A real-life case history

cramped airline seats Back in the Fall of 2004, my husband PC and the rest of the family set out for a long hike. It was a sunny and wonderful day. To make a long story short, PC was doing a bit of rough-housing with our dog and took a bad tumble, falling full length on the rough ground. Fortunately he was wearing heavy duty denim jeans and there was no broken skin. But after we got home we saw he had an impressive bruise down the side of  his leg, from mid-thigh to his calf. The bruise lasted a couple of days and faded away and we thought no more about it.

Along came the week-end. (Why do medical emergencies always happen over a weekend?) Saturday night, over a matter of just a couple of hours his knee and leg became swollen and very tender and painful to the touch. He had streaks of bright red running down his leg. Very strange, I had never seen anything like it. Frantic searching on PubMed suggested it might be deep vein thrombosis, a blood clot buried deep somewhere in the veins of his leg. But I thought DVT was generally a risk in obese and or sedentary couch potatoes? PC was anything but sedentary, he was a slender and very fit guy who hiked and ran many miles each week.

Nevertheless, I was worried and sent an email to my favorite CLL specialist, Dr. Timothy Call of Mayo. I heard back within hours (thank you Tim for that bit of long distance and pro-bono weekend patient care!). Yes, he said, it was most likely DVT (deep vein thrombosis) and I had better get PC to the emergency room right away rather than wait until Monday morning to see his regular doctor. Sure enough, ultrasound confirmed a clot in his popliteal vein, just behind his knee.  Not much blood was getting past the blockage and all that backed up blood was causing his leg to swell painfully.  The picture at the bottom of this article is not an exaggeration – that is what PC’s leg looked like, if you also throw in a few bright red streaks running down the length of his leg.

Left untreated, a possible serious complication of clots such as this is that they can break away and travel in the blood stream to other places such as the lungs, only to get stuck there again. A blood clot in the lungs is called a pulmonary embolism. Less likely, the clot can get all the way to the brain, in which case it can cause a stroke.  This is the reason for considering DVT a medical emergency. I am told that untreated DVTs in the legs carry a 3% chance of death due to lung embolism. It would have been ironic to lose my husband four years earlier to a simple fall while playing tag with the dog, while we were so focused and hell-bent on fighting his CLL. Those four years were so precious, I would not trade them for anything in the world.

So, why am I writing about this purely random happenstance, a guy playing with his dog and tripping over his own two large feet? How is any of this of direct relevance to CLL patients? Because I learned there is a connection between increased risk of DVT and CLL, as well as many of the drugs used in treatment of CLL patients add to that risk. As a CLL patient your chances of getting a DVT are significantly higher under some circumstances and it is important you learn about them. Another case of what you don’t know can kill you faster than you can say deep vein thrombosis.

What causes blood clot formation?

Generally, there are several reasons why clots may form. I will limit myself to the risk factors that you may come across as a card carrying member of the CLL club.

  • If you are the proverbial couch potato, or you are a frequent flyer sitting for hours on end in a cramped economy seat immobilized by extra large individuals on either side, you are at increased risk of getting a blood clot in your legs. Blood flows slowly when you are not moving around and that gives it a chance to congeal and form a clot.
  • Other circumstances where immobilization cannot be avoided are hospitalization after surgery, having your leg in a cast etc.
  • Another risk factor for developing blood clots is physical trauma to the walls of a blood vessel, as in a deep bruise. General inflammation of blood vessels increases risk of blood clots.
  • Smoking is a definite risk factor for blood clots. Don’t tell me you are surprised. Smoking is a high risk factor for every bad thing, take my word for it. Would you quit if I told you it makes you go bald? Impotent? Just kidding, I have not seen such studies yet, but one can always hope. Some guys seem to be more worried about going bald than lung cancer or strokes.
  • Did you know that most cancers carry the penalty of increased risk of DVT? I have more to say about this with particular reference to CLL further down in this review; ditto for several drugs popular with our guys.
  • Increased tendency of the blood to clot due to very high platelet counts is not usually a problem we have to worry about – most of our guys have too few platelets on account of CLL. Let me also be clear and point out that increased white blood count in the ranges seen in CLL patients does not cause thickening of blood.
  • There is a very long list of various drugs that increase risk of blood clots.  We discuss a couple of them below.

Some of these risk factors are shown below in the diagram.  “Venous stasis” means slow moving blood flow, say due to sitting in cramped airline seats.  “Vascular injury” is self evident, as in a deep bruise or inflammation of some sort. “Hypercoagulability” is thick and viscous blood, possibly due to specific drugs you may be taking. Any one of these is no big deal. But combine them together and you get a perfect storm.  PC had vascular injury, hypercoagulability due to IVIG therapy and cancer (CLL) – three risk factors that put him over the top for DVT risk.

DVT risk

Cancer and risk of blood clot formation

I was not aware that having active cancer – of any kind – increased risk of thromboembolism (a bit of jargon, means the same thing as blood clots forming and gumming up the works). The very recent article below from Mayo Clinic looked at roughly 1,600 of their patients with blood clots over a period of 17 years (1984 – 2000). After accounting for all other known risk factors, they concluded cancer was an independent risk factor for blood clot formation in the arms, abdomen, legs etc. You are almost twice as likely to have a leg blood clot if you have cancer, compared to the general population.

Mayo Clin Proc. 2011 Jan;86(1):25-30.

The association of active cancer with venous thromboembolism location: a population-based study.

Tafur AJ, Kalsi H, Wysokinski WE, McBane RD, Ashrani AA, Marks RS, Crusan DJ, Petterson TM, Bailey KR, Heit JA.

Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

Abstract

OBJECTIVE: To test active cancer for an association with venous thromboembolism (VTE) location.

PATIENTS AND METHODS: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN, residents with incident VTE during the 35-year period 1966-2000 (N=3385). We restricted analyses to residents with objectively diagnosed VTE during the 17-year period from January 1, 1984, to December 31, 2000 (N=1599). For each patient, we reviewed the complete medical records in the community for patient age, gender, and most recent body mass index at VTE onset; VTE event type and location; and previously identified independent VTE risk factors (ie, surgery, hospitalization for acute medical illness, active cancer, leg paresis, superficial venous thrombosis, and varicose veins). Using logistic regression we tested active cancer for an association with each of 4 symptomatic VTE locations (arm or intra-abdominal deep venous thrombosis [DVT], intra-abdominal DVT, pulmonary embolism, and bilateral leg DVT), adjusted for age, gender, body mass index, and other VTE risk factors.

RESULTS: In multivariate analyses, active cancer was independently associated with arm or intra-abdominal DVT (odds ratio [OR], 1.76; P=.01), intra-abdominal DVT (OR, 2.22; P=.004), and bilateral leg DVT (OR, 2.09; P=.02), but not pulmonary embolism (OR, 0.93).

CONCLUSION: Active cancer is associated with VTE location. Location of VTE may be useful in decision making regarding cancer screening.

PMID: 21193652

How about CLL? Does that increase risk?

I knew sort of vaguely that cancer increased the risk of blood clots. But I did not know that there was any special connection between CLL and blood clots. The latest abstract below puts in concrete terms:

Leuk Res. 2010 Dec 12. [Epub ahead of print]

Chronic lymphocytic leukaemia is a risk factor for venous thromboembolism.

Whittle AM, Allsup DJ, Bailey JR.

Department of Haematology, Queens Oncology Centre, Castle Hill Hospital, Cottingham, East Yorkshire HU16 5JQ, UK.

Abstract

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in cancer patients. The literature is sparse on the incidence in the most common lymphoid malignancy, chronic lymphocytic leukaemia (CLL). We calculated the incidence rates for VTE in an unselected UK CLL clinic population at 1.45% per patient year. This represents a tenfold increase over previously published estimates of incidence in the general population and a twofold increase over that of the local hospital inpatient population. In our cohort, the risk of VTE was related to stage C disease. Clinicians should be aware that CLL patients are at risk of VTE.

PMID: 21156322

Ten times higher risk of VTE (another three letter acronym, stands for venous thromboembolism or if you prefer plain English, blood clots in the veins) for CLL patients than in the general population – especially if you are Stage C disease. Did you know that?

Role of common CLL drugs in blood clots

Even patients who are leery of signing up for chemotherapy are willing to consider therapeutic drugs that help them fight CLL related anemia and infections. IVIG (intravenous immunoglobulin infusions) have been around for awhile. These are immunoglobulin (Ig) molecules collected painstakingly (and very expensively) from many gallons of blood donated by generous volunteers. Since CLL patients invariably fall victim to downward spiral of Ig counts (IgG counts are the ones to focus on), getting IVIG therapy is one way of improving this situation.

Immunoglobulins play a very important role in our immune defenses and CLL is one of a handful of diseases for which IVIG therapy has been formally approved by the FDA. Most physicians do not like to prescribe it and most insurance companies sure as heck do not like to pay for it – it is expensive and often  in chronic short supply – but with persistence it is possible to get IVIG therapy prescribed. Remember, in life you get what you are able to negotiate for yourself.

Immunoglobulin products have become a whole lot safer in recent years, with very strict controls over how they are manufactured and supplied. Blood products always carry a non-zero risk of unanticipated contaminations and cross infections. That risk has diminished greatly over the years. As for allergic responses to IVIG therapy, as long as the drug is administered slowly and proper precautions are taken, most people are able to handle the infusion quite well.

But did you know that IVIG therapy “thickens blood” and high doses of IVIG increase your risk of blood clots significantly? As it turned out, that little fact is what saved my husband back in 2004. I came across this little abstract below as I frantically searched PubMed database on that memorable weekend. PC had just had his routine IVIG therapy and I wondered if it had anything to do with anything. This is what popped up in my search. Who knew. And the author was no one other than my friend Tim Call, who promptly responded to my frantic email confirming the likelihood of DVT as a potential diagnosis, requiring an immediate trip to the emergency room.

Mayo Clin Proc. 2000 Jan;75(1):83-5.

Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: case report and literature review of intravenous immunoglobulin-related thrombotic complications.

Go RS, Call TG.

Division of Hematology and Internal Medicine, Mayo Clinic Rochester, Minn 55905, USA.

Abstract

Thrombosis resulting from intravenous immunoglobulin infusion is a relatively unknown complication. We describe a patient who developed deep venous thrombosis of her left arm shortly after intravenous immunoglobulin administration. In addition, we review the thrombotic incidences reported in the literature and the possible association with hepatic veno-occlusive disease after bone marrow transplantation. Measures that can potentially prevent this complication are discussed.

PMID: 10630762

You can also read a lot more about blood clot issues after IVIG therapy in this Medscape article (you can read the whole article for free, but you may have to login or register to become a member – no charge).

Thrombotic Complications After Intravenous Immunoglobulin Therapy in Two Patients

Geoffrey G. Emerson, M.D., Ph.D., Christopher N. Herndon, B.S., Antoine G. Sreih, M.D.

Conclusion

Intravenous immunoglobulin therapy may be complicated by the development of thrombosis in both arterial and venous circulation. The mechanism that underlies this adverse effect is unknown but may involve alterations in blood viscosity. We recommend caution when treating patients with IVIg, particularly if they have risk factors for thrombosis or if they are obese. When treatment with IVIg is essential, close follow-up should continue for at least 2 weeks after completion of therapy.

Growth Factor drugs

Another popular pick-me-up drug with CLL patients is erythropoietin. “Epo” drugs such as “Aranesp”, “Epogen” and “Procrit” are popular because these growth factors are often able to increase red blood cell counts and hemoglobin levels in anemic patients. Until very recently, manufacturers were even allowed to bombard us with direct-to-consumers advertisement of these “miracle” drugs on TV. I have never been a real fan of these growth factors, please see our earlier articles “Dark side of Epo” and “Getting darker”.

But did you know that one of the risks of treatment with these growth factors is increased risk of blood clots? Below is an abstract in venerable JAMA, an exhaustive review of all clinical information available in the Cochrane database. This is heavy duty stuff folks, as credible as it gets.

JAMA. 2008 Feb 27;299(8):914-24.

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.

Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold PR, Dorr DA, Kuzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M.

VA Chicago Healthcare System, Department of Medicine, Northwestern University Feinberg School of Medicine, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA. cbenne@northwestern.edu

Abstract

CONTEXT: The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs.

OBJECTIVE: To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer.

DATA SOURCES: A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008).

STUDY SELECTION: Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.

DATA EXTRACTION: Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE.

DATA SYNTHESIS: Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20).

CONCLUSIONS: Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

PMID: 18314434

Revlimid (lenalidomide)

The list of chemotherapy drugs that can increase risk of blood clots is too large and frankly beyond my ability to summarize in this article. But one particular drug that deserves special mention – Revlimid (lenalidomide).

Risk of blood clots in multiple myeloma patients treated with Revlimid has been well documented. The manufacturer’s website prominently displays deep vein thrombosis and pulmonary embolism as potential risk factors

DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with MM who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

Not as much is known about potential for blood clots in CLL patients treated with Revlimid. We are Johnny-come-lately to the Revlimid party. MM folks were there long before us. But just about every detailed clinical trial protocol I have seen (but maybe not in the cartoon versions you guys get along with the consent forms) mentions this risk and either mandates concurrent “Coumadin” therapy (Coumadin is used to thin blood, reduce the risk of blood clots) or warns investigators to keep a sharp eye out for problems along these lines and to consider initiating blood thinning regimens immediately if they suspect blood clots. Most protocols require that patients be asked about their prior history of any blood clots as well as other family history of similar problems. A couple of trials have inclusion criteria that make sure they only recruit people who are not contra-indicated for blood thinning therapy, should it become necessary down the road.

Editorial

All of this caution about use of Revlimid and risk of blood clots is prudent, the right way to do things in a manner that protects patients. The problem is that Revlimid is available for use outside of well conducted clinical trials. Who is setting the guidelines for safety of patients being treated with this drug outside of well designed clinical trials?  Where are clearly spelled out “Best Practices”?

I use the term “strip-mall oncologist” as a snarky reference to less than well informed oncologists.  Many of our patients have no choice but to depend on their not-so-well-informed services. How many of them know about the potential risk of blood clots in patients undergoing Revlimid therapy? How many of them read the clearly spelled out risk factors for this drug on the manufacturer’s website, before one of their patients has a for-real DVT or even more dangerous, a heart attack or stroke?

By the way, dexamethasone and other corticosteroid drugs (prednisone, methylprednisolone) are sometimes used to tame down the “tumor flare” reaction associated with Revlimid therapy. Unfortunately, steroid drugs such as these also add to the risk of blood clots.

So, here you are, teensy bit of a couch potato in spite of your best resolutions, with a personal and/or family history of blood clots.  You used to smoke in your distant youth but have succeeded in kicking the habit in recent years.  Well, let’s be honest, we are all friends here – almost kicked the habit.

You are no stranger to steroid drugs; maybe you also needed a few shots of Epo to take the edge off the anemia you had been struggling with in the past. You have pretty late stage CLL  and you are undergoing Revlimid therapy under the supervision of your local oncologist. Suddenly you start experiencing TIA – transient ischemic attacks – mini strokes in layperson language.  TIA is kid stuff that often leads to the full-fledged variety of stroke that can leave you drooling out of the corner of your mouth and confined to your bed for the rest of your life.

And your oncologist says oops, perhaps you should be on blood thinners and maybe we should have been monitoring your PTT (time it takes for blood to clot) on a regular basis. Oops indeed.

I repeat once again, what you don’t know can hurt you. What your oncologist does not know can kill you. If at all possible, try to get experienced medical help, especially if you decide to take a path less traveled and use less well understood drugs and/or their combinations. I realize you may not always have that choice with regard to where you get your medical care. The next best thing is for you, yourself, to be well informed about things that can go bump in the night. That is what we try to do here, teach you things you really need to know, so that you can ask your doctor about them ahead of time, make sure you have covered all your bets as best as you can.

DVT