[Recurrent thromboses and hemorrhagic complications in patients with antiphospholipid syndrome during therapy with warfarin plus aspirin].
OBJECTIVE
To estimate the frequency of relapses of thrombotic and hemorrhagic complications during moderately intensive therapy for antiphospholipid syndrome (APS) with warfarin with and without aspirin.


METHODS
Eighty-two patients diagnosed as having the antiphospholipid syndrome were examined. Group 1 patients (n = 49) received warfarin alone as an antithrombotic drug; Group 2 patients (n = 33) had a combination therapy with warfarin plus aspirin. The efficiency of therapy was evaluated from the number and rate of recurrences of thromboses and transient ischemic attacks (TIA) and its safety was assessed from the frequency and number of hemorrhages during the study. The genetic variants of cytochrome P450 CYP2C9 were determined in 52 of the 82 patients; mutations in the gene for vitamin K epoxide reductase complex 1 (VCORC1) were revealed in 22 patients.


RESULTS
During the follow-up, antithrombotic therapy was ineffective in 18.4 and 36.6% of the Groups 1 and 2 patients, respectively (p = 0.07). The rate of poor outcomes (thromboses and TIA) was 7 and 14.8 cases per 100 person-years, respectively. The first six months of warfarin therapy proved to be most risky for thrombotic events to occur--this period was responsible for 37% of bleedings. Hemorrhagic complications of antithrombotic therapy developed in 46.9 and 60.6% of Groups 1 and 2 patients, respectively (p = 0.26). Major hemorrhages were observed more frequently in the combination (warfarin plus low-dose aspirin) therapy group than in the warfarin monotherapy group. Mutant cytochrome P450 gene variants (CYP2C9*2 and CYP2C9*3) were present in 38.5% of the patients; VCORC1 gene mutations were observed in 27.3%. The number of nasal and gingival hemorrhages was increased in patients with CYP2C9*3 and homozygous VCORC1 gene mutations.


CONCLUSIONS
Moderately intensive warfarin therapy (international normalized ratio 2.0-3.0) could generally reduce the frequency of recurrent thrombotic events by at least 2-fold as compared with that before warfarin administration. The efficiency of using warfarin alone or in combination with aspirin in APS was found to be similar; and its safety was higher during monotherapy therefore it is undesirable to combine warfarin with antiaggregants in real clinical practice. The determination of CYP2C9 and VCORC1 genotypes in patients with APS before warfarin use allows excessive hypocoagulation and related hemorrhages to be avoided.
Kondrat'eva
L V
LV
Patrusheva
N L
NL
Patrushev
L I
LI
Aleksandrova
E N
EN
Kovalenko
T F
TF
Ostriakova
E V
EV
Reshetniak
T M
TM
D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D006470:Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D055502:Secondary Prevention; D013927:Thrombosis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D064417:Vitamin K Epoxide Reductases; D001241:Aspirin