BLEEDING & CLOTTING DISORDERS



Coagulation Basics

Coagulation is a process by which blood forms fibrin-bound platelet plugs to stop bleeding.  Fibrin threads play a key role in holding platelets together to form a durable Platelet Plug.  Disorders of blood coagulation can lead to an increased risk of abnormal clotting (thrombosis) or bleeding (hemorrhage). 

Clotting Cascade

·        Fibrin is formed from Fibrinogen in a series of reactions called the Clotting Cascade.

·       Enzymes that comprise the clotting system are called Clotting Factors.

·       Clotting Factor III is the primary cellular initiator of Clotting Cascade

·       Activation of Vitamin K-dependent Clotting Factors II, VII, IX, and X results in the conversion of Prothrombin to Thrombin which in turn initiates the conversion of soluble Fibrinogen to insoluble Fibrin, leading to the formation of a stable meshwork around the platelet plugs.

·       Damaged Vascular Walls trigger activation of blood Clotting Cascade by exposing the Collagen present under the layer of Endothelial Cells to the bloodstream.

Platelets

·        Thrombocytes (also called Platelets) circulate through the bloodstream to constantly monitor and coordinate blood coagulation.

·       Platelets convert Arachidonic Acid (AA) to Thromboxane (TXA2) via the Cyclooxygenase enzyme (COX-1) pathway.

·       Thromboxane constricts blood vessels and causes Platelets to Clump together

·       Platelet life-span is 8 to 10 days

Platelet Aggregation

·       When there is an injury to the blood Vessel Wall, the free-floating sentinel Platelets rush to the affected area and clump together (aggregate) to form a Plug to seal off the leak to prevent bleeding.

·       Once Platelets circulating in the blood adhere to exposed Collagen, they start to secrete the following chemical mediators:

1)     Thromboxane (TXA2) to stimulate Platelet Aggregation for blood clotting

2)     Serotonin (5-HT) to constrict blood vessels to prevent bleeding

3)     Thromboplastin (Clotting Factor III) to initiate the Clotting Cascade

·        Platelet Aggregation at Vascular Endothelium Injury Sites is a Prerequisite for the ensuing Clotting Cascade.

·       Both Platelet Aggregation and Clotting Cascade are involved in Thrombus Formation

·       Aspirin inhibits TXA2-induced Platelet Aggregation by irreversibly inactivating COX-1

·       Plavix (clopidogrel) inhibits TXA2-induced Platelet Aggregration

Endothelium

·        Vascular Endothelial Cells convert Arachidonic Acid (AA) to Prostacyclin (PGI2) by the Cyclooxygenase enzyme (COX-2) pathway.

·       Prostacyclin dilates blood vessels and inhibits Platelet Aggregation.

·       Persantine (dipyridamole) stimulates the release of PGI2 from blood vessels.

Natural Blood Thinners

After the leak has been repaired with a blood clot (thrombus), the body reacts by releasing the following chemical messengers to counteract the effects of endogenous clotting mediators:

·       Prostacyclin (PGI2) that inhibits Platelet Aggregation to promote blood thinning

·        Tissue Plasminogen Activator (TPA) that activates Plasminogen into Plasmin (a thrombolytic substance) that has the capacity to degrade and dissolve fibrin-based thrombus clots.

·       Antithrombin (AT), a naturally occurring Thrombin Inhibitor, binds to Heparin as a cofactor to inhibit Factor II (Thrombin) and Factor X.

Heparin is a group of straight-chain Anionic mucopolysaccharides

Drug Therapy Types

1)     Anticoagulants

·        Coumadin or Warfarin as Vitamin K Antagonists

·        Unfractionated Heparin (UFH) and Low Molecular Weight Heparin (LMWH)

2)     Antiplatelet Agents

·        Aspirin

·        Aggrenox (Aspirin / Dipyridamole Combo)

·        Aggrastat or Tirofiban for Intravenous Use

·        Integrilin or Eptifibatide for Intravenous Use

·        Persantine or Dipyridamole

·        Plavix or Clopidogrel

·        Pletal or Cilostazol

·        Reopro or Abciximab for Intravenous Use

·        Ticlid or Ticlopidine

3)     Thrombolytics

·        TPA for Intravenous Use

·        Activase or Alteplase (Recombinant TPA) for Intravenous Use

·        Streptokinase for Intravenous Use

·        Urokinase for Intravenous Use

Coagulation Monitoring

Anticoagulation medications including Warfarin are often prescribed to help prevent blood from clotting.  Patients with Atrial Fibrillation (AF) usually take Warfarin to reduce the risk of Strokes and Heart Attacks.  Anticoagulant Therapy should therefore be monitored frequently to avoid excessive bleeding due to over-dosing of the medication.  The blood testing to assess coagulation status includes the PT test using the INR as a standard unit of measurement. 

Standard Blood Tests

·        Prothrombin Time (PT) in seconds for the blood to clot

·        Traditional PT Ratio = (Patient PT ÷ Control PT)

·        International Sensitivity Index (ISI) to convert PT into INR

·        International Normalized Ratio (INR) = (Patient PT ÷ Control PT)^ISI

·        Log INR = ISI x Log of PT Ratio of the Patient over the Control

·        INR testing used to monitor Coumadin or Warfarin Therapy

·        INR testing within target range will reduce the risk of bleeding and clotting

·        INR is about 1.0 in Healthy People

·        INR therapeutic range for Atrial Fibrillation (AF) is between 2 and 3

·        INR therapeutic range for Mechanical Heart Valve (MHV) is between 3 and 4

·        Activated Partial Thromboplastin Time (aPTT) in seconds for blood clotting

·        aPTT for monitoring Heparin Anticoagulant Therapy

Portable PT-INR Monitor

·        Approved by the FDA

·        Covered by Medicare and most Insurance Companies

·        Used as a Point-Of-Care (POC) Device for self-testing by Patients at Home

·        Prescribed by your Doctor so that you can do the test yourself

·        PT-INR testing on a regular basis helps those who are on Warfarin Therapy

·        CoaguChek XS PT-INR Meter manufactured by Roche

CAUTION

The downside of blood thinners is that they pose a risk of bleeding that may manifest itself in the form of Purple Skin Bruises. Therefore, dose-related blood thinning Therapy should be monitored Once a Week by the Patient at Home using a Portable PT-INR meter to adjust the dose to keep INR level within the target therapeutic range. 

OTC Supplements as Blood-Thinners

1)     Aspirin, 81 mg

·        Inhibits TXA2-induced Platelet Aggregration

2)     Ginkgo Biloba Leaf, 200 mg

·        Inhibits Platelet Aggregration induced by platelet-activating factor (PAF).

·        200 mg of Leaf Powder equivalent to 4 mg of (50:1) Leaf Extract

3)     Omega 3 Fish Oil, 1000 mg

·        Inhibits Platelet Aggregration by releasing Prostacycline (PGI3)

·        EPA 180 mg and DHA 120 mg from Fish Oil inhibit Platelet Aggregration

4)     Vitamin E, 400 IU

·        Inhibits Platelet Aggregration by promoting Prostacycline (PGI2) Synthesis

·        Estrogens in birth control pills can deplete Vitamin E.

Bleeding Disorders

• Selective Serotonin Reuptake Inhibitor (SSRIs) increase the Risk of Bleeding Disorders
• Serotonin Stored in the Delta Granules of Platelets
• Serotonin stimulates Platelet Aggregation, resulting in Blood Clotting
• SSRIs block Reuptake of Serotonin by Platelets, depleting Platelet Serotonin Content
• SSRIs inhibit Platelet Aggregation, resulting in Blood Thinning