Hereditary Thrombophilia: A Case of Subacute Pulmonary Embolism in a 68-Year-Old Female with a Mutation in the PROC Gene

Thrombophilia, also known as hypercoagulability or prothrombotic condition, typically arises from an imbalance that occurs either in the coagulation pathway or in the anticoagulation/fibrinolytic system due to various hereditary or acquired factors.[1] Thrombophilia can be associated with deficiencies of natural anticoagulants (antithrombin, protein C [PC], and protein S), elevated homocysteine values, and elevations or other changes in fibrinogen and coagulation factors. Conversely, acquired thrombophilia occurs as a result of secondary diseases, such as autoimmune disorders (antiphospholipid syndrome), trauma, or malignancy.[2] [3] The main clinical manifestations of thrombophilia are venous thromboembolism (VTE), such as deep vein thrombosis, pulmonary embolism, intracranial vein thrombosis, portal vein thrombosis, mesenteric vein thrombosis, etc. Certain types of thrombophilia can be manifested as acute coronary syndromes, ischemic stroke, and other arterial thrombotic events.[4] Hereditary thrombophilia is typically autosomal-dominant and has a reported population prevalence of approximately 7%; patients with hereditary thrombophilia can have a risk of VTE that is 3 to 20 times greater than that of the general population.[5] Genetic testing is conducive to confirming the diagnosis of hereditary thrombophilia in families with a known mutation.

We report an interesting case of hereditary thrombophilia in a patient who harbored a PROC gene mutation.

A 68-year-old elderly female with coronary atherosclerosis and type 2 diabetes presented to the local hospital with recurrent episodes of chest tightness and chest pain while visiting Tibet. She was found to have diminished oxygen saturation (sO2 84%), increased D-dimer (1.64 mg/L, reference < 0.5 mg/L), C-reactive protein (CRP; 9.27 mg/L), and T-wave inversion in V1–V5 leads of the electrocardiogram. Oxygen intake provided relief for her symptoms. Following her discharge from the hospital, she experienced a decrease in activity tolerance and developed chest tightness and dyspnea after walking a short distance of 300 to 400 m. Consequently, the patient sought medical attention at the emergency clinic of our hospital. Blood tests revealed the following results: PaO2 74.8 mm Hg, PaCO2 36.6 mm Hg, sO2 95%, D-dimer 1.163 mg/L, fibrin–fibrinogen degradation products 15.75 mg/L; myocardial injury marker: NT-pro-B-type natriuretic peptide 1,071.89 pg/mL, troponin-I, creatine kinase-MB negative; CRP 27.4 mg/L. In the family history, her mother had a cerebral infarction at 54 years and died at 56 years. Her brother had a cerebral hemorrhage at 38 years, a cerebral infarction with impaired limb mobility at 45 years, and an amputation of the lower limb due to arterial thrombosis and limb necrosis at 62 years. Her sister had arterial thrombosis in the lower limb at 55 years, so that she was unable to walk and had an amputation of the limb at 69 years due to necrosis.

Physical examination upon admission: a few wet rales could be heard at the bottom of the left lower lung, P2 > A2. The joints were normal, with marked edema of the left lower extremity. Laboratory examination: D-dimer 2.258 mg/L, PC activity assay: 59% (reference range: 70–140%). Doppler echocardiography demonstrated right ventricular wall thickening, dilatation of the main pulmonary artery, and left ventricular ejection fraction of 62%. Ultrasound of the deep veins of the left lower limb demonstrated thrombosis, and computed tomography of pulmonary arteries (CTPA) suggested multiple pulmonary emboli in both lungs with decreased perfusion in the corresponding areas ([Figs. 1] and [2]). We hypothesized that the patient's condition was not characterized by an acute onset, and the severity of the symptoms was not as pronounced as initially anticipated. Given the patient's family history of thrombosis, we also performed the Thrombosis and Hemostasis Gene Panel test, revealing that there was a point mutation in the PROC gene (PROC: NM_001375607;exon5:c.561_576dup:p.E196Pfs*33) that would lead to a defect in PC function and an enhanced risk of thrombosis. The diagnosis of hereditary thrombophilia was thus confirmed, even though there were additional risk factors—the patient's advanced age, long-distance travel, and non-O blood group. Following the thorough diagnostic work-up, the patient received subcutaneous injections of enoxaparin sodium 60 mg twice per day. After a 10-day treatment period, a noticeable reduction in the circumference of the patient's left lower limb was observed. The D-dimer levels also declined from 2.258 to 0.804 mg/L. The ultrasound indicated that there was little change in the thrombosis of the deep veins. Following the switch from enoxaparin sodium injection to a daily dose of 20 mg of rivaroxaban, the patient was discharged from the hospital. Nevertheless, she was readmitted to the hospital 1 month later since her left lower limb swelled again, without chest tightness or dyspnea. The ultrasound revealed acute thrombosis of the small saphenous vein in the left lower extremity. In light of the ineffectiveness of rivaroxaban, we substituted this with warfarin sodium tablets 3 mg per day while administering enoxaparin sodium injection. The dose of warfarin was modified according to the international normalized ratio and gradually increased to 7.5 mg per day, and the patient had no hemorrhagic tendency. After 10 days of treatment, the swelling in the leg resolved, and the ultrasound showed a reduction in thrombosis of the left small saphenous vein compared with the previous. Throughout the 1-month follow-up after discharge, the patient had no recurrence of symptoms and did not manifest any discomfort. Echocardiography did not indicate thickening of the right ventricular wall, and CTPA suggested the presence of mild chronic thrombosis in the basal segment of the lower lobe of both lungs.

Fig. 1 Pulmonary emboli on CTPA upon admission. Partial filling defects in the main pulmonary arteries bilaterally, which are more prominent on the right side. CTPA, computed tomographic pulmonary angiography.

Fig. 2 Pulmonary perfusion at different phases on subtracted computed tomographic pulmonary angiography (CTPA). A filling defect in the right pulmonary aortic trunk, leading to insufficient perfusion of the lower lobe of the right lung in pulmonary artery phase (A, B), which improved because of the formation of collateral circulation through the bronchial artery in arterial phase (C, D).

Upon reviewing the patient's medical history, several intriguing and unexpected findings were identified for further discussion. Despite the existence of multiple pulmonary emboli on CTPA, there were no apparent symptoms of hypoxia in this patient, which could be attributed to the presence of a dual blood supply from the pulmonary and bronchial arteries in the lung. Considering the suboptimal response to rivaroxaban, the patient was transitioned to warfarin. Although numerous studies have highlighted the benefits of rivaroxaban in patients with hereditary thrombophilia, the efficacy of this medication was not satisfactory for this patient. Rivaroxaban primarily targets factor Xa, which plays an indispensable role in the formation of the prothrombinase complex (Xa + V + PF3 + Ca²⁺).[6] It has been observed that the prevalence of the FV Leiden mutation in families with hereditary PC deficiencies can be up to 19% of cases,[7] and although this was not assessed in this patient due to financial constraints, the patient may carry this mutation. This mutation provides a competitive advantage in substrate binding at factor Xa-related active sites, potentially resulting in an increased synthesis of Xa + V + PF3 + Ca²⁺ and diminishing the effectiveness of rivaroxaban.[6] Hence, switching to warfarin as an alternative to rivaroxaban has been recommended for patients with thrombophilia-related gene mutations and high risk of thromboembolism.[8] Genetic polymorphism is a crucial factor contributing to substantial individual variations in warfarin response. A genome-wide association study identified the essential impacts of polymorphisms in the cytochrome P450 enzyme 2C9 (CYP2C9) gene and the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene.[9] According to a randomized controlled trial conducted by Caraco et al, the time taken to achieve a stable therapeutic dose in the CYP2C9 gene-directed warfarin treatment group was shortened from 32 to 14 days compared with the conventional group. Moreover, the proportion of smaller bleedings diminished from 12.5 to 3.2%.[10] Therefore, it has been proposed to consider genetic testing to guide the appropriate dosage of warfarin for individuals with hereditary thrombophilia. Warfarin genetic testing was performed in our patient, revealing a GA mutation heterozygous for the VKORC1 gene. A previous study has indicated that individuals carrying the G allele may experience increased levels of VKORC1 mRNA and protein expression, leading to heightened VKORC1 activity and enhanced synthesis of coagulation factors. Accordingly, this requires an increase of the maintenance dose of warfarin, as observed in our patient.[11]

To summarize, this case demonstrates that patients presenting with symptoms such as chest tightness, chest pain, and dyspnea, along with elevated D-dimer levels, diminished oxygen saturation, and clear signs of thrombosis on ultrasound, CTPA, and other imaging tests are supposed to be considered for hereditary thrombophilia if they also have an apparent family history of thrombosis and have ruled out acquired factors as the cause of thrombosis and hypercoagulability. The presence of mutated genes can be identified through the Thrombosis and Hemostasis Genetic Panel assay. Routine screening is recommended for patients with no obvious trigger for VTE, a clear family history of VTE, or recurrent VTE. Antithrombotic therapy is the primary treatment for hereditary thrombophilia, although there is currently no cure. Commonly prescribed therapeutic agents include the new oral anticoagulant rivaroxaban and the vitamin K antagonist warfarin. The state of the coagulation system can vary among patients. Rivaroxaban primarily exerts its anticoagulant effect by directly inhibiting coagulation factor Xa, while warfarin impacts the synthesis of coagulation factors by inhibiting vitamin K. These differing mechanisms of action can result in varying coagulation factor levels, prothrombin time, and other indicators among individuals, leading to diverse responses to different anticoagulant medications. Furthermore, individual genetic factors, drug interactions, dietary habits, and other variables can influence drug metabolism and efficacy. It is possible that this patient may have complex coagulation abnormalities, such as abnormalities in coagulation factors, contributing to her inadequate response to rivaroxaban. Warfarin, on the other hand, may offer broader coverage for certain complex coagulation abnormalities due to its impact on the synthesis of coagulation factors rather than solely inhibiting coagulation factor Xa activity. The factor Xa assays calibrated for the appropriate Xa inhibitor are reliable but not widely available, which prevented this patient from undergoing testing using this assay.

Publication History

Article published online:
16 August 2024

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