Libyan Journal of Medical Sciences

CASE REPORT
Year
: 2021  |  Volume : 5  |  Issue : 4  |  Page : 168--170

Failure of therapeutic enoxaparin to prevent massive deep vein thrombosis and cerebral venous sinus thrombosis in a pregnant patient with combined factor v leiden mutation and antithrombin iii deficiency


Husam Nabil Abduljabbar Al-Dubai1, Yousef Mohammed Hailan1, Abdulrahman Al-Mashdali1, Akram Fadhl Mohammed Al-Warqi2, Bisher Sawaf1,  
1 Department of Internal Medicine, Hamad General Hospital, HMC, Doha, Qatar
2 Department of Radiology, Hamad General Hospital, HMC, Doha, Qatar

Correspondence Address:
Dr. Husam Nabil Abduljabbar Al-Dubai
P.O. Box: 3050, Doha
Qatar

Abstract

Women with combined inherited thrombophilia are at high risk of developing thrombotic events, especially when they are pregnant. Low-molecular-weight (LMW) heparins are the preferable agents for anticoagulation during pregnancy. Despite the fact that they have been proven to be effective in the treatment and prevention of venous thromboembolism, thrombotic events can still happen. Here, we report a case of a 40-year-old white pregnant woman with combined factor V Leiden mutation and antithrombin III deficiency who developed massive deep vein thrombosis and cerebral venous sinus thrombosis despite being on therapeutic doses of enoxaparin.



How to cite this article:
Abduljabbar Al-Dubai HN, Hailan YM, Al-Mashdali A, Mohammed Al-Warqi AF, Sawaf B. Failure of therapeutic enoxaparin to prevent massive deep vein thrombosis and cerebral venous sinus thrombosis in a pregnant patient with combined factor v leiden mutation and antithrombin iii deficiency.Libyan J Med Sci 2021;5:168-170


How to cite this URL:
Abduljabbar Al-Dubai HN, Hailan YM, Al-Mashdali A, Mohammed Al-Warqi AF, Sawaf B. Failure of therapeutic enoxaparin to prevent massive deep vein thrombosis and cerebral venous sinus thrombosis in a pregnant patient with combined factor v leiden mutation and antithrombin iii deficiency. Libyan J Med Sci [serial online] 2021 [cited 2022 Jun 29 ];5:168-170
Available from: https://www.ljmsonline.com/text.asp?2021/5/4/168/338634


Full Text



 Introduction



Hereditary thrombophilia is a genetic disease that increases the risk of venous and arterial thrombosis. Factor V Leiden and prothrombin gene mutations account for 50%–60% of cases. Protein S, protein C, and antithrombin III deficiencies are responsible for the majority of the remaining cases.[1],[2],[3],[4] Patients with more than one inherited thrombophilia are at higher risk of developing venous thrombosis.[5],[6] Although anticoagulation is the mainstay treatment for patients who develops thrombosis, managing these patients remains a challenge due the high risk of recurrence.[7]

 Case Report



Our patient is a 40-year-old white woman, with history of anithrombin III deficiency and factor V Leiden mutation, confirmed by genetic testing at the age of 13. Due to prior recurrent thrombotic events, she was taking warfarin for lifelong anticoagulation. Anticoagulation regimen was changed to therapeutic doses of enoxaparin (70 mg twice a day subcutaneously) at start of pregnancy.

At 8 weeks gestation, she presented to the hospital with left leg pain. Doppler ultrasonography confirmed deep vein thrombosis involving the left posterior tibial vein, the left proximal superficial femoral vein, and the left common femoral vein [Figure 1]. The patient was admitted to the hospital and started on unfractionated heparin (UFH) infusion which was given for 5 days. She improved symptomatically and was discharged on higher doses of therapeutic enoxaparin (80 mg twice a day subcutaneously).{Figure 1}

Five days after discharge, the patient presented again to the emergency department with severe headache that was associated with recurrent vomiting. Brain imaging (computed tomography/magnetic resonance imaging/magnetic resonance venography [MRV]) confirmed thrombosis of the straight sinus, right transverse and sigmoid sinuses, and right internal jugular vein [Figure 2]. The patient assured that she was adherent to taking enoxaparin at home, and therapeutic effect of enoxaparin was confirmed by therapeutic level of anti-Factor Xa, also. Here, a multidisciplinary meeting involving internal medicine, neurology, hematology, and obstetrics teams was held and the decision was made to keep her on UFH infusion. The patient's symptoms resolved after 5 days of UFH infusion. To ensure that there is no evidence of thrombosis recurrence, she was kept on UHF infusion for a total of 14 days with close clinical observation. After that, she was switched back to enoxaparin 80 mg twice a day subcutaneously. She was observed for few more days and therapeutic level of anti-Xa activity was confirmed. Then, she was discharged home.{Figure 2}

Five days later, the patient developed vaginal bleeding and came to the emergency department. After clinical evaluation and ultrasonography, she was found to have incomplete abortion. She was admitted to the hospital and underwent evacuation of products of conception. After a discussion between the patient and the hematology team regarding anticoagulation management, it was decided to start warfarin with a target international normalized ratio (INR) between 2 and 3. After 4 months of anticoagulation, cranial MRV was repeated and confirmed recanalization of the previously thrombosed right-sided straight sinus, transverse and sigmoid sinuses, and internal jugular vein.

 Discussion



Patients with familial thrombophilia, particularly those with factor V Leiden mutation, can have a second thrombotic defect, and carriers of two (or more) defects seem to be at a higher risk for thrombosis than their relatives with a single defect.[6],[8] In addition, pregnancy confers an increased hypercoagulability tendency. The level of coagulation factors I, II, VII, VIII, IX, and C progressively increases during pregnancy, while the level of anticoagulant proteins such as protein S decreases.[9],[10],[11] The risk of thrombosis is further accentuated in pregnant women who have inherited thrombophilia.[12],[13],[14]

Pregnant women with inherited thrombophilia may require anticoagulation to prevent thrombotic events during pregnancy. The decision to give anticoagulation is based on multiple factors including the type of thrombotic defect, personal and family history of previous thrombotic events, and whether the patient is already receiving long-term anticoagulant therapy.[15],[16] Low-molecular-weight (LMW) heparin is the preferred anticoagulant for most pregnant women.[16] A systematic review of studies of the use of LMW heparin for prevention or treatment of venous thromboembolism in pregnancy concluded that LMW heparin was both safe and effective.[17]

Managing our patient was a challenge due to limited treatment options. Warfarin is a known teratogen that should be avoided during pregnancy, especially in the first trimester.[18],[19] Owing to the lack of evidence on efficacy and fetal safety, oral direct thrombin inhibitors and oral direct factor Xa inhibitors could not be used. The option to terminate the pregnancy and treat the patient with oral anticoagulant was discussed with her. However, the patient refused this option and insisted to continue her pregnancy after its viability was confirmed by obstetric team. Our only option was UFH which resulted in a significant clinical improvement.

 Conclusion



Pregnant women with combined inherited thrombophilia are still at risk of developing massive thrombotic events even if they are on therapeutic dose of enoxaparin. Treating such patients remains a challenge due to limited treatment options. Giving UFH infusion seems to improve patient's symptoms. However, further studies are needed to confirm this result.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

We would like to thank internal medicine residency program for scientific support.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

References

1Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism – Results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost 1997;77:444-51.
2Margaglione M, Brancaccio V, Giuliani N, D'Andrea G, Cappucci G, Iannaccone L, et al. Increased risk for venous thrombosis in carriers of the prothrombin G–>A20210 gene variant. Ann Intern Med 1998;129:89-93.
3Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: A qualitative overview and proposed classification system. Ann Intern Med 2003;138:128-34.
4Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008;112:19-27.
5Martinelli I, Mannucci PM, De Stefano V, Taioli E, Rossi V, Crosti F, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: A study of 150 families. Blood 1998;92:2353-8.
6Koeleman BP, Reitsma PH, Bertina RM. Familial thrombophilia: A complex genetic disorder. Semin Hematol 1997;34:256-64.
7Santamaria MG, Agnelli G, Taliani MR, Prandoni P, Moia M, Bazzan M, et al. Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment. Thromb Res 2005;116:301-6.
8Mustafa S, Mannhalter C, Rintelen C, Kyrle PA, Knöbl P, Lechner K, et al. Clinical features of thrombophilia in families with gene defects in protein C or protein S combined with factor V Leiden. Blood Coagul Fibrinolysis 1998;9:85-9.
9Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008;359:2025-33.
10McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997;78:1183-8.
11Hellgren M, Blombäck M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition. Gynecol Obstet Invest 1981;12:141-54.
12Friederich PW, Sanson BJ, Simioni P, Zanardi S, Huisman MV, Kindt I, et al. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: Implications for prophylaxis. Ann Intern Med 1996;125:955-60.
13Grandone E, Margaglione M, Colaizzo D, D'Andrea G, Cappucci G, Brancaccio V, et al. Genetic susceptibility to pregnancy-related venous thromboembolism: Roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. Am J Obstet Gynecol 1998;179:1324-8.
14Gerhardt A, Scharf RE, Zotz RB. Effect of hemostatic risk factors on the individual probability of thrombosis during pregnancy and the puerperium. Thromb Haemost 2003;90:77-85.
15James AH. Prevention and management of venous thromboembolism in pregnancy. Am J Med 2007;120:S26-34.
16Bates SM, Rajasekhar A, Middeldorp S, McLintock C, Rodger MA, James AH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Venous thromboembolism in the context of pregnancy. Blood Adv 2018;2:3317-59.
17Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: A systematic review of safety and efficacy. Blood 2005;106:401-7.
18Iturbe-Alessio I, Fonseca MC, Mutchinik O, Santos MA, Zajarías A, Salazar E. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986;315:1390-3.
19Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: Clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet 1987;41:566-83.