New Perspective on Smudge Cells

What exactly are smudge cells (also known as basket cells)? In patients with Chronic Lymphocytic Leukemia (CLL), it is a comment used to describe cells that look exactly like that, a cell that has been run over by a steam roller and flattened out. They are formed as a result of the action of the blood being spread out over the glass slide used to make the differential. There are apoptotic lymphocytes , more fragile than regular lymphocytes.
Conventional wisdom was that they were an artefact and only the presence of them was all that was needed to be reported. Some labs went even further by adding a drop of bovine albumin to the blood before making a smear, since this additive preventing the lymphocytes from becoming damaged while the smear was made. Since it is possible for smudge cells to be present in a normal blood smear, the presence of smudge cells by itself do not indicate a pathological condition. Before CLL can be diagnosed, flow cytometry is required.
For patients with diagnosed CLL, the presence of smudge cells was noted, but no measurement of them was done.
Two recent articles may change that:

Johansson P. Et al , ‘Percentage of smudge cells determined on routine blood smears is a novel prognostic factor in Chronic Lymphocytic Leukemia, Leuk Res 2010:34:892-8.

Nowakovski, GS et al, Percentage of smudge cells on routine blood smears predicts survival in chronid lymphocytic leukemia.

Basically a smudge cell is a lymphocyte lacking a protein called vimentin in its cytoskeleton. Vimentin is responsible for the rigidity and integrity of cells, as well as playing a role in activation and transduction. Leukemic cells that are ZAP70/CD38 positive will have vimentin and be resistant to becoming smudge cells and be virulent . Leukemic cells that lack vimentin will become smudge cells and be less virulent.
Therefore a smear from a patient with a high percentage of smudge cells will have less virulent cells and a better outcome than a patient with few smudge cells.
The challenge will be twofold, determining how to consistently identify smudge cells, and how to present the data in a consistent form.

The Medical Laboratory’s role in Systemic Inflammatory Response Syndrome

In 1992, a new syndrome was introduced by the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM), called Systemic Inflammatory Response Syndrome (SIRS). It is defined as 2 or more of the following variables:
- Temperature of more than 38° C or less than 36° C
- Heart rate of more than 90 beats per minute
- Respiratory rate of more than 20 breaths per minute or a PaCO2 level of less than 32 mm HG
- WBC count of >12,000/μL or < 4,000/μL or > 10% bands.
So what happens in SIRS?
Basically some insult occurs to the body which responds by having the basic inflammatory response. Part of that response is the release of cytokines that have the goal of returning the body back to a healthy state. However, if whatever caused the inflammatory response is not treated, or worsens, the amount of cytokines released cause destruction, not healing. This is known as a ‘cytokine storm’, resulting in hypotension leading to end organ dysfunction.
So what can the lab do to help diagnose SIRS?
Measuring cytokines such as Interleukin 6 would help, but this is not practical in most labs.
Being aware of the WBC count is the first step. As noted above, that is one of the criteria that has to be filled in the diagnosis of SIRS. While an elevated WBC is usually indicative of infection, the haematologist must also beware that other causes can cause an increase in the WBC count, such as leukemia and stress. A decrease in WBC isn’t usually associated with sepsis, but because infection can cause the increased transfer (or pooling) of neutrophils to the infection before the bone marrow can respond by releasing more into circulation.
Then there’s the subject of bands. Immature neutrophils, referred to as bands because that’s what the nuclear material in the cell looks like, a band. Under the eye of an experienced haematologist, bands can be identified when a manual differential is done.
Unfortunately, when it comes to the topic of band identification, sometimes it’s easier for theologians to discuss how many angels can stand on the head of a pin than it is for experience haematologist to agree to what a band cell is. Some labs avoid this minefield altogether by lumping in the neutrophil and band count together and leaving it up to a pathologist to comment if there are an increased number of bands present. Trivial point here, the term ‘shift to the left’, was used to indicate an increased number of bands present.
An arterial blood gas can be used to measure the PaCO2 level. If the level is <32 mmHG, that can be indicative of SIRS as well.
One of the cytokines released, Interleukin 6, will stimulate the release of C-Reactive Protein (CRP). An increase of CRP could also help diagnose SIRS.
A positive blood culture could also be a warning sign that SIRS is happening. Sepsis is one of the causes of SIRS.
Not the only cause though, and that is something the lab has to be aware of. Other causes of SIRS include ischemia, trauma or a combination of other insults, such as serious burns.
The important thing to remember is this, SIRS can become a serious threat to the well being of the patient. It is the laboratory’s job to be aware of it, and to help diagnose it.

D-Dimer and DIC

The D-Dimer Test is an important tool for the diagnosis of pathological thrombosis such as Deep Vein Thrombosis (DVT) and Pulmonary Embolism(PE). Being able to identify patients at risk of these cardiovascular diseases can lead to prompt intervention with anticoagulant therapy preventing long term damage or death.
However the D-Dimer can also be used to help diagnose another coagulaopathy, Dessiminated Intravscular Coagulation. Basically something (ie trauma, septicaemia) triggers the coagulation system to initiate clotting. Tiny thrombi are then formed, blocking off the microcirculation and causing red blood cells to fragment, leading to organ dysfunction and anemia.
Unlike DVT and PE though, DIC is not a single entity, but a complex syndrome that has many different causes.
To help determine if a patient has DIC, The Subcommittee on DIC of the International Society on Thrombosis and Haemostasis (ISTH) developed a point system to help determine if "overt" DIC is present:

1. platelet count (more than 100 = 0; less than 100 = 1; less than 50 = 2)

2. elevated fibrin degradation products (FDP) (no increase = 0; moderate increase= 2; strong increase= 3)

3. Prothrombin Time (PT) upper limit of ref. range ( less than 3 secs = 0; more than 3 secs = 1; more than 6 sec. = 2)

4. fibrinogen level ( more than 100 mg/dl = 0; less than 100 mg/dl = 1)

Score of 5: compatible with overt DIC
(Taylor FB Jr, Toh CH, Hoots WK, et al, and the Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327-1330.)
Notably absent from this list is the presence of schistocytes, red cells fragmented from circulating through the microthrombi blocking capillaries.
Platelet counts and PT are standard lab tests. Fibrinogen testing is not. As for elevated FDP, this too was, and still is, not a standard lab test, especially in smaller labs. The FDP test is used to measure the amount of fibrinolysis (breakdown of fibrin) present. It makes sense that in DIC there will be an abnormal amount of fibrin being formed, and at the same time an abnormal amount of fibrinolysis taking place. But one test that can be used to measure fibrinolaysis is the D-Dimer test. An increased D-Dimer test may be used to determine if there is an increased level of elevated fibrin degradation products. However, other conditions can cause an increased D-Dimer, and it is up to the lab to determine what level of D-Dimer will be used as the cutoff to be used in the ISTH grading system mentioned above.
For further information refer to :
Wada H, Gabazza EC, Asakura H, et al. Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the International Society of Thrombosis and Hemostasis (ISTH) and of the Japanese Ministry of Health and Welfare for overt DIC. Am J Hematol. 2003;74:17-22.
So in conclusion; the ISTH has a score to determine if DIC is present, the D-dimer can be used once a cutoff level has been determined for the method used, and the presence of schistocytes cannot be used to diagnose DIC.

Tricorder Watch

So what could be the Holy Grail of diagnostic equipment? The Tricorder®, that workhorse of the Star Trek TV series would be an obvious choice. With it’s flashing lights and whirring noises, it could measure three different parameters, weather patterns, geology and biology.
In the hands of Dr. Leonard ‘Bones’ McCoy the Tricorder® could diagnose any medical mystery. All it took was a few brief waves of his hand and the Chief Medical Officer of the Starship Enterprise was able to tell a dramatic Kirk and a calm Spock what the creature of the week was.
Point of Care (POC) instruments claim to be Tricorder®, but are they? What makes a good Tricorder®?
First of all it has to be portable. POC instruments are certainly that.
Second of all, they have to non invasive. Unfortunately, POC still need to penetrate skin to get a drop of blood in order to provide a result.
Finally, a Tricorder® will not harm the patient. No one ever gets sick because of McCoy placing it over them.
But despite all the promise that this futuristic diagnostic instrument offers, there are still some modern day realities that would have to be considered if tomorrow one was developed.
You still need to train someone how to interpret the data produced. To be effective, it would have to be in the hands of a healer, not a technologist.
Which brings me to the second point; you would still need a technologist to do the QC and maintenance of the Tricorder®. You couldn’t send one on the away team if it wasn’t working properly.
The Labvocate is constantly on Tricorder® watch, and there are a few developments in progress. This will be discussed in the future.

COPD vs. Global Warming

One more thought about COPD. Previously I wrote that there will be a rise in the number of cases of this condition, as well as becoming the third cause of death worldwide.
Why the increase? Air pollution is targeted as the main cause, especially in developing countries that don't have strict emission standards fro automobiles and industry.
So while there is much debate about whether or not climate change is due to air pollution. Has that caused the wild climate changes lately? At the risk of being called a heretic I'll say the jury is still out on that.
However, the rise of COPD is a definite indicator that air pollution needs to be decreased.
Then maybe we can all start breathing alittle bit easier.

COPD- Future Diagnostic Challenge

If you were to have a group of 100 Canadians in a room, four of them would have heart disease, one of them would be newly diagnosed with cancer, eight would have kidney disease and three of them would have type one diabetes. You would need to have a room holding a thousand Canadians before you would find one with AIDS.
But back to that original room of one hundred, there would a significant amount coughing and hacking from COPD (Chronic Obstructive Pulmonary Disease), twenty five percent to be exact. Currently, COPD is the fourth cause of death in the world, behind heart disease, CVA and lower respiratory infections.
Yet this is a condition that goes largely undiagnosed and treated until it is too late.
Why?
One reason could be that COPD is a broad based term for a number of different diseases. It also doesn't have a set criteria of classification. When does that annoying cough you've had for a month actually become defined as COPD?
But one reason it may go undiagnosed is because the test used to test for COPD is not found in the traditional medical disciplines of Medical Laboratory Science or Diagnostic Imaging. COPD is diagnosed by a test called spirometry.
This procedure measures airflow from lungs and determines if there are any obstructions present which could be causing COPD.
In 2000, it was estimated that 13 million Americans were undiagnosed with COPD. An office version of spirometry would be used the measure the forced expiratory volume at 6 seconds (VEV6) to screen for COPD.
Whatever version of spirometry used, this a test diagnostic facilities should investigate the feasibility of implementing. Accreditation agencies should also be involved to make sure that all spirometry testing is standardized. Finally, clinicians and patients should be educated about this test and the impact COPD will have on Canada's healthcare system.
If anything, it will help those 1 in 4 Canadians breathe a little bit more easier.

Apologies

First of my apologises for neglecting this blog. The last year has been an exciting one, 'thriving on chaos' as Tom Peters would put it. Hopefully I will be able to soon expand on that.
It is gratifying to see that there are people who read this blog and I thank them.
So what will I be trying to achieve with this blog in the following year?
First of all, I'm going to shoot for at least one posting per week.
Second of all, I'm going to still focus on matters concerning laboratory medicine.
But I'm going to add reflections on what I've been doing for the last year. I will be referring to Tom Peters and William Demings more this year. I might even throw in some references to the Book of Job as well, since I think that should be required reading for anyone working in Health Care.
Finally, I will be adding some posts about how lab medicine is affecting my own personal health.
Thank you for taking the time to read my posting. I look forward to your thoughts and comments.
Regards,
Mark Hawkins