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Health Protocols

Blood Clot Prevention

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 section titled "secondary hemostasis").
      • 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.32
    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.33
    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.34
    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.
      • 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.
  2. 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.35,36
      • Intervention: Vitamin C also appears to lower plasma fibrinogen levels, as suggested by some clinical trials and epidemiological studies.37,38
    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.39
    3. 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 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.
    2. 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.40

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.