Conduita terapeutică în cazul evenimentelor trombotice recurente într-o sarcină

Introduction

One of the leading causes of maternal mortality and morbidity in the developed world is venous thrombembolism, a direct complication of deep vein thrombosis (DVT). The risk of this cosequence may be diminished with proper treatment and prophylaxis^(1,2).
Although the incidence of venous thrombembolism is low (2 cases/1000 pregnancies)⁽²⁾, this risk is approximately five times higher than the risk among non-pregnant women⁽³⁾. The procoagulant changes are physiologic and considered to be preparatory measures for the hemostatic challenge of delivery. More than 50% of thrombotic events occur before 20 weeks of gestation, but reported data show that they may occur throughout the pregnancy^(4,5). The risk of thrombotic events increases moreover up to 6 weeks after delivery, probably because of the endothelial damage to the pelvic vessels that occurs during delivery⁽⁶⁾, but there is evidence indicating that an increased risk persists up to 12 weeks after delivery⁽⁷⁾.
Venous thrombosis is a multi-causal disease; a previous pregnancy-related venous thrombosis, a high Body Mass Index, hyperemesis leading to dehydration and immobility^(8-10), thrombophilias and tobacco use are among the strongest risk factors for this condition.
Little data is available from randomized trials involving pregnant women to guide the prophilaxy, diagnosis and treatment of uncomplicated superficial or deep venous thrombosis in pregnancy; the management tools and decision-making strategies are mostly derived from observational studies, trials involving non-pregnant patients or trials involving pulmonary thrombembolism (PTE).
The diagnosis of thrombosis in pregnancy must include both clinical examination and imaging diagnosis tools. Clinical examination would be insufficient to diagnose thrombosis in pregnancy because specific signs and symptoms - such as  lower extremity edema, dyspnea and mild tachycardia - are frequently inaccurate and difficult to differentiate from the physiologic changes of pregnancy. The two most common symptoms of DVT are pain and swelling of the lower extremity, about 80% of pregnant women with DVT experiencing these symptoms⁽⁵⁾. Since the risk of DVT and venous thromboembolism (VTE) is increased during pregnancy and postpartum, and morbidity and mortality are considerable, a low threshold for further testing is recommended.
The LEFt clinical score was recently used to help in estimating the pretest probability of DVT during pregnancy.  It includes three variables of interest:  left (L) calf circumference (a difference of ≥2 cm or more from the right calf is positive), edema (E), and first-trimester presentation (Ft), that predict the likelihood of a diagnosis of deep-vein thrombosis in pregnancy⁽¹¹⁾. The current initial test of choice to assess suspicion of deep-vein thrombosis is compression duplex ultrasonographic examination, including the evaluation of the ilio-femoral region^(12,13).
A study of single compression Doppler ultrasonographic examination involving more than 200 pregnant and postpartum women indicated that this test was a very reliable screening test hence can safely rule out the diagnosis of deep-vein thrombosis⁽¹³⁾. If the test reveals a negative result and the clinical suspicion of DVT remains high, it may be judicious to repeat the test after 4-7 days. It would also be safe to withold anticoagulation while waiting to repeat the test⁽¹⁴⁾.
If the result of compression Doppler ultrasound is negative and there is no suspicion of DVT, the patient may return to routine observation. Otherwise, if there is a discordance between clinical presentation and ultrasound examination, if Doppler testing is abnormal or if the suspicion of pelvic DVT is high, further evaluation is recommended and Magnetic Resonance Imaging (MRI) may be considered^(15,16).
Other examinations that contribute at deep vein thrombosis or PTE diagnostic arsenal are chest X-ray, electrocardiography, ventilation-perfusion lung scanning, computed tomographic (CT) pulmonary angiography (CTPA) - the first line test to diagnose pulmonary embolism (PE) in non-pregnant patients, used with abstention in pregnant patients. D-dimer levels increase progressively throughout gestation and measurements are “abnormal” in most uncomplicated pregnancies, thus losing diagnostic usefulness. Their contribution is still considerable in ruling out venous thrombembolism in non-pregnant patients⁽¹⁷⁾.

Case presentation

A 27-year-old primipara presented to the hospital with a history of tobacco use, superficial thrombophlebitis and family thrombotic events (mother and sister with DVT), reporting burning pain in the right calf accompanied by palpable thrombosed, visibly distended vein of the right lateral calf, local erythema and edema at 13 weeks of gestation. 
Physical examination revealed erythema and swelling, consistent with DVT. Therefore, Duplex ultrasonographic (US) evaluation of the right lower limb was recommended. The test revealed no lack of compressibility of the deep venous system of the lower right limb, but a thrombus was found more than 5 cm below the safenopopliteal junction, affecting 2 cm of the small saphenous vein. Hence, superficial thrombophlebitis (ST) was diagnosed on the basis of the patient’s symptoms and aforementioned ultrasonographic examination. The patient was encouraged to continue her usual daily activities and a treatment with topical heparin and elastic support was recommended. Clinical and US follow-up after 7 days revealed satisfactory progress, relief of pain and swelling with fading erythema.
The patient presented again to our departement, at 22 weeks of gestation, claiming similar symptoms to the previously described episode, this time the pain and distended veins being located in the right internal thigh. The evaluation and management were the same as for the previous episode. Recurrent ST was diagnosed, this time at the level of great saphenous vein, more than 5 cm below the saphenofemoral junction, affecting 3 cm of the vein. Follow-up revealed favorable evolution and remission of symptoms.
Considering patients’ history and both episodes of ST, a testing for inherited thrombophilia was offered and performed for the patient. The aforementioned testing revealed a negative result. 
At 34 weeks of gestation, the patient presented once again to our department with acute increasing pain and swelling of her right thigh. The physical examination revealed positive Homans sign, reddish purple discoloration of the internal thight and swelling; the difference between the right and left calf circumference was calculated as +1.7 cm. Chest auscultation revealed no abnormalities, oxygen saturation was 98%, and pulse rate was 110 beats per minute. Duplex ultrasonographic imaging of the right lower extremity and pelvic veins revealed evidence of intraluminal echogenic material at the level of saphenous arch with 3.3 cm proximal extention through its opening into the common femoral vein and no other abnormalities. The diagnosis of DVT of the right lower extremity was made, and the patient was admitted to the hospital for further monitoring and treatment. The location of DVT in the right lower extremity during pregnancy is atypical, as 88% of patients present DVT in the left lower extremity, simulating a May-Thurner-like syndrome. 
The main objectives for the treatment of DVT are to prevent PE, reduce morbidity and prevent or minimize the risk of developing the post-thrombotic syndrome (PTS). 
Laboratory tests were performed to assess hepatic, pancreatic (considering recurrent episodes of superficial migratory thrombophlebitis) and renal function. The results came back within normal limits, with a creatinine level of 0.9 mg/dL at the upper limit of normal during the 3rd trimester of pregnancy. 
Anticoagulation with LWMH (enoxaparin, 1 mg per kilogram twice daily, intramuscular) was initiated. The patient was advised to keep an elevated position of the leg during bedrest in order to reduce swelling and to use compression stockings. 
The signs and symptoms of DVT progressively remitted during hospital stay, and in the absence of new symptoms the patient was disharged one week later after having another Doppler examination performed. The test showed stable thrombus at the aforementioned site. Discharge treatment indication from the hospital included continuation of anticoagulation throughout the pregnancy with tinzaparin (175 units per kilogram once daily, intramuscular). The treatment regimen was changed in order to improve the patients’ adherence.
The rest of the pregnancy went uneventful regarding thrombosis-related conditions. Throughout the pregnancy, the fetus has reached all developemental milestones and no abnormalities were noted.
Caesarean section was elected as route of delivery, as the fetus was in breech presentation and the procedure was scheduled at 39 weeks of gestation. Anticoagulation was withold 36 hours before surgery, and the procedure went well, with no bleeding complications. A healthy female baby was delivered, who weighted 2800 g, and APGAR score was 9. 
To minimize postpartum bleeding complications, thromboprophilactic doses (enoxaparin 3000 units every 12 hours, intramuscular) were resumed 6 hours after caesarean section and therapeutic doses of heparin (enoxaparin, 1 mg per kilogram twice daily, intramuscular) were delayed until 48 hours after delivery. The lactation started on second day after delivery and no postpartum complications appeared. 
Because of neonatal jaundice, the hospital stay of the mother and baby was longer than expected (6 days). Discharge indications for the mother included continuation of anticoagulation for at least 3 months postpartum with tinzaparin (175 units per kilogram once a day, intramuscular), clinical and US follow-up 6 weeks postpartum. 
The six-week postpartum follow-up revealed favorable outcome. The patient requested ablactation and based on contradictory evidence on the use of warfarin during breastfeeding, the patient was only then switched on oral warfarin (4 mg once a day), coadministered with heparin, with closely monitoring INR level every 48 hours after administration of the dose. Dose adjustments were made in order to reach target INR level of 2-3. An INR of 2.4 was reached on day 4 after initial warfarin dose and heparin were discontinued.
Three months later, the patient underwent compression Doppler ultrasound which exhibited a smaller, stable clot in the same area as the last examination. Warfarin anticoagulation has been further recommended for at least 3 more months in the absence of new symptoms.
Currently, the patient is under gynecological routine surveilance in our service and under vascular surveillance in an internal medicine service, and is still under oral anticoagulant therapy. 

Discussions

A systematic review recently published suggests that the anatomic distribution of deep vein thrombosis in pregnant women differs from that for non-pregnant patients⁽¹⁸⁾. The involvement of the left leg was reported in 88% of patients. One may speculate that a May-Thurner-like syndrome caused by compression of the left iliac vein by the gravid uterus, at the point where it crosses the right iliac artery, plays an important role in the increased incidence of left iliofemoral deep vein thrombosis in the third trimester of pregnancy. This strong evidence makes the anatomical distribution of DVT in the lower right extremity of our patient atypical.
Optimal prophylaxys and treatment of thrombotic events are required in order to obtain a good outcome and includes both non-pharmacologic and pharmacologic measures. 
Non-pharmacologic treatment with elastic compression stockings have been shown to lower the pain and swelling associated with deep-vein thrombosis, but their use did not prevent PTS⁽¹⁹⁾.
The prophilaxys of thromboembolic events in pregnancy tipically involves unfractionated heparin (UFH) or low molecular weight heparin (LMWH),  which do not cross the placenta or enter breast milk. The subcutaneous route of administration is preferred. UFH was replaced by LMWH use for the treatment of venous thrombembolism in pregnancy, mainly based on extrapolation of data obtained from trials involving non-pregnant patients and observational studies that emphasized the safety of LMWH in prgnancy⁽²⁰⁾. Moreover, LMWH have been shown not to be associated with an increased risk of severe postpartum hemorrhage^(21-23).
Specific agents include dalteparin (200 international units [IU] per kilogram of body weight daily or 100 IU per kilogram twice daily), enoxaparin (1.5 mg per kilogram daily or 1 mg per kilogram twice daily) and tinzaparin (175 units per kilogram daily)⁽²⁰⁾.
UFH may be preferred if creatinine clearance is less than 30 mL/min, if the patient weights >150 kg or if the patient is likely to have immediate surgery because of its shorter half life and reversibility with protamine as compared with LMWH(24).
Another therapeutic agent, warfarin, crosses the placenta and teratogenic effects as chondromalacia, mid-face hypoplasia, scoliosis, short proximal limbs, short fingers and CNS abnormalities  have been described when warfarin is administered during the first trimester⁽²⁷⁾.
There is insufficient experience to evaluate the risks and benefits of direct thrombin inhibitors as dabigatran and anti-factor Xa inhibitors such as rivaroxaban in pregnancy⁽²⁶⁾.
Thrombolysis in pregnancy is exclusively reserved for massive life-threatening PE with altered hemodynamic balance or for proximal deep-vein thrombosis that is compromising leg viability⁽²⁷⁾.
As a limitation of this case report we mention the fact that the novelty of the report does not come from the therapeutic point of view, as the management and treatment do not differ depending on the side of DVT, but from the fact that even if most of the cases of DVT during pregnancy involve the left lower extremity, our patient meets the statistics validated for the general popula­tion and not for pregnant patients, which emphasize the greater frequency of DVT in the right lower extremity. Moreover, the originality of the reported case stems from the fact that few specific cases on uncomplicated ST and DVT during pregnancy, which describe the complete management of patients, are found in literature, most of the data coming from trials on DVT complications, such as PTE.
According to the American Collage of Chest Physicians 2012 guidelines, prophylactic or intermediated dose of LMWH for 6 weeks is only recommended for SVT located ≤5 cm from saphenofemoral or saphenopopliteal junctions or affecting ≥5 cm of vein, and the therapeutic decision was made in concordance with this aspect for both episodes of SVT. Our patient did not meet the criteria for LMWH while being diagnosed with SVT. The screening for inherited thrombophilia was negative, so only when DVT was certified, LMWH therapy was started based on current guidelines. 
The treatment options can influence the timing of delivery. Also, the route of delivery should be carefully selected while anticoagulation management should be optimized depending on this aspect. If opting in favour of induced vaginal delivery, temporarily discontinuing the use of LMWH would be prudent to minimize the risk of bleeding and permit epidural anesthesia if required. Women should be counseled to discontinue injections of heparin if labor starts or is suspected. Epidural anesthesia is usually delayed until at least 24 hours after the last dose, given a small risk of epidural hematoma associated with administration of epidural anesthesia before that time. 
Postpartum, LMWH should only be administered 4 hours after spinal anesthesia or the removal of an epidural catheter. The management of anticoagulation therapy if caesarean section is elected as route of delivery was thoroughly discussed in the above case report.
In case of early recognition of signd and symptoms of DVT during pregnancy, proper management may be initiated in time and beneficial outcome might be reached.

Conclusion

Although the anatomical distribution of DVT during pregnancy might be atypical, the awareness of thrombotic events may prevent potentialy life-threatening complications for both the mother and the fetus, and optimal management most probably leads to a favorable outcome. 

The autors declare that they have no competing interests.