Mechanical heart valve thrombosis during pregnancy under non-warfarin anticoagulation therapy: Two-case report and literature review

Abstract

Anticoagulation drugs should be used for patients with mechanical heart valve (MHV) in case of potential risk of thrombosis. Pregnant women with MHV have to change therapies due to teratogenic effect of some anti-coagulation drugs. European Society of Cardiology clinical guidelines for the management of cardiovascular diseases during pregnancy gives specific suggestions for anticoagulation therapy.We have treated 2 patients with mechanical heart valve thrombosis (MVT) during pregnancy: One received low molecular weight heparin (LMWH) throughout the pregnancy and developed MVT at the third trimester of pregnancy; one developed MVT at the first trimester when replacing vitamin K antagonists (VKA) with LMWH. These patients raised secondary reflection on the balance between clinical guideline and personalized medicine. During LMWH therapy, we should dynamically monitor patients’ anti-activated factor X (anti-Xa) level to evaluate coagulation function during pregnancy. When a pregnant woman with MHV develops symptoms of acute heart failure, stuck mechanical valve should be paid attention to and surgery should be promptly performed if necessary.

A mechanical heart valve thrombosis (MVT) during pregnancy is one of the most dangerous conditions due to its disastrous complications both on mother and fetus^[1]. Due to gestational hypercoagulable state and interruption of anticoagulation therapy, the risk for prosthetic valve thrombosis surges. Moreover, the risk for teratogenesis of warfarin makes the anticoagulation therapy special and risky during pregnancy; while pregnant patients who substitute warfarin with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) are faced with threats of mechanical heart valve (MHV)^[2]. In a dilemma, we should be fully aware of the risk behind every therapy and monitor corresponding biochemical markers regularly to avoid risk to the maximum extent. We present our experience of 2 pregnant patients with stuck mechanical mitral valve due to replacement of warfarin with LWMH during pregnancy.Besides, we give a brief review of current guidelines on the anticoagulation therapy of patients with MHV during pregnancy.

1. Case representation

1.1. Case 1

A 26-year-old female in her 36th gestational week was admitted to the obstetric ward at the Second Xiangya Hospital on June 16, 2019, with aggravated dyspnea, tachypnea, and palpitation. The patient was in New York Heart Association (NYHA) functional classification class IV. At the age of 13, she had received a prosthetic mitral valve replacement due to severe rheumatic mitral stenosis. She had used vitamin K antagonists (VKA) until her pregnancy, while she substituted her oral anticoagulation therapy with continuous heparin therapy. After multidisciplinary consultation, a preliminary diagnosis of acute heart failure or pulmonary embolism was made. Routine pre-operative preparations were done on emergency basis. Because of the instability of hemodynamic condition,cesarean section was performed after poor control of symptoms. Her operation proceeded uneventfully, and a healthy boy was born with minimal blood loss.

The patient was admitted to the intensive care unit (ICU) and benefited from full hemodynamic monitoring with insertion of a central venous line, peripheral arterial line, with continuous electrocardiogram and blood pressure monitoring, serial evaluation of arterial blood gases, correction of acidosis, and control of serum electrolytes. Multidisciplinary team closely observed the patient after surgery. Paroxysmal ventricular fibrillation occurred at the first day in ICU, and her heartbeat was recovered through continuous cardiac external compression and electrical defibrillation. Later we used extra-corporeal membrane oxygenation (ECMO) and cardiac-resynchronization-therapy (CRT) to maintain her hemodynamic condition. To figure out the heart condition, we performed transthoracic echocardiography and confirmed the diagnosis: An MVT in the mitral position, which may result from her decision to cease taking warfarin when she got pregnant. Given the critical situation, mitral valve replacement surgery was performed successfully on the 7th day postoperatively; on the 20th postoperative day, she was discharged in good condition.

1.2. Case 2

A 32-year-old woman was admitted for termination of pregnancy at the 13th weeks gestation on June 5, 2020. In 2007, she had received a MHV replacement due to severe rheumatic mitral stenosis. After the surgery, she kept oral warfarin therapy until determination of pregnancy, when she replaced warfarin with LMWH (Enoxaparin, 5 000 units twice daily). One month later, she went to see a cardiovascular surgeon for feeling of chest congestion and palpitations. With the help of transthoracic echocardiography (TTE), the diagnosis of stuck mitral valve was confirmed. On April 22, she received mitral valve replacement and thrombectomy with cardiopulmonary bypass (CPB) under general anesthesia. With a good postoperative recovery, she came to obstetric ward for termination of pregnancy. With normative treatment, medical abortion (mifepristone+misoprostol) underwent uneventfully. Following delivery, warfarin was restarted to achieve the international normalized ratio (INR) target as her pre-natal level (between 2.0 and 3.0) and enoxaparin was administered to bridge the period until normal INR was achieved.

2. Discussion

Pregnant patients with MHVs, especially in the mitral position, present a harsh dilemma. During pregnancy a series of changes in hemostasis contribute to a state of hypercoagulability and a higher risk of stuck mechanical valve^[1].Acute MHV malfunction during pregnancy is lethal to the patients, with high fetal and maternal morbidity and mortality^[3], while urgent cardiac surgery comes with a high rate of fetal loss^[4]. According to the Registry of Pregnancy and Cardiac Disease (ROPAC) involving 212 pregnant patients with MHV, 4.7% developed MVT^[5]; a Meta-analysis in 2017 showed that the risk of thromboembolic complication was 2.7%-8.7%, varying with the choice of anticoagulation therapy^[6].

Currently, anticoagulation therapies differ widely, but none was proved to be superior above others in all respects. Some evidence indicates that the use of VKAs throughout pregnancy, under strict INR control, is the safest regimen to prevent valve thrombosis^[7-8]. However, VKA use in the first trimester results in dose-dependent embryopathy (limb defects, nasal hypoplasia) in 0.6%-10.0% of cases^[9]. There are 0.7%-2.0% risk of fetal diseases (e.g. ocular and central nervous system abnormalities, intracranial haemorrhage) in the second and third trimester^{[5, 10]}. The risk of teratogenesis of warfarin can be decreased only if the required dose of warfarin to achieve effective anticoagulation is less than 5 mg/d^[11]. Although not supported by strong evidence, UFH and LMWH are advocated by the most recent guidelines to avoid harm to the fetus because they do not cross the placenta^[12] and LMWH is possibly superior to UFH for preventing valve thrombosis^[13]. LMWH is recommended only if weekly anti-activated factor X (anti-Xa) level monitoring and dose-adjustment are available.

According to current guideline, such patients should stick to VKAs until pregnancy. During pregnancy, the choice of proper medical therapy becomes complicated and risky. We present 3 common therapies according to the 2018 European Society of Cardiology (ESC) guidelines^[13] and our experience.

If the mother only uses low-dose VKA to prevent thrombosis (e.g. warfarin <5 mg/d), she is supposed to continue VKAs for the duration of pregnancy instead of changing medicine, as the risk of teratogenesis is negligible under low-dose VKA. This is the most well-established recommendation in the guideline with low-risk of MVT (0-4%)^[5]. In this scenario, doctors should continue to monitor INR regularly in conformity with current guidelines. As for the second therapy, if the mother uses high-dose VKA (˃5 mg/d) before pregnancy, it’s recommended to replace VKA with UFH or LMWH in the first trimester of pregnancy to avoid the potential harm to the fetus. When changing therapy, doctors should monitor anti-Xa level each day and adjust the dose until peak anti-Xa level reaches 1.0- 1.2 U/mL. Goland et al^[14] believed that to ensure an adequate level of anticoagulation, the trough (pre-dose) anti-Xa level should also be routinely monitored in those pregnant women, which is safe to the patient when reaching 0.6 U/mL. Moreover, activated partial thromboplastic time (aPTT) should be monitored every week when using UFH in the first trimester. In the second and third trimester, it is safer to switch back to VKA and monitor INR routinely. With anti-Xa level monitoring, the risk of MVT is 5.8%-7.4% according to existing evidence. The last choice, though less well established by evidence, is to replace VKA with LMWH or UFH throughout pregnancy under close monitoring of anti-Xa level. This choice is unquestionably safe for the fetus, but puts unnecessary risk of MVT for the mother on the whole. With normative monitoring, the reported risk of MVT is 4.4%-8.7%^[9]. For all the therapies above, patients should switch to UFH or LMWH at week 36, and use intravenous UFH (aPTT≥2 times the control) at least 36 hours before delivery and stop UFH 4-6 hours before delivery in case of serious hemorrhage during the perinatal stage.

In both of our cases, the anticoagulation therapy is consistent with the ESC guideline; however, anti-Xa level was not monitored routinely to get hold of the coagulation function of the patients, which may lead to insufficient LMWH dose and result in MVT consequently.Due to increased renal clearance and physiological hypercoagulation state during pregnancy, the dose requirement of LMWH should be increased obviously according to the anti-Xa level; otherwise relatively inadequate LMWH is associated with the risk of valve thrombosis^[5].Güner et al^[15] reported 3 cases of MVT occurring in LMWH therapy and regular follow-up of anti-Xa levels. Despite recommendation of LMWH by recent reports and guidelines, LMWH is not equal to complete elimination of PVT risk even with monitoring of peak anti-Xa level. Nevertheless, LMWH guarantees the safety for both the mother and the fetus to the greatest extent.

Clinical trials have been an alternative therapy combining LMWH with a low dose of VKA may achieve a slight increase in INR and adequate anticoagulation, but there is no relevant evidence. Guideline of the American College of Chest Physicians (ACCP) recommends combination of warfarin with low-dose aspirin for MHV pregnant women with risk factors of thromboembolism, such as atrial fibrillation,older generation MHV, etc^[16]. Data from the ROPAC study^[5] demonstrate that 13 patients were administered aspirin along with other anticoagulation regimes in the second and third trimester, and none of them developed MVT. However, hemorrhagic events are relatively higher in patients using anticoagulation regimes plus aspirin comparing to those who were treated without aspirin. Without patients used aspirin as monotherapy, this sample size is too small for a persuasive conclusion.A study exploiting Bayesian network Meta-analysis (NMA) may further determine which anticoagulation regimen is more beneficial for patients with MHVs during pregnancy in the future^[2].

When treating women of childbearing age in need of heart valve replacement, tissue heart valve or heart valve repair instead of mechanical heart valve could be chosen in case of adverse event during pregnancy, as data have shown that despite inferior durability, pregnant patients with tissue valves underwent less morbidity and less fetal loss than those with mechanical valves^[17]. Before MHV replacement, cardiac surgeons must apprise them of the risks of thrombosis and fetal loss connected with anticoagulation during pregnancy^[18]. Throughout the pregnancy delivery and the postpartum, women with MHVs should be supported by a multidisciplinary team and receive specialized instructions and care.

When treating pregnant women with MHVs, transferring totertiary hospital in time is essential for the safety of both the pregnant woman and the fetus. Multidisciplinary services by obstetrician and cardiac surgeon are also very important. Physicians should track the pregnant patients’ coagulation function on a regular schedule simultaneously. They should be fully aware of the risk of MVT as well as the possibility of cardiac failure caused by other reasons, and the majority of gestational prosthetic valve thromboses occur when heparin replaces warfarin therapy with the commencement of the pregnancy^{[14, 19]}. In these cases, the initial symptoms of prosthetic valve thrombosis are similar to those of other types of acute heart failure, while patients with stuck mechanical valve should be treated by thoracic surgery immediately. When a patient with typical symptoms of acute heart failure cannot be relieved by commonly used drugs (digoxin, diuretics, etc.), we should consider the possibility for prosthetic valve thrombosis and conduct TTE immediately to evaluate patient’s heart condition.

In a nutshell, the anticoagulation therapy is a hard choice balancing between the maternal and fetus safety, and each therapy contains risk. Therefore, the physician should demonstrate the pros and cons of each option, recommend therapy strategies according to current data, experience and economic factors, and respect the selection of the patient. Once determining a therapy, doctors should monitor the corresponding indicators regularly to evaluate the anticoagulation function of the patient and change the dose accordingly.

Conflict of Interest

The authors declare that they have no conflicts of interest to disclose.

Note

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