Hi beavis,
The short answer is: Blame it on Protein C and Protein S. Cancer
patients, for largely unknown reasons, develop resistance to Protein
C. Antibodies to Protein S develop in cancer patients as well. Both
of these proteins are responsible for coagulation regulation - they
prevent unnecessary coagulation, and with decreased levels of these
proteins, patients are highly prone to develop blood clots.
About 90% of all cancer patients develop a tendency towards increased
coagulation, known as being in a hypercoagulable state, with about 10%
actually developing deep vein thrombosis (DVT). Even with this
increased risk, anticoagulant therapy is usually not initiated
prophylactically, as it is difficult to regulate, particularly in
cancer patients. Cancers associated with DVT (stomach, lung,
pancreatic, and intestinal)are adenocarcinomas - cancers that begin in
cells that line the inside of organs.
Several factors contribute to increased clotting in a cancer patient
(of any kind). Cancer patients frequently have a higher than normal
platelet count, causing the blood to become a bit ?Sticky?, increasing
risk of clotting. Cancer cells, when destroyed by chemotherapy, often
release substances that promote blood clotting. Lack of exercise and
movement promote clotting, especially in bed or chair bound patients.
Surgery and chemotherapy can trigger clotting due to vein wall
injuries, and chemotherapy can reduce the amount of naturally produced
anti-coagulants. Some studies suggest that folate deficiency in cancer
patients can affect the anti-clotting process.
Coagulation is a complex cascade involving multiple factors, and is
activated in cancer. Coagulation is further stimulated by
chemotherapy, radiation, or surgery. Even though it is well known that
cancer can activate the coagulation cascade, the reasons why are still
not totally clear. Activation of the coagulation system may also cause
increased tumor growth, and this increases chances of a poor outcome.
Certain tumor types can even shut down the anti-clotting process.
In a healthy person, blood circulates freely, and the plasma
coagulation factors circulate, unactivated. Once the clotting
process begins, other intrinsic factors prevent excess clotting. Any
abnormalities in either the coagulation or anti-coagulation process
can lead to a hypercoagulable state. Cancer patients are fairly
resistant to the anti-coagulation factors. Simply put, when a cancer
patient undergoes what should be a normal clotting process, the
process goes out of control, because the anti-coagulation factors are
not working correctly.
Clotting factors are proteins, and are numbered 1 to 13 ( I to XIII).
When a blood vessel trauma occurs (cut, puncture), these 13 factors
(proteins) are activated, in a specific order. In about half of the
elderly population, Factor VIII inhibitors are activated, with no
known cause. There is no definitive answer, but some studies suggest
that cancers damage our immune system. It may be that Factor VIII
antibodies are produced, in an effort to destroy cancer cells. It is
known that Protein C, Protein S, and antithrombin III, factors that
prevent clotting (natural anti-coagulants) are increased in cancer
patients, but the reason is not completely understood. Platelets that
have been called into play (activated) cause production of thrombin, a
clotting factor.
A simple view:
An intact blood vessel lining produces substances to inhibit platelet
aggregation during normal blood flow. These substances are
prostacyclin, antithrombin III, and protein C activator. An injured
blood vessel exposes the vessel lining, which causes platelet
adherence. The injury releases thromboplastin (tissue factor). This in
turn reacts with Factor VII, and activates the rest of the
coagulation cascade as such: Tissue factor and Factor VIIa activate
factor X, forming factor Xa. Factor Xa then activates
prothrombin(Factor Iia) to produce thrombin. Thrombin converts
fibrinogen to fibrin (factors I and Ia). Fibrin forms a mesh together
with platelets, that seals a break in the vessel wall. Factor V and
factor VIII speed up the conversion of factor X to factor Xa by
factor IXa (this is done by factor VIII) and accelerates the
conversion of prothrombin to thrombin as done by factor Xa.
Factors that Inhibit (Slow Down) Clot Formation:
Protein C, Protein S and thrombomodulin form a complex (group of
proteins) that can inactivate factor VIII and factor V. Protein C,
Protein S and thrombomodulin complex is activated by thrombin.
Antithrombin (formerly called antithrombin III) serves to block the
actions of multiple clotting factors (called inhibition). Inhibition
is depicted with the red lines that end in a filled circle. The filled
circle denotes the factor that is inhibited.
Tissue factor pathway inhibitor works to inhibit the formation of factor Xa.
All of the above interactions are required in order to maintain the
hemostatic balance (hemo=blood, stasis=state of not flowing/moving),
which prevents excessive bleeding or excessive clotting.
As the vessel injury heals, the clot is dissolved through an enzymatic
process called fibrinolysis (?lysis? means ?to dissolve?) This
coagulate-anti-coagulate dance is a very delicate balance in a healthy
person. In a cancer patient, the cascade is turned upside down!
Tumor cells can produce high-viscocity proteins, called mucins that
stimulate clot production. Mucins can bind to blood vessel walls, and
stimulate platelet aggregation. This causes the clotting cascade to
begin.
CancerSourceRN
http://www.cancersourcern.com/Nursing/CE/CECourse.cfm?courseid=62&contentid=20166#_Toc482680703
Med Info
http://www.medinfo.ufl.edu/year2/coag/regulate.html
.
American Academy of Family Physicians
http://www.aafp.org/afp/971015ap/971015a.html
M. Peterson Design
http://www.mtpetersondesign.com/Heparins.html
MUCIN Acquired Protein C deficiency seen in malignancies (cancer)
For a detailed explanation, with an illustration:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Clotting.html
Cancer BackUp
http://www.cancerbacup.org.uk/Resourcessupport/Practicalissues/Travel/QAs/848
This University of Illinois site has a good illustration of the clotting process.
University of Illinois
http://www.med.uiuc.edu/hematology/PtClotInfo.htm
Additional Information:
?New research conducted at the American Red Cross Jerome H. Holland
Laboratory for Biomedical Sciences in collaboration with scientists at
EntreMed, Inc. has identified a molecule that may lead to a novel way
to shrink cancerous tumors. Experts have long known that a protein
called "tissue factor pathway inhibitor" (TFPI) is a critical
component in the process of blood coagulation (clotting). The new
study found that TFPI also plays an important role in the process of
angiogenesis, or the growth of new blood vessels.
According to Dr. Dudley Strickland, one of the study's authors and
head of the Vascular Biology Department at the Holland Lab, there is a
link between blood clotting and angiogenesis.?
Red Cross News
http://www.redcross.org/news/bm/holland/010430angio.html
Malignancies with the highest rates of thromboembolism include
mucin-producing adenocarcinomas of the gastrointestinal tract followed
by tumors of the lung, breast, and ovary. Myeloproliferative disorders
and leukemias are also associated with an increased incidence of
thromboembolism.?
http://www.merck.com/mrkshared/mm_geriatrics/sec9/ch70.jsp
More explanation of cancer and clotting:
CancerHelp
http://www.cancerhelp.org.uk/help/default.asp?page=6345
Prevent Clots
McMaster University: How to Prevent Clots in Cancer Patients
http://www.fhs.mcmaster.ca/pubrel/clots.htm
Pharmion Pharmeceuticals has a nice illustration of a clot formation:
http://www.innohepusa.com/corporateweb/innohepus/home.nsf/AttachmentsByTitle/PatientBrochure.pdf/$FILE/PatientBrochure.pdf
? Small molecules stored within large proteins in the body can stop
cancer cells from creating new blood vessels. Many enzymes that a
tumor uses to invade surrounding tissue generate these angiogenesis
inhibitors, but a tumor can locally override the effect of the
inhibitors by generating angiogenesis stimulators?
The Scientist
http://www.the-scientist.com/yr2000/aug/research_000821.html
For a very detailed description (beyond the scope of this question) of
the clotting process involving mucins:
Cancer Research
http://cancerres.aacrjournals.org/cgi/content/full/60/23/6714
If any part of my answer is unclear, or if I have duplicated
information you already have, please request an Answer Clarification,
before rating, so I may assist you further.
Regards,
crabcakes-ga
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