140 S . P . Butt et al .: J Extra Corpor Technol 2024 , 56 , 136 – 144
Figure
1 . Flow chart showcasing heparin resistance management .
described HR in non-surgical patients as failure to achieve therapeutic aPTT despite more than 35,000 U / day of UFH [ 36 ]. Following subsequent updates , the topic has been entirely omitted . It is not surprising , therefore , that the ISTH survey revealed significant variability in the definitions of HR used by different centres [ 35 , 37 ].
Diagnosing HR in the ICU therefore requires a high index of suspicion , and is best done by combining pharmacological , laboratory , and clinical data . We know that several conditions predispose patients to HR . ATIII , which is essential to Heparin response may be low in many ICU patients , either hereditarily or acquired in response to sepsis , disseminated intravascular coagulation , liver diseases or exposure to extracorporeal circuits , e . g ., CRRT , ECMO , etc . While ATIII supplementation is a common practice [ 37 ] andmayimproveHeparinresponse , the level of ATIII that classifies as sufficiently low to cause HR has not been defined . While some platelet count drop can be expected with UFH therapy , when indicated , clinicians must rule out Heparin Induced Thrombocytopaenia which may explain HR [ 38 ]. Elevated platelet counts or elevated procoagulant acute phase reactants e . g ., fibrinogen , factor VIII , and or von Willebrand factor , in response to sepsis , DIC , CoViD , H1N1 , etc . may also lead to HR as measured by aPTT [ 39 ].
In patients requiring high doses of UFH , it would be advisable to correlate aPTT against anti-Xa levels . If the anti-Xa is therapeutic despite aPTT being low , then further therapy may be monitored using this assay instead of aPTT . In cases where the anti-Xa are also low , either uses a higher dose of UFH and consider ATIII supplementation if the levels are deemed low , a practice that is not uncommon [ 40 ]. In cases where there are clinical indications , e . g ., consistent precipitous drop in platelet counts , frequent need of extracorporeal circuit change out , thromboembolic events , etc ., HIT must be ruled out .
It may also be reasonable to switch patients requiring high doses of UFH to one of the direct thrombin inhibitors ( DTI ) e . g ., Argatroban or Bivalirudin , that act independently of ATIII , and do not cause immune-mediated thrombocytopaenia . Dosing may need to be adjusted to renal function [ Bivalirudin ] and hepatic function [ Argatroban ] and the anticoagulant activity may be monitored using aPTT and or anti-IIa assays . Sadly , there are no approved reversal agents for either of these DTIs , which means patients going for urgent surgeries or procedures must be managed in collaboration with the surgical team , balancing the risks based on indication of anticoagulation and risks of bleeding during the surgery .
Post-operative considerations
Patients who are receiving UFH pre-operatively are at a greater risk of having HR intra-operatively and post-operatively [ 41 ]. Some case series have shown a significant association between pre-operative UFH use , HR , and fatal myocardial infarction post-coronary artery bypass surgery [ 42 ]. High incidence of HR is also noted in patients on pre-operative LMWH and infective endocarditis is also at risk of intra-operative HR [ 43 , 44 ]. Patients with low pre-operative ATIII and undergoing