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importantly Factor IIa and Xa . By inactivating thrombin , it prevents the conversion of fibrinogen to fibrin ; this prevents the formation of clots and prolongs the clotting time of blood . Typically , the dosage of UFH for cardiac surgery procedures with cardiopulmonary bypass ( CPB ) is 300 – 400 IU / Kg . With this dosage , normally the activated clotting time ( ACT ) reaches the target within a range of 400 – 480 s [ 3 ].
Anticoagulation is essential in cardiac procedures as the patient ’ s blood is exposed to foreign surfaces of the heart-lung machine , surgical stress , and room air . This contact triggers the coagulation cascade , leading to life-threatening clotting complications if the patient is not properly anticoagulated . Issues such as consumptive coagulation , excessive postoperative bleeding and thromboembolic events can arise [ 4 ].
Methodology
The methodology involved in diagnosing heparin resistance ( HR ) includes evaluating ACT and HR assays . To identify management strategies , a comprehensive literature review was carried out , encompassing studies investigating heparin dosage adjustments , antithrombin supplementation , and alternative anticoagulants in cardiac surgery patients with HR . A systematic search of related studies on HR was conducted across various scholarly databases such as Google Scholar , PubMed , and Embase , using specific keywords . The inclusion criteria for selecting studies included relevance to HR management in cardiac surgery patients and publication in peer-reviewed journals . This search yielded 59 studies that satisfied the predetermined inclusion criteria .
Discussion Heparin resistance
Heparin resistance can occur anywhere from 4 % to 26 % of the time , depending on the first heparin bolus given and the target ACT level needed to start CPB [ 5 ]. HR is defined as the inability to achieve a desired ACT or a decreased slope on the Heparin Dose-Response ( HDR ) curve after adequate heparin dosage . A commonly accepted definition for HR is that > 500 U / kg body weight of heparin is required to achieve an ACT of 480 s [ 6 , 7 ].
The HDR curve aims to account for variability in an individual ’ s heparin response . Two ACT samples are taken one after a known concentration of heparin and extrapolation from the curve gives a specific concentration of heparin required to achieve a specific ACT . A heparin sensitivity index ( HSI ) < 1 s / U / kg usually is indicative of HR [ 4 ].
Heparin resistance can complicate the continuing management of anticoagulation during and after surgery . To overcome this , the patient may require a higher dose of heparin , alternative anticoagulants , or supplementation with ATIII concentrate to achieve the desired anticoagulant effect . This in turn may pose an increase in the risk of bleeding complications if specific protocols are not in place demonstrating how to deal with this . Additionally , HR may be associated with other underlying factors suchas inflammation , genetic variations , or medications , which can further impact surgical outcomes .
Identifying HR before surgery is crucial to optimize anticoagulation strategies . This can be achieved through laboratory tests such as the ACT , or HR assays . By recognizing patients with HR , healthcare providers can adjust the anticoagulation regimen , potentially reducing the risk of complications and improving surgical outcomes Mechanisms of heparin resistance
The mechanisms underlying HR are multifaceted and involve ATIII levels , the interaction between heparin and ATIII , and the function of ATIII is mentioned in Tables 1 and 2 .
Since heparin exerts its effects by catalyzing the anticoagulant activity of ATIII , it has been suggested that antithrombin deficiency is the main cause of HR . Adults ’ average ATIII activity ranges from 80 % to 120 %, and its deficiency is typically described as ATIII activity below 80 %. Lemmer et al . looked at ACT levels after heparin induction of > 600 IU / kg and found in 53 patients with HR that after administering 500 units of ATIII in 45 patients and 1000 units in 8 patients the mean ACT levels rose from 492 s to 798 s demonstrating the use of ATIII to treat HR during CPB . Although there was an apparent lack of correlation between kaolin ACT levels and ATIII activity noted after > 600 IU / kg heparin in 53 patients , this suggests there may be an alternative mechanism present for HR [ 8 ].
Assuming ATIII deficiency is the main cause of HR , the reduction can be the result of a congenital deficiency ( which has a prevalence of 1 in 3000 people ) and these patients tend to have a range of 40 – 60 % of normal [ 5 ].
The use of heparin preoperatively 48 h prior contributes to HR , as does enoxaparin . ATIII levels have been seen to decline at approximately 5 – 7 % a day as the thrombin / ATIII complex is cleared via the reticuloendothelial system leading to HR . Although this is still up for debate and may not be clinically significant [ 6 , 7 ], the exact mechanism is still to be determined and it is thought that it may even be a function of the ACT test when compared with high-dose thrombin test time [ 8 ].
Thrombocytosis can also lead to HR as platelet factor 4 ( PF4 ) released from activated platelets binds to UFH , therefore reducing the bioavailability of heparin . PF4 is also a crucial player in heparin-induced thrombocytopenia ( HIT ), a severe immune complication of heparin therapy . Antibodies to PF4 / heparin complexes can develop after heparin exposure and lead to platelet activation , culminating in life-threatening thrombosis [ 9 ]. It has been established that PF4 and heparin can form multimolecular complexes , and heparin-induced conformational changes in PF4 render it antigenic , leading to the generation of pathogenic antibodies [ 9 ]. These antibodies bind to FccIIA receptors on platelets , triggering platelet activation and contributing to the prothrombotic state associated with HIT [ 10 ].
HR may appear shortly after the onset of thrombocytopenia in these patients . HR in these cases may be due to the neutralization of heparin by PF4 released from activated platelets as previously mentioned . In HIT , a progressive decline in platelet count of more than 50 % from baseline or to less than 100,000 / lL is typical [ 11 ]. Accelerated heparin clearance is