Blood Clot Prevention
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 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 A2.41 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.42 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 eight 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.43-46 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.47,48 COX-2 may also contribute to drug resistance in some cancers, and its expression in cancer has been correlated with a poor prognosis.48
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.49 Clopidogrel activity can be enhanced when combined with aspirin,50 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 (Clopidogrel in Unstable angina to prevent Recurrent Events) trial 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.51 Similar results were also observed in the COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) trial, in which short-term combination therapy (four weeks) lowered risk of heart attack, stroke, and death in patients with a previous heart attack (9% risk reduction).52 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.53,54
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, coenzyme Q10 (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.55,56 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.57 Additional evidence suggests warfarin can be combined safely with antiplatelet nutrients, such as garlic,58 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 section titled "Testing Clotting Function").
For over 50 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.59
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 showed60:
- 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 showed61:
- 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 showed62:
- 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 showed63,64:
- 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 thrombosis65 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 showed66:
- 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 showed67:
- 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 Food and Drug Administration (FDA) advisory panel voted overwhelmingly in favor of this oral anticoagulant for the treatment of patients with atrial fibrillation,68 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.68
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 patients62
Metformin and Blood Clot Prevention
Blood clots in atherosclerotic vessels are the leading cause of death in people with diabetes.69 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.70-74
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.75
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 DVT.74 Metformin use has been associated with a lower mortality rate in patients with diabetes and related tendency to thrombosis.76 In patients with polycystic ovarian syndrome and related insulin resistance, metformin use was associated with improved mitochondrial function and reduced platelet reactivity.77 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.78
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 (eg, "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,79 lower bone mineral density,80 and osteoporotic fracture.81
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]).82,83
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.84 Unstable anticoagulation has been associated with diets low in vitamin K,82 and a strong association between variations in INR and highly variable vitamin K intake exist.83 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.85
In a small, open-label crossover study, nine patients (average age 50 years old) with a history of unstable INR received 500 mcg/day of vitamin K for eight weeks. In five of the nine 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.86
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.87 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 compared two groups of 35 patients on warfarin therapy with fluctuating INR values receiving 150 mg vitamin K1 or a placebo daily for six 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%.85
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 with the control group, patients receiving vitamin K showed a 3.6% increase in TTR.88
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 six 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 mcg or 150 mcg increased the amount of time patients had an INR within the therapeutic range (by 2.1% and 2.7%, respectively), 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.89
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.1
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 DVT 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)90,91; 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.92
Testing Clotting Function93,94
Several different lab tests assess clotting function. The appropriateness of each test depends on several variables (ie, 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 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 (ie, 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.