a 23-year - old man ( 192 cm , 106.4 kg ) presented to the authors for pulmonary thromboembolism and was scheduled for pulmonary artery thrombectomy . he has been diagnosed with aps after the treatment of deep vein thrombosis in his right leg at another hospital four years earlier , and he had been prescribed an anticoagulant medicine . two weeks before the patient 's hospital admission , he stopped taking the medication at his discretion . tenderness , edema , and skin ulcers occurred in both his lower extremities . during his hospital stay , the patient developed dyspnea , and pulmonary thromboembolism was diagnosed in both his descending pulmonary arteries and lower lobe segmental and subsegmental arteries via echocardiography and chest computed tomography . the result of the lung perfusion scan that was performed was also suitable for pulmonary thromboembolism . the preoperative diluted russell 's viper venom time ( drvvt ) result was 112.80 s ( reference : 24 - 37.5 s ) , and the silica clotting time ( sct ) was prolonged to 185.6 s ( reference : 23.4 - 39.2 s ) . the mixing test was not corrected , and the result was 112.80 s with the patient plasma , and 73.3 s with the mixed plasma . the anticardiolipin antibodies ( acas ) igg , and igm were positive , the antithrombin iii was 85% of the normal level , the protein c was reduced to 66% , and the protein s was reduced to 57% . enoxaparine 120 mg was injected via the subcutaneous tissue twice a day and prednisolone was administered during the preoperative period . an abnormal coagulation profile was observed ; prothrombin time / international normalized ratio ( pt / inr ) was 1.9 , prothrombin time ( pt ) was 22.3 s and activated partial thromboplastin time ( aptt ) was 79.1 s. preoperative estimated pulmonary arterial systolic pressure ( pasp ) was 76 mmhg . radial artery catheterization was performed , and midazolam ( 13 mg ) , sufentanil ( 150 g ) , and vecuronium ( 10 mg ) were injected for induction of anesthesia . the routine monitoring devices for cardiac surgery and intravenous anesthetics were used for maintenance of anesthesia . initial point - of - care testing ( poct ) results were the following : arterial oxygen tension was 201 mmhg under a 50% fraction of inspired oxygen ( fio2 ) , and plasma hematocrit was 54% . the activated coagulation time ( act ) was 165 s after induction and 951 s after injection of 336 mg of heparin to begin cpb . cpb was started after insertion of the cannulas into the aorta , superior vena cava , and inferior vena cava . after the temperature was lowered to 20 , pulmonary thrombectomy and endarterectomy were performed , following which intermittent total cardiopulmonary bypass using aortic - cross - clamp was conducted to clear the operating field . forty minutes after the administration of heparin , the act was checked again and found to be 627 s. generally , such a result would be considered acceptable for a cpb operation , but concerns about the occurrence of catastrophic aps in this case , prompted the empirical administration of 100 mg of heparin via injection . the act was again measured 5 min after the injection and was found to be 1200 s. after 3 hours , the act was found to be 629 s. an additional 80 mg of heparin was thus administered , and the act was found to be 1001 s 5 min after that injection . it was decided that protamine would not be administered due to worries about the occurrence of postoperative thrombotic complications . the total injected dose of heparin was 516 mg , and the total cpb time was 248 min . at the end of the surgery the estimated blood loss ( ebl ) during surgery was 1,000 ml and urine output was 1,100 ml . the patient was transferred to the intensive care unit ( icu ) without experiencing significant bleeding . the immediate postoperative pt / inr was 1.63 and aptt was over 180 s. the goal of the postoperative anticoagulation therapy was pt / inr 3.0 with intravenous heparin infusion during the npo period and with oral warfarin after that . the patient was discharged 12 days after surgery without specific complications . a 34-year - old man ( 160.5 cm , 48.9 kg ) the patient had been diagnosed with sle and aps after being admitted to the hospital for treatment of palpitations and dyspnea ten years earlier , and he had taken an anticoagulant medication . during the outpatient clinic follow - up , 24-hr holter monitoring revealed the increasing frequency of non - sustained atrial fibrillation . the aptt was 57.8 s and drvvt was 47.2 s ( reference : 25.9 - 35.7 s ) . the result with patient plasma from the mixing test was 27.3 s , and the mixed plasma result was 37.6 s , while sct was 52.1 s ( reference : 22.3 - 42.7 s ) . in addition , the patient was positive for la , negative for aca igg , and had borderline results for aca igm . anesthesia induction and maintenance were performed as usual , and routine cardiac anesthesia monitoring was done . the act level increased from 129 s to 850 s after the injection of 150 mg of heparin . after the insertion of cannulas into the aorta , superior vena cava , and inferior vena cava , cpb was started . one hour after the administration of heparin , the act level was found to have decreased to 524 s. therefore , an additional 50 mg of heparin was injected . after the mitral annuloplasty , valvuloplasty was performed , and weaning from cpb was attempted . due to the risk of thrombosis , a half dose ( 75 mg ) of protamine was administered . five minutes after the injection of protamine , the act level was found to be 220 s. the total administered dose of heparin during the surgery was 200 mg , and the total cpb time was 52 min . the immediate postoperative pt / inr was 1.39 and aptt was over 180 s. postoperative prophylactic anticoagulation was maintained with warfarin . ten days after the operation , the patient was discharged without specific complications . a 65-year - old woman ( 153 cm , 62.9 kg ) presented to the authors for mv leaflet mass excision . she already had percutaneous mitral valvuloplasty 10 years ago , mv replacement with tissue valve 8 years ago , and mv thrombectomy and mv replacement with mechanical valve 7 years ago . since the final surgery , she had been on an anticoagulation regimen with warfarin . recently she had gone to emergency room after experiencing sudden onset language disturbance , and had been diagnosed with left middle cerebral artery territory infarction . she also underwent routine follow - up transesophageal echocardiography ( tee ) and a mobile mass was found which was attached to the prosthetic mv leaflet . to prevent an embolic event and decrease the size of the thrombus , the patient was started on heparin several days before the surgery was scheduled . despite heparinization the surgeon therefore considered that the patient might have a disease causing a hypercoagulable state and ordered laboratory examinations to investigate this possibility . the results of the tests were as follows : protein c ( - ) , protein s ( - ) , antithrombin iii 80 ( 80 - 120% ) , aca igm 15.5 mg / dl ( < 20 ) , aca igg negative , la ( + ) , drvvt 69.1 s ( reference : 24 - 37.5 s ) , sct 137.2 ( reference : 23.4 - 39.2 s ) , mixing test with patient plasma 137.2 s , mixing test with mixed plasma ( 1 : 1 ) 99.3 s. twelve weeks later , the la test was performed again , and the patient was finally diagnosed with aps . preoperative pt / inr was 1.37 and aptt was 59.8 s. the planned surgery was mv leaflet mass excision . the patient 's left radial artery was cannulated under local anesthesia for invasive blood pressure monitoring . the patient 's basal act was 113 s and 180 mg of heparin was administered for vessel cannulations . the act level increased to 742 s and cpb was begun after insertion of cannulas into the aorta , superior vena cava and inferior vena cava . twenty minutes after the start of cpb , the act level was found to be 826 s , and an additional 60 mg of heparin was administered . the target act level during cpb was over 800 s. after 50 min , the act level had decreased to 682 s , and another 100 mg of heparin was given . at the end of cpb , the act level was 668 s , and the surgeon decided not to administer protamine , concerned about possible postoperative thrombotic complications . one hour after the cessation of cpb , the act level decreased to 577 s. the total time of cpb was 99 min , and the total administered dose of heparin was 340 mg . the immediate postoperative pt / inr was 2.93 and aptt was over 400 s. due to a bleeding tendency , 30 mg of protamine was administered to the patient . with that exception warfarin was used for prophylactic anticoagulation and the patient was discharged 9 days after the operation . a 23-year - old man ( 192 cm , 106.4 kg ) presented to the authors for pulmonary thromboembolism and was scheduled for pulmonary artery thrombectomy . he has been diagnosed with aps after the treatment of deep vein thrombosis in his right leg at another hospital four years earlier , and he had been prescribed an anticoagulant medicine . two weeks before the patient 's hospital admission , he stopped taking the medication at his discretion . tenderness , edema , and skin ulcers occurred in both his lower extremities . during his hospital stay , the patient developed dyspnea , and pulmonary thromboembolism was diagnosed in both his descending pulmonary arteries and lower lobe segmental and subsegmental arteries via echocardiography and chest computed tomography . the result of the lung perfusion scan that was performed was also suitable for pulmonary thromboembolism . the preoperative diluted russell 's viper venom time ( drvvt ) result was 112.80 s ( reference : 24 - 37.5 s ) , and the silica clotting time ( sct ) was prolonged to 185.6 s ( reference : 23.4 - 39.2 s ) . the mixing test was not corrected , and the result was 112.80 s with the patient plasma , and 73.3 s with the mixed plasma . the anticardiolipin antibodies ( acas ) igg , and igm were positive , the antithrombin iii was 85% of the normal level , the protein c was reduced to 66% , and the protein s was reduced to 57% . enoxaparine 120 mg was injected via the subcutaneous tissue twice a day and prednisolone was administered during the preoperative period . an abnormal coagulation profile was observed ; prothrombin time / international normalized ratio ( pt / inr ) was 1.9 , prothrombin time ( pt ) was 22.3 s and activated partial thromboplastin time ( aptt ) was 79.1 s. preoperative estimated pulmonary arterial systolic pressure ( pasp ) was 76 mmhg . radial artery catheterization was performed , and midazolam ( 13 mg ) , sufentanil ( 150 g ) , and vecuronium ( 10 mg ) were injected for induction of anesthesia . the routine monitoring devices for cardiac surgery and intravenous anesthetics were used for maintenance of anesthesia . initial point - of - care testing ( poct ) results were the following : arterial oxygen tension was 201 mmhg under a 50% fraction of inspired oxygen ( fio2 ) , and plasma hematocrit was 54% . the activated coagulation time ( act ) was 165 s after induction and 951 s after injection of 336 mg of heparin to begin cpb . cpb was started after insertion of the cannulas into the aorta , superior vena cava , and inferior vena cava . after the temperature was lowered to 20 , pulmonary thrombectomy and endarterectomy were performed , following which intermittent total cardiopulmonary bypass using aortic - cross - clamp was conducted to clear the operating field . forty minutes after the administration of heparin , the act was checked again and found to be 627 s. generally , such a result would be considered acceptable for a cpb operation , but concerns about the occurrence of catastrophic aps in this case , prompted the empirical administration of 100 mg of heparin via injection . the act was again measured 5 min after the injection and was found to be 1200 s. after 3 hours , the act was found to be 629 s. an additional 80 mg of heparin was thus administered , and the act was found to be 1001 s 5 min after that injection . it was decided that protamine would not be administered due to worries about the occurrence of postoperative thrombotic complications . the total injected dose of heparin was 516 mg , and the total cpb time was 248 min . at the end of the surgery the estimated blood loss ( ebl ) during surgery was 1,000 ml and urine output was 1,100 ml . the patient was transferred to the intensive care unit ( icu ) without experiencing significant bleeding . the immediate postoperative pt / inr was 1.63 and aptt was over 180 s. the goal of the postoperative anticoagulation therapy was pt / inr 3.0 with intravenous heparin infusion during the npo period and with oral warfarin after that . a 34-year - old man ( 160.5 cm , 48.9 kg ) was presented to the authors for mitral valve ( mv ) replacement . the patient had been diagnosed with sle and aps after being admitted to the hospital for treatment of palpitations and dyspnea ten years earlier , and he had taken an anticoagulant medication . during the outpatient clinic follow - up , 24-hr holter monitoring revealed the increasing frequency of non - sustained atrial fibrillation . the aptt was 57.8 s and drvvt was 47.2 s ( reference : 25.9 - 35.7 s ) . the result with patient plasma from the mixing test was 27.3 s , and the mixed plasma result was 37.6 s , while sct was 52.1 s ( reference : 22.3 - 42.7 s ) . in addition , the patient was positive for la , negative for aca igg , and had borderline results for aca igm . anesthesia induction and maintenance were performed as usual , and routine cardiac anesthesia monitoring was done . the act level increased from 129 s to 850 s after the injection of 150 mg of heparin . after the insertion of cannulas into the aorta , superior vena cava , and inferior vena cava , cpb was started . one hour after the administration of heparin , the act level was found to have decreased to 524 s. therefore , an additional 50 mg of heparin was injected . after the mitral annuloplasty , valvuloplasty was performed , and weaning from cpb was attempted . due to the risk of thrombosis , a half dose ( 75 mg ) of protamine five minutes after the injection of protamine , the act level was found to be 220 s. the total administered dose of heparin during the surgery was 200 mg , and the total cpb time was 52 min . the immediate postoperative pt / inr was 1.39 and aptt was over 180 s. postoperative prophylactic anticoagulation was maintained with warfarin . a 65-year - old woman ( 153 cm , 62.9 kg ) presented to the authors for mv leaflet mass excision . she already had percutaneous mitral valvuloplasty 10 years ago , mv replacement with tissue valve 8 years ago , and mv thrombectomy and mv replacement with mechanical valve 7 years ago . since the final surgery , she had been on an anticoagulation regimen with warfarin . recently she had gone to emergency room after experiencing sudden onset language disturbance , and had been diagnosed with left middle cerebral artery territory infarction . she also underwent routine follow - up transesophageal echocardiography ( tee ) and a mobile mass was found which was attached to the prosthetic mv leaflet . to prevent an embolic event and decrease the size of the thrombus , the patient was started on heparin several days before the surgery was scheduled . despite heparinization , however , the thrombus showed no change in size on tee . the surgeon therefore considered that the patient might have a disease causing a hypercoagulable state and ordered laboratory examinations to investigate this possibility . the results of the tests were as follows : protein c ( - ) , protein s ( - ) , antithrombin iii 80 ( 80 - 120% ) , aca igm 15.5 mg / dl ( < 20 ) , aca igg negative , la ( + ) , drvvt 69.1 s ( reference : 24 - 37.5 s ) , sct 137.2 ( reference : 23.4 - 39.2 s ) , mixing test with patient plasma 137.2 s , mixing test with mixed plasma ( 1 : 1 ) 99.3 s. twelve weeks later , the la test was performed again , and the patient was finally diagnosed with aps . preoperative pt / inr was 1.37 and aptt was 59.8 s. the planned surgery was mv leaflet mass excision . the patient 's left radial artery was cannulated under local anesthesia for invasive blood pressure monitoring . the patient 's basal act was 113 s and 180 mg of heparin was administered for vessel cannulations . the act level increased to 742 s and cpb was begun after insertion of cannulas into the aorta , superior vena cava and inferior vena cava . twenty minutes after the start of cpb , the act level was found to be 826 s , and an additional 60 mg of heparin was administered . the target act level during cpb was over 800 s. after 50 min , the act level had decreased to 682 s , and another 100 mg of heparin was given . at the end of cpb , the act level was 668 s , and the surgeon decided not to administer protamine , concerned about possible postoperative thrombotic complications . one hour after the cessation of cpb , the act level decreased to 577 s. the total time of cpb was 99 min , and the total administered dose of heparin was 340 mg . the immediate postoperative pt / inr was 2.93 and aptt was over 400 s. due to a bleeding tendency , 30 mg of protamine was administered to the patient . with that exception warfarin was used for prophylactic anticoagulation and the patient was discharged 9 days after the operation . the three case mentioned above according to the recently revised guidelines for aps the criteria for definite aps include one or more episodes of thrombosis , a symptom related to thrombosis , and a positive antiphospholipid antibody test ( apl test ) result on two or more occasions that are at least 12 weeks apart . the reason for such a time interval requirement is that about 4 - 5% of healthy individuals can present positive results temporarily due to infections or drugs taken . two important autoimmune antigens related to the pathophysiologic mechanism of aps that have been discussed are -2-glycoprotein-1 ( 2gpi ) and prothrombin . the coupling of 2gpi and the autoimmune antibody induces blood coagulation in vivo through the signal - transporting system of the cell , but in vitro , the coagulation time is delayed by the addition or formation of negatively charged phospholipids ( pl ) . prothrombin ( coagulation factor ii ) also forms prothrombin / antiprothrombin complex , which binds with pl , delaying the coagulation time in vitro . the formation or addition of pl triggered coagulation time delay in the test ( aptt and drvvt ) . as the apl in the patient plasma bound with pl in the normal plasma , the delay of the coagulation test was not corrected in the mixed - coagulation test . the pt is thus not useful in the detection of apl because excessive phospholipids in the form of tissue thromboplastin are added . there are two different prophylactic settings : primary thromboprophylaxis for patients who have not yet experienced a thrombotic event , and secondary thromboprophylaxis for patients who have already had a previous thrombotic event . for primary prophylaxis , patients are prescrived low dose aspirin , and for secondary prophylaxis , patients take warfarin with target pt / inr 2.0 to 3.0 . aps patients are more vulnerable than the general public to cardiac valvular disease because if endocardial injury ( mainly on the left side of the heart ) due to the pressure or jet of blood flow occurs , the pl in the cell are exposed , which induces microthrombi . the valve injury thus progresses due to the fibrotic change of the microthrombi . among the apl antibodies , the autoimmune antibody to 2gpi is frequently detected in paitents with chest pain syndrome or those who are undergoing acute coronary events . such patients may undergo surgery using cpb , which makes the selection of an appropriate coagulation test or method particularly important . in aps patients , several factors must be considered to be able to choose which coagulation test to perform or which laboratory values to use as the guidelines for the anticoagulation therapy . this is the case because the coagulation test results can be misinterpreted in aps and because the use of cpb can induce an immunologic and a coagulative response . there has thus far been no consensus regarding which is the best method of anticoagulation is , and only a handful of cases that seem to point in the direction of any particular method have been reported . in some studies , either the standard dose ( 3 mg / kg ) or an increased dose ( sheikh et al .   recommended a heparin dose that doubles the baseline act level . the use of the act as means to measure blood coagulation is accompanied by a number of problems , namely : ( 1 ) there may be patients with increased baseline act levels ; ( 2 ) half of aps patients may have thrombocytopenia ; and ( 3 ) the heparin response may vary due to a patient 's low level of antithrombin iii . in the cases discussed here , all three of our patients ' baseline act levels were in the normal range . in addition , adequate prolongations of act levels were achieved with the standard dosage of heparin in our patients . ducart et al .   maintained a plasma heparin level of over 2.5 iu / ml . in some cases , measurement of the antifactor xa level has been recently introduced , but there is yet no conclusion as regards which method is most effective and leads to the fewest complications . adequate diagnostic tools and guidelines must be established according to the hospital circumstances as well as the patient 's individual risk factors , and the optimal anticoagulation effect that does not increase the bleeding must be maintained . moreover , the neutralization of heparin with protamine after the completion of cpb should be carefully done . in some reports , protamine was not used to prevent catastrophic aps . in the first case discussed here , although the act level was prolonged during both the operation and the weaning from cpb , a standard dose of heparin was administered regardless of the act result , and protamine was not injected during weaning from cpb due to worries about the occurrence of severe complications , such as catastrophic aps . in the second case , in the third case , a minimal dose of protamine ( 30 mg ) was administered in the icu postoperatively due to a bleeding tendency . in such cases , the surgical procedure can be completed simply through the use of any of the above methods , but considering the risk of bleeding , it is reasonable to determine the appropriate dose through the continuous infusion of protamine ( for example 50 mg / hr ) until the dose no longer causes bleeding . the syndrome 's exact cause has not yet been determined , but it is believed that operations and infections may trigger it . to prevent this , infections should be controlled through administration of appropriate antibiotics , and a parenteral anticoagulant should be taken by patients who will undergo surgery peripartum and by patients with rashes associated with sle . it has been reported that heparin administration to maintain the pt / inr level at about 3 , and steroid use to prevent the release of cytokine from necrotic tissue , may help prevent infection . taking all these factors into consideration , the anesthesiologist should use caution in interpreting the results of the coagulation panel and in preventing thrombosis during the perioperative period . further studies are also necessary for the maintenance and monitoring of an adequate anticoagulation level , especially during cpb in aps patients .
antiphospholipid syndrome ( aps ) is a rare disease in which patients display prolonged coagulation test results in vitro , but usually develop thrombotic symptoms in vivo . 
 patients with aps are at increased risk of valvular heart disease or coronary vascular disease , conditions that often necessitate cardiac surgery via bypass . 
 the management of anticoagulation during cardiopulmonary bypass ( cpb ) is particularly challenging in these patients because of the unique features of aps . 
 patients with aps are constantly at risk of arterial and venous thrombotic events . 
 therefore it is very important to maintain proper anticoagulation perioperatively , especially during cpb . in this paper , we present three successful cases of aps patients who underwent cardiac surgery with cpb .