Different Classes of Anticoagulant Drugs in Clinical Use. Is there a Class Effect?

Hippocrates first proposed ‘Blood thinners’ in ancient Greek medicine. Historically, extracts from many plants, bloodletting, leech bleeding, acid fruits and clear wines were considered as anticoagulants. Although, Haycraft in 1884 identified the anticoagulant in the saliva of European medicinal leech, later named hirudin, the extract was found to be too toxic. Following Jay McLean’s discovery of an anticoagulant in 1916, and naming of this anticoagulant as ‘heparin’ by Howel and Holt in 1918 and Howel’s purification of this compound in 1925, it was only in 1930s that the effective anticoagulant treatment started. Soon after the discovery of the first oral anticoagulant, dicoumarin in 1935, the purified injectable preparations of heparin were used. Later, other types of antithrombotic and anticoagulant treatment, including antiplatelet drugs, snake venoms, direct and indirect thrombin inhibitors, activated protein C, direct Factor Xa inhibitors and recombinant hirudins have since been introduced [1]. Warfarin, a conventionally used oral anticoagulant, despite its limitations of drugfood, drug-drug interactions, need for frequent PT/INR monitoring, adverse drug reactions, bleeding, warfarin-induced skin necrosis, frequent need for dosage adjustments because of changes in the dietary patterns, effects due to VKORC polymorphism, has stood the test of time and still continues to be used in clinical practice. Recently the New Oral Anticoagulant drugs, direct Factor Xa such as Rivaroxaban, Apixaban and Edoxaban and direct thrombin inhibitors such as Dabigatran were approved by the USFDA. There are several limitations in the use of NOACs such as the lack of an effective test to monitor their anticoagulant activities, the lack of an effective antidote, and dose adjustments in patients with renal impairment [2]. Thus, a bewildering wide array of anticoagulant drugs are now available for use and it is interesting to see whether or not these drugs representing different classes of anticoagulant drugs, especially direct thrombin and direct Factor Xa inhibitors have any class effects in terms of differences in their clinical outcomes.


Short Communication
Hippocrates first proposed 'Blood thinners' in ancient Greek medicine. Historically, extracts from many plants, bloodletting, leech bleeding, acid fruits and clear wines were considered as anticoagulants. Although, Haycraft in 1884 identified the anticoagulant in the saliva of European medicinal leech, later named hirudin, the extract was found to be too toxic. Following Jay McLean's discovery of an anticoagulant in 1916, and naming of this anticoagulant as 'heparin' by Howel and Holt in 1918 and Howel's purification of this compound in 1925, it was only in 1930s that the effective anticoagulant treatment started. Soon after the discovery of the first oral anticoagulant, dicoumarin in 1935, the purified injectable preparations of heparin were used. Later, other types of antithrombotic and anticoagulant treatment, including antiplatelet drugs, snake venoms, direct and indirect thrombin inhibitors, activated protein C, direct Factor Xa inhibitors and recombinant hirudins have since been introduced [1]. Warfarin, a conventionally used oral anticoagulant, despite its limitations of drugfood, drug-drug interactions, need for frequent PT/INR monitoring, adverse drug reactions, bleeding, warfarin-induced skin necrosis, frequent need for dosage adjustments because of changes in the dietary patterns, effects due to VKORC polymorphism, has stood the test of time and still continues to be used in clinical practice. Recently the New Oral Anticoagulant drugs, direct Factor Xa such as Rivaroxaban, Apixaban and Edoxaban and direct thrombin inhibitors such as Dabigatran were approved by the USFDA. There are several limitations in the use of NOACs such as the lack of an effective test to monitor their anticoagulant activities, the lack of an effective antidote, and dose adjustments in patients with renal impairment [2]. Thus, a bewildering wide array of anticoagulant drugs are now available for use and it is interesting to see whether or not these drugs representing different classes of anticoagulant drugs, especially direct thrombin and direct Factor Xa inhibitors have any class effects in terms of differences in their clinical outcomes.
Direct thrombin inhibitors such as dabigatran and bivalirudin currently established for treatment and prevention of cardiac thromboembolism and venous thromboembolism (VTE) are reported to be repeatedly associated with a significantly increased frequency of thrombosis on abnormal cardiac endothelium when directly compared against indirectly acting therapeutic anticoagulants in studies with sufficient patient numbers and duration [3]. Other direct thrombin inhibitors such as bivalirudin, dabigatran, argatroban, desirudin indicated for therapeutic or prophylactic use. However, in clinical trials of sufficient patient numbers and sufficient duration where direct thrombin inhibitors have been compared against another active anticoagulant, there was increased incidence of myocardial infarction and/or ischemia, or coronary stent or cardiac valve thrombosis [3,[4][5][6][7][8][9] ( Table 1). One clinical trial was prematurely stopped when dabigatran was compared against warfarin patients for patients with mechanical heart valves when dabigatran caused high rate of adverse events including stroke presumably related to valve thrombosis [10]. A metaanalysis including ximelagatran and dabigatran and other antithrombotic drugs for atrial fibrillation concluded that warfarin provided superior protection against myocardial infarction compared with ximelagatran or dabigatran [11]. In one study dabigatran was also evaluated against warfarin in patients with mechanical heart valves and it was concluded that dabigatran was associated with increased rates of thromboembolic and bleeding complications. The trial was stopped early because of an excess of thromboembolic and bleeding events in the dabigatran group. Most thromboembolic events in the dabigatran group occurred in patients who had started the study drug within 7 days after valve surgery and fewer in patients who had undergone valve implantation more than 3 months before randomization. Possible explanations of study investigators, as to why there was the increase in thromboembolic complications, include inadequate plasma levels of the drug and a mechanism of action that differs from that of warfarin [10]. However, thromboembolic events were also reported among patients with higher trough plasma levels of dabigatran in both groups suggesting that lower-than-expected drug levels do not fully explain the increase in the rate of thromboembolic events. Perhaps the tissue factor-and contact-activation-generated thrombin during surgery might overwhelm a pharmacokinetically controlled dabigatran level [10]. Warfarin and heparin inhibit thrombin and other clotting factors. So far no increased incidence of cardiac thrombosis have been reported with new oral Factor Xa inhibitors such as rivaroxaban and apixaban and indirect specific inhibitor of Factor Xa such as fondaparinux has been reported [3].
The exact reason or the mechanism for increased cardiac thrombosis in anticoagulation with direct thrombin inhibitors is not known. Thrombin besides having procoagulant effects also has anticoagulant effects through the activation of the protein C pathway. Perhaps following complete inhibition of the thrombin, there is none available to bind with thrombomodulin to trigger the activation of protein C to activated protein C to exhibit its endogenous anticoagulant properties via inhibition of FVa and FVIIIa. As a result increased FVa in the presence of FXa converts prothrombin to thrombin. Similarly increased FVIIIa in the presence of FIXa converts FX to FXa thereby converts prothrombin to thrombin.
Thus increased thrombin generation through these feedback loops may be responsible for the increased incidence of cardiac thrombosis seen in patients who received thrombin inhibitors. One possible reason as to why unfractionated heparin is better than the thrombin inhibitors is that unfractionated heparin is capable of triggering increased expression of Tissue Factor Pathway Inhibitor (TFPI) from the endothelium. TFPI is a protease inhibitor containing three Kunitz type domains [12]. The first domain combines with factor VIIa and inhibits it. The second domain combines with FXa and inhibits it. The function of the third domain is not completely understood. Thus TFPI by combining with tissue factor (TF), FXa, FVIIa forms a TFPI-TF-FXa-FVIIa quaternary inhibitory complex [13].
Furthermore, the TF induced thrombin generation is downregulated by TFPI and the functional protein C pathway [14].
Thrombin-Thrombomodulin complex links coagulation with the fibrinolysis by Thrombin Activatable Fibrinolytic Inhibitor (TAFI) [15,16]. The interactive role of the thrombin-thrombomodulin complex, TFPI, protein C, APC, TAFI in coagulation pathway needs further exploration and may hold the key in the further understanding of the increased incidence of cardiac thrombosis in patients administered with thrombin inhibitors. Personalized or individualized tailored therapy with a right anticoagulant at the right dosage to the right patient at the right time may help in avoiding adverse outcomes.