Blood Thinners

Blood Thinners.

    PKGhatak,MD

If you watch an artist painting a portrait you will notice that the paint comes out of a paint tube like toothpaste and the artist takes a portion of paint and a few drops of paint thinner and mixes to the thinness the painter likes, and then proceeds. We are not talking about blood thinners like that here, it refers to drugs that delay the clotting of blood within the living body and in medicine, it is known as prolongation of clotting time.

Why and how blood clots.
Blood is a viscous fluid and contains blood cells, water, various proteins, nutrients and oxygen and other substances. Various proteins are present in the liquid part of the blood called plasma, some of these proteins are involved in clot formation and another group in dissolving blood clots. All of these proteins remain in the blood in an inactive state and an initiator is required to start the process like cars have accelerators and brakes but the driver decides which one to push to speed or stop the car.

In response to injuries, the first responder to the scene is Platelet. The platelets enlarge in size, the surfaces become knobby and sticky, adhere to each other and release several chemicals. The aggregated platelet globs plug gaps in blood vessels and the released chemicals that start a chain of events, handing down the product to the next step, like passing the baton in a relay race leading to the formation of clots. This leg of clot formation is called Platelet derived clot pathway.
At the same time, the injured tissue also releases a tissue clotting factor; another series of clotting chain reactions begin. This path is called Tissue derived pathway. These two paths meet down the chain, leading to the formation of a solid clot. These clot promoters are known as clotting factors and are designated by Roman numerical I to XIII. Factors II, VII, IX, X are synthesized in the liver and depend on vitamin K. In addition, Calcium and other substances are also required in clot formation are called co-factors.


Clot dissolving process:
The inner wall of blood vessels is lined with endothelial cells. In response to clot formation, these cells release a clot dissolving factor- tissue Plasminogen Activator (tPA). It acts on a protein, Plasminogen, present in blood clots. Plasminogen is converted to Plasmin. Plasmin is a powerful enzyme and it breaks down fibrin fibers and thereby dissolves clots. This group of drugs is commonly called clot busters.

Currently, available thrombolytic agents (clot busters) are Streptokinase, Recombinant tissue plasminogen activator, Reteplase, and Tenecteplase. These drugs are given by IV and patients are monitored continuously.

Natural Anticoagulants:
Antithrombin, heparin, protein C, and protein S slow down clot formation and prevent clot propagation. Clot promoters and regulators are kept in dynamic equilibrium to ensure the normal circulation of blood.

Anticoagulants:
Heparin:
It is a naturally occurring anticoagulant, present in the Basophils of blood and Mast cells of tissues. Heparin was first detected in the liver cells of dogs (hence the name heparin - hepar=liver), Intestine of pigs and cows is the primary source of heparin. It is available in three forms- Unfractionated UFH, Fractionated or Low molecular LMWH, and synthetic heparin – Fondaparinux. Heparin delays clot formation and prevents the extension of clots.

UFH binds with Antithrombin III(ATIII). This complex acts mainly on clotting factor Xa (activated factor X) and to a lesser degree on other factors and inactivates them at various stages of clot formation.
LMWH like UFH combines with ATIII and acts on clotting factor Xa; and unlike heparin, it has minimal action on other clotting factors.
Fondaparinux acts directly and only on clotting factor Xa, antithrombin is not required.

Heparin, in any form, must be given by injection. Because heparin has a short half-life, continuous intravenous infusion is preferred. A laboratory test-activated Partial Prothrombin Time (aPPT) is used to monitor the heparin dose.


Vitamin K Antagonist (Blood thinner):
  1. Drugs that interfere with vitamin K in the liver in the synthesis of clotting factors are known as vitamin K antagonists. Warfarin (coumadin) has been in use for a long time. To use it, in an effective and safe way, a Prothrombin Time test is necessary. The results are reported as a ratio of the patient's test result in relation to a standard number called INR (International Normalized Ratio). The therapeutic range of INR varies according to the patient's clinical diagnosis. An INR in excess of the recommended range may lead to bleeding in the brain or other vital organs.

Certain vegetables, containing significant amounts of vitamin K, and nutritional supplements containing vitamin K should not be taken when on coumadin. Several drugs interfere with the action of coumadin - some drugs prolong INR, and others depress INR. Before taking over-the-counter pills or prescribed medicine, one must check with doctors or pharmacists when on coumadin.

   2. Direct Acting Anticoagulant (DOA):
Two groups of DOAs are currently available and can be administered orally. One group acts directly on factor Xa, the other on Thrombin (factor IIa). DOA has the advantage over coumadin because no food and only a few drugs interfere with DOA. A fixed dose is generally given to patients. It acts quickly and no blood test is required to monitor this drug. Most of them are cleared by kidneys and use in renal failure is risky. DOA also causes excessive bleeding but less frequently than coumadin. And the anticoagulant effect is not reversible except for dabigatran

Rivaroxaban and Apixaban are examples of direct acting Xa inhibitors.
Dabigatran is an example of a factor IIa inhibitor.
The very high price of DOAs limits their wider use.

The use of DOA in patients with artificial heart valves is not possible because factor XII becomes activated when blood comes in contact with mechanical valves. DOA has no effect on factor XII, whereas Coumadin is effective. And the incidence of cerebral bleeding in DOA use is significant and prohibits its wider use.

3. Naturally occurring anticoagulants:


a). Antithrombin III: It is produced in the liver but not dependent on vitamin K. It inactivates thrombin and clotting factors IXa and Xa. Heparin greatly enhances its actions. Antithrombin deficiency may be inherited and also seen in renal failure and cirrhosis of the liver.

b).   Protein C and S: are synthesized in the liver and are vitamin K dependent. Protein C inactivates clotting factors Va and VIIIa. Protein S acts as a cofactor for Protein C.
The gene for protein C is located on chromosome 2.  The deficiency of Protein C is associated with spontaneous clot formation. FDA has approved a recombinant human protein C for use in severe sepsis cases.

4. Antiplatelet Drugs:
This group of drugs is specially important because they prevent blood clots in the Arterial side of the circulation. Antiplatelet drugs are used extensively in post-op coronary bypass graft surgery, coronary stent placement, myocardial infarction, cerebrovascular diseases, and peripheral vascular diseases. It is not used as a clot inhibitor on the venous side of the circulation.
Antiplatelet drugs are classified according to the enzymes they inhibit. Its use results in the prevention of platelet aggregation and release of platelet clotting factors, thereby preventing soft clot formation and the chain reactions leading to firm clot formation.

Blockers of P2Y12 receptors on ADP: Examples of these groups are clopidogrel (Plavix), prasugrel, ticagrelor.
Irreversible Cyclooxygenase inhibitors: example- aspirin.
Reversible Cyclooxygenase inhibitors: example - NSAIDs
Phosphodiesterase inhibitors: for example- cilostazol.
Adenosine uptake inhibitors: for example- Dipyridamole (Persantin)
Thromboxane inhibitors: example- aspirin.

When and why Anticoagulants are necessary:
Stagnant blood promotes spontaneous clotting. Very obese people are at risk of blood clots in the leg veins. Prolonged bed rest from disease or disability causes venous blood to clot in pelvic or leg veins. Recent leg or pelvic bone fractures or surgery on joints and bones have increased of risk of clotting. Pregnancy and recent childbirth are risky times for a woman. Cancers of solid organs and malignancy of bone-marrow cells promote blood clots. When blood has too many cells, as in polycythemia or leukemia blood clots are likely complications. When circulation is slow in the legs as in congestive heart failure or patients with varicose veins blood may clot. Prolonged forced sitting, as it happens in long airplane rides or cars, is a known risk factor.
Certain illnesses promote micro level blood clots in all tissues and organs. This situation leads to deaths in most cases. This entity is called Disseminated Intravascular Clotting (DIC). Sepsis produces a similar picture. ITTP (Idiopathic Thrombotic Thrombocytopenia) produces a similar situation. Thrombocytosis, a condition where platelet count is very high, also predisposes to clot formation.

Inherited clotting disorders:
A deficiency of protein C, protein S, and antithrombin leads to spontaneous venous thrombosis.
Other causes of increased risk of thrombosis are - oral contraceptives, sex hormones, and high homocysteine levels in the blood.

Besides these conditions, an anticoagulant is used to prevent blood clots inside the chambers of the heart. Blood clots in the left sided heart chambers get pushed out into circulation and may block the blood supply to the brain and other vital organs. Patients having episodes of atrial fibrillation and recent myocardial infarction are specially prone to clotting. A clot from the right ventricle or clots from leg or pelvic veins carried to the right ventricle are pushed into the Pulmonary artery and produce pulmonary embolism. When heart valves are infected with bacteria or fungi, vegetation grows on heart valves and dissemination of infected vegetation to other organs frequently occurs. Aortic and mitral valves are more prone to infected vegetation.
Prevention of stroke and pulmonary embolism are common reasons for anticoagulants are used. Anticoagulants may produce serious gastrointestinal or major cerebral bleeding. Patients taking multiple drugs are at higher risk of bleeding because of the interaction between drugs. It is a serious problem and requires careful planning.

When clot lysis drugs are used:
When the arterial circulation of an organ is blocked by clots, immediately removable clots are essential. This is particularly important in strokes, myocardial infections, pulmonary embolisms, and arterial blockage of limbs. Thrombolytic agents are administered intravenously and patients are monitored carefully because the risks of bleeding are high. Many institutions have strict guidelines for its use. In situations where the thrombolytic agent is contraindicated, IV heparin is the initial choice followed by oral anticoagulant- long or short terms, based on the underlying conditions. 

 

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