindblad B
        • Wakefield TW
        • Whitehouse WM
        • et al.
        The effect of protamine sulfate on platelet function.
        Scand J Thorac Cardiovasc Surg. 1988; 22: 55-59
        • Ammar T
        • Fisher CF.
        The effects of heparinase 1 and protamine on platelet reactivity.
        Anesthesiology. 1997; 86: 1382-1386
        • Shigeta O
        • Kojima H
        • Hiramatsu Y
        • et al.
        Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass.
        J Thorac Cardiovasc Surg. 1999; 118: 354-360
        • Cobel-Geard RJ
        • Hassouna HI.
        Interaction of protamine sulfate with thrombin.
        Am J Hematol. 1983; 14: 227-233
        • Mittermayr M
        • Margreiter J
        • Velik-Salchner C
        • et al.
        Effects of protamine and heparin can be detected and easily differentiated by modified thrombelastography (Rotem): An in vitro study.
        Br J Anaesth. 2005; 95: 310-316
        • Meesters MI
        • Lancé MD
        • van der Steeg R
        • et al.
        The value of the thromboelastometry heparinase assay (HEPTEM) in cardiac surgery.
        Thromb Haemost. 2015; 114: 1058-1063
        • Bolliger D
        • Szlam F
        • Azran M
        • et al.
        The anticoagulant effect of protamine sulfate is attenuated in the presence of platelets or elevated factor VIII concentrations.
        Anesth Analg. 2010; 111: 601-608
        • Nielsen VG.
        Protamine enhances fibrinolysis by decreasing clot strength: Role of tissue factor-initiated thrombin generation.
        Ann Thorac Surg. 2006; 81: 1720-1727
        • Ni Ainle F
        • Preston RJS
        • Jenkins PV
        • et al.
        Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation.
        Blood. 2009; 114: 1658-1665
        • Chu AJ
        • Wang ZG
        • Raicu M
        • et al.
        Protamine inhibits tissue factor-initiated extrinsic coagulation.
        Br J Haematol. 2001; 115: 392-399