Thrombin plays a central role in the generation of blood clots to stop bleeding. However, a blood clot that forms and remains in a vessel of the body (thrombus) can cause vascular obstruction.
Direct Thrombin Inhibitors
For decades, researchers devote themselves on developing effective, safe, and most convenient anticoagulant agent.
Most anticoagulants used are effective but fails to treat the problem in a long term basis. Direct thrombin inhibitor is the most effective agent where researchers are concentrating their work on developing it further.
Compared to heparin, direct thrombin inhibitors require no preceding factors prior to their effect on thrombin. This is in stark contrast to heparin, which has no activity against thrombus-bound thrombin.
In addition to these details, several other factors may make direct thrombin inhibitors a more attractive pharmacologic agent for vascular patients.
1. What is Direct Thrombin Inhibitor (DTI)?
Heparins have been the primary agent used for over 50 years, but due to the difficulty to administer and limitations of the drug, direct thrombin inhibitor was developed in the treatment of venous diseases. Some of its types were expected to replace heparin.
Heparin was introduced into clinical use in 1935 and remains the most common anticoagulant in use today but due to the increasing demand and need for a faster way of treating venous diseases, direct thrombin inhibitor has been the answer for the job.
2. Direct Thrombin Inhibitor works in two ways:
The first way is with bivalent direct thrombin inhibitor. It simultaneously blocks the active site and act as competitive inhibitors of fibrin.
Bivalirudin, an example of bivalent direct thrombin inhibitor has favorable pharmacokinetic properties which seems to be an appropriate anticoagulant among the others.
The second way is with univalent direct thrombin inhibitor. It only blocks the active site which allows it to inhibit unbound and fibrin-bound thrombin.
Direct thrombin inhibitors are administered as a single subcutaneous injection and do not require monitoring.
3. Oral and Parenteral Direct Thrombin Inhibitor
Oral direct thrombin inhibitor represents the newest era of anticoagulation developed to prevent and treat venous diseases.
Ximelagatran is one type of oral direct thrombin inhibitor. It is used to prevent and treat deep vein thrombosis. Compared to warfarin, Ximelagatran shows more effectiveness but it was withdrawn in the market due to the effects of hepatic toxicity found in patients.
Parenteral direct thrombin inhibitor is now being used for pediatric patients with contraindications to heparin. Hirudin and lepirudin is an example of parenteral direct thrombin inhibitor.
Lepirudin was the first approved direct thrombin inhibitor. It is a recombinant derivative of hirudin, the anticoagulant present in the saliva of medicinal leech.
4. Oral Direct Thrombin Inhibitor Vs. Warfarin
Both oral direct thrombin inhibitor and warfarin are taken orally by patients and a contraindication to pregnant women. However, oral direct thrombin inhibitor exhibits more advantages than warfarin.
Oral direct thrombin inhibitor has a fixed dosing; anti-coagulant response is predictable; it has fast effects showing immediate coagulation; and has a wider therapeutic index than warfarin.
5. Is Direct Thrombin Inhibitor safe
The direct thrombin inhibitor is approved by FDA (Food and Drugs Administration) for treating venous thrombosis and preventing blood clots. But in some trials done with the use of these anticoagulants, it’s suggested that it might cause heart attacks.
There is no monitoring activity available for DTIs compared to other anticoagulants like warfarin and heparin.
- Rick Silver, Ilia Atanelishvili, Tanjina Akter, Kelley Kajdasz, Dulaney Wilson, Paul J. Nietert, J. Terrill Huggins, Kristin B. Highland, & Galina S. Bogatkevich (2018). Safety and Suitability of a Direct Thrombin Inhibitor, Dabigatran Etexilate, in Scleroderma-Associated Interstitial Lung Disease (SSc-ILD) Patients.
6. Direct Thrombin Inhibitors available in the US:
There are four parenteral direct thrombin inhibitors which are approved by the FDA (Food and Drugs Administration) that is available in North America. These are hirudin and argatroban, bivalirudin and desirudin.
Ximelagatran was not included because of the side effect it has on the liver. These are mostly used for treating heparin-induced thrombocytopenia (HIT). Lepirudin is approved by the FDA in the treatment of heparin-induced thrombocytopenia (HIT).
7. Direct Thrombin Inhibitor for Acute Coronary Syndromes
Patients with Acute Coronary Syndromes still remain to be at risk of myocardial infarction commonly known as heart attack despite using aspirin and other anticoagulants like heparin.
During trials with the use of direct thrombin inhibitors, it caused a reduction to possible outcomes of death and myocardial infarction in patients at the end of the course, both at the same time, compared to heparin.
Serious bleeding was also found to occur less in patients using the direct thrombin inhibitor bivalirudin than those who received heparin.
However, the use of hirudin among the individuals have shown a different result for it displayed a higher incidence of bleeding, making it not recommended in the treatment of acute coronary syndrome (ACS).
8. Dosage Guidelines for Direct Thrombin Inhibitor
Before you can start taking a direct thrombin inhibitor, consider consulting a hematologist and obtain laboratory exams like CBC, PTT (Partial Thromboplastin Time) at least daily during treatment. Stop taking heparins, warfarin, etc.
The dosage is provided by the doctor and must be given attention. Follow-ups are expected especially for any possible complications.
9. Direct Thrombin Inhibitor Vs. Vit. K Antagonist
Direct thrombin inhibitor has advantages over Vit. K antagonists. For example, it has lesser drug interaction and predictable therapeutic effects.
But if the treatment of venous thromboembolism in patients is involve, Vit. K antagonists like warfarin have been dominantly used in patients because of its half-life (40 hours) compared to the shorter life of direct thrombin inhibitor.
Because of this, with the usage of direct thrombin inhibitors, the patient will have to strictly adhere to drug use guidelines compared to usage of Vit. K antagonists.
10. Direct Thrombin Inhibitor in the treatment of stroke
The direct thrombin inhibitor used in preventing stroke for nonvalvular atrial fibrillation is Dabigatran (Pradaxa). It was also recently found to treat venous thromboembolism.
It has a lower risk of bleeding and safer to use than warfarin. But the disadvantages of dabigatran includes a twice-daily dosing, dyspepsia, and higher cost.
Warfarin prevents ischaemic stroke in patients with non-valvular atrial fibrillation, but the dose adjustment, coagulation monitoring, and bleeding risk limit its use.
The oral direct thrombin inhibitor ximelagatran represents as a potential alternative especially in high risk patients with atrial fibrillation.
- READ MORE