Anticoagulant therapy: art or science?!

Introduction: Vitamin K (AVK) antagonists warfa-rin, acenocoumarol and phenprocoumon are the most widespread drugs for the prevention and treatment of arterial and venous thromboembolic disorders despi-te the introduction of the 4NOACs. The efficacy and safety of AVK therapy is ensured by maintaining the INR in the therapeutic window, a difficult aspect in daily practice. Frequently, the AVK dose should be „titrated“ and it is different from case to case, some-times from one week to the next for the same case, a phenomenon due to environmental factors, associated medication, but especially to individual characteristics. VKORC and CYP2C9 gene mutations account for 30% of the variability of INR, and the concurrent presence of 2 mutations is a rare phenomenon being reported less than 10 cases in literature. In the absence of a clear algorithm, management of oral anticoagulant therapy with AVK in such patients is challenging.

Methods: A 51-year-old smoker patient with a history of venous thromboembolic events and currently under treatment with Warfarin presented in our department requiring an evaluation for the anticoagulation brid-ging therapy as the patient was supposed to undergo a lower tract endoscopy. From the medical history of the patient, we note that at the age of 42, he was diagnosed with a post-thrombotic post-thrombotic syndrome in the inferior limbs, (anamnestic the patient presented clinical signs and symptoms of DVT 10 years ago, but the diagnosis was not certified by venous ultrasound). Treatment with Acenocoumarol was initiated without an effective anticoagulation due to a significant INR variability of 1.2 to 13 in 24 hours, despite exhaustive controls and dose changes (12 mg/day alternating with 4 mg) with the occurrence of frequent episodes of epis-taxis and painful bilateral hematomas.

Results: Four years ago, a thrombophilia was also de-tected, Leiden mutation and protein C and S deficiency. At that time, at the recommendation of the hematolo-gist, the patient received warfarin therapy and continu-ed to have fluctuating levels of INR, under high drug doses (10 mg/day). Based on our previous experience with patients experiencing an ineffective anti-coagu-lation (resistance to AVK), we genotyped cytochrome P450 2C9 (CYP2C9) and (VKORC1). The result hi-ghlighted a CYP2C9 2 * 2 polymorphism, associated with the C1173T mutation of the VKORC gene, both of which determined an increased sensitivity to com-monly used doses of Warfarin that cause an important hemorrhagic risk. In this context, in the absence of cle-ar recommendations and consensus, we opted to stop treatment with AVK and start Dabigatran with a good clinical outcome.

Conclusions: Although in recent years there have been many attempts to develop pharmacogenetic algorithms for initiating AVK therapy that include, besides clinical factors, also genetic factors useful in identifying alte-red enzyme variants that could affect the metabolism of drugs, there is still insufficient evidence regarding cost-effectiveness to support routine testing prior to initiation of therapy. However, in daily practice, the existence of these mutations through their effects can lead to increased mortality and morbidity. In these ca-ses, NOAC could be a solution, but they have not been tested in clinical trials in patients with thrombophilia. In conclusion, this case, by associating multiple genetic disorders of coagulation, highlights the daily challen-ges that anticoagulant treatment determines.

ISSN – online: 2734 – 6382
ISSN-L 1220-658X
ISSN – print: 1220-658X
The Romanian Journal of Cardiology is indexed by:
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CODE: 379
CME Credits: 10 (Romanian College of Physicians)