What is anticoagulation therapy?

Anticoagulation or blood-thinning is a medical domain that employs chemical compounds to prevent or reduce the clotting of blood within the vessels. In healthy homeostatic conditions, the body regulates a constant balance between the blood clot formation and destruction. However, this equilibrium is disturbed in conditions known as thromboembolic disorders. Here, the blood abnormally clots within the vessels causing turbulence in the blood flow to tissues and organs, leading to injury and eventual death of the affected site. A clot may locally obstruct a vessel of its origin(thrombus) or travel to another vital site (emboli) such as vessels of the heart or brain to produce life-threatening emergencies such as heart attack or stroke. Atrial fibrillation and venous thromboembolism are two such common thromboembolic disorders that are leading causes of morbidity and mortality worldwide.

Anticoagulants are, therefore, oral and parenteral drugs widely popular for their effectiveness in managing these disorders. Their use as both an emergency resort and an as prophylactic agent has been extensively studied and approved. This non-invasive procedure with a low risk of complications statistically demonstrates significant improvement in morbidity and mortality. It is estimated around six million Americans are annually affected by atrial fibrillation alone and require emergency or prophylactic anticoagulation.

How do anticoagulants work?

Anticoagulants targets synthesis of proteins known as clotting factors that together cause coagulation cascade i.e. a series of event leading to clot formation within the blood vessels. Most common of the anticoagulants available today are vitamin K antagonists that inhibit its contribution to clotting factor activation and synthesis. Adequate amounts of vitamin K are required by the liver to effectively manufacture vitamin K dependent clotting factors.

PT or prothrombin time is a practical test that evaluates appropriately the ability of blood to form clots. An International normal ratio is then deduced from this PT readings to closely monitor the response of anticoagulant drugs.

When is anticoagulation therapy indicated:

Anticoagulation therapy is indicated in the following life-threatening emergencies:

Deep Vein Thrombosis(DVT): Anticoagulation therapy is the cornerstone of Venous thromboembolism treatment and is initiated immediately within suspected patients. This modality prevents the sequelae of DVT in approximately 90% of treated patients.
Stroke: Anticoagulants are frequently prescribed to patients with recent stroke to prevent early recurrence and to improve neurological outcomes.
Heart attack: anticoagulation medications are used in conjunction with anti-platelet drugs to manage the acute coronary syndrome.

Its prophylactic use can be employed in the following conditions:

atrial fibrillation,
stent thrombosis,
pulmonary embolism,
post-heart attack,
post-stroke.

What drugs are commonly used for anticoagulation therapy?

There are four major classes of anticoagulant drugs that are currently used worldwide. These differ from each other due to their mechanism of action and include:

Vitamin K antagonists (coumarin anticoagulants),
Low molecular weight heparin (LMWH),
Direct thrombin inhibitors,
Factor Xa Inhibitors.

VITAMIN K ANTAGONISTS(VKA):

Vitamin K antagonists are proposed to be the most frequently used drugs worldwide. Used for long-term anticoagulation therapy, they exhibit their anticoagulant effect by inhibiting an enzyme called vitamin K epoxide reductase. They are used with caution due to their narrow therapeutic index and unpredictable dose-response relationship. The most common VKA is the oral warfarin sold under the brand name Coumadin and Jantoven. Warfarin is best suited for anticoagulation in sites with of sluggish blood flow such as veins and blood pools behind artificial and natural valve, or in dysfunctional cardiac atria. Thus, common clinical indications for warfarin use are atrial fibrillation, artificial heart valves, deep venous thrombosis, and pulmonary embolism, etc.

LOW MOLECULAR WEIGHT HEPARINS (LMWH) AND HEPARIN:

Fractioned from naturally occurring heparin LMWH edges over its parent drug due to its longer half-life, better bioavailability, predictable anticoagulant response, lower risk of heparin thrombocytopenia, and osteoporosis risk. Recent meta-analyses of clinical trials on unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) demonstrate their similarities with both producing a 4% risk of recurrent DVT, a 2% risk of pulmonary embolism (PE), and a 3% risk of major bleeding. Examples of this class of drugs include Heparin, Enoxaparin, and Dalteparin, etc.

THROMBIN INHIBITORS

Thrombin inhibitors are available in many parenteral preparations such as powder, and injectable, etc. therefore, they are not suitable for long term use as vitamin K antagonists. Frequently used thrombin inhibitors include Bivalirudin, Argatroban, Dabigatran, and Anti-thrombin III, etc.

FACTOR XA INHIBITORS

These newer class drugs are now being used as substitutes to vitamin K antagonists and heparins, with multiple clinical trials showing their efficacy and improved safety profiles over warfarin. Common drugs in this class include; Apixaban, Fondaparinux, Rivaroxaban, and Edoxaban, etc.

What are the complications of anticoagulation therapy?

Acute hemorrhage is the most dreaded but fortunately uncommon adverse effect associated with all anticoagulants. Approximately 2% of patients experience major bleeding within the first 3 months of heparin therapy and 1-3% thereafter per year. The mortality rate associated with any major bleeding episode secondary to anticoagulation therapy is estimated to be 13%.
Warfarin associated necrosis and osteoporosis.
Thrombocytopenia or low platelet count is associated with unfractionated heparin and can occur in patients treated with heparin for more than 4 days.
Purple toes syndrome: rare symptoms that appear 3-8 weeks post warfarin therapy. It is characterized by the painful , purple lesions that arise suddenly on toes and side of feet and blanches with pressure.
Milder side effects include headache, lethargy, dizziness, abdominal pain, bloating and hypersensitivity reactions, etc.

When is anticoagulant therapy contraindicated?

Anticoagulation therapy is avoided or contraindicated in the following conditions as here their risks outweighs the benefit produced. Examples of such in

Patients with active bleeding,
Patients with bleeding disorders,
Pregnant women (fetal bleeding and birth defect have been reported in women using warfarin therapy during pregnancy),
Patient with active cardiac infection (such as pericarditis or infective endocarditis),
Patients with abnormal vessel anatomy (such as the cerebral aneurysm or dissecting aorta),
Patients with active ulcer complain,
Patients undergoing surgery, etc.

Can anticoagulation therapy be continued at home?

Yes, anticoagulation medications are continued in patients on long term anticoagulation therapy for instance patients with a history of repeated DVT or stroke. Vigilant monitoring is required in such individuals, with current guidelines recommending repeating PT/INR test every four weeks in patients with warfarin. The availability of devices that monitor INR levels at home has further enhanced the attractiveness of this therapy in regards to costs, reversibility, and easy monitoring. The devices used for home monitoring are typically small, lightweight, and are easy to use by both patients themselves and their care providers. A cohort study reported a high rate of clinically significant agreement among self-measurements of the PT values with a portable monitor and laboratory-generated PT results. Concluding the use of the portable monitor as the primary method for measuring the PT can be recommended in selected patients receiving long-term anticoagulant treatment

References:

Fung YC. Biomechanics: circulation. Springer Science & Business Media; 2013 Apr 17.

McCurdy SA, White RH. Accuracy and precision of a portable anticoagulation monitor in a clinical setting. Archives of internal medicine. 1992 Mar 1;152(3):589-92.

Anderson DR, Harrison L, Hirsh J. Evaluation of a portable prothrombin time monitor for home use by patients who require long-term oral anticoagulant therapy. Archives of Internal Medicine. 1993 Jun 28;153(12):1441-7.

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2008 Jun 1;133(6):160S-98S.

Ufer M. Comparative pharmacokinetics of vitamin K antagonists. Clinical pharmacokinetics. 2005 Dec 1;44(12):1227-46.

Peterson CE, Kwaan HC. Current concepts of warfarin therapy. Archives of internal medicine. 1986 Mar 1;146(3):581-4.

Weitz JI. Low-molecular-weight heparins. New England Journal of Medicine. 1997 Sep 4;337(10):688-99.

Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. New England Journal of Medicine. 2005 Sep 8;353(10):1028-40.

Burke DT. Prevention of deep venous thrombosis: an overview of available therapy options for rehabilitation patients. American journal of physical medicine & rehabilitation. 2000;79(5 Suppl):S3-8.

Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. The American journal of medicine. 2015 Dec 1;128(12):1300-5.

Patel NJ, Deshmukh A, Pant S, Singh V, Patel N, Arora S, Shah N, Chothani A, Savani GT, Mehta K, Parikh V. Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010: implications for healthcare planning. Circulation. 2014 Jun 10;129(23):2371-9.

Jaffer A, Bragg L. Practical tips for warfarin dosing and monitoring. Cleveland Clinic journal of medicine. 2003 Apr 1;70(4):361-71.

Anticoagulation therapy