Human blood is in a constant battle to maintain the ability to quickly seal a damaged blood vessel through clot formation while ensuring that unwanted clots aren’t created that could lead to disability or death.
Human bodies are continually adapting and modifying their responses to maintain a viable organism. It is important to be able to selectively decide which things will come in and which will go out. Humans want blood to stay within the blood vessels. The border that must be maintained is the endothelium of the vessels which is the outer cell layer in contact with the blood. They also want to be able to transport substances from the blood into tissues but need the blood to stay in place.
There are various challenges to keeping viable gateways in the endothelium that will be selective for gases and nutrients, for example, while keeping the blood from leaving through these gateways. In multi-celled organisms blood is life, carrying oxygen need to fuel the plethora of functions within the trillions of cells of the body.
The body tends to optimize, not minimize or maximize. The surest way to keep blood in the blood vessels is to maximize the body’s ability to close off holes and injuries via forming clots. However, while a clot can effectively patch holes it can also occlude the vessels themselves, closing off portions of the circulatory system. Those tissues downstream from the clot become hypoxic and are at risk for necrosis. A heart attack and a stroke are examples of cell death from the hypoxia caused by vessel occlusion. If you minimize the chance of this blocking off of the circulatory system, then blood can easily escape the blood vessels, compromising life. A happy medium must be maintained to ensure that leaks can be plugged but not with such intensity that circulation is compromised.
The endothelium is normally a slick interface that facilitates blood circulation and produces molecules that inhibit platelet aggregation and adhesion, cholesterol deposits, and the proliferation of smooth muscle cells. It also selectively determines the movement of macromolecules into and out of the tissues outside the blood vessels. Tissue damage occurs via a number of mechanisms: infection, oxidative stress from free radicals, hypoxia, non-laminar blood flow and sheer stress, environmental irritants such as tobacco; and hyperlipidemia.
Tissue damage to the endothelium is the signal for the healing mechanisms to spring into action. Large damage will create large responses. Small damage such as the hundreds of holes that develop in the blood vessels daily are repaired with less aggressive measures.
There are over 40 substances in the blood and body tissues that affect coagulation. Some of these inhibit clot formation, others encourage it. Anticoagulant medications work by targeting one or more of these substances, thus the large number of these drugs on the market. The challenge for using any of these drugs is with artificially trying to manipulate the body’s delicate balance between the effectiveness of its procoagulants and anticoagulants.
There are two primary mechanisms the body uses to prevent the loss of blood (hemostasis) that anticoagulation therapy addresses: the formation of the platelet plug and blood coagulation.
Conditions where blood doesn’t flow as it should, as in atrial fibrillation and peripheral artery disease, put the patient at risk for developing clots because of the disruption of the laminar flow resulting in pooling of blood, like eddies in a fast moving stream, that allows procoagulants to increase in concentration instead of being flushed downstream as is the case in normal flowing blood. When these procoagulants, such as prothrombin, reach critical levels, the clotting cascade is initiated and a clot begins to form. Continual anticoagulant therapy is indicated in these conditions.
Once vascular injury has occurred, particularly from widespread atherosclerosis and the larger damage from heart attacks or angioplasty, it is much more likely for clotting to occur resulting in further life-threatening events. In these cases, the procoagulants take the upper hand requiring artificial assistance to keep the hemostatic balance. Anti-platelet agents are a primary prophylactic treatment to try to stave off heart attacks and strokes. Aspirin is one such medication. In high doses (150-350 mg/day) aspirin can slow a clot’s spread and formation that occurs during a heart attack. It can act within 30 minutes at these doses. It is used prophylactically (81 mg/day is typical) to discourage platelets from aggregating on damaged vessels that cause disruption in the normal blood flow. The most effective anti-platelet medications (Glycoprotein IIb/IIIa inhibitors such as Reopro) are given intravenously and are nine times more effective than aspirin. Plavix (clopidogrel) is indicated when aspirin isn’t effective enough. It’s effectiveness falls between IV therapy and aspirin.
Clots that form in the venous system can cause deep vein thrombosis (DVT) in the extremities. When these clots break off they travel to the lungs where they cause pulmonary embolism (PE), a life-threatening condition. These clots require anticoagulants that inhibit the clotting cascade. The mainstay drugs for this are unfractionated heparin (administered in the hospital), low-molecular weight heparin (Lovonox)(can be self-injected at home), and the oral anticoagulant warfarin (Coumadin). Heparin works by binding with one of the body’s natural anticoagulants antithrombin III increasing its efficacy up to 2000 times. The effect of heparin depends on the size of the heparin molecules, with the larger ones having a greater effect. Because of this mixture of molecular size it is difficult to predict the total effect. Low molecular weight heparin contains only the small molecules making it less likely to cause unwanted bleeding and being more consistent in its dosing.
The typical treatment for DVT and PE is Heparin for a week to 10 days along with warfarin. After this initial period heparin is stopped since warfarin will have reached its effective blood concentration. Warfarin is continued for a period depending upon the risk for developing further clots. If given prophylactically, such as after a knee replacement surgery, treatment may be stopped within a few weeks to a few months. In patients with known defects in their clotting mechanisms or those with idiopathic hyper-coagulability it may be advised to take it indefinitely.
While heparin and warfarin have been used effectively for over 50 years there are some inherent problems with them that fuel the search for more effective and safer drugs. The problems are: they have a small therapeutic window of adequate anticoagulation without bleeding, there is a highly variable dose-response relationship among individuals that require regular (monthly) monitoring, and there are multiple drug and dietary interactions that can acutely effect its effectiveness.
Currently, there are a number of drugs in development that may simplify the lives of patients and their physicians. These new drugs are an improvement over warfarin in that they target just one clotting factor, versus the multiple sites for heparin and warfarin, making the action much more predictable and requiring no monitoring of bleeding times. The clinical trials have indicated that these new drugs (such as Xarelto and Pradaxa) are as effective as warfarin with similar side-effects. The expected greater costs will be offset by the reduction in doctor visits for PTT-INR (prothrombin time and internationalized normalization ratio). The convenience coupled with the fact that it has been reported that patients present outside the therapeutic range 50% of the time will greatly improve the management of hyper-coagulability.
References
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Nature Medicine 15, 665 – 673 (2009) Published online: 24 May 2009 | doi:10.1038/nm.1955. A shear gradient–dependent platelet aggregation mechanism drives thrombus formation. Warwick S Nesbitt1,5, Erik Westein1,5, Francisco Javier Tovar-Lopez2, Elham Tolouei3, Arnan Mitchell2, Jia Fu1, Josie Carberry3, Andreas Fouras4 & Shaun P Jackson1
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