Biochemical Pathways and Pharmaceutics

 Vitamin-K Antagonist: Coumarin (Warfarin, Dicumarol and phenprocoumon)-  These drugs exhibit their anticoagulant activity by acting as competitve inhibitors of the enzyme (E.C.1.1.4.1) Vitamin-K Epoxide Reductase. Inhibition of the enzyme prevents the reduction of oxdised vitamin-k.  Therefore, the Hepatic Gamma-glutaryl-Carboxylase enzyme is starved of an essential co-factor required for its biological activity. HGGC is required to activate Factors 10,9,7,and 2 these factors are essential to the maturation of both the Intrinsic and Extrinsic clotting pathways.

Warfarin Therapy, like several other anticoagulant therapy, must be monitored by quantitative measurement methods. Measuring (PT and APTT) followed by (INR) referencing is  almost routely done in the clinical setting.

 Cation Chelators:   EDTA, Citrate, Oxalate, Flourine, and Heparin.

These organic molecules can serve as Anticoagulation agents in a clinical setting, but the use has been limited. These molecules exhibit their anticoagulant activity by Chelating Calcium and  Magnesium ions from the reaction solution. Calcium and Magnesium are essential metal ion co-factors for several enzymatic reactions. These molecules all share a predominantly negatively charged chemical state.

These Chelators can also be used to treat Heavy metal ion poisoning.

 PLASMIN:

A Serine Protease involved in the process of fibrinolysis. Fibrin, when activated by Factor-13 forms strong covalent crosslinkages between adjacent firbrin subunits by facilitating the binding of specific residues on the fibrin sub-unit.  The crosslinkage can be lysed by the activity of a serine protease called Plasmin. Plasmin is produced by the activity of (Tissue Plasmingen Activator) and (EC.3.4.21.73) Urokinase on inactive Plasminogen.

When converted from plasminogen into plasmin, it functions as a serine protease, cutting C-terminal to these lysine and arginine residues. Fibrin monomers, when polymerized, form protofibrils. These protofibrils contain two strands, anti-parallel, associated non-covalently. Within a single strand, the fibrin monomers are covalently linked through the actions of coagulation factor XIII. Thus, plasmin action on a clot initially creates nicks in the fibrin; further digestion leads to solubilization

Lysis of Fibrin produces Fibrin Degradative Products or (FDP's). A clinically significant FDP is the D-Dimer protein whose concentration is routely assayed in cases of Deep Vein Thrombosis, Acute Myocardial Infractions, Disseminated intravascular coagulation (DIC), Pulmonary Embolism, and as a reference point when managing  cases using Anticoagulants or Fibrinolytic therapy.

Auto-regulation of the Fibrinolysis is achieved by the activity of alpha-2 Antiplasmin and Alpha-2 Macroglobulin on Plasmin, and also by the activity of Plasminogen activator 1 & 2 on (EC.3.4.27.73) Urokinase and Tissue Plasminogen Activator.

Plasmin activity is also reduced by the activity of Thrombin-Activatable-Fibrinolysis-Inhibitor.

Plasmin is also indicated in the lysis of Complement Convertase 3.

 Direct Thrombin  Inhibitors:

Members of this drug class include: Hirudin, Bivalirudin, and Argatroban. These drugs work by acting as competitive inhibitors of Factor-2(Thrombin); this is possible by the binding of these drugs to the Active site or the exosite-1 of the Thrombin protease enzyme.

Divalent Thrombin Inhibitors: Hirudin & Bivalirudin bind to both the Active site and the exosite,

Univalent thrombin Inhibitors: Argatroban & Dabigatran bind to the active site only.

Hirudin is a naturally  occuring Direct Thrombin inhibitor derived from the Medicinal leech (Hirudo Medicinalis).

Direct Thrombin Inhibitor activity is monitored by the ECT assay Ecarin Clotting Time. Ecarin is a compound obtained from snake venom.