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HITT and alternative anticoagulation: current concepts
British Journal of Anaesthesia 91 (3): 445±52 (2003)
Correspondence HIT/HITT and alternative anticoagulation: current concepts
D. J. W. Knight D. Selwyn K. Girling Nottingham, UK EditorÐWe read with interest the review article on HIT/HITT.1 We wish to add the following to the discussion regarding the use of heparin in patients with a history of heparin-induced thrombocytopenia (HIT). In Europe, danaparoid is licensed for use in pregnant patients with HIT. It has been used in at least 13 pregnant mothers with HIT,6 and of the four neonates that were tested for antiXa activity in their cord blood, none were found to be positive. This indicated that danaparoid did not cross the placenta. Patients needing cardiopulmonary bypass who had HIT several months previously but had no HIT antibodies preoperatively, have
S. Lakshmanan B. Saha D. Rittoo Manchester, UK EditorÐWe are pleased that our review of an important and perhaps previously under-reported and under-studied subject has created interest. Although we did not elaborate, we did state that low molecular weight heparin (LMWH) is less likely to cause heparin-induced thrombocytopenia (HIT) and related antibodies when discussing prevention of HIT.1 LMWH has replaced unfractioned heparin (UFH) in many parts of Europe and North America and is used with increased frequency in all clinical settings including the intensive care unit. Its mechanism of action, pharmacokinetics and pharmacodynamics, combined with the reduced rate of HIT,8 and less need for laboratory monitoring have led to greater use of LMWH. We agree with Knight and colleagues, that the use of LMWH in the ICU, in particular with the two most common extracorporeal circuitsÐhaemodialysis (HD) and continous veno-venous haemo®ltration (CVVH)Ðhas not been studied adequately. Its use, however, has been studied in the chronic-HD setting with mixed results. The major bene®t afforded in chronic HD is an improvement in serum lipids with decreased triglycerides, total cholesterol and apoprotein B concentrations.9 10 A randomized controlled trial comparing the use of LMWH (dalteparin) vs UFH in patients with acute renal failure or SIRS undergoing acute CVVH, demonstrated that LMWH can be used with CVVH in the ICU. However, it is at a higher cost than using standard heparin.11 There was neither a signi®cant difference in the time to failure of the ®lters, in the incidence of bleeding complications, nor in the incidence of HIT between the groups. The platelet counts were signi®cantly reduced in both groups and the only difference was the cost; CVVH with dalteparin cost more per day than with UFH. We would like to take this opportunity to highlight the following alternatives to UFH in patients requiring CVVH. (a) LMWH heparin can be considered as ®rst line for CVVH in the ICU settingÐthe bene®ts have been highlighted. LMWH should be discontinued if HIT is suspected, as there are better alternatives and the risk of continuing outweighs the bene®t.12 (b) In HIT without systemic effect, use either (i) Heparinoids: danaparoidÐbut perform in vitro heparin induced platelet aggregation assay with danaparoid (ii) Intermittent haemodialysis without heparinÐif severe heparin unrelated coagulopathy exists (iii) Regional anticoagulation with citrate, or (iv) Prostanoids. (c) In HITTS, use direct thrombin inhibitorsÐhirudins such as lepirudin and argatroban. Finally, we agree with Knight and colleagues, that the con®rmation and quanti®cation of HIT during CVVH is dif®cult for the reasons quoted in their letter. The letter from Lakshmanan and colleagues, is also of interest and we would entirely agree that in pregnant patients requiring heparin and suspected to have HIT, the heparinoid, danaparoid, is the drug of choice for acute treatment and prophylaxis due to its low placental permeability. In addition, there are case reports
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003
Downloaded from http://bja.oxfordjournals.org/ at University of Oklahoma on March 30, 2015
EditorÐWe read with interest the Editorial by Pravinkumar and Webster,1 but were disappointed that the authors did not expand on heparin-induced thrombocytopenia (HIT)-rate-reduction by empiric use of low molecular weight heparin (LMWH). Many of the traditional uses of unfractionated heparin (UFH) have been superceded by the introduction of LMWH, including treatment of deep venous thrombosis, pulmonary embolism, and acute coronary syndromes. One of the under-explored therapeutic indications of LMWH is as the anticoagulant of choice for critically ill patients requiring continuous veno-venous haemo®ltration (CVVH). We recently reported our experience in 52 consecutive patients to the Intensive Care Society of Great Britain.2 Traditionally, it is believed that LMWH has a lower HIT rate than UFH,3 but there is little evidence to support the extrapolation of this bene®t to critically ill CVVH patients. Major risk factors for the development of HIT are using high-dose heparin and continued heparin treatment for greater than 5 days.1 These criteria are almost always ful®lled as part of standard CVVH therapy. It seems logical, therefore, that a HIT rate greater than that commonly quoted of 3% is likely in this group of patients. There is surprisingly little published data for the HIT rate in UFHtreated CVVH patients, although approximately 4.7% has been suggested.4 This is compared with a HIT rate of approximately 2% in our series using LMWH.2 There are a number of dif®culties with reported haemo®ltration HIT rates. The diagnosis is primarily clinical, and con®rmatory laboratory tests are slow to perform and the results are relatively insensitive. In one study, 61% of patients clinically diagnosed as suffering from HIT failed to have the diagnosis con®rmed by antigen assays.5 The low platelet count in HIT is associated with a paradoxical increase in thrombotic tendency. Consequently, when HIT is clinically suspected during CVVH, we introduce danaparoid as an alternative anticoagulant, whilst awaiting laboratory con®rmation. The regime has been used on three patients so far (two further patients have been treated subsequent to the published abstract)2 with good effect. We would like to congratulate Pravinkumar and Webster on an excellent article but would suggest that during CVVH therapy, UFH HIT prevention (or at least rate reduction) with LMWH is better than treatment of the established syndrome.
been treated successfully with heparin for the cardiopulmonary bypass, but with strict avoidance of preoperative and postoperative heparin.7
Correspondence
E. Pravinkumar N. R. Webster Aberdeen, UK 1 Pravinkumar E, Webster NR. HIT/HITT and alternative anticoagulation: current concepts. Br J Anaesth 2003; 90: 676±85 2 Knight DJW, Selwyn D, Harvey R, Girling K. Dalteparin anticoagulation for veno-venous haemo®ltration in a teaching hospital intensive care unitÐ1 year experience. Br J Anaesth 2003; 90: 558P 3 Walker CPR, Royston D. Thrombin generation and its inhibition: a review of the scienti®c basis and mechanism of action of anticoagulation therapies. Br J Anaesth 2002; 88: 848±63 4 Bouman CS, Oudemans-van Straaten HM, Tijssen JGP, Zandstra DF, Kesecioglu J. Effects of early high-volume continuous venovenous hemo®ltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomised trial. Crit Care Med 2002; 30: 2205±21 5 Hourigan LA, Walters DL, Keck SA, Dec GW. Heparin-induced thrombocytopenia: a common complication in cardiac transplant recipients. J Heart Lung Transplant 2002; 21: 1283±9 6 Chong BH, Magnani HN. Danaparoid for the treatment of heparin induced thrombocytopaenia. In: Heparin Induced Thrombocytopaenia. Marcel Dekker Inc, 2001; 343±8 7 Potzsch B, Klovekorn WP, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin induced thrombocytopenia. N Engl J Med 2000; 343: 515 8 Warkentin TE, Levine MN, Hirsch J, et al. Heparin induced thrombocytopenia in patients treated with low molecular weight heparin or unfractioned heparin. N Engl J Med 1995; 332: 1330±5 9 Vlassopoulos D, Noussias C, Hadjipetrou A, et al. Long term effect of low molecular weight heparin on serum lipids in hypertriglyceridemic haemodialysis patients. J Nephrol 1997; 10: 111±4 10 Deuber HJ, Schulz W. Reduced lipid concentrations during four years of dialysis with low molecular weight heparin. Kidney Int 1991; 40: 496±500 11 Reeves JH, Cumming AR, Gallagher L, et al. A controlled trial of low molecular weight heparin (dalteparin) versus unfractioned heparin as anticoagulant during continuous venovenous haemodialysis with ®ltration. Crit Care Med 1999; 27: 2224±8 12 Greinacher A, Michels I, Mueller-Eckhardt C. Heparin associated thrombocytopenia: the antibody is not heparin speci®c. Thromb Haemost 1992; 67: 545±9
446
13 Lindhoff-Last E, Bauersachs R. Heparin induced thrombocytopeniaalternative anticoagulation in pregnancy and lactation. Semin Thromb Hemost 2002; 28: 439±46 14 Koster A, Meyer O, Hetzer R, et al. Some new perspectives in heparin-induced thrombocytopenia type II. J Extra Corpor Technol 2001; 33: 193±6 15 Von Segesser LK, Mueller X, Marty B, et al. Alternatives to unfractioned heparin for anticoagulation in cardiopulmonary bypass. Perfusion 2001; 16: 411±6 16 Antoniou T, Kapetanakis EI, Theodoraki K, et al. Cardiac surgery in patients with heparin-induced thrombocytopenia using preoperatively determined dosages of iloprost. Heart Surg Forum 2002; 5: 354±7
DOI: 10.1093/bja/aeg606
Downloaded from http://bja.oxfordjournals.org/ at University of Oklahoma on March 30, 2015
describing the safety of danaparoid during lactation. The use of alternative anticoagulants during pregnancy and lactation was beyond the scope of our review and had been recently reviewed by Lindhoff-Last and colleagues.13 We would take issue with the suggestion that heparin should be used in patients who had HIT/HITT in the past and who require cardiopulmonary bypass (CPB). There exist alternative, more useful therapies. HIT type II is a serious complication, particularly in patients undergoing cardiovascular surgery that involves CPB. In their letter, Lakshmanan and colleagues quoted correspondence that appeared in the New England Journal of Medicine,7 which in turn attracted criticism for reporting data from an unpublished study. Considerable and signi®cant ethical concerns were raised as a result of that letter. Available treatment for alternative anticoagulation during CPB includes: (a) HirudinsÐargatroban, a lepirudin with or without anti-platelet drugs such as a GPIIb/IIIa receptor blocker (abciximab) or inhibitor (tiro®ban)14 15 (b) HeparinoidsÐdanaparoid (c) Heparin sodium only after pretreatment with iloprost16 (d) Combination of UFH with a potent antiplatelet agent, especially short-acting GPIIb/IIIa antagonists.14
Correspondence HIT/HITT and alternative anticoagulation: current concepts
D. J. W. Knight D. Selwyn K. Girling Nottingham, UK EditorÐWe read with interest the review article on HIT/HITT.1 We wish to add the following to the discussion regarding the use of heparin in patients with a history of heparin-induced thrombocytopenia (HIT). In Europe, danaparoid is licensed for use in pregnant patients with HIT. It has been used in at least 13 pregnant mothers with HIT,6 and of the four neonates that were tested for antiXa activity in their cord blood, none were found to be positive. This indicated that danaparoid did not cross the placenta. Patients needing cardiopulmonary bypass who had HIT several months previously but had no HIT antibodies preoperatively, have
S. Lakshmanan B. Saha D. Rittoo Manchester, UK EditorÐWe are pleased that our review of an important and perhaps previously under-reported and under-studied subject has created interest. Although we did not elaborate, we did state that low molecular weight heparin (LMWH) is less likely to cause heparin-induced thrombocytopenia (HIT) and related antibodies when discussing prevention of HIT.1 LMWH has replaced unfractioned heparin (UFH) in many parts of Europe and North America and is used with increased frequency in all clinical settings including the intensive care unit. Its mechanism of action, pharmacokinetics and pharmacodynamics, combined with the reduced rate of HIT,8 and less need for laboratory monitoring have led to greater use of LMWH. We agree with Knight and colleagues, that the use of LMWH in the ICU, in particular with the two most common extracorporeal circuitsÐhaemodialysis (HD) and continous veno-venous haemo®ltration (CVVH)Ðhas not been studied adequately. Its use, however, has been studied in the chronic-HD setting with mixed results. The major bene®t afforded in chronic HD is an improvement in serum lipids with decreased triglycerides, total cholesterol and apoprotein B concentrations.9 10 A randomized controlled trial comparing the use of LMWH (dalteparin) vs UFH in patients with acute renal failure or SIRS undergoing acute CVVH, demonstrated that LMWH can be used with CVVH in the ICU. However, it is at a higher cost than using standard heparin.11 There was neither a signi®cant difference in the time to failure of the ®lters, in the incidence of bleeding complications, nor in the incidence of HIT between the groups. The platelet counts were signi®cantly reduced in both groups and the only difference was the cost; CVVH with dalteparin cost more per day than with UFH. We would like to take this opportunity to highlight the following alternatives to UFH in patients requiring CVVH. (a) LMWH heparin can be considered as ®rst line for CVVH in the ICU settingÐthe bene®ts have been highlighted. LMWH should be discontinued if HIT is suspected, as there are better alternatives and the risk of continuing outweighs the bene®t.12 (b) In HIT without systemic effect, use either (i) Heparinoids: danaparoidÐbut perform in vitro heparin induced platelet aggregation assay with danaparoid (ii) Intermittent haemodialysis without heparinÐif severe heparin unrelated coagulopathy exists (iii) Regional anticoagulation with citrate, or (iv) Prostanoids. (c) In HITTS, use direct thrombin inhibitorsÐhirudins such as lepirudin and argatroban. Finally, we agree with Knight and colleagues, that the con®rmation and quanti®cation of HIT during CVVH is dif®cult for the reasons quoted in their letter. The letter from Lakshmanan and colleagues, is also of interest and we would entirely agree that in pregnant patients requiring heparin and suspected to have HIT, the heparinoid, danaparoid, is the drug of choice for acute treatment and prophylaxis due to its low placental permeability. In addition, there are case reports
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003
Downloaded from http://bja.oxfordjournals.org/ at University of Oklahoma on March 30, 2015
EditorÐWe read with interest the Editorial by Pravinkumar and Webster,1 but were disappointed that the authors did not expand on heparin-induced thrombocytopenia (HIT)-rate-reduction by empiric use of low molecular weight heparin (LMWH). Many of the traditional uses of unfractionated heparin (UFH) have been superceded by the introduction of LMWH, including treatment of deep venous thrombosis, pulmonary embolism, and acute coronary syndromes. One of the under-explored therapeutic indications of LMWH is as the anticoagulant of choice for critically ill patients requiring continuous veno-venous haemo®ltration (CVVH). We recently reported our experience in 52 consecutive patients to the Intensive Care Society of Great Britain.2 Traditionally, it is believed that LMWH has a lower HIT rate than UFH,3 but there is little evidence to support the extrapolation of this bene®t to critically ill CVVH patients. Major risk factors for the development of HIT are using high-dose heparin and continued heparin treatment for greater than 5 days.1 These criteria are almost always ful®lled as part of standard CVVH therapy. It seems logical, therefore, that a HIT rate greater than that commonly quoted of 3% is likely in this group of patients. There is surprisingly little published data for the HIT rate in UFHtreated CVVH patients, although approximately 4.7% has been suggested.4 This is compared with a HIT rate of approximately 2% in our series using LMWH.2 There are a number of dif®culties with reported haemo®ltration HIT rates. The diagnosis is primarily clinical, and con®rmatory laboratory tests are slow to perform and the results are relatively insensitive. In one study, 61% of patients clinically diagnosed as suffering from HIT failed to have the diagnosis con®rmed by antigen assays.5 The low platelet count in HIT is associated with a paradoxical increase in thrombotic tendency. Consequently, when HIT is clinically suspected during CVVH, we introduce danaparoid as an alternative anticoagulant, whilst awaiting laboratory con®rmation. The regime has been used on three patients so far (two further patients have been treated subsequent to the published abstract)2 with good effect. We would like to congratulate Pravinkumar and Webster on an excellent article but would suggest that during CVVH therapy, UFH HIT prevention (or at least rate reduction) with LMWH is better than treatment of the established syndrome.
been treated successfully with heparin for the cardiopulmonary bypass, but with strict avoidance of preoperative and postoperative heparin.7
Correspondence
E. Pravinkumar N. R. Webster Aberdeen, UK 1 Pravinkumar E, Webster NR. HIT/HITT and alternative anticoagulation: current concepts. Br J Anaesth 2003; 90: 676±85 2 Knight DJW, Selwyn D, Harvey R, Girling K. Dalteparin anticoagulation for veno-venous haemo®ltration in a teaching hospital intensive care unitÐ1 year experience. Br J Anaesth 2003; 90: 558P 3 Walker CPR, Royston D. Thrombin generation and its inhibition: a review of the scienti®c basis and mechanism of action of anticoagulation therapies. Br J Anaesth 2002; 88: 848±63 4 Bouman CS, Oudemans-van Straaten HM, Tijssen JGP, Zandstra DF, Kesecioglu J. Effects of early high-volume continuous venovenous hemo®ltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomised trial. Crit Care Med 2002; 30: 2205±21 5 Hourigan LA, Walters DL, Keck SA, Dec GW. Heparin-induced thrombocytopenia: a common complication in cardiac transplant recipients. J Heart Lung Transplant 2002; 21: 1283±9 6 Chong BH, Magnani HN. Danaparoid for the treatment of heparin induced thrombocytopaenia. In: Heparin Induced Thrombocytopaenia. Marcel Dekker Inc, 2001; 343±8 7 Potzsch B, Klovekorn WP, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin induced thrombocytopenia. N Engl J Med 2000; 343: 515 8 Warkentin TE, Levine MN, Hirsch J, et al. Heparin induced thrombocytopenia in patients treated with low molecular weight heparin or unfractioned heparin. N Engl J Med 1995; 332: 1330±5 9 Vlassopoulos D, Noussias C, Hadjipetrou A, et al. Long term effect of low molecular weight heparin on serum lipids in hypertriglyceridemic haemodialysis patients. J Nephrol 1997; 10: 111±4 10 Deuber HJ, Schulz W. Reduced lipid concentrations during four years of dialysis with low molecular weight heparin. Kidney Int 1991; 40: 496±500 11 Reeves JH, Cumming AR, Gallagher L, et al. A controlled trial of low molecular weight heparin (dalteparin) versus unfractioned heparin as anticoagulant during continuous venovenous haemodialysis with ®ltration. Crit Care Med 1999; 27: 2224±8 12 Greinacher A, Michels I, Mueller-Eckhardt C. Heparin associated thrombocytopenia: the antibody is not heparin speci®c. Thromb Haemost 1992; 67: 545±9
446
13 Lindhoff-Last E, Bauersachs R. Heparin induced thrombocytopeniaalternative anticoagulation in pregnancy and lactation. Semin Thromb Hemost 2002; 28: 439±46 14 Koster A, Meyer O, Hetzer R, et al. Some new perspectives in heparin-induced thrombocytopenia type II. J Extra Corpor Technol 2001; 33: 193±6 15 Von Segesser LK, Mueller X, Marty B, et al. Alternatives to unfractioned heparin for anticoagulation in cardiopulmonary bypass. Perfusion 2001; 16: 411±6 16 Antoniou T, Kapetanakis EI, Theodoraki K, et al. Cardiac surgery in patients with heparin-induced thrombocytopenia using preoperatively determined dosages of iloprost. Heart Surg Forum 2002; 5: 354±7
DOI: 10.1093/bja/aeg606
Downloaded from http://bja.oxfordjournals.org/ at University of Oklahoma on March 30, 2015
describing the safety of danaparoid during lactation. The use of alternative anticoagulants during pregnancy and lactation was beyond the scope of our review and had been recently reviewed by Lindhoff-Last and colleagues.13 We would take issue with the suggestion that heparin should be used in patients who had HIT/HITT in the past and who require cardiopulmonary bypass (CPB). There exist alternative, more useful therapies. HIT type II is a serious complication, particularly in patients undergoing cardiovascular surgery that involves CPB. In their letter, Lakshmanan and colleagues quoted correspondence that appeared in the New England Journal of Medicine,7 which in turn attracted criticism for reporting data from an unpublished study. Considerable and signi®cant ethical concerns were raised as a result of that letter. Available treatment for alternative anticoagulation during CPB includes: (a) HirudinsÐargatroban, a lepirudin with or without anti-platelet drugs such as a GPIIb/IIIa receptor blocker (abciximab) or inhibitor (tiro®ban)14 15 (b) HeparinoidsÐdanaparoid (c) Heparin sodium only after pretreatment with iloprost16 (d) Combination of UFH with a potent antiplatelet agent, especially short-acting GPIIb/IIIa antagonists.14