Thrombin inhibitor by Ray Sahelian, M.D.
March 12 2016


Thrombin is a key clot promoter. Thrombin is an enzyme that presides over the conversion of a substance called fibrinogen to fibrin, which helps form a blood clot. Thrombin is has been widely characterized for its roles in hemostasis, inflammation, and cell signaling.


Natural Supplements that have anti-clotting ability
Certain supplements have blood thinning potential and should be considered by doctors as a way to reduce the risk for blood clots. These natural supplements include:

EGCG, the extract from green tea, may prevent platelet aggregation almost as potently as aspirin
Fish oils thin the blood and have many other benefits
Garlic could be helpful
Vitamin E may reduce the risk of blood clots in women, such as venous thromboembolism.
Ginger is a very healthy herb to eat daily and has mild anti platelet activity along with the ability to break down fibrin.
Ginkgo biloba herbal extract
Nattokinase enzyme has fibrinolytic activity. Only use nattokinase under medical supervision.
     This is a partial list.


Thrombin use in Surgery

Thrombin has been purified from numerous sources and used as a clinical aid for topical hemostasis for more than 60 years. Due to both its ease of use and apparent effectiveness, thrombin has become used routinely as an aid for topical hemostasis in nearly all types of surgical procedures, including but not limited to cardiovascular, orthopedic, neurologic, general, gynecologic, and dental procedures.


Direct thrombin inhibitor

Bivalirudin, lepirudin, and argatroban are a new class of anticoagulants. The mechanism of action of these agents differs from heparin in that they directly inhibit the active site of thrombin, and they do not require an interaction with antithrombin III to produce their anticoagulant effect. Furthermore, contrary to heparin, direct thrombin inhibitor agents inhibit only the activity of thrombin whereas heparin, through its activation of antithrombin III, indirectly inhibits factors IIa (thrombin), Xa, IXa, XIa and XIIa.
   Thromboembolism is a common cause of death and disability. Heparin or warfarin, the current standard management for thromboembolism may cause serious bleeding complications. Hirudin, the most potent natural thrombin -specific inhibitor, was first isolated from leech salivary fluid. Synthetic thrombin -specific inhibitors are rationally designed based on the knowledge on the structures of the activate site of thrombin. Thrombin -specific inhibitors are the current best choice for the treatment of heparin-induced thrombocytopenia (HIT). Bivalirudin (hirulog-1 or Angiomax), in adjunct to aspirin, was approved for prevention of thrombosis in patients with unstable angina following angioplasty. Argatroban has been used for the treatment of HIT, peripheral and cerebral thrombotic diseases.

   Two parenteral direct thrombin inhibitors, lepirudin and argatroban, have FDA approval for the management of heparin-induced thrombocytopenia. Ximelagatran, an oral prodrug of the direct thrombin inhibitor melagatran, has shown efficacy in the prevention and treatment of venous thromboembolism as well as stroke prevention in patients with atrial fibrillation. Fondaparinux is a synthetic pentasaccharide, which binds to antithrombin, thereby indirectly selectively inhibiting factor Xa. Fondaparinux is FDA approved for the prevention and treatment of venous thromboembolism.


Stroke. 2014 Jan 28.Thrombin Inhibitor Argatroban Reduces Stroke Damage in 2 Different Models.

Thrombin time

Thrombin time compares a patient's rate of clot formation to that of a sample of normal pooled plasma. Thrombin is added to the samples of plasma. If the plasma does not clot immediately, a fibrinogen deficiency is present. The thrombin time is used to diagnose bleeding disorders and to assess the effectiveness of fibrinolytic therapy. Reference values for thrombin time are 10 to 15 seconds or within 5 seconds of the control.

Level pro thrombin

The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. They are used to determine the clotting tendency of blood, in the measure of warfarin dosage, liver damage and vitamin K status. The reference range for prothrombin time is usually around 12-15 seconds; the normal range for the INR is 0.8-1.2. It is used in conjunction with the activated partial thromboplastin time (aPTT) which measures the intrinsic pathway.


Thrombin level and Deep Vein Thrombosis

Measurement of thrombin generation, using a commercially available assay, can identify patients who are not likely to experience recurrent venous thromboembolism (VTE) and, therefore, may not require long-term anticoagulation therapy. After experiencing a VTE, patients typically receive anticoagulation with a vitamin K antagonist for at least 3 to 6 months. Unfortunately, after stopping this therapy, up to one third of patients will experience a recurrence, which carries a fatality rate of about 5%. A primary goal of thrombosis research is finding a way to separate the patients destined for a recurrence from those who will have no further problems. Being able to discriminate between these groups could markedly reduce the use of anticoagulation therapy and all of its well-known risks. Thrombin generation is significantly lower in patients who remain clot-free during follow-up. Compared with thrombin generation greater than 400 nM, values between 400 and 300 nM and below 300 nM cut the risk of recurrence by 58% and 63%, respectively. There is no thrombin generation value that completely ruled out the possibility of recurrent clots.


Argatroban - Direct Thrombin Inhibitor

Heparin has historically been used as the anticoagulant of choice in the management of a number of thrombotic diseases. Recognition of the limitations of heparin has led to the development of a newer class of anticoagulants, the direct thrombin inhibitors. Argatroban is a synthetic small molecule that selectively inhibits thrombin at its active site. In clinical trials, argatroban has been shown to be an effective anticoagulant in patients undergoing percutaneous coronary interventions. In patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia complicated by thrombosis, argatroban significantly decreases the risk of thrombotic events.


Review article
Int J Mol Sci. 2016. The Importance of Thrombin in Cerebral Injury and Disease. There is increasing evidence that prothrombin and its active derivative thrombin are expressed locally in the central nervous system. So far, little is known about the physiological and pathophysiological functions exerted by thrombin in the human brain. Extra-hepatic prothrombin expression has been identified in neuronal cells and astrocytes via mRNA measurement. The actual amount of brain derived prothrombin is expected to be 1% or less compared to that in the liver. The role in brain injury depends upon its concentration, as higher amounts cause neuroinflammation and apoptosis, while lower concentrations might even be cytoprotective. Its involvement in numerous diseases like Alzheimer's, multiple sclerosis, cerebral ischemia and haemorrhage is becoming increasingly clear. This review focuses on elucidation of the cerebral thrombin expression, local generation and its role in injury and disease of the central nervous system.