pregnancy is associated with an increased risk of thrombosis among women with mechanical prosthetic heart valves .
an anticoagulation management is important for both , mother and fetus.1 ) an increased thrombogenicity in pregnancy may be associated with several factors such as inherited coagulation defects , which may result in recurrent pregnancy loss and other thromboembolic complications.2 ) herein , we present a pregnant patient who had a history of recurrent pregnancy loss and developed recurrent prosthetic heart valve thrombosis ( phvt ) despite optimal anticoagulation .
a 23-year - old pregnant woman ( 10 weeks of gestation ) with mechanical mitral prosthetic valve ( operated 5 years ago ) was due to an exertional dyspnea admitted to our hospital .
she did not notify her medical doctor about her pregnancy and had continued to intake 7.5 mg of warfarin on her own .
the international normalized ratio ( inr ) was 2.4 on admission and the blood pressure was 130/80 mm hg .
transthoracic echocardiography on admission revealed increased doppler gradients ( maximum / mean gradient : 17/10 mm hg ) and decreased mitral valve area ( mva ) of 1.5 cm indicating a prosthetic valve obstruction .
transesophageal echocardiography delineated a thrombus area of 1.5 cm on the mitral prosthesis ( fig .
thrombolytic therapy ( tt ) with low dose ( 25 mg ) and slow infusion ( 6 hours ) of tissue - plasminogen activator ( tpa ) was administered as described recently.3 ) after tt , the mva increased to 2.8 cm and the transmitral gradient decreased ( maximum / mean gradient : 11/5 mm hg ) with a complete lysis of the thrombus ( fig .
an elective curettage was performed to avoid a potential embryopathy due to the relatively high dose warfarin consumption .
two years later , the patient suffered from two pregnancy losses at the 18th and 20th week respectively .
anticardiolipin immunoglobulin ( ig ) g and igm , lupus anticoagulant and toxoplasma antibodies were studied and showed all negative results .
genetic testing was performed using cvd strip assay kit ( viennalab diagnostic gmbh ) and no mutations were observed in the factor v leiden , factor v h1299r , prothrombin g20210a , factor xiii v34l , methylenetetrahydrofolate re ductase ( mthfr ) c677 t , plasminogen activator - inhibitor 1 4g-5 g , gpiiia l33p , ace , apob r3500q and apoe .
however , homozygous mutations of mthfr a 1298c , and heterozygous mutations of -fibrinogen 455 g - a were detected .
one year ago , the patient became pregnant again and suffered another episode of obstructive phvt in the 33rd week of her gestation despite strict anticoagulation ( low molecular weight heparin with effective antifactor xa levels in the first trimester and inr between 2.5 and 4 in the second and third trimester ) .
she delivered by cesarean section an alive and healthy newborn at the end of the 37th week of gestation .
methylenetetrahydrofolate reductase a 1298c homozygous and -fibrinogen 455 g - a heterozygous mutations were detected in a pregnant patient with a history of recurrent pregnancy loss and a recurrent prosthetic valve thrombosis despite optimal anticoagulation .
the pathogenesis of phvt is multifactorial and pregnancy is one of the risk factors that may enhance thrombosis.4)5 ) there is a 4-fold to 10-fold increased thrombotic risk throughout gestation and postpartum period.6 ) on the other hand , some women affected by thrombophilia show an increasing hypercoaguable state during their pregnancy and may suffer obstetrical complications such as recurrent pregnancy loss.2 ) approximately 20% of the thromboembolic events in pregnancy are arterial and the other 80% are venous.7 ) the relationship between genetic mutations and phvt and/or miscarriage in pregnancy is unknown .
a reduction in mthfr level or an activity by specific gene mutations induces hyperhomocysteinemia , characterized by mild to moderate increased plasma homocysteine levels , that has been shown to be a risk factor for arterial or vascular thrombotic events , including myocardial infarction , stroke , deep vein thrombosis and recurrent spontaneous abortus.8)9 ) to our knowledge , mthfr a 1298 c mutation related with recurrent phvt was not reported previously .
beta - fibrinogen 455 g / a polymorphism is a gene mutation that may lead to alterations in the activity of fibrinogen which plays an active role in the coagulation cascade.10 ) in several publications , it has been shown to be associated with an increased erythrocyte aggregation and to predispose the development of stasis in coronary arteries and the left atrium.10)11 ) this gene mutation may also contribute to a thrombus formation on surfaces such as prosthetic valves that is already prone to stasis .
however this potential relationship has not been reported also . in the presented case was the mutation heterozygous for the fibrinogen 455g / a allele and it remains unclear whether this may be especially related to recurrent phvt and/or miscarriages in the presence of additional homozygous mthfr a 1298 c mutation .
since surgical treatment carries a high mortality risk not only for the mother but also for the fetus during a pregnancy with phvt , tt may be a reasonable option and seems effective and safe with low doses and slow infusion rates.3)4)5 )
 an effective anticoagulation is critical in pregnant patients with prosthetic heart valves . 
 inherited disorders may interfere with the coagulation cascade and may be associated with obstetrical complications as well as with prosthetic valve - derived complications . 
 the patient in the present case had a history of recurrent prosthetic heart valve thrombosis ( phvt ) despite an effective anticoagulation . 
 she underwent a thrombolysis with low - dose prolonged infusion of tissue - type plasminogen activator for the management of her recurrrent prosthetic valve thrombosis . 
 the genetic testing showed homozygous mutations of methylenetetrahydrofolate reductase ( mthfr ) a 1298 c and heterozygous mutations of -fibrinogen 455 g - a . 
 inherited disorders such as mthfr a 1298 c and fibrinogen 455g / a polymorphisms may be involved in the pathogenesis of recurrent phvt and/or pregnancy loss . 
Introduction
Case
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