Recurrent Venous and Arterial Thrombosis By Prothrombin p.R596Q Heterozygous Mutation in a Chinese Patient: A Case Report and Literature Review

Objective: To investigate the causes of recurrent thrombosis in a young Chinese patient and review the related literature.

Methods: To review the patient's medical history, routine imaging and laboratory testing (including anticoagulant protein activity), and extract DNA of peripheral blood from the patient to detect gene mutation of 76 coagulation and thrombosis-related genes using Hi-Q™ Sequencing. The positive results were amplified by PCR and verified by Sange sequencing, and the related literature was reviewed.

Results: The male patient, 23 years old, was hospitalized on April 6^th, 2018 because of "repeated chest pain, hemoptysis and asthma for 7 days". The patient underwent thrombolysis in the local hospital in 2015 because of deep vein thrombosis in the right lower extremity. In 2016, he took warfarin orally for intracranial venous sinus thrombosis for one year, and stopped taking the medicine 2 months before this admission. He Had a history of chronic hepatitis B. There was no inducements for the above symptoms before admission. Chest CT examination on April 3^th showed that there were infection foci in the lower lobe of the right lung, sub-pleural shadow in the middle lobe of the right lung and the lingual lobe of the left lung, and bilateral pleural adhesion was possible. Pulmonary CTA showed that there were filling defects in the main trunk of both pulmonary arteries. There was no abnormality in the arteriovenous vessels of both lower extremities by B-mode ultrasonography. Chest CT scan after transferred to our hospital showed inflammation and a few strings in both lungs, pericardial effusion: widening of pulmonary artery, bilateral pleural effusion with local expansion of lower lung tissue. D-dimer was 27.59 mg/L. After diagnosed as pulmonary thrombosis, pulmonary infection and chronic viral hepatitis B, the patient was treated with "Rivaroxaban 10mg Bid" for anticoagulation, symptomatic anti-infection and reducing pulmonary artery pressure. Relevant examinations after admission indicated that there were no obvious abnormalities in blood routine , biochemical testing, autoantibody, ANCA and sputum culture. C-reactive protein was 93.6 mg/L, blood homocysteine homocysteine level was within normal range, and multicolour B ultrasonography indicated the formation of venous thrombosis in the right lower extremity. Fibrinogen: 4.9g/l, D-dimer: 14.64mg/L; Antithrombin activity: 94.2%, Protein S activity: 89.1%, Protein C activity: 90%. From April 14^th, he was treated with 0.6ml q12h of enoxaparin and from April 24^th with warfarin . Because of swelling of the right lower extremity, the right external iliac artery and the right lower extremity venous thrombosis were detected by mutilcolour B ultrasonography on April 26^th. The patient refused to undergo IVC filter implantation and continued with warfarin anticoagulation therapy.

During hospitalization, all exon regions and lateral intron regions of 76 genes closely related to coagulation and thrombosis diseases were sequenced using Ion PI™ Hi-Q™ Sequencing 200 Kit. The results indicated that prothrombin (NM000506) exon 14 c.1787G > A heterozygous missense mutation resulted in p.R598Q. The presence of this mutation was confirmed by PCR amplification of patient's DNA. Both SIFT database and Polyphen2 database predicted that the mutation site might affect protein function; the p. R596Q mutation was detected in a 60-year-old male patient with deep venous thrombosis (PMID: 23265743). R598 is a highly conserved amino acid, which participates in the formation of prothrombin Na + ion binding ring. R598Q causes conformational changes, keeping thrombin in enzymatic activity, and increases the risk of thrombosis (PMID: 29382582).

Conclusion: The heterozygous mutation of prothrombin p. R596Q is the molecular pathological cause of the recurrent multiple site venous and artery thrombosis in this young Chinese patient. The mutation is reported firstly in China.