Systemic thrombosis with prothrombin Belgrade mutation in a Chinese patient: A case report

Abstract

BACKGROUND

Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired. Hereditary thrombophilia may arise from various gene mutations, some of which have not even been adequately reported or poorly understood. Previous studies reported a rare and novel missense mutation in the prothrombin gene (p.Arg596Gln), known as prothrombin Belgrade. The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated.

CASE SUMMARY

We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation. The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis, alongside a family history of cerebral thrombosis, and no traditional risk factors or abnormal coagulation function. Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation, c.1787G>T (p.Arg596Gln), which was responsible for the major etiology of the systemic thrombosis.

CONCLUSION

This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.

Key Words: Arg596Gln; Belgrade mutation; Thrombophilia; Prothrombin; Case report

Core Tip: The aim of our present study is to display a novel missense mutation in the prothrombin gene (p.Arg596Gln) in a Chinese patient with onset of cerebral venous thrombosis. Considering that prothrombin Belgrade mutation mechanism and treatment are still not fully elucidated, we provide the understanding about hereditary risk factors of cerebral venous thrombosis and trigger the further exploration of effective and exact therapeutic options and management on cerebral venous thrombosis caused by prothrombin Belgrade mutation.

INTRODUCTION

Thrombophilia is characterized by abnormal blood coagulation, with tendency toward an increased risk of thromboembolism, particularly in the venous system[1]. Universally recognized risk factors for thrombophilia are composed of inherited conditions (e.g., deficiencies of protein C, protein S, and antithrombin, as well as the factor V “Leiden” and prothrombin G20210A mutation) and acquired ingredients (e.g., antiphospholipid syndrome, myeloproliferative neoplasms, cancer)[2]. These elements may contribute to heightened coagulation pathways, irregular anticoagulant functions, or issues with fibrinolysis[3,4]. These complex factors and mechanism play a significant role in clarifying and defining the etiology and pathogenesis of deep vein thrombosis, pulmonary embolism and cerebral venous thrombosis.

Regarding the hereditary factor, common gain-of-function mutations like the factor V “Leiden” and prothrombin (factor II) G20210A mutation, have been extensively studied[5]. Additionally, a novel and rare c.1787G>T prothrombin mutation was first reported in two Serbian families with recurrent thrombosis at a young age a decade ago, resulting from a substitution of arginine with glutamine at position 596 (p.Arg596Gln) in the gene encoding prothrombin (called “prothrombin Belgrade”)[6]. The mutation contributes to substantially impairment of thrombin-antithrombin binding and an increased risk of thrombophilia and antithrombin resistance (ATR)[7]. In this instructive case report, we exhibit a case that a Chinese patient was presented with onset of cerebral venous sinus thrombosis and further evolved into systemic thrombosis due to the prothrombin Belgrade mutation. We hope to raise awareness of this disease and provide new insights into the pathogenesis and potential treatment strategies of this novel genetic mutation.

CASE PRESENTATION

Chief complaints

A 26-year-old woman with severe paroxysmal headache accompanied by nausea and vomiting for twelve days.

History of present illness

The patient suffered from severe paroxysmal headache accompanied by nausea and vomiting for twelve days. On October 19, 2022, the patient developed a burst headache without paying attention. On October 23, 2022, the headache recurred, accompanied by nausea, vomiting and left neck pain. The head computed tomography scan revealed no obvious abnormalities, while carotid duplex ultrasound indicated left internal jugular vein occlusion.

History of past illness

Apart from family history, the patient had no risk factors for thromboembolic events like pregnancy, hormone replacement therapy, or infections. Furthermore, she presented no history of hypertension, coronary artery disease, or diabetes mellitus.

Personal and family history

The patient was a non-smoker and non-drinker. Family history revealed thrombotic conditions in the sense that her father and sister had the record of cerebral thrombosis. No other family members had undergone genetic testing.

Physical examination

On admission, the patient exhibited left hemi-cranial distending pain with cervical unsymmetric radicular pain. The rest of the general physical and neurological examination was normal.

Laboratory examinations

Laboratory findings on the complete blood count revealed the presence of neutrophilia, lymphopenia and monocytosis. Coagulation tests showed elevated D-dimer levels. Protein C, antithrombin III, lupus anticoagulant, anti-cardiolipin antibodies were normal, except for a mildly low value of protein S. Liver and renal function tests, along with serum electrolytes, were within normal limits. In consideration of her family history and onset age, whole genome sequencing was performed on the patient, pointing out a c.1787G>T (p.Arg596Gln) heterozygous missense mutation in the prothrombin gene.

Imaging examinations

The cerebral computed tomography scan showed a hypodense shadow in the left cerebellar hemisphere, suggesting venous cerebral infarction. Cerebral magnetic resonance angiography was performed and revealed complete thrombosis of the left transverse sinus (Figure 1A). Further cerebral vascular angiography further confirmed thrombosis and occlusion of left transverse sinus and internal jugular vein (Figure 1B).

Figure 1 Imaging examinations. A: Cerebral magnetic resonance angiography revealed thrombosed left transverse sinus; B: Cerebral vascular angiography revealed thrombosis and occlusion of left transverse sinus and internal jugular vein.

FINAL DIAGNOSIS

A final diagnosis of cerebral venous sinus, thrombosis upper extremity venous thrombosis, and lower extremity deep venous thrombosis was made.

TREATMENT

The patient received subcutaneous low molecular weight heparin as well as symptomatic treatment during hospitalization and rivaroxaban therapy after discharge.

OUTCOME AND FOLLOW-UP

However, she returned to the hospital with numbness and pain in her left upper limb in October 2023. After inquiring about medication compliance, she reported having stopped taking anticoagulants for three months. The ultrasound suggested thrombosis of the left internal jugular vein, superficial veins of left upper limb, left axillary vein and left subclavian vein, as well as bilateral thrombosis of the common femoral vein, superficial femoral vein, deep femoral vein, and popliteal vein. The computed tomographic pulmonary angiography was performed and revealed partial pulmonary artery branch embolism in the lower lobes of bilateral lungs. The reexamination of cerebral magnetic resonance angiography indicated residual but decreasing thrombosis of left internal jugular vein, sigmoid sinus, and transverse sinus. Likewise, this patient continued to receive anticoagulant treatment.

DISCUSSION

For young-onset female patients with a family history of thrombosis or recurrent thrombosis events, an inherited predisposition to thrombophilia may significantly contribute to the underlying causes and development of the condition. Inherited thrombophilia can be derived from two different mechanisms: Increased concentrations of procoagulants (gain-of-function disorders) or deficiencies/dysfunctions in the endogenous anticoagulants (loss-of-function disorders) under the circumstance of genotypic milieu[1,8]. Loss-of-function disorders typically have a lower morbidity than gain-of-function disorders, whereas they present more powerful risk factors for thrombosis. In addition to the common hereditary factors, such as thrombophilia - factor V Leiden and prothrombin G20210A, other rare mutations are noteworthy. In this report, we present a novel and infrequent prothrombin Belgrade genetic mutation contributing to recrudescent systemic thrombosis in a young-onset patient.

Prothrombin Belgrade mutation was first proposed in Serbia in 2013, characterized by a G-to-A change at nucleotide position 1787. This alteration results in an arginine-to-glutamine substitution at amino acid position 596 (p.Arg596Gln) within the prothrombin gene[6,9]. Arg596Gln mutation carriers demonstrate decreased fibrinogen clotting activity, impaired procoagulant activity and impaired antithrombin inhibition, shifting the function balance of thrombin towards the procoagulant pathway, which should be the main cause of thrombus embolism in Arg596Gln carriers. A previous study on prothrombin Arg596 related mutations highlighted that the prothrombin Arg596Gln mutation was also an important risk factor for venous thromboembolism in Chinese patients[10].

Furthermore, ATR is one of the most essential hereditary thrombotic mechanisms and ATR caused by prothrombin Belgrade mutation has been reported in Serbia, China, and Japan[6,9-12]. Thrombin-generation assay suggested that the mutant prothrombin functioned to arouse resistance against inhibition by antithrombin, further facilitating blood coagulation[7]. Taking account of the ATR property, selecting an appropriate anticoagulant drug is crucial for the treatment of prothrombin Belgrade mutation. In this case, the patient suffered from recurrent attacks of thrombosis, progressing from cerebral venous sinus thrombosis to systemic thrombosis. A possible reason for recurrence could be drug withdrawal or the therapeutic regimen. It remains to be established whether warfarin is the optimal choice for managing pulmonary thromboembolism due to ATR. Given the high risk of severe thrombosis being fatal, any kind of possibility cannot be neglected. There are many types of anticoagulant drugs with different mechanisms. Despite the fact that the case report fails to draw clear guidelines for the treatment of the disease, it serves as an inspiration and a reminder for selection of anticoagulants. Whether an indirect thrombin inhibitor, such as heparin, or factor Xa inhibitor, such as rivaroxaban, is the best choice for systemic thromboembolism due to ATR remains to be determined. Moreover, examination of ATR assay should be prioritized alongside genetic testing. Furthermore, more stringent and regular follow-up is of great necessity.

CONCLUSION

In conclusion, our case report displays a novel missense mutation in the prothrombin gene (p.Arg596Gln) in a Chinese patient with recurrent thrombosis. Given that the mechanism and treatment of the prothrombin Belgrade mutation are still not fully elucidated, we provide valuable insights into the hereditary basis of thrombophilia and considerations for targeted therapeutic strategies in managing prothrombin Belgrade mutation.