138 S . P . Butt et al .: J Extra Corpor Technol 2024 , 56 , 136 – 144
Table 1 . Illustration of heparin resistance mechanism . Antithrombin deficiency
Congenital
Acquired
Reduced levels of AT Decreased synthesis ( e . g ., liver disease , malnutrition ). Reduced synthesis and or stability secondary Increased clearance ( e . g ., nephrotic syndrome ) to the gene mutations [ 15 , 16 ] Increased consumption ( heparin therapy )
Functionally defective AT Upregulated haemostatic system ( sepsis , infective endocarditis , DIVC , DVT , PE )
Mutations leading to reduced activity
ECMO , IABP Medications ( e . g ., asparaginase ) [ 17 ]
Table 2 . Illustration of heparin resistance diagnosis .
Non-antithrombin mediated
Increased heparin binding to other proteins , cells and non-endothelial surfaces . High platelet count 300,000 cells / mm 3 ( due to the activation of PF4 , a strong inhibitor of heparin ). Low albumin concentrations 35 g / dL ( albumin exhibits heparin-like action ). Preoperative relative hypovolemia ( dehydration leading to increased concentration of other compatible molecules binding to heparin ). Medications ( egg , andexanet Alfa ).
another mechanism associated with HR . A study suggested that immune dysregulation in HIT , leading to reduced levels of regulatory cytokines , can contribute to the clearance of heparin and compromise its anticoagulant effect [ 12 ]. Temperature also plays a role in heparin clearance . When a procedure is normothermic , the liver metabolic rate is higher , and therefore so is the heparin clearance . In opposition , when deep hypothermia is utilized , the heparin clearance rate is considerably lower [ 13 ]. Understanding the factors influencing heparin clearance is vital in optimizing therapeutic strategies for individuals with HR . Heparin resistance can result from increased heparin-binding protein levels , low ATIII levels , increased heparin clearance levels ( due to splenomegaly in liver disease ), and high factor VIII and fibrinogen levels [ 12 ].
A study by Kimura et al . aimed to identify clinical predictors of HR in patients undergoing cardiovascular surgery . It found that 30.7 % of the 287 patients experienced HR . Analysis revealed that infective endocarditis ( IE ), platelet count , and serum fibrinogen and albumin levels were associated with HR . After adjustments for baseline ACT and initial heparin dose , IE ( odds ratio 4.57 ) and albumin levels 3.5 g / dL ( odds ratio 3.17 ) were identified as independent predictors of HR . Patients with IE had significantly lower HSI compared to those with other conditions . All patients with HR required additional heparin , and 17 received human antithrombin-III concentrate . The study concluded that infective endocarditis and preoperative hypoalbuminemia are significant independent predictors of HR , indicating a need for further research to optimize anticoagulation strategies for these high-risk patients [ 14 ].
Several methods are available to help diagnose HR including ACT , Activated Partial Thromboplastin Time ( aPTT ), Thromboelastography ( TEG ), Rotational Thromboelastometry ( ROTEM ) and Anti-Factor Xa Assay .
One review by Levy et al . discusses the clinical perspectives and management strategies for HR [ 18 ]. The authors emphasize that HR should be suspected when higher doses of heparin are required to achieve a therapeutic range of activated partialthromboplastin time ( aPTT ), and ACT tests . The chromogenic anti-factor Xa test can also be used to detect UFH function . Furthermore , a study by Bharadwaj et al . explores the occurrence of HR in patients undergoing open-heart surgeries . The authors highlight the importance of achieving therapeutic anticoagulation during procedures like CPB . They emphasize that HR , defined as the inability to achieve therapeutic anticoagulation , has been reported in up to 22 % of patients undergoing open-heart surgeries [ 19 ]. Another study by Muedra et al . investigates the relationship between antithrombin activity , anticoagulant efficacy of heparin therapy , and perioperative variables in patients undergoing cardiac surgery requiring CPB [ 20 ]. The authors explore factors that can influence HR in this surgical population .
Lastly , a review by Warnock et al . provides an overview of heparin ’ s indications and mechanisms , including its use during cardiac surgery to prevent excess coagulation [ 21 ]. The article emphasizes the broad utilization of heparin in hospitals , for various off-label indications , and highlights its effectiveness in preventing thrombotic events during cardiac surgical procedures . Consequences of heparin resistance in cardiac surgery
Cardiac surgery involving CPB is a complex procedure that requires effective anticoagulation to prevent thromboembolic events . However , HR , characterized by suboptimal response to heparin therapy , can pose significant challenges during these surgeries . The consequences of HR in cardiac surgery require focusing on the increased risk of thromboembolic events , impaired surgical outcomes , prolonged hospital stay , and elevated healthcare costs .
Chen et al . emphasized the significant interpatient differences in heparin responsiveness , which may result in