Heparin resistance

Young E, Prins M, Levine MN, et al. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thromb Haemost 1992 67 639-643. 

Interestingly, FpA also increased despite maximal anticoagulation with heparin. The correlation between increased FpA plasma levels and increased incidence of complications and ischemic events indicated the involvement of heparin-resistant thrombin activity into the failure of the intervention... 

Oltrona L, Eisenberg PR, Lasala JM, et al. Association of heparin resistant thrombin activity with acute ischemic complications of coronary interventions. Circulation 1996 94 2064-2071. 

B.J. Hunt, and J.M. Murkin, Heparin resistance after aprotinin. Lancet 341 126, 1993. 

Col J, Col-Debeys C, Lavenne-Pardonge E, Meert P, Hericks L, Broze MC, Moriau M. Propylene glycol-induced heparin resistance during nitroglycerin infusion. Am Heart J 1985 110(1 Pt l) 171-3. 

Becker RC, Corrao JM, BoviU EG, Gore JM, Baker SP, Miller ML, Lucas FV, Alpert JA. Intravenous nitroglycerin-induced heparin resistance a quahtative antithrombin in abnormality Am Heart J 1990 119(6) 1254-61. 

There have been reports of heparin resistance associated with glyceryl trinitrate (105) (SEDA-16, 196), but subsequent review of this interaction showed no clinical relevance, provided that heparin anticoagulation is monitored closely (106,107). 

Habbab MA, Haft II. Intravenous nitroglycerin and heparin resistance. Ann Intern Med 1986 105(2) 305. 

These patients often appear to have heparin resistance, requiring relatively high doses of UFH to achieve a therapeutic response. ... 

Many patients with acute VTE and myocardial infarction have a diminished response to heparin, presumably because of variations in the plasma concentrations of heparin-binding proteins. Some patients have been reported to have acute elevations in factor VIII, preventing the prolongation of the aPTT by UEH. In some cases, antithrombin deficiency may be the culprit. The recommended management of patients with heparin resistance is to adjust the UEH dose based on anti-factor Xa concentrations. Approximately 50% of patients with this heparin resistance have dissociation between aPTT and heparin concentration as a result of an elevated factor VIII concentration. If anti-factor Xa concentrations cannot be measured readily, the dose of UEH should be increased until a therapeutic aPTT is achieved. 

Brill-Edwards P. Heparin resistance. In Ginsberg JS, Kearon CJH, eds. Clinical Decisions in Thrombosis and Hemostasis. Hamilton, Ontario, Canada, BC Decker, 1998 117-122. 

THROMBATE III (Bayer) is a plasma-derived product that is used to treat AT-III deficiency, the first inherited trait discovered which was identified in 1965. The condition is associated with thrombophilia caused by low levels of AT-III or the presence of altered AT-III activity. Both conditions can result in excessive blood clotting. Acquired AT-III deficiency is another condition that occurs in situations with high risk of thrombosis such as trauma, burns, and sepsis. GTG Biotherapeutics conducted chnical trials with ATryn in high-risk situations such as surgery or child de-Hvery to prevent deep-vein thrombosis in hereditary AT-III-deficient patients and heparin-resistant patients with acquired AT-III deficiency undergoing coronary bypass. A pharmacokinetic study in patients with hereditary AT-III deficiency indicated that the administration of the recombinant product resulted in an increase in blood... 

Heparin resistance in patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB). 

II Heparin resistance Dose-ranging trial, nine dose groups, CABG 36... 

III Heparin resistance Double-blind, placebo-controlled in heparin-resistant patients/CPB 54... 

III Heparin resistance Active-controlled trial in heparin-resistant patients 47... 

Heparin Resistance in Coronary Artery Bypass Craft Patients Dose-finding Study... 

Based on the results of this Phase II trial, two Phase III studies were conducted to test the potential benefit of supplementing rhAT levels in patients with an acquired deficiency state who demonstrate heparin resistance. 

Two identical Phase III placebo-controlled, double-blind, multicenter studies were conducted in heparin-resistant patients scheduled for cardiac surgery requiring CPB. The study objective was to establish whether heparin-resistant patients who receive rhAT are less likely to require FFP as a source of AT to achieve an ACT >480 seconds, as compared to patients receiving placebo [104, 105]. The secondary objectives were to compare the effect of rhAT and FFP on laboratory measures of plasma levels of AT, thrombin activity, and fibrinolysis. Specifically, the trials addressed whether rhAT, at a dose of 75 U kg , increases plasma AT levels and inhibits thrombin activity and fibrinolysis more effectively, than 2 units of FFP alone. One study (AT97-0502) enrolled 54 patients (rhAT placebo=27 27). The second study (AT97-0504) enrolled 52 patients (rhATplacebo=28 24). 

One dosing cohort received 75 U kg rhAT, and the other cohort received a normal sahne placebo (both as single bolus intravenous injection). Heparin resistance was defined as failure to achieve an ACT of >480 seconds after receiving a total dose of 400 U kg heparin intravenously after anesthesia induction and surgical incision, but just prior to CPB. The proportion of rhAT patients who required administration... 

Using concentrations of heparin, that are inhibitory to SMC proliferation, causes SM-type a-actin expression to be up-regulated [295,296]. In plasma-derived serum however, heparin is not able to modify a-actin expression, indicating that its action is related to an antiproliferative action [296]. Barzu et al. [297], have isolated in vitro a subpopulation of rat aortic SMC that is heparin-resistant in terms of growth inhibition, but differentiation responsive (increased SM-type a-actin expression) to heparin treatment. This finding is in line with the theory that heparin acts on SMC differentiation and proliferation through distinct pathways. 

Pleym H, Videm V, Wahba A, Asberg A, Amundsen T, Bjella L, Dale O, Stenseth R. Heparin resistance and increased platelet activation in coronary surgery patients treated with enoxaparin preoperatively. Eur J Cardiothorac Surg (2006) 29, 933-40. 

Habbab MA, Haft JI. Heparin resistance induced by intravenous nitroglycerin. A word of caution when both drugs are used ccmcomitantly. Arch Intern Med (1987) 147,857-60. 

LeporNE, Amin DK, Berberian L, Shah PK. Does nitrc ycerin induce heparin resistance Clin Cardiol 9Z9) 12,432-4. 

Schoenenbeiger RA, Menat L, Weiss P, Marbet GA, Ritz R. Absence of nitrc lycerin-in-duced heparin resistance inhedtl volunteers. Eur Heart J( 992) 13,411-14. 

Heparin resistance is defined as the requirement of more than 35,000 units in a 24-h period to maintain a therapeutic activated partial thromboplastin time. In some cases, elevated factor VIII levels can factitiously lower the aPPT without influencing heparin activity measured by anti-Xa assays, leading to a misdiagnosis of heparin resistance. A case of apparent heparin resistance due to increased factor VIII levels in an elderly male with infective endocarditis was reported [18 ]. 

Thota R, Ganti AK, Subbiah S. Apparent heparin resistance in a patient with infective endocarditis secondary to elevated factor VIII levels. J Thromb Thrombolysis 2012 34(l) 132-4. 

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