Blood Clots

Note: there are new oral anticoagulants being developed that will (perhaps) replace warfarin (coumadin) - vitamin K antagonists. One of these, ximelagatran (Exanta; AstraZeneca) had been approved for use in Europe, but not in the USA and it was subsequently withdrawn from the Eurpean market due to liver toxicity.

Another oral anticoagulant, dabigatran(a factor IIa inhibitor), may become available in 2007 and unlike ximelagatran, its predecessor, it hasn't shown any liver toxicity over the short term. This investigational oral anticoagulant looks to be as good at the injected LMWH drug enoxaparin, in the preventioin of venous thromboembolism after orthopedic surgery. The oral drug is more convenient than the injectable enoxaparin. Longer term data is needed and will become available in ongoing studies. See American Society of Hematology(ASH) 48th Annual Meeting and Exposition: Abstract 573. Presented December 11, 2006 and Medscape Medical News - conference coverage. Note that there is also the factor Xa inhibitor rivaroxaban (Bayer and Ortho-McNeil) in development which has completed phase II testing and is starting phase III.

Another new drug in development for the treatment of life-threatening deep vein thrombosis is Idraparinux. This drug is a direct inhibitor of coagulation factor Xa and only requires once-weekly subcutaneous dosing vs the daily dosing when low molecular weight heparin is used. In the phase 3 clinical trial reported at the ASH 48th Annual Meeting in Orlando, Florida (Abstract #6, presented 12/10/06) Idraparinux was found to be as effective as standard therapy with almost the same incidence of recurrence for DVTs (2.9% vs 3.0%), but for the PE group there was a higher recurrence for the new drug than the standard therapy (3.4% vs 1.6%). Medscape Medical News - conference coverage.

Patients with hormone refractory prostate cancer(and other cancers as well) are at increased risk of deep venous thrombosis, pulmonary embolism, central venous catheter related clotting, heparin-induced thrombocytopenia and disseminated intravascular coagulation. Each of these potential side effects are discussed below as well as possible treatments.

A paper published in The Oncologist 2003;8:381-388, AK Kakkar et al, Venous Thrombosis in Cancer Patients: Insights from the FRONTLINE Survey, highlights the need for patients to educate themselves on blood-clotting events and risk. The paper is on-line at http://theoncologist.alphamedpress.org/cgi/content/full/8/4/381

This paper indicates that "venous thromboembolism is a common complication in cancer patients and an important cause of morbidity and mortality." Yet medical oncologists were reported to use thromboprophylaxis in less than 5% patients. Also 20% of respondents, were using aspirin for prevention (even though there is no reliable evidence that aspirin is effective for prevention in cancer patients.) Thus, you may find yourself in the position of needing to educate your medical oncologist in the risks involved. Some particular cautions:

if you are or will be taking an estrogenic drug for your treatment, you should immediately discuss with your oncologist the need for phrophylactic Coumadin. If you plan to have a port installed, consider taking Coumadin to anticoagulate yourself following port installation(perhaps starting with low molecular weight heparin following the surgery). DVTs are the most common form of blood clots, occurring most frequently in the legs, but can occur elsewhere. Extreme fatigue may accompany clots lodging in the lungs (PE). Swelling, pain may be present in DVTs.

Clots may become life-threatening emergencies -- especially if they break free in the veins and move to the heart, lungs, or the brain -- resulting in a heart attack or stroke. Call 911 or get to the nearest emergency room quickly.

Name or Abbreviation	Definition/explanation
aPTT or PTT	Partial thromboplastin time, activated.
Coumadin	A brand name oral prescription drug for anticoagulation
DIC	Disseminated intravascular coagulation
DVT	Deep Venous Thrombosis, a blood clot. Affects deep, large veins which are surrounded by muscle.
Embolism	An embolus is a clot (or a piece of plaque that acts in the same manner as a clot) that travels from the site here it formed to another location in the body. The embolism can lodge in an artery at the new location and block the flow of blood there.
Fibrinolysis	Consumption of clots and clotting factors
Hemostasis	The arrest of bleeding from an injured blood vessel
Heparin	An I-V anticoagulant drug, administered 24 hours/day in the hospital. Sometimes abbreviated as UFH which stands for Unfractionated Heparin.
HIT	Heparin-induced thrombocytopenia.
Homeostasis	The balance of coagulation and fibrinolysis
INR	International Normalized Ratio
LMWH	Low Molecular Weight Heparin, given by subcutaneous injection. Fragmin® (dalteparin sodium,) Lovenox® (enoxaparin sodium) and Inohep® (tinzaparin) are examples.
PE	Pulmonary Embolism, a blood clot in the lungs. A pulmonary embolus is a blockage of an artery in the lungs by fat, air, clumped tumor cells, or a blood clot. Most often they are caused by blood clots from the veins, especially veins in the legs or in the pelvis (hips).
PRO TIME(PT)	Short for Prothrombin Time. Used to monitor warfarin therapy and to compute INR.
q(time)	q = every, as in every 3 weeks(q3 weeks or q21 days)
Superficial veins	veins located in the fatty tissue just under the skin. Not surrounded by muscle.
Thrombocytopenia	Low platelets count.
Thrombosis	Clot formation inside a vein or artery and thrombi are blood clots
Thrombophlebitis	Involves inflammation of a vein caused by a blood clot inside the vein. In superficial thrombophlebitis, the clot is in a vein that is just below the surface of the skin.
Warfarin	The generic form of coumadin.

A more lengthy explanation of clot and embolisms is the following from the NCI website.

Blood clots. Fibrin clots. Blood clots are the clumps that result from coagulation of the blood. A blood clot that forms in a vessel or within the heart and remains there is called a thrombus. A thrombus that travels from the vessel or heart chamber where it formed to another location in the body is called an embolus, and the disorder, an embolism (for example, pulmonary embolism). Other names are: Clot; Emboli; Thrombi.

Arterial embolism. A sudden interruption of blood flow to an organ or body part. This is caused when the artery that supplies the blood to that organ or body part is blocked by an embolus (blood clot or atherosclerotic plaque) that has moved in the bloodstream from its point of origin to a new location. The point of origin for the embolus can be the heart or a large blood vessel.

The Risk of Blood Clotting

A medical specialist in prostate cancer commented that half the men who die from prostate cancer, actually die of heart-related problems, such as heart attacks, strokes, and blood clots. The bad news is that there is no certain way to identify clotting risk in advance for prophylactic(preventive) treatment. Some more bad news is that the only preventive treatment carries a risk of hemorrhaging. The best you can do is to become aware of this risk and take it seriously. Make it a regular topic of review with your oncologist (who is usually also a hematologist). The next best thing you can do is to become aware of the symptoms in case you are hit by this problem.

M. Mandala et al¹ state that thromboembolic complications are the 2nd leading cause of death for cancer patients. Coagulation -- blood clots -- favor metastatic disease. They state that only 15% of cancer patients actually develop a deep venous thrombosis(DVT) or a disseminated intravascular coagulation(DIC), but the risk is significantly increased by chemotherapy, hormone therapy, surgery and central venous catheters -- all things that prostate cancer patients may employ in the course of their disease.

Several of us on the hrpca support list have experienced a DVT firsthand. Thus, we are prepared to share meaningful experiences if you should be concerned about this problem and its treatment. DVTs do not of themselves cause death. In the event a DVT breaks up so that pieces can flow to the lungs, an event called a PE can occur. This is a blockage of blood flow in the lungs which can lead to heart failure.

Many hrpca patients are on various chemotherapy protocols. It is instructive to read some of the clinical trial reports -- especially for the taxanes(taxol, taxotere) when combined with emcyt(estramustine phosphate). Emcyt adds a risk of thromboembolic events. Here's some statements from several trials, "two thromboembolic events(one arterial embolus and one deep venous thrombosis) occurred at the 70mg/m2 dose level in patients without a prior history of vascular disease" (this was with taxotere and 14mg/kg emcyt" and this, "...four vascular events were observed, including deep venous thromboses in two patients and cerebrovascular accidents in two patients," (note that after this finding that prophylactic warfarin and aspirin was started). Yet a 3rd trial found that, "The incidence of thromboembolic events during therapy was 9% and included one arterial thrombus, one deep venous thrombus and two superficial venous thromboses." One last trial(Sinibaldi, docetaxel 70mg/m2 q3 weeks, estramustine 280mg q6 hours for 5 doses q3 weeks) had this result: "no thromboembolic events were reported in this study, which utilized daily warfarin prophylaxis(42 patients). See CJ Logothetis, MD, "Docetaxel in the Integrated Management of Prostate Cancer," Oncology, June 2002, Supplement, pp 63-72 for more about these trials.

Explanation of Clotting

Blood clotting is, of course, a natural process that closes up wounds and keeps us from bleeding to death. It is a fairly complicated biological process that is the first step in healing of wounds. Due to reasons that are not understood, blood can also clot inside the veins. Blood in the arteries is more turbid due to pumping, and the walls of the arteries and their valves -- flex more than the veins; thus, clotting is less of a problem of the arteries and they have the additional problem of atherosclerosis.

Most clotting starts at the location farthest from the heart, with the longest, straight runs -- the legs. The risk drops when you move your legs, exercise and help that blood move back toward your heart. However, clots can start in any veins; for example, one of us experienced a clot in the jugular vein at the location of an implanted Medi-Port(this is a central venous catheter)³. Clots are also formed when blood stops moving, as for example, when you sit in a cramped airline seat and fold your legs under you. The same clotting can occur if you lie quietly in a hospital bed for days without moving.

Once a clot forms, it usually remains in place -- a fortunate event. If the clot is dissolved at that point, the problem is resolved, and your life is saved. If the clot breaks loose and goes to the lungs, you may experience a pulmonary embolism, which results in destruction of lung cells and, possibly, death. A moving clot may move to the heart, where it causes a pulmonary thrombosis -- a heart attack. Or it can move to the brain and cause a stroke.

Risk Factors for Blood Clotting

First, cancer itself increases your chances of clotting. Reports indicate that about 15% of cancer patients develop blood clots, but post mortem studies show that the incidence rate is closer to 50%, since all clotting doesn't show up clinically. Any estrogenic drugs (Emcyt, DES, PC SPES) increase your chances of developing a clot. High levels of testosterone can result in excess estrogen levels which might make you more susceptible to clotting events. The installation of a CVC(Port) for administration of IV drugs is a wonderful convenience, but it also increases your chances of a clot. Even the use of Heparin, a particular anticoagulant, can, in a paradoxical twist of processes, lead to a blood clot, via a potential side effect, called HIT (heparin induced thrombocytopenia -- see below).

There is no accepted medical criterion for deciding when to apply prophylactic treatment. Our opinion, in light of our own experiences -- is that when you incur 2 or 3 or these risk factors, you should be pressing your oncologist hard to consider Coumadin.

What Does Having a Blood Clot Feel Like?

The first symptoms of a clot are likely to be edema (swelling) and/or pain in the area of the blood clot. Sometimes there are, however, no 'symptoms'.

Benson's experience:
A friend pointed out that I didn't get religion about DVT's until I had one. He was right. If I had written this paper 6 months ago, I would have seen that I had a definite blood-clotting situation. The correct action for me would have been to present these risks to my docs and insist that we begin prophylactic treatment with Coumadin. At that time--and even now--the risk of clotting was far worse than the risk of hemorrhaging.

I had the following risk factors: (1) PCa; (2) high-dose testosterone(leading to higher levels of estrogen) and (3) a Port installed. I might have had a 4th risk as my port is flushed with heparin. If I had experienced a HIT from the heparin, this might have led to the clot, but I did not have HIT diagnosed. (Note that not all ports require heparin flushes -- there are several brands available).

My symptom was a minor swelling in my neck, but there was no pain for more than a week. It did, however, catch the interest of my oncologist. A week later, however, the swelling was an inch in diameter and elongated. By that time, it was also sensitive. The oncologist prescribed an MRI to examine the problem. It is likely that the swelling will be sore in most cases. This may be enough to cause your physician to have an MRI done; that will identify any clots without doubt.

Hansen's experience was different:
Of course, DVTs may cause no symptoms. In my case, a DVT wasn't diagnosed until after I was diagnosed with a pulmonary embolism. There was no swelling and no pain associated with the DVT and the PE symptoms were only a major shortness of breath when walking up stairs -- confused with an upper respiratory infection. But, no pain. It was, perhaps, a couple of weeks before I was hospitalized in order to be put on IV Heparin -- not because of any lack of attention of my primary care physician, but because I did not seek medical help. I was lucky not to have had any permanent damage to my lungs occur. In the above case, the likely cause of the DVT and PE was being on an estrogenic drug. A later superficial thrombus probably had a mechanical cause -- namely enlarged(due to prostate cancer invasion) lymph nodes pushing on a vein(s) reducing the rate of blood flow. In this case, swelling was readily apparent.

Another patient(HP) writes:
I have had three DVT episodes, so perhaps I can pass some information on to others. When I have had a DVT episode, my legs (usually both) start to ache, and it is very uncomfortable to walk on them. You try to lie down with your legs up. A DVT refers to a deep vein thrombosis, also known as a clot, formed in a deep vein in one or both legs. The clot prevents blood from returning to the heart. The clot hangs in there until it dissolves or until it breaks free. In the later case, it then continues through the veins into the lungs, where it may hang up in a small vein or capillary, causing what is known as a lung embolism, perhaps the most painful event a person can feel. My embolism kept me hospitalized for ten days, and caused permanent damage to one of my lungs. A second DVT dissolved with no apparent damage. A third DVT caused the clot to pass through the lungs, through the heart and lodged into the brain, causing a minor stroke, which after six months recovery, I am now fairly free from.

After the first DVT I was put on coumadin. Coumadin did not work for me. After the second and third DVT, the doctors switched me from Coumadin to heparin, which I am now on, and which seems to work for me. Heparin is given by injection, and I take two injections a day. I have been on heparin for over 2 ½ years now. DVT’s are not to be trifled with. A lung embolism can kill you. A stroke can damage you permanently. Any of you that are on Coumadin to prevent DVT’s and their sequels should stay on it, and be thankful you are not on heparin. (I suspect that HP was on low molecular weight heparin).

The Danger

To emphasize the danger: If the clot should break loose and move to the lungs, heart or brain, the symptoms are unmistakable and catastrophic. Think severe chest pain, heart attack, and stroke. It is time to call 911; your life is in peril.

Treatments for Blood Clots

A blood clot -- caught at the early stage -- may put you into the hospital 3 - 7 days. Treatment protocols vary on this. The standard practice in the past has been to hospitalize patients with blood clots. In this case, the initial treatment is I-V Heparin, a relatively fast-working blood thinner that anticoagulates you to prevent additional blood clots from forming. Success in this stage of treatment is measured by clotting time (PTT or aPTT). This may take 3-4 days.

The next stage of treatment is to convert the Heparin therapy to Coumadin pills, which will become your maintenance treatment. As with the Heparin, the Coumadin dose is adjusted upward and downward until you reach a stable INR (International Normalized Ratio, a mathematical conversion of PT) level of 2-3. Coumadin is usually started after 1-2 days on I-V heparin and both are continued until your INR reaches the 2-3 level. Coumadin(warfarin) is a slow acting drug and takes several days to stablize at a given INR level -- 3 - 5 days or more.

NOTE: be aware that there are many drugs that affect anticoagulation with Coumadin -- some that increase INR are ketoconazole, various anti-inflammatories, some antibiotics(of which ketoconazole is one), omeprazole(Nexium), Lovastatin, and more). ALSO, there are drug-herbal interactions to consider: Ginkgo affects anticoagulants and antiplatelet agents, Ginseng can decrease the effectiveness of warfarin(lower INR). And some supplements can have an impact also -- high doses of Vitamin E, high doses of Vitamin C are examples. Let your doctor know what you are taking, drug, herb and supplement-wise.

The purpose of the hospital stay is to be able to treat you immediately in case the clot breaks loose and to get your anticoagulated fast with I-V heparin to prevent additional clot formation. This must be treated as a dangerous situation. It also permits frequent blood tests to monitor progress in controlling clotting time.

However, the other method now being used is to not hospitalize the patient. Upon diagnosis of a DVT or any blood clot, there is an option to immediately start you on Low Molecular Weight Heparin(LMWH).² This is a prescription drug available at most pharmacies. Reference (2), table 2 lists LMW heparins. LMWH does not require monitoring of aPTT or INR. LMWH is available from pharmacies as pre-filled syringes and you can be trained to do the injections yourself at home.

Aspirin, sometimes recommended as an anticoagulant for DVT/PE prevention/treatment, is not effective. Stephen Strum wrote on P2P, "Aspirin does not work on anti-thrombin III which is lowered by estrogens. Aspirin works on platelet aggregation or stickiness. Therefore, it provides no real protection against the pro-thrombotic effects of estrogenic compounds like DES, Estradiol, Emcyt, PC SPES and even PC PLUS. " (p2p - see www.pcri.org). Aspirin is more effective in preventing arterial thrombosis (myocardial infarction, stroke) than venous thrombosis (deep venous thrombosis, pulmonary embolism). The explanation for this difference seems to be that platelets play a larger role in causing arterial thrombosis.

Precautions: Patients are usually instructed to not take aspirin while taking Coumadin(warfarin) or any NSAIDs(non-steriodal anti-inflammatory drugs) for that matter. Since aspirin is often used by patients, the precaution against simultaneous use of warfarin and aspirin is usually on the prescription bottle you get from the pharmacy. The exact wording is, "Do not take aspirin or aspirin containing products without knowledge and consent of your physician." For a fairly lengthy list of drugs and supplements that either increase or decrease INR readers should consult the prescribing information at

http://www.coumadin.com/hcp/hcp.shtm. Tylenol is an option for treatment of pain if you are on warfarin.

Vena Cava Filters (or Inferior Venacaval Filters - placed internally). These filters may be an option for some subset of patients -- mainly those for whom conventional anticoagulation is contra-indicated. These reduce the risk of PE, but have a high risk of other clotting complications such as DVTs.

Treatment of Blood Clots with Coumadin(warfarin)

Coumadin (warfarin) is taken once a day, preferably at dinner time so that dosage changes can be made the day that you have your INR measured. The therapeutic range of INR to prevent clotting is usually considered 2-3 -- an INR for someone not on anticoagulation drugs is 0.9 - 1.1.

If you are taking a treatment dose of Coumadin (because of having a thrombotic event), you will want to get your PT/INR checked frequently. Depending on the stability of your INR, you might have it checked twice a week or once a month. Your doctor will determine this. The oncologist will then recommend adjusting the dose appropriately. When the INR is less than 2, the dose of Coumadin is increased. When the INR is greater than 3, the dose of Coumadin is decreased. Two articles in the New England Journal of Medicine discuss the INR for prevention of recurrent venous thromboembolism.^5,6 Although P.M. Ridker et al⁵ indicate an INR of 1.5-2 is adequate, C. Kearon et al⁶ say that the 2-3 range is the best. Discuss this with your physician as he will ultimately set the INR goal for you.

If you are taking a prophylactic treatment of Coumadin, your physician will need to set the INR criterion because he will also be concerned about the possibility of bleeding. INR levels above 4 increase the risk of serious bleeding. He will also need to watch the INR on a regular basis to adjust the dose appropriately.

Note this: Bleeding has been reported to be three times more common in patients with INRs of 3 - 4.5 than in patients with INRs of 2-3. Hence the desire to stay in the 2-3 range.

How Long Do I Take Coumadin?

This is a judgment call for you and the physician. Make sure your physician is aware of your ongoing risk factors so you don't stop prematurely. You may need to continue indefinitely. If, however, the risk factors disappear, then your main concern may be the possibility of bleeding, in which case you may want to reduce or eliminate the Coumadin prophylaxis.

Other Potential Causes of Thrombotic Events of Concern to HRPCA Patients

A full review of these subjects is beyond the scope of this paper. For further information, consult the references and the citations that are listed there. Many of the references are available through Medscape on-line. A brief overview is presented below.

CVC - Central Venous Catheters^3,4 - a Port.

The long term use of CVCs has been associated with the occurrence of upper-limb deep venous thrombosis (UL-DVT or UEDVT - Upper Extremity DVT). Cancer and chemotherapy increase the risk There is an associated risk of a PE and a PE may be the 1st sign of this disease. Patient related risk factors for CVC-related DVTs are³ - high platelet count, cancer-related activation of clotting, CVC-related activation of clotting, chemotherapy-related activation of clotting and thrombophilic molecular abnormalities. Some of the risk factors associated with the port itself are³ -

Risk Factor	Possible Action to Reduce this Risk
Catheter Tip Positions	Locate tip at the junction of the superior caval vein and the right atrium
Side of Insertion	Left-sided insertion has higher risk, implying that right-sided insertion is better.
Insertion Technique	Ultrasonographic-assisted placement was better than external landmark-guided technique for CVCs in the internal jugular vein.

Other CVC related risk factors are previous CVC insertion, CVC-related infections, chemical structure, catheter diameter and number of lumens. Talk with the physician who will be doing the port installation about these so that they can be minimized.

Melina Verso et al³, in their review article, indicate the following incidence rates for venous thromboembolism associated with CVCs:

Event	Clinically overt	screened by venography	Lung-scan proven rate
UL-DVT	.3-28.3%	27-66%	-
PE	15-25%	-	25% & 30%

The explanation for the above differences is that many UL-DVT events are asymptomatic -- the clots possibly not completely closing the vein thus allowing continued blood flow. The first six weeks after installation of a port is the highest risk time period for thromboembolic complications.

It is important to note that the benefits of having a port installed appear to far outweigh the risks for most patients. Both the authors of this paper have ports installed. Just be certain that the physician installing the port has significant experience with their installation and has a good track record (your oncologist or oncology nurse will probably have a good idea as to how good the surgeon/interventional radiologist is. Be sure to ask.

If blood clots are such a risk with ports, why isn't everyone who gets a port installed anticoagulated? Some doctors are concerned with the risk for bleeding on anticoagulants such as warfarin(Coumadin), others may not be aware of the risk for clots associated with ports and then there are studies that contradict one another as far as showing a benefit. The review article by M. Verso et al³ has an extensive review of the trials and results involving cancer patients with anticoagulants. These were all prophylactic use(prevention).

The 1st trial mentioned(Bern HM et al, 1990), was with 1mg warfarin, started 3 days before port installation and continuing for 90 days vs a control group without warfarin. The warfarin group had 9.5% clots(4 of 42 patients) and the control group had 37.5%(15 of 40 patients) and the conclusion was low, fixed dose of warfarin could prevent CVC-related DVTs. Another study (Monreal M et al, 1996) compared Dalteparin 2500 U vs no tx, 90 days. In this trial, those who received Dalteparin(a LMWH) had a 6% CVC-DVT rate vs 62% in the untreated group. From these two studies, The American College of Chest Physicians has recommended LMWH or low-dose warfarin for the prevention in patients with CVCs. There are other studies in the review paper, some contradictory and there is/are other trials in progress evaluating this use. I cannot find a trial that evaluates therapeutic levels of warfarin (INR 2-3) for prevention of CVC related DVTs or a comparison of INR 2-3 vs 1mg warfarin with likely a normal INR. The author(HH), having had a DVT before port installation, already was on coumadin with an INR 2-3.

Another good reference is Letaia et al⁴-- their recommendation/ conclusion is that "anticoagulation of indwelling central lines should be considered in all cancer patients who do not have a specific contraindication."

HIT - Heparin-induced thrombocytopenia ^{7, 8, 9, 10, 11, 12, 13}

Heparin (UFH) and low molecular weight heparin (LMWH) are drugs used for anticoagulation therapy. There is a 1% - 5% chance that any exposure to these drugs can result in a serious drug reaction called heparin-induced thrombocytopenia or HIT. HIT is paradoxically associated with creating blood clots, not bleeding as is normally the risk with reduced platelet counts.

There are two types of HIT that have been associated with heparin.⁷ Type I, which is described as a transient drop in platelets(a mild drop), is non-immune-mediated(no antibody generation), usually occurs within 4 days of heparin use and is described as generally reversible. L. Rice et al⁸ indicates that type I is an old designation as an "early, mild, clinically inconsequential heparin-induced thrombocytopenia (that) was advanced years ago...." Clinically inconsequential probably relates to the asymptomatic nature of 'type I'.

The other type of HIT -- type II -- is called delayed-onset heparin-induced thrombocytopenia⁸ and is well described in the "summaries for patients" that the Annals of Internal Medicine provides:⁹

"What is the problem and what is known about it so far?
Heparin is a blood thinner that prevents or treats abnormal blood clots in the veins. It also causes several complications. One serious complication is an "autoimmune" reaction. In this complication, heparin molecules combine with a body protein called platelet factor 4. This leads to the production of antibodies that attack blood platelets, which are necessary for forming blood clots. The damaged platelets may trigger uncontrolled clot formation. This life-threatening situation, known as heparin-induced thrombocytopenia, occurs in 3% of heparin-treated patients. Although heparin-induced thrombocytopenia usually occurs within 5 to 12 days after starting heparin therapy, doctors are starting to realize that heparin-induced thrombocytopenia may begin or may be recognized more than 12 days after the start of heparin therapy (delayed-onset heparin-induced thrombocytopenia). "

Note: SA Spinler et al⁷ say that delayed-onset is usually between 5 and 10 days, typically more than 4 days BUT can occur within 12 hours of reexposure for cases where the previous heparin was given within 100 days.

Even though both UF Heparin and LMW Heparin have a risk for HIT, TE Warkentin et al¹² found that HIT and associated clotting events were more common in patients on heparin(UFH) than those on LMWH -- at least for short term use. But, since HIT can occur with LMWH, one would not want to treat HIT with LMWH¹⁰ -- Two FDA approved drugs are available for the management of HIT (Argatroban and lepirudin).

Since heparin(UFH) is often used to flush CVCs(Ports) -- there is an added risk for HIT associated with this use. Not all ports require a heparin flush, however. Since platelet counts are routinely monitored prior to chemotherapy(the CBC), your oncologist should be alerted to any problems. This is complex, as some chemotherapies also decrease platelet counts - but that change doesn't drive clotting as HIT does. I have not found any mention of HIT in conjunction with ports.^3,4

Lastly, L. Rice et al⁸ provide the following information regarding occurrence: For those who receive therapeutic(you have a PE or DVT or some other need for heparin therapy) IV UFH, HIT occurs in 3% of the patients. For those who receive lower doses from uses such as subcutaneous injection or a heparin flush, low-molecular weight heparins, or even whatever might leach from heparin-coated catheters -- the incidence rate is 0.5% to 1%. Whether this holds true for the repeated heparin flushes of long term CVC use isn't stated.

As an editorial in the NEJM (NEJM, Volume 332:1374-1376 May 18, 1995 Number 20, Heparin-Induced Thrombocytopenia and Thrombosis, Editorial) states, low platelet counts(thrombocytopenia) in and of itself, rarely is a threat to patients. It is the associated events that produce major side effects and death -- these include deep venous thrombosis, disseminated intravascular coagulation, pulmonary embolism, cerebral thrombosis, myocardial infarction, and ischemic injury to the legs or arms.

DIC - Disseminated Intravascular Coagulation¹⁴

Yet another blood clot related phenomena that will be covered here is DIC. The word hypercoagulation or massive clotting is used to describe DIC -- basically, the body loses control of the processes of clot formation(coagulation) and clot dissolution (fibrinolysis). Massive clotting uses up all the clotting factors, leading to major bleeding. There are multiple diseases that can lead to DIC, cancer being one of them and prostate cancer is one so identified. Having both thrombosis(clotting) and hemorrhaging occurring simultaneously represents a medical emergency.

A very simplified look at the process of DIC might be this:

Time	Event	Result
Start	hypercoagulation	Microvascular(multiple small clots in various organs) and large vessel involvement(DVT). Potential organ damage.
Then	fibrinolysis	Clot dissolution - consumption of clots and bleeding clotting factors.
Then	Unable to maintain stable clot formation	Hemorrhage - This may be the 1st time at which DIC gets diagnosed.

Hemorrhaging is serious, but the large number of blood clots is what leads to the most side effects and possible death.

There are two types of DIC identified in reference (14) -- acute and chronic. The Merck Manual uses the term subacute instead of chronic.

Chronic DIC is most often seen in cancer patients -- localized events such as DVTs -- and the balance clot formation and dissolution is still mostly maintained. Hence abnormal bleeding is uncommon. Acute DIC is another matter -- this is the serious event -- and it does occur in cancer patients. Acute DIC is considered potentially life threatening and as such is an oncologic emergency. In acute DIC, there is a complete breakdown of the normal clotting/clot dissolution process. Platelets get consumed, leading to thrombocytopenia and contributes to the bleeding.

For information on laboratory tests and management of DIC, see reference (14). Lab tests such as the D-Dimer assay and the FDP assay, while non-specific are mentioned as being the most effective tests to assist in diagnosis of DIC.

Liver Disease-Related Coagulation Disorders

The liver synthesizes both coagulation factors and inhibitors of coagulation. It also removes from circulation activated coagulation factors and FDPs which are polypeptides resulting from the breakdown of clotting material(fibrinogen and fibrin).

If you have liver failure due to primary liver disease, liver metastases or liver damage due to chemotherapy, radiation therapy or other drugs drugs that cause liver dysfunction you may have an increased risk of DIC since the balance between clotting and clot dissolution is then impaired.

A recent article has reviewed the use of warfarin and low-molecular weight heparin in cancer patients.(15) Cancer and venous thromboembolism (VTE) are all too often associated with each other. Furthermore, VTE is a significant cause of cancer deaths. Cancer patients who have venous thromboembolism are usually put on long-term warfarin therapy. The authors list the following as problems with warfarin long-term in cancer patients:

The alternative anticoagulation drug -- LMWHs offer the following advantages over warfarin in cancer patients with VTEs:

Author: Howard Hansen
Date: 11/19/2003 and updated 1/18/05; 12/13/06 and 9/17/08

Note: The author is not a medical doctor and cannot render medical advice. As a prostate cancer patient, this was written in an attempt to understand blood clotting and how it affects me. I make no claims that this review is definitive, complete or authoritative and I request any contributions to, or clarification of the subject which might contribute to the issue or inquiry. In conjunction with a medical team, every cancer patient must make their own decisions regarding treatment options. Because blood clots can be life threatening, your own medical team's directions should be carefully followed.

Ackknowledgments: Bob Benson and Bill Aishman have provided useful input for this paper.

The U.S. Agency for Healthcare Research and Quality (AHRQ) has published some booklets on blood clots.

1. Mandala M, Ferretti G, Cremonesi M, Cazzaniga M, Curigliano G, Barni S.,Venous thromboembolism and cancer: new issues for an old topic, Crit Rev Oncol Hematol. 2003 Oct;48(1):65-80.

2. ERIC J. RYDBERG, M.D., JOHN M. WESTFALL, M.D., M.P.H., and RICHARD A. NICHOLAS, M.D., Low-Molecular-Weight Heparin in Preventing and Treating DVT, American Family Physician, March 15, 1999,
http://www.aafp.org/afp/990315ap/1607.html

3. Melina Verso, Giancarlo Agnelli, Venous Thromboembolism Associated With Long-Term Use of Central Venous Catheters in Cancer Patients, Journal Journal of Clinical Oncology, Vol 21, Issue 19 (October), 2003: 3665-3675.

4. Anthony Letaia,b, David J. Kutera, Cancer, Coagulation, and Anticoagulation, The Oncologist, Vol. 4, No. 6, 443-449, December 1999
http://theoncologist.alphamedpress.org/cgi/content/full/4/6/443

5. Ridker P. M, Goldhaber S. Z., Danielson E., Rosenberg Y., Eby C. S., Deitcher S. R., Cushman M., Moll S., Kessler C. M., Elliott C. G., Paulson R., Wong T., Bauer K. A., Schwartz B. A., Miletich J. P., Bounameaux H., Glynn R. J., the PREVENT Investigators, Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism, N Engl J Med 2003; 348:1425-1434, Apr 10, 2003; published at www.nejm.org on Feb 24, 2003

6. Kearon C., Ginsberg J. S., Kovacs M. J., Anderson D. R., Wells P., Julian J. A., MacKinnon B., Weitz J. I., Crowther M. A., Dolan S., Turpie A. G., Geerts W., Solymoss S., van Nguyen P., Demers C., Kahn S. R., Kassis J., Rodger M., Hambleton J., Gent M., the Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators, Comparison of Low-Intensity Warfarin Therapy with Conventional-Intensity Warfarin Therapy for Long-Term Prevention of Recurrent Venous Thromboembolism
N Engl J Med 2003; 349:631-639, Aug 14, 2003.

7. Sarah A. Spinler, William Dager, Overview of Heparin-Induced Thrombocytopenia; Posted 10/30/2003 to Medscape((free registration is required for Medscape). Am J Health-Syst Pharm 60(20):S5-S11, 2003.
http://www.medscape.com/viewarticle/463456

8. L Rice et al, Delayed-Onset Heparin-Induced Thrombocytopenia, Annals of Internal Medicine, Volume 136, No. 3, 5 Feb. 2002, pp. 210-215. Also the Reply to two Letters published in: L Rice et al, Delayed On-Set Heparin-Induced Thrombocytopenia, Annals of Internal Medicine, 4 November, Vol. 139, Issue 9, pp. 790-791.

9. Annals of Internal Medicine, SUMMARIES FOR PATIENTS, Delayed-Onset Heparin-Induced Thrombocytopenia, 5 February 2002, Volume 136 Issue 3, Page I34.

10. Andreas Greinacher, Treatment Options for Heparin-Induced Thrombocytopenia, Posted 11/11/2003 to Medscape (free registration is required for Medscape). Am J Health-Syst Pharm 60(20):S12-S18, 2003.
http://www.medscape.com/viewarticle/463457

11. Warkentin TE, Heparin-induced thrombocytopenia, Curr Hematol Rep. 2002 Sep;1(1):63-72.

12. Theodore E. Warkentin, M.D., Mark N. Levine, M.D., Jack Hirsh, M.D., Peter Horsewood, Ph.D., Robin S. Roberts, M.Tech., Michael Gent, D.Sc., and John G. Kelton, M.D., Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin, NEJM, Volume 332:1330-1336 May 18, 1995 Number 20.

13. Deitcher S.R., Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies, Semin Thromb Hemost. 2003 Jun;29(3):247-58.

14. BH Gobel, "Disseminated Intravascular Coagulation in Cancer: Providing Quality Care," Topics in Advanced Practice Nursing e-Journal 2(4), 2002. Go to http://www.medscape.com/viewarticle/442737 for the full text. Registration is required for Medscape access(free). Posted 10/14/2002.