**3. Anticoagulation**

Anticoagulant drugs are the first line of treatment for the prevention and treatment of thrombosis. This includes unfractionated heparin, low molecular weight heparin, fondaparinux, vitamin K antagonists (warfarin), and direct oral anticoagulants, which have a better safety profile than warfarin and have been shown to be equally effective, gradually replacing older agents [25].

The use of anticoagulants for primary prophylaxis has selected indications, such as for transient risk factors (prolonged hospitalization, postoperative status, certain orthopedic conditions) or may be considered for patients with high-risk hereditary thrombophilia, although for the latter there are not a large number of studies to support this indication [11, 26].

A patient who has developed a deep vein thrombosis and/or pulmonary embolism, whether provoked or unprovoked, should begin treatment with a direct oral anticoagulant for 3–6 months, according to the 2020 guidelines developed by the American Society of Hematology. It is also recommended that patients who have developed an unprovoked episode of deep vein thrombosis and/or pulmonary embolism or in whom a chronic risk factor can be identified should continue to receive secondary prophylaxis with either a standard or low-dose direct oral anticoagulant [10, 27].

For the purpose of secondary prophylaxis of various low-risk thrombophilias, the most recent studies recommend the use of direct oral anticoagulants instead of vitamin K antagonists, as the former possess a similar efficacy profile but with a better safety profile in terms of minor or major bleeding events. In high-risk thrombophilia, there is little data available to support the use of direct oral anticoagulants. A recent study testing the use of Rivaroxaban for secondary prophylaxis of high-risk antiphospholipid syndrome showed no additional benefit over traditional treatment, but an increased risk of bleeding [28, 29].

#### **3.1 Factor V Leiden**

In patients carrying the factor V Leiden mutation, no benefit of long-term anticoagulation has been shown in asymptomatic patients with no history of thrombosis. Although, short-term anticoagulation may be beneficial when other transient risk factors are identified. It is also recommended that women with or without a history of venous thromboembolism refrain from using estrogen-containing contraception and hormone replacement therapy [30].

Following an unprovoked venous thromboembolism event, the evidence favors long-term anticoagulation over short-term anticoagulation as secondary prophylaxis, although the duration has not been established but may be extended indefinitely if the risk of bleeding permits [31].

As a therapeutic agent, any direct oral anticoagulant can be used, as this is in line with the latest guidelines for the management of thromboembolism and the conclusion of several studies [29].

### **3.2 Prothrombin mutations**

Carriers of heterozygous mutations, in the absence of other risk factors, do not require anticoagulation as primary prophylaxis [32].

After a first episode of deep vein thrombosis and/or pulmonary embolism associated with a reversible risk factor, it is recommended that the patient undergo anticoagulation therapy for at least 3 months, which may continue throughout life in case of recurrence [10, 32].

The initial treatment of venous thromboembolism is direct oral anticoagulation, although not all patient groups are suitable for this therapy, such as patients with antiphospholipid syndrome or extreme bodyweight. LMWH should be given before dabigatran and edoxaban [10, 32].

If treatment with direct oral anticoagulants is not possible, it is recommended to start warfarin therapy concomitantly with LMWH or fondaparinux for at least 5 days, monitoring INR, which should be in the range of 2.0–3.0 [33].
