Prothrombin Gene Mutation as a Teaching Tool: An Autobiographical Case Report

The prothrombin G20210A factor II mutation carrier status has been reported to cause complications during pregnancy. This report presents the case of a patient diagnosed with heterozygous prothrombin G20210A factor II mutation at 29 years of age during preconception genetic screening. The patient had two uncomplicated pregnancies. The patient underwent laparoscopic cholecystectomy with a complicated postoperative course. The complications included deep vein thrombophlebitis (DVT), portal vein thrombosis (PVT), and pulmonary embolization (PE). The treatment options and contraceptive choices are also discussed in this report. Our report discusses the subsequent risks inherent in a heterozygote following the administration of oral contraceptives, prolonged immobilization related to lower extremity trauma, and extended motor vehicle excursion.


Introduction
Prothrombin G20210A factor II mutation can cause life-threatening complications. The prevalence of heterozygous prothrombin G20210A factor II mutation is < 6% in Caucasians and < 1% in African and Asian populations [1]. The mutation has been reported to cause increased pregnancy loss and even maternal mortality [2]. Furthermore, the choice of using estrogen-containing contraceptives over progestin-only contraceptive methods in carriers of this mutation remains controversial in terms of safety. Progestin-only contraceptives have been shown to decrease the risk of venous thromboembolism relative to estrogencontaining contraceptives [2]. Prothrombin mutation alone is generally insufficient to cause venous thrombosis, particularly in heterozygotes. However, most patients are unaware of their prothrombin gene mutation status as most of them do not experience thrombotic events during their lifetime [3].
In addition to the effect on pregnancy and maternal health choices in patients with the mutation, there is a lifelong risk of thrombophlebitis, pulmonary emboli, and portal vein thrombosis triggered by immobilization, trauma, and surgery. This may be explained by the higher-than-normal prothrombin level seen in these patients, resulting in increased thrombotic risk. The prothrombin G20210A factor II mutation remains the second-most common cause of inherited thrombophilia in the United States [4].
This report presents the case of a patient with a heterozygous prothrombin G20210A factor II mutation, discusses the various complications experienced by the patient related to the mutation, and covers the different strategies used to manage and prevent further complications.

Case Presentation
The patient (ERL) was diagnosed with a heterozygous prothrombin gene mutation at the age of 29 years through preconception genetic screening and laboratory tests. Following the diagnosis, oral contraceptive Desogen® (ethinyl estradiol and desogestrel) was discontinued as an estrogen-containing oral contraceptive, and Depo-Provera®, a medroxyprogesterone injection, was prescribed. This substitution was based on the increased risk of blood clots associated with estrogen-containing oral contraceptives [2]. After the birth of her two children (in 2008 and 2011), she was prescribed progestin-only contraceptives. At 41 years of age, the patient slipped and landed on her left knee. Three weeks later, she took an extended trip to visit family. Upon returning, her left leg "grew heavy." When she developed difficulty breathing, she sought emergency care. The emergency department diagnosed the patient with a deep vein thrombosis (DVT), and computed tomography (CT) pulmonary angiogram ( Figure 1) revealed bilateral pulmonary emboli. The patient was administered an anticoagulant, warfarin, and oral contraceptives were discontinued. She continued warfarin therapy for nine months. Following the warfarin therapy, her primary physician switched her to aspirin (81 mg daily). At 47 years of age, she underwent a laparoscopic cholecystectomy. Her surgeon administered lowmolecular-weight heparin in the form of enoxaparin sodium (Lovenox) before surgery to manage potential thrombosis. No thromboprophylaxis was administered after surgery. However, 10 days post-surgery, the patient developed an occlusive left portal venous thrombosis and a non-occlusive thrombus in the right portal vein. The patient was treated with an intravenous bolus of 6,800 units of unfractionated heparin. She then received a heparin titration of 25,000 units at 1,400 units per hour until she was discharged 72 hours later. At discharge, she transitioned to long-term anticoagulation with 20 mg of rivaroxaban (Xarelto) for six months.
The patient remained at this dose for six months. After consulting with her hematologist, they agreed to decrease the dose to 10 mg since no other clotting events had occurred, and the patient desired to take the lowest efficacious dose possible.

Discussion
We describe the case of a 47-year-old woman (ERL) who had two uncomplicated pregnancies despite being diagnosed with heterozygous prothrombin G20210A factor II mutation during preconception screening. During the next 18 years, she developed many previously reported complications associated with the mutation [2]. These complications included portal vein thrombosis following laparoscopic cholecystectomy. However, as of 2022, only six cases of portal vein thrombosis following cholecystectomy have been reported [5][6][7][8][9][10] (Table 1). Moreover, only one case has been reported on portal vein thrombosis following cholecystectomy associated with the prothrombin G20210A mutation factor II [8] (Table 1).

Reference
Year   Prothrombin gene mutation alone is generally insufficient to cause venous thrombosis, particularly in heterozygotes [11]. However, potentially deadly blood clots may form in association with other contributing risk factors. Clots resulting from an identifiable inciting event including surgery and long periods of immobilization, such as hospitalization and travel, are considered to provoke clots [12]. The unprovoked clots reported in the literature are caused by unknown etiologies [12].
Blood clots, both provoked or unprovoked, influence a healthcare provider's decision to initiate anticoagulation therapy and determine the duration of therapy. Current treatment guidelines recommend administering a direct oral anticoagulant (DOAC), such as apixaban, dabigatran, edoxaban, and rivaroxaban, in all patients with acute venous thromboembolism (VTE) [13]. The duration of this therapy should be at least three to six months. Lifelong treatment is advised for many patients with unprovoked VTE, even those without an inherited thrombophilia diagnosis [13].
The prothrombin G20210A factor II mutation poses a modest risk of VTE recurrence, even in heterozygotes. The presence of this mutation or carrier state alone may not warrant the side effects of indefinite antithrombotic therapy [14]; however, as our patient demonstrates, the risk is lifelong and potentially lifethreatening. In such cases, prolonged treatment is advised after multiple thrombosis episodes.
Antithrombotic prophylaxis for patients with inherited thrombophilia undergoing surgery is more complicated. The American College of Chest Physicians published guidelines for perioperative management of antithrombotic therapy; however, post-operative guidelines are lacking. Patients with a history of VTE are at a significantly increased risk of recurrent VTE after surgery [15]. A study of patients who underwent laparoscopic colorectal surgery revealed that extending anticoagulation into the post-operative period decreases the rate of VTE with no increased risk of major bleeding [16].

Conclusions
This case summarizes the course of a patient who developed a portal vein thrombosis after laparoscopic cholecystectomy with a diagnosed heterozygous prothrombin G20210A factor II mutation. Patients with inherited thrombophilia are at an increased risk of developing acute VTE after surgery and the literature supports continuing anticoagulation post-operatively to reduce VTE risk. This warrants further investigation into the benefits of antithrombotic prophylaxis following surgery for patients with inherited thrombophilia and reevaluation of the current approach.
The learner (TM) interest in internal medicine and hematology of this case would help physicians gain a perspective on detecting abnormalities in coagulation.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.