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Health Protocols

Blood Clot Prevention


You may not know it, but if you are over 50 the greatest threat to your continued existence is the formation of abnormal blood clots in your arteries and veins.

The most common form of heart attack occurs when a blood clot (thrombus) blocks a coronary artery that feeds your heart muscle. The leading cause of stroke occurs when a blood clot occludes, or obstructs, an artery supplying blood to your brain. Formation of vascular blood clots is also a leading cause of death in cancer patients because cancer cells create conditions that favor clotting.

While normal blood clots are a natural part of healing, abnormal arterial and venous blood clots are a significant cause of death and disability (Mannucci 2011).

The good news is that health-conscious individuals already take a wide variety of nutrients through their diet and supplement program that drastically reduce their risk of developing thrombosis, which is the medical term for an abnormal vascular blood clot.

Certain individuals, however, have underlying medical conditions that predispose them to developing thrombotic events. These include atherosclerosis, mechanical heart valves, atrial fibrillation, venostasis, blood clotting disorders, and cancer. These individuals must take special precautions to protect against thrombosis.

Conventional medicine offers drugs proven to reduce thrombotic risk via specific mechanisms. These drugs fail, however, to neutralize the broad array of mechanisms that can induce a thrombotic event, which is why a comprehensive thrombosis prevention program is so critically important to those at high risk.

This protocol first discusses some technical details about thrombosis, the conventional drugs that doctors prescribe, and important blood tests to consider. It then reveals little-known methods of inhibiting a multitude of thrombotic risk factors that mainstream doctors overlook.

Life Extension believes patients succumb to thrombotic events, even when taking powerful anti-coagulation drugs such as warfarin, because their doctors failed to suppress the many other underlying risk factors that cause abnormal clots to form inside a blood vessel.

The Flaws of Mainstream Therapies

The most effective means of blood clot management is prevention. For high-risk patients, mainstream prophylaxis against thrombosis and its complications often includes powerful anti-clotting medications. These require careful monitoring and inconvenient dietary restrictions.

Conventional medications used to prevent blood clots, such as warfarin (Coumadin®), increase the potential for serious bleeding as well as the risk of mortality from traumatic injuries (Dossett 2011). Moreover, warfarin may lead to significant long-term side effects, such as increased risk of atherosclerosis and osteoporosis.

Life Extension has identified a strategy to reduce the detriments of long-term warfarin therapy. Judicious use of vitamin K2 has been shown in peer-reviewed studies to reduce the fluctuation in coagulation status associated with warfarin therapy. This notion runs contrary to that of conventional medicine, whose best advice is to totally eliminate vitamin K from the diet during warfarin therapy, an outdated guideline that compromises vascular and skeletal health.

Next-generation anticoagulant medications that overcome these vascular and skeletal risks are emerging, yet they still lack sufficient data from clinical trials to solidify them as first-line treatments. The most promising of these new drugs is dabigatran (Pradaxa®); however, early trials indicate that dabigatran may be more effective for reducing stroke risk in patients with atrial fibrillation (Peetz 2010; Houston 2009).

Life Extension emphasizes that optimal thrombosis risk reduction can never be viewed in isolation, but must encompass a global strategy. Measures to reduce the risk of blood clots include reducing chronic inflammation, maintaining healthy body weight, reducing cholesterol, suppressing homocysteine levels, and lowering blood pressure. Additionally, the use of scientifically studied nutrients to target abnormal platelet aggregation can intervene in the thrombotic process before it causes a life-threatening medical emergency.

What is a Blood Clot?

A normal blood clot consists of a "clump" of blood-born particles that have become "stuck" together inside a blood vessel; this usually occurs at the site of a blood vessel injury and is part of the normal healing process. However, clotting also can occur in areas where blood flow is slow or stagnant, such as in a blood vessel occluded, or obstructed, by atherosclerotic plaque. A blood clot that develops in a blood vessel or the heart and remains there is called a thrombus, while a blood clot that has broken loose and floats freely through the circulatory system is called an embolus.

Blood clots are made up of:

Platelets: Small fragments of larger cells called megakaryocytes, platelets circulate through the blood and carry important substances such as proteins and other cellular signaling molecules. A platelet has a lifespan of about 7–10 days.

Red Blood Cells: The most common type of blood cell, red blood cells transport oxygen from the lungs and distribute it to all the tissues of the body.

White Blood Cells: The cells of the immune system, white blood cells originate in the bone marrow as stem cells that differentiate into various types of immune cells.

Fibrin: A web-like proteinaceous gel, fibrin binds the other components of the clot together.

Thrombotic Disease

A clot formation can be especially dangerous if it blocks blood flow to organs or tissues. For example, blockage of the coronary arteries (the blood vessels that directly supply oxygen to the heart muscle itself) can result in myocardial infarction (a heart attack), and death of heart muscle tissue.

An unstable thrombus can break away from the vessel wall and cascade freely through the bloodstream. This thrombus can become problematic if it becomes wedged in a blood vessel too small to allow its passage, obstructing blood flow and impairing oxygen delivery to tissue. This blockage is called an embolism. Cerebral embolism is one such example—an embolism in the small arteries of the brain can cause an embolic stroke.

Arterial thrombosis is associated with several life-threatening complications (Table 1). Clots in the veins (venous thrombosis) of the legs are relatively common, and pose a significant risk of forming emboli that can travel to the lungs, causing a potentially fatal pulmonary embolism.

Table 1. Complications of Thrombosis

Conditions caused by arterial thrombosis (blockage of arteries that carry oxygen-rich blood from the heart to other tissues):

  • Stroke: either slow-developing caused by thrombi, or rapid-onset caused by embolism.
  • Transient Ischemic Attack (TIA): a "mini-stroke" without tissue death.
  • Myocardial Infarction (heart attack): blockage of the coronary arteries that supply oxygen to the heart muscle.
  • Pulmonary embolism: life-threatening blockage of arteries in the lungs, starving the body of oxygen. Some estimates place the incidence of pulmonary embolism at more than 180,000 new cases per year, making it the third most common life-threatening cardiovascular disease in the US (Cushman 2004). A blood clot that leads to pulmonary embolism often forms in the legs as deep vein thrombosis (DVT; see below), but can also form in the atrium in those with atrial fibrillation. In about 40% of cases, the origin of the emboli is unknown (Flegel 1999).
  • Angina pectoris: reduction of blood supply to the heart, typically resulting in severe chest pain.

Conditions caused by venous thrombosis (blockage of veins that carry oxygen-poor blood back to the heart):

  • Deep vein thrombosis (DVT): a clot formed in a deep vein, usually in the legs. Quite common; data suggests that the lifetime risk of DVT is about 5% (Silverstein 1998). Unstable clots formed from DVT have the potential to break free and travel to the artery that supplies deoxygenated blood to the lungs, where they can cause a potentially fatal pulmonary embolism. Damage from DVT can also lead to post-thrombotic syndrome, a condition typified by leg pain, heaviness, swelling, or ulceration. More than one-third of women with DVT develop post-thrombotic syndrome (Kahn 2011).
  • Portal vein thrombosis: a rare blockage of the vein that carries blood from the abdomen to the liver. Portal vein thrombosis is relatively uncommon and usually associated with liver disease (Rajani 2010).
  • Renal vein thrombosis: a blockage of the vein that drains blood from kidney. This type of thrombosis is relatively uncommon and often associated with trauma to the abdomen.

Risk Factors for Thrombosis

The risk factors for thrombosis are believed to increase clotting through one or more of these three mechanisms: 1) altering or damaging the blood vessel lining (endothelium); 2) impairing or slowing the flow of blood; or 3) promoting a state that favors excess coagulation (hypercoagulation).

Alteration of the blood vessel lining (endothelium) produces areas of disturbance that are not necessarily tears, but may nonetheless mimic the physiology of vascular injury, thus encouraging the recruitment of platelets and the clotting process. Factors that pose a risk to endothelial cell health include:

  • Abnormal blood lipids, particularly elevated total cholesterol, LDL (low-density lipoprotein) cholesterol, triglycerides, and low HDL (high-density lipoprotein) cholesterol, pose a risk to endothelial cell health. Blood lipid values outside of optimal ranges (see Table 2, below) are one of the risk factors for atherosclerosis, which causes arterial plaques on blood vessel walls. Clots can form on or near the lipid-rich arterial plaques in vessel walls, disrupting blood flow and increasing heart attack or stroke risk. Scientific strategies for cholesterol risk reduction are available in Life Extension's Cholesterol Management protocol.
  • Elevated high-sensitivity C-reactive protein (hsCRP). hsCRP is an indicator of inflammation and blood vessel injury; high levels are predictive of future risk of heart attack or stroke (Ridker 2008). CRP also exerts several pro-thrombotic activities, and may be associated with risk of venous thrombosis (Lippi 2010).
  • Hypertension. Sustained high blood pressure compromises the integrity of the endothelium, and can cause endothelial activation and initiation of clotting (Schmieder 2010). For optimal endothelial protection and blood clot prevention, a target blood pressure of 115/75 mmHg is suggested. Those with blood pressure higher than the optimal range are encouraged to read Life Extension's Blood Pressure Management protocol.
  • Elevated glucose. Elevated blood glucose levels, even those that remain in the lab-normal range, may significantly increase the risk of developing a blood clot. In fact, a clinical study involving patients with coronary artery disease (CAD), found that patients with fasting glucose levels above 88 mg/dl had greater platelet dependent thrombosis than those with levels below 88 mg/dl. The authors of this study remarked: "The relationship is evident even in the range of blood glucose levels considered normal, indicating that the risk associated with blood glucose may be continuous and graded. These findings suggest that the increased CAD risk associated with elevated blood glucose may be, in part, related to enhanced platelet-mediated thrombogenesis" (Shechter 2000).

Life Extension suggests fasting glucose levels be kept between 70–85 mg/dL to limit glucose-induced platelet aggregation and to promote optimal overall health.

  • Excess abdominal body fat. Abdominal obesity, also known as android obesity, consists of excessive deposition of fat tissue around the trunk of the body (e.g. the belly). The fatty tissue around the trunk is prone to secrete inflammatory chemicals and cause high blood sugar and hypertension, all factors that pose dire risk to the health of the endothelial cells. Maintaining an ideal body weight is critical to reducing thrombosis risk.
  • Elevated homocysteine has been associated with a 60% increase in venous thrombosis risk for each 5 µmol/L increase in concentration (den Heijer 2005). Homocysteine damages the endothelium, increases endothelial cell and platelet activation, and lowers fibrinolytic (clot breakdown) activity (Di Minno 2010). Life Extension recommends keeping homocysteine levels below 7-8 µmol/L for optimal health (Table 2); guidelines for doing so are discussed in the Homocysteine Reduction protocol.
  • History of stroke, transient ischemic attack, heart attack, or coronary artery disease all indicate a susceptibility to arterial thrombosis and are among the strongest predictors of future thrombotic events.

*Note: In addition to these factors listed above, additional discussion of risk factors that compromise endothelial health (and therefore increase risk for thrombosis) can be found in the Life Extension Magazine article entitled "How to Circumvent 17 Independent Heart Attack Risk Factors".

Interrupted blood flow stimulates thrombosis by allowing the localized accumulation of circulating platelets and clotting factors and by increasing the probability of clotting reactions. Risk factors include:

  • Sedentary behavior, either as inactive lifestyle, or due to extended immobilization such as during hospitalization or long-distance travel (Lippi 2009). According to the CDC, adults aged 18+ should engage in at least 2.5 hours of moderate intensity aerobic exercise each week, and full-body strength training at least twice a week. Even greater health benefits are available through 5 hours of moderate-intensity aerobic exercise each week combined with full-body strength training two or more days a week.
  • Surgeries of the lower extremities (hip, knee, ankle) increase thrombosis risk either due to trauma to the veins during surgical manipulation, or immobilization during recovery (Stamatakis 1977). Without treatment, the incidence of deep vein thrombosis following total hip or total knee replacement surgery is as high as 40­–60% (Baser 2011).
  • Atrial fibrillation, the most common type of abnormal heart rhythm, can lead to blood pooling in the heart and subsequent clot formation in the left atrium, increasing stroke risk 5-fold (Xue 2010).

Hypercoagulable states (sometimes called thrombophilias) are conditions in which the nature or composition of the blood encourages coagulation. Some hypercoagulable states are inherited disorders that increase the activity of clotting factors or reduce the activity of natural anticoagulants. Some of the more common non-genetic hypercoagulable states include:

  • Thyroid disorders, which alter the balance of clotting factors and anticoagulants and can increase the risk of thrombosis. Hyperthyroidism (high thyroid function) increases the risk of thrombosis due to disruption of the clotting process, such as increased production of clotting factors, increased thrombin activity, and reduced rate of fibrinolysis (clot breakdown) (Erem 2011). Hyperthyroidism also can increase blood volume, which can lead to high blood pressure and cardiac arrhythmias, both of which are risk factors for thrombosis (Franchini 2006). In hyperthyroid patients, the incidence of arterial thrombosis, especially cerebral thrombosis, is between 8 and 10% (Burggraaf 2001). Hypothyroidism (low thyroid function) also increases the risk of thrombosis. Hypothyroid patients cannot clear clotting factors from the blood as quickly, have elevated levels of fibrinogen, and have reduced rates of fibrinolysis (Erem 2003).
  • Elevated plasma fibrinogen, the main coagulation protein, which may result from a variety of conditions such as smoking, thyroid disorders, or infection (Folsom 1995). A comprehensive review of observational studies estimated that a 98 mg/dL reduction in fibrinogen concentration would lead to a relative risk reduction of 80% in coronary heart disease (Folsom 1995).
  • Pregnancy, which shifts the balance of hemostatic factors towards coagulation and enhances the activation of platelets, especially in pre-eclampsia (preganacy-associated hypertension), which may affect 2–4% of pregnancies (de Maat 2011).
  • Cancer, which can increase risk of venous thrombosis 4- to 7-fold, especially in metastatic cancers or those where the infiltration of tumors or compression of blood vessels disrupt blood flow (Streiff 2011). Pancreatic, brain, and gastric cancers especially increase the risk of thrombosis (Streiff 2011).

Blood clots may be predictive of cancer risk as well. In a case-control study involving nearly 60,000 patients, the likelihood of developing any cancer within 6 months of diagnosis of venous thromboembolism (VTE) was 420% higher than that of the general population (Murchison 2004). Particularly, cancer of the ovary was more than 700% more likely, while non-Hodgkins lymphoma and Hodgkins disease were 500–600% more likely within a year of VTE.

Tumors exert a number of pro-thrombotic effects on the blood, as does chemotherapy itself (Kirwan 2003). Unfortunately, once cancer has progressed sufficiently to cause a blood clot, it is usually in an advanced stage, and the survival rate of patients diagnosed with cancer within one year of VTE is poor (Sorensen 2000).

Alarmingly, the close link between cancer and thrombogenesis appears to be underappreciated by conventional physicians. A small survey of oncologists revealed that 27% believed cancer patients were not at increased risk for clotting (Kirwan 2003). Similarly, another survey found that the majority of oncologists utilize thromboprophylaxis in cancer patients very rarely, despite the fact that VTE is a leading cause of death in this population (Kakkar 2003).

Additional risk factors include age, female sex, smoking, and obesity; additionally, surgery can increase thrombosis risk.

Table 2 shows the standard reference ranges and optimal levels recommended by Life Extension for blood parameters associated with risk of thrombosis or its complications.

Table 2. Recommended Blood Values and Pressure to Reduce Thrombosis Risk*
Blood Test Standard Reference Range Optimal
Total cholesterol 100-199 mg/dL 160-180 mg/dL
LDL cholesterol 0-99 mg/dL under 70-100 mg/dL
HDL cholesterol over 39 mg/dL over 50-60 mg/dL
Fasting Triglycerides 0-149 mg/dL under 80 mg/dL
Fasting Glucose 65-99 mg/dL 70-85 mg/dL
Homocysteine 0-15 µmol/L under 7-8 µmol/L
Fibrinogen 150-450 mg/dL 295-369 mg/dL
TSH 0.45-4.5 μIU/mL 1.0-2.0 μIU/mL
CRP 0-3.0 mg/L Men: under 0.55 mg/L
Women: under 1.0 mg/L
Blood Pressure Hypertension: over 139/89 mmHg 115 /75 mmHg
(Chobanian 2003)

*TSH=thyroid-stimulating hormone; LDL=low-density lipoprotein; HDL=high-density lipoprotein; CRP=C-reactive protein; μU/dL=microunits per deciliter; mg/dL=milligrams per deciliter; µmol/L=micromoles per liter; mg/L=milligrams per liter; mmHg: millimeters of mercury.

Blood Clotting Mechanisms

Hemostasis, a process that maintains the blood in a free-flowing state and helps stop bleeding during injury, is critical for survival. Blood clotting or coagulation is necessary to repair not only large injuries to blood vessels, but also the thousands of microscopic internal tears that happen daily under normal circumstances. Without a proper hemostatic response, the smallest of vessel injuries would lead to fatal hemorrhage (bleeding).

However, if the intricate balance among hemostatic mechanisms is disturbed, the tendency for a clot to become pathologic dramatically increases. The steps below briefly outline key aspects of the clotting process. This list also highlights points at which some drugs and natural compounds can combat derangement of the clotting system and offset thrombosis risk.

Normal blood clotting is a complex process, consisting of three major phases: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a clot that seals the hole until tissue repair occurs.

The following four steps summarize clot formation, and also highlight key areas that pharmaceutical drugs and some natural compounds target in order to impede clotting:

  1. Vasoconstriction: Endothelial damage occurs, leading to neurogenic vessel constriction and decreased blood flow near the site of injury. This creates a local environment that favors clotting. Examples of injuries that may initiate the clotting process include rupture of an atherosclerotic plaque, or homocysteine-induced endothelial damage.
    1. Damage to the endothelium liberates sub-endothelial collagen and tissue factor (factor III), which initiate the intrinsic and extrinsic clotting pathways, respectively, in the immediate area (details in "secondary hemostasis" below).
      • Intervention: Polyphenolic antioxidants, such as punicalagins from pomegranate, oligomeric procyanidins from grape seed, and trans-resveratrol, protect endothelial cells against injury and help maintain flexibility of blood vessels.

Primary hemostasis

  1. Platelet adhesion and activation
    1. As circulating platelets pass by the site of vessel wall injury, receptors on their surfaces bind to exposed collagen and membrane proteins on activated endothelial cells, causing adhesion of platelets at and around the site of injury. This adhesion is mediated by von Willebrand factor and P-selectin.
      • Intervention: Curcumin, a bioactive compound derived from the spice turmeric, acts to suppress P-selectin expression and limits platelet adhesion by this mechanism (Vachharajani 2010).
    2. Binding of the surface receptors leads to several molecular events that "activate" the platelets, causing release of adenosine diphosphate (ADP) from secretory granules within the platelet.
      • Intervention: Bioactive compounds in garlic work to suppress platelet granule release (Mousa 2010).
    3. ADP binds to surface receptors called P2Y1 and P2Y12 on nearby platelets. This binding causes increased synthesis of thromboxane A2 (TXA2) via conversion of the inflammatory omega-6 fatty acid arachidonic acid by the enzyme cyclooxygenase-1 (COX-1).
      • Intervention: Aspirin inhibits the activity of COX-1 for the entire lifespan of the platelet, which is about 7–10 days.
      • Intervention: The omega-3 fatty acids EPA and DHA from fish oil counteract the synthesis of TXA2 by competing with omega-6 fatty acids as substrates for the COX enzyme (Tapiero 2002).
    4. Binding of P2Y1 and P2Y12 by ADP also causes the expression of another surface receptor, called glycoprotein IIb/IIIa (GPIIb/IIIa). The significance of GPIIb/IIIa will be examined in the "platelet aggregation" section below.
      • Intervention: The "blood thinning" drugs Plavix® (clopidogrel) and Ticlid® (ticlopidine) block ADP from binding to the P2Y12 receptor for the entire lifespan of the platelet, which is about 7–10 days. The drug Effient® (prasugrel) is a reversible inhibitor of P2Y12; its effects last about 5–9 days.
    5. Additional factors, including newly synthesized thromboxane A2, increase expression of the surface receptor GPIIb/IIIa as well.
    6. This process of platelet activation is self-propagating among platelets that happen to be near each other, and near the site of blood vessel wall injury.
  1. Platelet aggregation
    1. Following the activation of platelets as described above, the expressed GPIIb/IIIa surface receptors bind a circulating protein called fibrinogen, which comprises about 4% of total blood protein.
      • Intervention: The B-vitamin niacin, which is well known for being heart-healthy, exerts some of its cardioprotective actions by lowering plasma fibrinogen levels, thus attenuating the proclivity for platelets to aggregate and form a clot (Philipp 1998; Johansson 1997).
      • Intervention: Vitamin C also appears to lower plasma fibrinogen levels, as suggested by some clinical trials and epidemiological studies (Khaw 1995; Wannamethee 2006).
    2. Fibrinogen can bind GPIIb/IIIa receptors on adjacent platelets, linking them together in a process known as platelet aggregation.
      • Intervention: Tomato bioactives inhibit the function of GPIIb/IIIa, thereby blocking platelets from 1) binding circulating fibrinogen, and 2) binding to each other (O'kennedy 2006).
    3. A circulating protein called apolipoprotein A-IV (apo a-IV) has recently been found to bind GPIIb/IIIa receptors on platelets. This reduces the receptors’ ability to interact with fibrinogen and inhibits platelet aggregation. ApoA-IV levels were also discovered to have a circadian rhythm, peaking at midnight and dropping to their lowest at 6AM—the time of day when we are most vulnerable to cardiac events related to blood clots (Xu 2018).
      • Intervention: Replacing saturated fats with monounsaturated and polyunsaturated fats increases blood levels of apoA-IV (Kratz 2003). Olive oil is a good source of apoA-IV-elevating monounsaturated fats (Pedret 2015).
    4. In a matter of seconds after vessel wall damage, platelet adhesion, activation, and aggregation culminate in the formation of a platelet plug, temporarily sealing off the injury.

Secondary hemostasis

  1. Coagulation: Simultaneously to the formation of the platelet plug, tissue factor and collagen that were liberated upon vessel wall injury initiate two separate but related coagulation pathways.
    1. Collagen interacts with factor XII to initiate the intrinsic coagulation cascade.
    2. Concurrently, tissue factor interacts with factor VII to initiate the extrinsic coagulation cascade.
    3. Both the intrinsic and extrinsic pathways converge into the common pathway, which, through a complex series of interactions, converts prothrombin (factor II) into an enzyme called thrombin. This process is locally self-propagating via a process known as amplification, in which thrombin feeds back into the intrinsic pathway to drive further conversion of prothrombin.
    4. Thrombin then acts upon circulating fibrinogen to convert it into fibrin.
      • Intervention: Heparin is a naturally occurring anticoagulant that enhances the action of antithrombin, a glycoprotein that suppresses the ability of thrombin to convert fibrinogen to fibrin, thus slowing the coagulation process. Heparin is helpful when administered during medical emergencies involving atrial fibrillation and deep-vein thrombosis (DVT).

      Rarely, some individuals develop a condition called heparin-induced thrombycytopenia (HIT) after receiving heparin. This is due to genetic differences in the immune response of these patients. Patients who develop HIT can be treated more safely with a new heparin alternative called fondaparinux.

      • Intervention: Dabigatran (Pradaxa®) is a direct thrombin inhibitor. Dabigatran directly inhibits the action of thrombin, preventing it from converting fibrinogen to fibrin.
    1. Individual fibrin particles associate with one another to form polymers, which themselves associate into a web-like gel that traps circulating white blood cells, red blood cells, and additional platelets.
      • The widely used anticoagulant drug warfarin (Coumadin®) interferes in several steps along both the intrinsic and extrinsic coagulation pathways by inhibiting the activity of vitamin K.
      • Vitamin K is required for activation of a number of factors (II, VII, IX, X, protein C, and protein S) involved in coagulation. Vitamin K facilitates carboxylation reactions required to activate these coagulation factors. After vitamin K successfully "carboxylates" a coagulation factor, it transitions to a less active form. In order for vitamin K to carboxylate additional coagulation factors, it must be recycled into its active form; this is accomplished by an enzyme called vitamin K epoxide reductase. Warfarin inhibits vitamin K epoxide reductase and impairs the recycling of vitamin K, thus slowing activation of factors required for coagulation.
    1. The fibrin gel and included blood cells and platelets then fuse with the platelet plug to reinforce the injury and completely seal it off until tissue repair can begin.


After clotting and coagulation is complete (usually between 3–6 minutes after injury), the trapped platelets within the clot begin to retract. This causes the clot to shrink, and pulls the edges of the injury closer together, squeezing out any excess clotting factors. Then the process of vessel repair can begin. Once healing is complete, the unneeded clot is dissolved and removed by a process called fibrinolysis.

Fibrinolysis involves the cleavage ("cutting") of the fibrin mesh by the enzyme plasmin to release the trapped blood cells and platelets, allowing the clot to "dissolve."

    1. An enzyme called tissue plasminogen activator (TPA) converts the inactive protein plasminogen into the active plasmin, which then cleaves the fibrin web.
      • Intervention: In some medical emergencies involving an embolic event, such as embolic stroke, pulmonary embolism, and myocardial infarction (heart attack), TPA can be administered intravenously to dissolve the blood clot and improve clinical outcome. TPA should be administered as soon as possible after an embolic event for maximum benefit.
      • Intervention: Nattokinase, a fermentation product from soy, is an enzyme that has been shown to increase the fibrinolytic activity of plasma in laboratory studies (Fujita 1995).

Regulation of Coagulation during Healthy Conditions

In the absence of a blood vessel injury, platelet activation and coagulation cascades must be kept in check or the risk for thrombotic disease increases. Several factors disable blood clotting when it is not needed:

Protein C and Protein S – These proteins associate with another protein called thrombomodulin, produced by healthy endothelial cells, to form a complex that blocks the activation of factor V and hence the conversion of prothrombin to thrombin.

  • Interestingly, the action of the protein C/S complex depends upon vitamin K. Therefore, vitamin K is not only critical for optimal coagulation when blood vessel injury has occurred, but it is also needed to limit the formation of thrombi during healthy conditions. Adequate vitamin K intake is paramount in ensuring hemostatic balance at all times.

Antithrombin – The liver produces this small protein and it is found in relatively high concentrations in blood plasma. It inhibits the activation of several coagulation factors and remains constantly active to limit thrombotic disease risk. When clotting is needed to repair an injury, the coagulation cascade initiated by the exposure of collagen and tissue factor overwhelms antithrombin and clotting is able to proceed.

As noted above, the anticoagulant heparin dramatically increases antithrombin activity. When administered intravenously, heparin can cause the anticoagulatory tendency of antithrombin to inhibit the clotting cascade, thus slowing clot formation.

Tissue Factor Pathway Inhibitor – This polypeptide blunts the ability of the extrinsic pathway to activate thrombin under healthy conditions. However, as with antithrombin, vessel wall injury overwhelms this coagulation inhibitor by liberating large amounts of tissue factor, allowing coagulation to proceed.

Plasmin – Healthy endothelial cells secrete tissue plasminogen activator, an enzyme that converts plasminogen into plasmin. Plasmin breaks down the fibrin web that holds clots together. Therefore, plasmin is constantly contributing to fibrinolysis by breaking down any clots that are not needed.

Prostacyclin (PGI2) – This fatty acid derivative is produced by healthy endothelial cells and by platelets via the action of the cyclooxygenase-2 enzyme. PGI2 counteracts the action of thromboxane A2, thereby suppressing platelet activation during healthy conditions. PGI2 also acts as a vasodilator to help maintain free blood flow during healthy conditions.

Nitric Oxide (NO) – NO is a signaling molecule involved in a vast array of biochemical functions. During healthy conditions, the endothelium produces NO via an enzyme called endothelial nitric oxide synthase (eNOS). eNOS contributes to vasodilation, thus reducing the risk of thrombosis.

Conventional Therapies for Blood Clots and Thrombosis Risk Reduction

Two classes of pharmaceutical drugs reduce the risk of thrombosis and its complications, antiplatelet drugs and anticoagulants. Reserved for emergency situations, a third class called thrombolytics/ fibrinolytics break up blood clots and limit tissue damage; tissue plasminogen activator (Activase®) and urokinase (Abbokinase) are two examples.

Antiplatelet drugs

Antiplatelet drugs inhibit platelet activation and aggregation, an early step in the clotting process. Several classes of antiplatelet drugs inhibit platelet aggregation and activation at a different point in platelet metabolism.

The most common antiplatelet drug is aspirin. It inhibits the enzyme cyclooxygenase (COX), which is responsible for synthesizing thromboxane A2 (Hall 2011). Thromboxane A2 is a factor secreted by platelets to recruit other platelets to the site of injury during the initial stages of the clotting process. The cyclooxygenase inhibitory effect of aspirin is permanent for the life of the platelet (about 7–10 days). Aspirin has been shown effective in preventing complications of several disorders, including hypertension, heart attack, and stroke (Patrono 2008). Importantly, ibuprofen can attenuate the COX inhibitory action of aspirin in platelets; therefore, if low-dose aspirin is being taken preventatively, ibuprofen for pain relief should be taken at least 8 hours apart from aspirin to ensure maximum effectiveness.

Interestingly, aspirin also inhibits the COX enzyme in endothelial cells, but does not exert an irreversible action here. Unlike platelets, endothelial cells contain DNA and RNA and can therefore synthesize new COX enzymes even after aspirin has bound to existing COX enzymes. This dichotomy of aspirin action in platelets versus endothelial cells is significant because the COX enzyme is critical for the synthesis of the anti-platelet, vasodilatory compound prostacyclin (PGI2). Healthy endothelial cells secrete prostacyclin to counteract the action of TXA2 and ensure that a clot does not continue to grow and occlude the blood vessel.

The difference between endothelial cell biology and platelet biology also explains why low-dose aspirin is cardioprotective. Low-dose aspirin does not impair endothelial secretion of prostacyclin because these cells quickly synthesize new COX enzymes and overwhelm low concentrations of aspirin. However, platelets do not synthesize new COX so that aspirin, even in low concentrations, suppresses platelet-derived TXA2 until new platelets arise from the bone marrow. Thus, low-dose aspirin is effective for reducing the risk of pathologic clot formation while maintaining optimal endothelial function.

Aspirin's inhibition of COX also helps explain its potential in cancer reduction as observed in several studies (Rothwell 2011; Rothwell 2010; Salinas 2010; Flossmann 2007). Several types of cancers (particularly breast, prostate, and colon) overproduce the pro-inflammatory enzyme COX-2, which appears to play a role in increasing the proliferation of mutated cells, tumor formation, tumor invasion, and metastasis (reviewed in Cerella 2010; Sobolewski 2010). COX-2 may also contribute to drug resistance in some cancers, and its expression in cancer has been correlated with a poor prognosis (Sobolewski 2010).

A second group of commonly prescribed antiplatelet drugs, including clopidogrel (Plavix™), prasugrel (Effient™), and ticagrelor (Brilinta™), are characterized by their ability to bind to the surface of platelets and block the P2Y12 ADP receptor, inhibiting the platelet from becoming activated. Clopidogrel, the most widely prescribed antiplatelet, is more effective than aspirin in its ability to reduce the aggregation of platelets (CAPRIE Steering Committee 1996). Clopidogrel activity can be enhanced when combined with aspirin (Becker 2008), and this combination has been tested for its efficacy, safety, and cost effectiveness for a variety of clinical applications. In some cases, the combination represents a significant improvement over clopidogrel alone.

In patients with acute coronary syndrome, the CURE trial (Clopidogrel in Unstable angina to prevent Recurrent Events) demonstrated that combining clopidogrel and aspirin resulted in a 20% reduction in risk of cardiovascular death, heart attack, or stroke, as compared to aspirin alone after a one year follow up. However, those in the clopidogrel group had an increased risk of bleeding (Yusuf 2001). Similar results were also observed in the COMMIT trial (Clopidogrel and Metoprolol in Myocardial Infarction Trial), in which short-term combination therapy (4 weeks) lowered risk of heart attack, stroke, and death in patients with a previous heart attack (9% risk reduction) (Chen 2005). In both trials the benefits of the combination therapy outweighed the moderate cost increase in treatment. However, for other applications, such as prevention of heart attack in high-risk individuals without established cardiovascular disease, or in the treatment of stable coronary artery disease, treatment with aspirin alone has proven safer and more cost effective than combination therapy (Bhatt 2006; Arnold 2011).

Other clinically important oral antiplatelets include dipyridamole (Persatine™) and cilostazol (Pletal™), which are platelet phosphodiesterase inhibitors. These drugs are used less frequently as large-scale clinical trials have not proved them to be more effective than aspirin and Plavix®.


Anticoagulants inhibit the transformation of fibrinogen into fibrin, one of the last steps in the clotting process that stabilizes a thrombus.

Warfarin has a lengthy list of interactions that can increase the risk of bleeding (hemorrhage). More than 205 pharmaceutical, nutritional, and herbal medicine interactions have been identified for warfarin. Some medications that can potentially interact with warfarin include aspirin, cimetidine, lovastatin, thyroid hormones, and oral contraceptives. Foods and nutritional ingredients such as onions, garlic, ginger, CoQ10, fatty fish, and vitamin E have been reported to increase the risk of bleeding when combined with warfarin; however, many of these reports are anecdotal and may not represent significant concerns (Ulbricht 2008; Shalansky 2007). Many nutritional ingredients that "thin the blood" do so by different mechanisms than warfarin. For instance, rather than interfering with coagulation they may inhibit platelet aggregation, a different step in blood clot formation.

While it is prudent to follow a conservative approach regarding warfarin's potential for interaction with a variety of pharmaceutical and nutritional agents, being overly cautious may cause potential cardiovascular health benefits to go unrealized.

In fact, warfarin combined with conventional antiplatelet drugs has been studied already in patients at high-risk for thrombosis (Vedovati 2010). Additional evidence suggests warfarin can be combined safely with antiplatelet nutrients, such as garlic (Macan 2006), as long as one takes these nutrients responsibly. The most important considerations for individuals who wish to take this approach are monitoring and awareness; patients must work closely with their healthcare practitioner and undergo regular blood testing to measure coagulant activity (see "Testing Clotting Function" below).

For over fifty years, vitamin K antagonists like warfarin (Coumadin) were the only orally bioavailable anticoagulant drugs; aspirin is not an anticoagulant drug, but rather reduces the ability of platelets to stick together in primary hemostasis. However, use of vitamin K antagonists like warfarin in patients has been plagued by problems.

Warfarin treatment risks multiple medication (and food) interactions, the problem of variable pharmacologic effect, a narrow, brittle therapeutic index, and a relatively slow onset of action, all of which serve to place patients at risk. 

For example, an underappreciated analysis showed that 44% of bleeding complications with warfarin occurred in patients anticoagulated excessively with the drug, and 48% of clotting events (thromboembolic) occurred in patients anticoagulated inadequately with the drug (Oake 2007). 

However, over the past several years, many novel, orally bioavailable anticoagulant drugs have become available in the United States.

These new medications target critical anticoagulant factors like factor X and thrombin (factor IIa). These novel, oral anticoagulant drugs include dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis).


Dabigatran (Pradaxa), a direct thrombin inhibitor, is approved in the United States for use in the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation, treatment of deep venous thrombosis and pulmonary embolism, and to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism.

  • The RE-COVER study in patients with acute venous thromboembolism showed (Schulman 2009):
    • The 6-month incidence of recurrent symptomatic venous thromboembolism and related deaths was similar, 2.4% (2.3% venous thromboembolism; 0.1% deaths) in patients treated with dabigatran versus 2.1% (1.9% venous thromboembolism; 0.2% deaths) in those treated with warfarin;
    • The rates of major bleeding episodes were similar in the dabigatran and warfarin groups (1.6% vs. 1.9%, respectively). However, the incidence of all bleeding events was lower with dabigatran (16.1%) than warfarin (21.9%).
  • The RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy, Warfarin, compared with Dabigatran) study in patients with non-valvular atrial fibrillation and at risk of thromboembolism showed (Wallentin 2010):
    • Stroke (including hemorrhagic stroke) rate per year was lower with a 150 mg dabigatran dose (1.11%) and statistically equivalent with a 110 mg dabigatran dose (1.53%) compared with warfarin (1.69%);
    • The rate of major bleeding with a 150 mg dabigatran dose was not different (3.11%; P=0.31) compared with warfarin (3.36%) but was lower with a 110 mg dose (2.71%; P=0.003); the rates of hemorrhagic stroke with the 110 and 150 mg dabigatran doses were lower than with warfarin (0.12% and 0.10% vs. 0.38%; P<0.001), as were the rates of intracranial hemorrhage (0.23% and 0.30% vs. 0.74%; P<0.001).
  • An analysis of seven trials involving over 30 000 patients, including two studies of stroke prophylaxis in atrial fibrillation, one in acute venous thromboembolism, one in acute coronary syndrome, and three of short-term prophylaxis of deep venous thrombosis showed (Uchino 2012):
    • Dabigatran was significantly associated with a higher risk of myocardial infarction or acute coronary syndrome (dabigatran [1.19%] vs. control [0.79%]; P=0.03);
    • The risk of myocardial infarction or acute coronary syndrome was similar when using revised criteria to include exclusion of short-term trials and was consistent using different methods and measures of association.


A factor Xa inhibitor, rivaroxaban (Xarelto) is approved in the United States for reducing stroke risk in non-valvular atrial fibrillation, treatment of deep venous thrombosis and pulmonary embolism as well as reduction in risk of recurrence of deep venous thrombosis and pulmonary embolism, and prophylaxis of deep venous thrombosis after knee replacement and hip replacement surgery.

  • The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study evaluated rivaroxaban for prevention of stroke or embolization in patients with non-valvular atrial fibrillation at risk of stroke, and showed (Patel 2011; Fox 2011):
    • Rivaroxaban was similar to warfarin for risk of stroke and embolism (2.1% vs. 2.4% per year);
    • Similar rates were observed between patients taking rivaroxaban and those taking warfarin in terms of all bleeding events (14.9% vs. 14.5% per 100 patient-years) and major bleeding events (3.6% vs. 3.4% per 100 patient-years).
      • In addition, the rates of intracranial hemorrhage and fatal bleeding were less with rivaroxaban therapy (0.4% vs. 0.8%, P=0.003 and 0.5% vs. 0.7%, P=0.02, respectively).
  • The EINSTEIN study compared oral rivaroxaban to traditional therapy with low molecular weight heparin (enoxaparin) and a vitamin K antagonist in patients with acute, symptomatic deep venous thrombosis (Bauersachs 2010) and showed:
    • Rivaroxaban therapy was similar (non-inferiority test) to enoxaparin/vitamin K antagonist therapy with respect to recurrent venous thromboembolism (2.1% vs. 3.0%; P<.001)
    • The principal safety outcome of major or clinically relevant non-major bleeding occurred at similar rates in both treatment arms (dabigatran vs. enoxaparin/vitamin K antagonist).


Apixaban (Eliquis), an inhibitor of free and clot-bound factor Xa as well as prothrombinase activity, is approved in the United States for the treatment of deep venous thrombosis and pulmonary embolism; reduction in risk of recurrent deep venous thrombosis and pulmonary embolism following initial therapy; reduction in risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation; and prophylaxis of deep venous thrombosis, which may lead to pulmonary embolism, in patients who have undergone hip or knee replacement surgery.

  • The Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) trial evaluated the efficacy and safety of different doses of apixaban compared with placebo in patients with a recent venous thromboembolism who completed prior anticoagulation therapy and showed (Agnelli 2013):
    • The incidence of recurrent venous thromboembolism and venous thromboembolism-related mortality was 1.7% in both apixaban dose groups compared with 8.8% in the placebo group (P<0.001);
    • The rates of major bleeding were similar across the treatment groups (2.5 mg of apixaban: 0.2%; 5 mg of apixaban: 0.1%; placebo: 0.5%).
  • The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial compared apixaban with the vitamin K antagonist warfarin in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke and showed (Granger 2011):
    • Compared with warfarin, apixaban therapy was better in preventing stroke or embolism (1.27% vs. 1.60% per year; P<0.001 for non-inferiority and P=0.01 for superiority);
    • The rate of major bleeding per year with apixaban was better (2.1%) than with warfarin (3.1%) (P<0.001).

At the time of this writing, a fourth oral anticoagulant, edoxaban (Savaysa), has been submitted for regulatory approval, and although in October 2014 the FDA advisory panel voted overwhelmingly in favor of this oral anticoagulant for the treatment of patients with atrial fibrillation (Daiichi Sankyo 2014), this drug is not yet approved for this indication in the United States.

Be aware that although there appear to be a variety of advantages associated with the new oral anticoagulants in comparison with warfarin, there is also controversy.

For example, many of the studies submitted for FDA approval with the new oral anticoagulants utilized so-called non-inferiority designs and statistical tests in order to show that the newer drugs are at least as good as the vitamin K antagonist warfarin in reducing the risk of thromboembolic events as well as supporting safety, in particular in the context of major bleeding like intracranial hemorrhage. However, one criticism of non-inferiority test suggests that the relative benefits of these newer drugs versus warfarin has been overstated (given the limitations of the trial designs).

Also, although some outcomes may “appear” better (or safer) with specific new anticoagulants, the patient populations are similar, but not the same (nor are the trial designs), and the idea that one agent is necessarily better than another at the current time is not supportable. However, one (dabigatran) of the new oral agents has a potential safety signal – though very controversial at the current time, some data suggest an increase in heart attack and acute coronary syndrome in some patients with the use of this new drug (Daiichi Sankyo 2014).

General advantages of the new oral anticoagulants (compared with warfarin)

  • More rapid onset of action;
  • No need for frequent blood test monitoring;
  • Far more predictable, consistent pharmacologic effects;
  • Dramatically reduced drug-drug and drug-food interactions;
  • Similar (or better) short-term efficacy for reduction of clotting events (thromboembolism);
  • Similar (or improved) short-term safety (eg, major bleeding risk).

General disadvantages of the new oral anticoagulants

  • High(er) cost relative to warfarin;
  • No specific antidote to counteract bleeding (in contrast to high-dose vitamin K to reverse warfarin’s effects), though protein C concentrate has been used;
  • Lack of long-term safety data and adequate data to support use in pregnancy, patients with mechanical heart valves, and patients with severe kidney disease;
  • Potential safety signal observed with at least one of the new drugs (dabigatran), suggesting an increase in heart attack and acute coronary syndrome risk in at least some vulnerable patients (Uchino 2012)

Metformin and Blood Clot Prevention

Blood clots in atherosclerotic vessels are the leading cause of death in people with diabetes (Hess 2011). Metformin, a medication used to treat diabetes, has been demonstrated to reduce diabetes-related cardiovascular changes and disease, as well as deaths related to diabetes and to all causes (Batchuluun 2014; Triggle 2014; Fung 2015; Anfossi 2010; Lu 2014).

Emerging research indicates that metformin’s cardiovascular benefits may be related to an antithrombotic action. In a study in experimentally-activated platelets, treatment with metformin preserved mitochondrial function, decreased free radical production, and reduced platelet activation and aggregation. This effect was confirmed in normal and diabetic laboratory animals, in which metformin treatment prevented platelet-induced blood clots in arteries and veins. Importantly, metformin was not associated with any increase in bleeding time, spontaneous bleeding, or gastric ulcer (Xin 2016).

Early research in humans supports a role for metformin in improving platelet function and preventing blood clots. A study that compared diabetic subjects taking metformin to medically similar individuals not using metformin found metformin use was associated with a lower risk of deep vein thrombosis (DVT) (Lu 2014). Metformin use has been associated with a lower mortality rate in patients with diabetes and related tendency to thrombosis (Roussel 2010). In patients with polycystic ovarian syndrome and related insulin resistance, metformin use was associated with improved mitochondrial function and reduced platelet reactivity (Randriamboavonjy 2015). Another study found diabetic patients treated with metformin had lower platelet production of a free radical called superoxide anion than those treated with other glucose-lowering medications, and their platelet superoxide production was similar to that seen in healthy subjects (Gargiulo 2002).

Vitamin K and Warfarin

Besides its dualistic role in coagulation (recall that the coagulation factors II, VII, IX, and X are vitamin K-dependent, but so are the anti-thrombotic factors protein C and S), vitamin K is central to bone and vascular health as well. Just as several coagulation factors must undergo vitamin K-dependent carboxylation before they become active, a number of proteins involved in bone formation and stability require this same activation; warfarin can disable these proteins too, leading to compromised bone integrity. Moreover, a protein in blood vessels, matrix GLA protein, works to keep blood vessels flexible by inhibiting calcification of vascular cells (e.g. "hardening" of the arteries). Matrix GLA protein must also be carboxylated by vitamin K to function properly; thus, vitamin K epoxide reductase inhibition can compromise vascular elasticity.

Tragically, there is poor appreciation within mainstream medicine for enhanced risk of conditions associated with vitamin K antagonist treatment, including vascular calcification (Schurgers 2004), lower bone mineral density (Rezaieyazdi 2009), and osteoporotic fracture (Gage 2006).

Many conventional physicians have been reluctant to supplement a warfarin regimen with low dose vitamin K in order to stabilize coagulation time and guard against long-term detriments associated with vitamin K antagonist therapy. Peer-reviewed scientific literature indicates that this strategy can decrease dangerous fluctuations in coagulant status during warfarin treatment (as measured by wide variations in prothrombin time [PT] standardized for the international normalized ratio [INR]) (Sconce 2005; Couris 2006).

There are several potential reasons for fluctuating INR values during warfarin treatment, including genetic polymorphisms in vitamin K-related genes, interactions with other drugs, and dietary vitamin K intake (Lurie 2010). Unstable anticoagulation has been associated with diets low in vitamin K (Sconce 2005), and a strong association between variations in INR and highly variable vitamin K intake exist (Couris 2006). Consistent intake of a low dose of vitamin K, with appropriate adjustment of warfarin dosage, has been shown in several studies to stabilize INR values. This is likely due to maintenance of constant body stores of the vitamin and minimizing the effects of dietary fluctuations (Sconce 2007).

In a small, open-label crossover study, 9 patients (average age 50 years old) with a history of unstable INR received 500 mcg/day of vitamin K for 8 weeks. In 5 of the 9 patients, variability in INR decreased (as measured by the reduction in viability between INR measurements at several time-points) and achieved a therapeutic range within an average of 14 days. On average, warfarin doses were increased by 50% to achieve a stable INR value during the vitamin K supplementation (Ford 2007).

The amount of time that INR stays within a therapeutic range (called the TTR) is another measurement of INR variability. On average, patients on coumarin anticoagulant therapy only maintain their INR within the therapeutic range 50–60% of the time, despite careful monitoring (Reynolds 2004). Three studies have shown that combination therapy of vitamin K and coumarin anticoagulants can significantly increase TTR, especially in patients with unstable coagulation control. A small study by Sconce et al. (2007) compared two groups of 35 patients on warfarin therapy with fluctuating INR values receiving 150 mg vitamin K1 or a placebo daily for 6 months. Variability in the test group decreased at the end of the study compared to the control group, and the amount of time patients maintained their INR in the therapeutic range increased by 13%.

In a second study, two groups of 100 patients on a coumarin anticoagulant were assigned to receive either 100 mcg vitamin K1 or placebo. Unlike previous studies, however, this study was not limited to patients with unstable control of anticoagulation. Compared to the control group, patients receiving vitamin K showed a 3.6% increase in TTR (Rombouts 2007).

A larger study of 400 patients from two anticoagulation clinics were randomized to receive either a placebo or 100, 150, or 200 mcg of vitamin K once daily with their coumarin anticoagulant for a period between 6 and 12 months. Although this study also was not limited to patients with a history of unstable INR, the results showed that doses of 100 or 150 mcg increased the amount of time patients had an INR within the therapeutic range (by 2.1% and 2.7%), compared to the control group. Moreover, these patients had twice the chance of maintaining their INR within the therapeutic range for extended periods of time (Gebuis 2011).

Vitamin K supplementation in those taking warfarin should be conducted under careful supervision by a healthcare practitioner.

Heparin is a natural anticoagulant that stimulates the activity of antithrombin III and prevents the assembly of fibrinogen molecules into fibrin. Several heparin derivatives, including low-molecular-weight heparin, unfractionated heparin, and fondaparinux (a synthetic heparin derivative) are also clinically important. Heparin and its derivatives are given by injection (Mannucci 2011).

Other potential therapies currently being investigated make use of thrombolytic (clot-dissolving) agents. These include: the co-administration of a clot-dissolving thrombolytic drug and an anticoagulant (warfarin) for deep vein thrombosis treatment; directly infusing the thrombolytic drug tissue plasminogen activator (tPA) into clots in the brain (through a minimally invasive surgical technique) or clots in the leg (by injection) (Johnson 2011; Chang 2011); and the administration of red blood cells coated with tPA to patients, which increases the lifetime of the drug and reduces the likelihood that it will cause excess bleeding (Murciano 2003).

Testing Clotting Function

Several different lab tests assess clotting function. The appropriateness of each test depends on several variables (i.e. which type of "blood-thinning" medication the person is taking, if the person has any genetic predispositions to clotting dysfunction, etc.). A healthcare practitioner should help determine the test most appropriate in each situation.

Clot-based assays test the time it takes for a sample of blood plasma to clot. They are used to test the function of the latter stages of clotting (fibrin formation). Different types of clot-based assays exist to test for deficiencies in different parts of the coagulation cascade. (Recall there are three "pathways" involved in secondary hemostasis: intrinsic, extrinsic, and common pathways.)

Prothrombin time (PT test or PT/INR) measures the time (in seconds) it takes for a blood sample to clot after the addition of a platelet activator inhibitor and a clotting factor (tissue factor). The PT test is most often used to monitor coagulation status during warfarin therapy. This test is useful for assessing factor VII activity.

Due to variation in laboratory methodology, the results of this test are reported as the international normalized ratio (INR), which can correct for this variability. Conditions that affect coagulation (like vitamin K deficiency or warfarin use) prolong clotting time, while those that affect platelet activity (like taking aspirin) have no effect on the test.

A target INR range of 2.0 to 3.0 is typically recommended for individuals being treated with anticoagulant medication.

Because the PT test does not reveal antiplatelet activity, patients on combination warfarin/antiplatelet therapy with either antiplatelet drugs and/ or antiplatelet nutrients should undergo regular bleeding time tests (see below) and PT tests. By using these two tests in concert, a balanced program of conventional anticoagulant therapy plus antiplatelet drugs and/ or antiplatelet nutrients can be uniquely tailored to an individual.

Activated partial thromboplastin time (aPTT) is a related test that measures clotting in response to different clotting factors; specifically, the aPTT test does not measure factor VII activity (i.e. this test focuses on the intrinsic pathway). This test is typically used to measure the efficacy of heparin on clotting (heparin prolongs the aPTT time) but other anticoagulants can increase aPTT clotting time as well.

Platelet Function assays test the ability of platelets to become activated or aggregate, which occurs in the initial stages of the clotting process. They are less sensitive to the effects of coagulation factors. In other words, platelet function assays test primary hemostasis, while coagulation assays test secondary hemostasis.

The bleeding time test is a simple test in which blood pressure is maintained by use of a blood pressure cuff while small cuts or "pricks" are made on the fingertip or lower arm. The time for bleeding to stop (a measurement of platelet plug formation) is measured. A normal result is 1 to 9 minutes, depending on which method is used.

Light transmittance aggregometry (LTA) is a standard technique in which platelet-rich plasma is exposed to an aggregating agent (like collagen or ADP), and the clumping of platelets is measured by their ability to block the transmission of light. This technique can be used to monitor the efficacy of antiplatelet drugs, or can detect genetic platelet defects such as von Willebrand disease.

The Platelet Function Analyzer (PFA) is a relatively new instrument that measures the effect of an aggregating agent (collagen, ADP, or others) on platelet aggregation in conditions simulating arterial blood flow. As platelets flow through the instrument, they are forced through a small opening (simulating a vessel tear), and the time for a thrombus to form over the opening (called closure time) is reported. Some local labs typically offer this test, and those interested in having the PFA test should discuss it with their physicians.

Platelet count determines whether blood platelets fall within a healthy range, (about 150,000 to 400,000 platelets per μL) although it does not determine whether the platelets are functioning properly.

From (Samama 2011; Rechner 2011)