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Thrombosis Prevention
Cancer Patients
In cancer patients, disorders related to blood clotting are frequently
observed. The biological processes leading to coagulation are probably
involved in the mechanisms of metastasis. About 50% of all cancer patients,
and up to 95% of those with metastatic disease, show some abnormalities
(a prethrombotic state) in the coagulation-fibrinolytic system. Thromboembolic
complications are seen in up to 11% of cancer patients, and hemorrhage
occurs in about 10%. Thromboembolism and hemorrhage, as a whole, are the
second most common cause of death after infection (Ambrus et al. 1975;
Lip et al. 2002).
In one study, subclinical changes in the coagulation-fibrinolytic system
were frequently detected in lung cancer patients. Five conventional tests
and a new standard of blood coagulation were prospectively recorded in
a series of 286 patients with new primary lung cancer: platelet count
(P); prothrombin time (PT); partial thromboplastin time (PTT); fibrinogen
(F); and d-dimer of fibrin (DD). A prethrombotic state--depicted by a
prolongation of PT, PTT, and increase of d-dimer of fibrin--was significantly
associated with an adverse outcome (van Wersch et al. 1991; Gabazza et
al. 1993; Buccheri et al. 1997).
Anticoagulant treatment of cancer patients, particularly those with
lung cancer, has been reported to improve survival. These interesting,
although preliminary, results of controlled trials lend some support to
the argument that activation of blood coagulation plays a role in the
natural history of tumor growth. Studies compared the effectiveness of
standard heparin with low molecular weight heparin (LMWH) in the treatment
of deep vein thrombosis (DVT). In both studies, mortality rates were lower
in the patients randomized to LMWH. The analysis of these deaths reveals
a striking difference in cancer-related mortality (Green et al. 1992;
Hull et al. 1992; Prandoni et al. 1992; Sciumbata et al. 1996; Hejna et
al. 1999).
Cancer-related mortality with standard heparin was 31% versus 11% with
low molecular weight heparin. This difference cannot solely be attributed
to thrombotic or bleeding events. Because large numbers of cancer patients
were included in the studies, it seems unlikely that there were more patients
with advanced tumors in the standard heparin group than in the low molecular
weight heparin group. Although it also is possible that standard heparin
increases cancer mortality, such an adverse effect has not been previously
reported. These considerations suggest that low molecular weight heparin
might exert an inhibitory effect on tumor growth (Collen et al. 2000;
von Tempelhoff et al. 2000; Mismetti et al. 2001; Prandoni 2001).
If your oncologist does not or will not test for thrombotic risk factors,
contact the Life Extension Foundation at (800) 544-4440.
CONVENTIONAL PREVENTION AND TREATMENT
Preventing thrombosis is essential. Inside a healthy circulatory system,
the body constantly prevents clotting. Coagulation/anticoagulation is
a "mechanism" that the body must maintain in perfect balance.
If this process fails, our lives can be in danger in a matter of minutes.
To function optimally, the body must keep blood flowing well in all
vessels, regardless of size. When a leak (or damage) occurs in an artery
or vein, the body must encourage the coagulation aspect of this balance
to seal the leak. However, when there is a significant disturbance or
a clot in the blood flow, the consequences are often lethal.
Because so many factors can contribute to coagulation and therefore
should be considered for prevention, it is difficult for conventional
medicine to control them all. Mainstream medicine can exert control on
some crucial steps in the coagulation cascade, but it may often fail to
influence them all.
PRESCRIPTION DRUGS
Several prescription drugs address different parts of the coagulation/anticoagulation
system:
- Coumadin (warfarin) inhibits the synthesis of vitamin K-dependent
coagulation factors such as Factors II, VII, IX and X and anticoagulant
proteins C and S.
- Aspirin inhibits platelet aggregation by interfering with thromboxane
synthesis.
- Ticlopidine (Ticlid) inhibits platelet aggregation by interfering
with the binding of fibrinogen to the platelet membrane. Ticlopidine
is a prescription drug that may be of particular value as an alternative
to aspirin. Ticlopidine is often considered in patients that have a
high risk of thrombotic stroke and are intolerant to aspirin.
- Heparin (administered intravenously) increases the activity of antithrombin
III, which prevents the conversion of fibrinogen to fibrin. Heparin
is not absorbed by the gastrointestinal (GI) tract and must be administered
intravenously. It is usually only used in emergency situations (e.g.,
after a stroke).
- Tissue plasminogen factor (t-PA) activates plasmin which breaks apart
fibrin. t-PA is used in emergency situations to dissolve blood clots.
Streptokinase is another tissue plasminogen factor drug. Both of these
drugs are administered intravenously in emergency thrombotic situations
(e.g., ischemic stroke or MI).
Platelet Aggregation Inhibitors (Platelet Anti-Aggregation Drugs)
Aspirin
More than any other medication, aspirin is used alone for the prevention
of recurrent strokes and transient ischemic attacks (TIAs). Aspirin acts
to inhibit blood clotting by reducing platelet aggregation (clumping),
thereby preventing the formation of platelet plugs. Aspirin inhibits cyclooxygenase,
which facilitates the production of thromboxane A2 (TA2). TA2 is a potent
inducer of platelet aggregation and vasoconstriction. In humans, platelet
cyclooxygenase can be completely inhibited with aspirin at doses as low
as 30 mg daily. A study compared the use of aspirin with warfarin in the
prevention of recurrent ischemic strokes: over a 2-year period, it was
found that aspirin, as well as warfarin, protected against stroke recurrence
and death (Mohr et al. 2001). Warfarin is prescribed for stroke recurrence
prevention in many patients who have had an ischemic stroke. Therefore,
aspirin is a reasonable, equally effective approach for some people, but
for persons with artificial heart valves and certain types of atrial fibrillation,
Coumadin has been shown to be more effective than aspirin in preventing
stroke (Hurlen et al. 2002).
Other Conventional Platelet Aggregation Inhibition Drugs
There are a number of other drugs that act as platelet aggregation inhibitors,
including dipyridamole, ticlopidine, and clopidogrel. As noted above,
aspirin can provide comparable platelet aggregation inhibition and related
risk reduction.
Anticoagulants
Coumarin Derivatives
Derivatives of Coumarin (e.g., generics warfarin and dicumarol) interfere
with the rate of synthesis of blood clotting factors II (prothrombin),
VII, IX, and X. As a result, prothrombin and partial thromboplastin times
are significantly altered by anticoagulants, but are not altered by antiplatelet
agents such as aspirin. Patients taking Coumarin derivatives are monitored
for PT and PTT times to optimize dosing and avoid excessive bleeding.
Coumadin (warfarin) is the most frequently prescribed drug for thrombosis
prophylaxis (prevention). It is an anticoagulant drug that was originally
isolated in 1939 from sweet clover. Interestingly, Coumadin is the active
ingredient found in many commercial rat poisons and insecticides. It works
by interfering with the synthesis of vitamin K-dependent coagulation factors.
Coumadin is used as a prophylaxis for myocardial infarction, stroke, arterial
thromboembolism, and deep venous thrombosis. It is also used in patients
with prosthetic heart valves.
Coumadin prolongs both PT and APTT, but PT is the one used to guide
treatment. However, the new standard is the International Normalization
Ratio (INR) which is described below. Bleeding is the primary adverse
effect of Coumadin therapy. Bleeding is related to the intensity of anticoagulation,
length of therapy, the patient's underlying clinical state, and the use
of other drugs that can affect blood coagulation or interfere with Coumadin
metabolism.
Minor bleeding from Coumadin therapy usually begins with ecchymoses
(purple patches on the skin). Then the mucous membranes are affected,
causing epistaxis (nosebleed) and subconjunctival hemorrhage (bleeding
under the mucous membranes covering the eyes and inner eyelids). Purple
toe syndrome is also associated with Coumadin therapy. Hematuria (blood
in the urine) may also occur. Major bleeding complications usually involve
gastrointestinal (GI) and intracranial bleeding.
Coumadin has an extremely long list of contraindications and drug interactions
(see the Cerebral Vascular Disease/Thrombotic Stroke protocol for a complete
list). Of particular concern is its use in elderly patients because they
are more susceptible to the effects of anticoagulants and have an increased
risk of hemorrhage. Several common drugs interact with Coumadin, including
acetominaphen, cimetidine, lovastatin, thyroid hormones, and estrogens
and oral contraceptives.
Caution: Do
not take aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), such
as ibuprofen (e.g., Motrin, Advil, Nuprin, etc.), ketop (e.g., Orudis,
Orudis KT, Oruvail), naproxen (e.g., Naprosyn, Aleve, Anaprox), or other
over-the-counter products while taking Coumadin, except under the supervision
of your doctor. Over-the-counter NSAIDs increase the risk of bleeding.
Consult your physician before taking any new prescription or over-the-counter
product. Always take Coumadin in the evening, preferably between 5 p.m.-7
p.m.
Combining Coumadin with Antiplatelet Agents
As has been previously described, Coumadin interferes with specific
coagulation factors that can induce a thrombotic event. Coumadin is classified
as an "anticoagulant" agent.
Aspirin, fish oil, vitamin E, and garlic inhibit platelet adhesion and
platelet aggregation and are classified as "antiplatelet" agents.
The inhibition of blood platelets' ability to adhere and/or aggregate
also decreases the likelihood of thrombosis.
In a perfect world, an individualized program would be designed to deliver
the optimal combination of anticoagulation and antiplatelet agents to
provide the broadest protection against thrombosis without inducing hemorrhage.
There is much debate and confusion about the interactions between dietary
nutrients and prescription antithrombotic medications regarding clot formation.
The concern expressed in some studies involves potential interactions
between Coumadin and antiplatelet agents such as ginkgo biloba, green
tea, vitamin E, garlic, and fish oil (Heck et al. 2000). There has been
apprehension that certain supplements put the patient at risk for bleeding
problems by adding to the overall effects of Coumadin.
As a result of this concern, some doctors advise patients who are taking
Coumadin to avoid any dietary supplement that could possibly cause increased
bleeding. A problem with this ultra-cautious approach is that it deprives
the patient of nutrients they may need to sustain life. It also prevents
the use of antiplatelet agents that act on hemostatic mechanisms, separate
from those of Coumadin, to reduce more effectively the risk of thrombosis.
There are major medical publications that confirm the importance of lowering
the incidence of cerebrovascular stroke and heart attack by such a two-pronged
approach using an agent with antiplatelet activity, for example, Coumadin
(Fasey et al. 2002; Hurlen et al. 2002).
A patient taking Coumadin has to be concerned that any food, drug, nutrient,
or other substance they put into their body may not only increase the
bleeding time, but also affect Coumadin metabolism, which may either increase
or decrease the effect of Coumadin on the International Normalized Ratio
(INR). The inherent variability that occurs in each individual taking
Coumadin makes it difficult to provide general guidance. For instance,
the underlying medical condition determines the degree of desired anticoagulation.
No studies have correlated optimal anticoagulant doses of Coumadin, as
measured by the INR reference range, with optimal doses of multiple antiplatelet
agents, as measured by the template bleeding time (TBT).
The template bleeding time is done in a physician's office where a template
device nicks the skin and the number of minutes it takes for blood flow
to stop is assessed by a nurse or lab technician. The "normal"
template bleeding time is up to 9 minutes. A bleeding time (BT) of 4-5
minutes might indicate increased thrombotic risk, although a BT over 9
minutes may indicate an increased hemorrhagic risk. However, what is really
important in this setting is the patient context, as discussed below.
As it relates to antiplatelet agents like fish oil and garlic, a BT
of 4-5 minutes could suggest a benefit of taking higher amounts of these
agents, whereas a BT over 9 minutes in a patient already on an antiplatelet
agent might indicate that antiplatelet agent doses are having a biological
effect and further dose increases should be avoided. The problem patients
face today is that there are no standards that document the ideal balance
between Coumadin and antiplatelet agents such as fish oil, garlic, vitamin
E, etc. Too much Coumadin and/or antiplatelet agents can cause hemorrhage,
whereas too little Coumadin and/or antiplatelet agent(s) can cause thrombosis.
In this setting or context, as with many medical issues, balance is the
key concept. The approach that the meticulous physician uses to achieve
this balance is called "titration." There is an art to titrating
doses to where the "happy medium" is reached. This is embraced
in the key medical concept of therapeutic index which relates to the equation:
TI (Therapeutic Index) = Therapeutic Benefits ÷
SideEffects of Therapy.
In an ideal setting, a physician would carefully monitor the INR and
the TBT to measure precisely the optimal level of anticoagulant and antiplatelet
agents, respectively, in an individual patient. For instance, a patient
with a heart valve replacement may have a desired INR range of 2.5-3.0,
while an optimal template bleeding time may be between 7-9 minutes. If
these tests were routinely conducted, a more scientific determination
of the ideal intake of Coumadin, fish oil, garlic, vitamin E, etc. could
be made.
Some early reports indicated that CoQ10 may reduce the anti-coagulant
efficacy of Coumadin (Spigset 1994). These reports have been contradicted
by a more recent study showing that CoQ10 does not affect Coumadin’s
anticoagulation mechanisms (Engelsen et al. 2003).
Heparin
Heparin inhibits thrombosis (clotting) via inactivating factor X and by
inhibiting the conversion of prothrombin to thrombin. Activation of factor
X is the major rate-limiting step in the coagulation cascade. By inhibiting
the activation of the fibrin-stabilizing factor by thrombin, heparin prevents
formation of a stable fibrin clot. Heparin also decreases the levels of
triglycerides by releasing lipoprotein lipase from tissues. The resultant
hydrolysis of triglycerides causes increased blood levels of free fatty
acids.
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