Kounis Syndrome: Subtypes and effects of mast cell mediators (Part 1 of 4)

Kounis Syndrome (KS) is an acute coronary syndrome that arises as a direct result of mast cell degranulation during an allergic or anaphylactic reaction.

KS usually presents as chest pain during an acute allergic or anaphylactic reaction. There are three recognized variants:

Type I: Patient has no predisposing coronary artery disease.

There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Coronary artery spasm that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

Type II: Patient has history of coronary artery disease. There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Plaque erosion or rupture that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

Type III: Patient has history of coronary artery disease and a drug eluting coronary stent. There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Thrombosis that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

A number of mast cell mediators have effects that can cause coronary spasm or thrombosis.  Beyond their direct effects, they also perpetuate an inflammatory cycle that results in activation and infiltration by inflammatory cells

Mediator Effect
Histamine Coronary vasoconstriction, activation of platelets, increase expression of tissue factor
Chymase Activation of interstitial collagenase, gelatinase, stromelysin resulting in plaque rupture, generation of angiotensin II, a powerful vasoconstrictor
Cathepsin D Generation of angiotensin II, a powerful vasoconstrictor
Leukotrienes (LTC4, LTD4, LTE4) Powerful vasoconstrictor, levels increased during acute unstable angina
Tryptase Activation of interstitial collagenase, gelatinase, stromelysin resulting in plaque rupture
Thromboxane Platelet aggregation, vasoconstriction
PAF Vasoconstriction, aggregation of platelets
Platelets Vasoconstriction, thrombosis

 

References:

Kounis Syndrome (allergic angina and allergic myocardial infarction). Kounis NG, et al. In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Symptoms, mediators and mechanisms: A general review (Part 2 of 2)

 

Gynecologic symptoms    
Symptom Mediators Mechanism
Irregular and painful menstruation Histamine (H1), bradykinin Smooth muscle constriction
Uterine contractions Histamine (H1), serotonin, bradykinin Smooth muscle constriction

Increased estrogen

 

 

Neurologic symptoms    
Symptom Mediators Mechanism
Appetite dysregulation Histamine (H1), histamine (H3), leptin Dysfunctional release of neurotransmitters, suppression of ghrelin
Disorder of movements Histamine (H2), histamine (H3) Dysfunctional release of neurotransmitters, increases excitability of cholinergic neurons
Memory loss Histamine (H1), histamine (H3) Dysfunctional release of neurotransmitters
Headache Histamine (H1), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

Low serotonin

 

Decreased blood flow to brain

Depression Serotonin (low), TNF, histamine (H1) Low serotonin

Disordered release of dopamine

Irregular sleep/wake cycle Histamine (H1), histamine (H3), PGD2 Dysfunctional release of neurotransmitters
Brain fog Histamine (H3), inflammatory cytokines Dysfunctional release of neurotransmitters, neuroinflammation
Temperature dysregulation Histamine (H3) Dysfunctional release of neurotransmitters, dysfunctional release of catecholamines

 

 

Miscellaneous symptoms    
Symptom Mediators Mechanism
Bleeding diathesis (tendency to bleed easily) Tryptase, heparin Participation in anticoagulation pathways

IgE-independent anaphylaxis; or, I haven’t been this excited on a Tuesday night in a long time

Mast cell patients are intimately familiar with the phenomenon of testing positive for allergies to things you know aren’t problems and negative for things that almost killed you.  If you ask any health care provider what the allergy antibody is, they will say it is IgE.  And for the most part, that is true.  But mast cell patients suffer reactions that do not demonstrate an IgE pathway to their allergies and anaphylaxis, and it is reason most of us suffer for years before being diagnosed correctly.

The idea that anaphylaxis is a function directly executed by IgE is a deeply ingrained part of western medicine.  In this model, IgE specific for an allergen binds to the allergen, and binds to the IgE receptor on mast cells and basophils, resulting in massive degranulation.

This is the classic model of anaphylaxis, with some creative license:

  1. You come into contact with something. Let’s say it’s Peanut, an anthropomorphic peanut.
  2. Immune cells called B cells think they once saw Peanut in a dark alley behind a bar. Peanut could have been waiting for a ride like any responsible peanut who has been drinking, but dark alley = shady = Peanut is trouble.
  3. The B cells make “Wanted!” posters with a picture of the peanut on it. Many, many posters.
  4. The B cells make lots of IgE to make sure every cell in the body sees the Wanted! posters. There will be nowhere for peanuts to hide. (I swear that as I was typing, I just heard the theme to the Good, the Bad and the Ugly.  I SWEAR.)
  5. Everyone knows that Peanut is a bad guy. They have seen the poster many times.  They do not need to see it again.  Do not show the poster again.  WE KNOW PEANUT IS BAD, IGE.  GO HOME, IGE, YOU’RE DRUNK.
  6. You guys know what happens next.  Peanut shows up.
  7. Someone remembers that IgE has been coming around the bar with the poster of Peanut. Peanut = bad guy.
  8. Everyone is hoping that if they tell IgE where Peanut is that IgE will leave them alone. No one really likes IgE but he is making such a big deal about Peanut and maybe Peanut is bad.  A little bad.  No one really knows but they know they do NOT want to deal with IgE if Peanut gets away.
  9. IgE and Peanut have a Western style gun duel at high noon. IgE captures Peanut by binding to him.
  10. While IgE is bound to Peanut, he also binds to a mast cell, which is like home base. IgE knows that Peanut is trouble and he is part of a Peanut gang and they are all bad, too.
  11. Mast cells deploy the tanks, duckboats, submarines, helicopters and fighter planes in the early allergy response to fight the Peanut gang. This causes massive inflammation with effects throughout the whole body.  Mediators released in the early response include histamine and tryptase.
  12. Mast cells start building more defenses and release them a little at a time later on in the late allergy response. Mediators released in the late response include prostaglandins and leukotrienes.

But we all know that it doesn’t always happen like this, because mast cell patients often have normal tryptase and IgE despite having a massive anaphylactic event, or even normal histamine or prostaglandins.

Last month, a comprehensive paper described alternative anaphylaxis pathways in mice that may be analogous to what is happening to mast cell patients having anaphylaxis that is not mediated by IgE.  That is to say, this pathway needs more research to know for sure if it is what is happening to us, but I have been watching the literature on this closely for a while and I100% think this is real.

There have now been multiple reports of the ability to induce anaphylaxis in mice while interfering with the IgE allergy pathway (either by not making IgE or the IgE receptor, or by treating the mice with anti-IgE, which blocks the IgE from binding to the receptor). Scientists found that by anaphylaxis could be mediated by IgG if the trigger was given intravenously. In particular, they were able to identify the murine IgG2b as the antibody subclass responsible.  In mice, IgG2b can cause anaphylaxis when IgE is not able to participate, at all.

The most important mediator in IgE anaphylaxis is histamine.  But the most important mediator in IgG anaphylaxis is platelet activating factor (PAF).  PAF levels have been linked with severity of anaphylaxis previously (I wrote a post about this around this time last year).  This could explain why many patients have normal tryptase, n-methylhistamine or histamine levels despite a very short amount of time elapsed from anaphylaxis. This is not a histamine show.  And maybe the reason so many mast cell patients cannot get complete relief despite taking huge doses of antihistamines is because histamine isn’t the PRIMARY issue.  (Author’s note: Please do not stop taking your antihistamines.  I love my antihistamines.  Just saying I think maybe there is something happening above histamine in these reactions.)

It’s also not just a mast cell show.  IgG can activate basophils, monocytes and macrophages, and neutrophils to release PAF.  Human neutrophils can mediate IgG dependent anaphylaxis when infused into mice.  So now we have a mechanism for anaphylaxis that is not IgE independent – it can also be mast cell independent.  Mind blowing. (Worth mentioning here that the phenomenon of mast cell independent anaphylaxis is not new or specific to IgG anaphylaxis – groups have found instances of mast cell independent anaphylaxis for almost thirty years.)

PAF levels are much higher in anaphylaxis patients than in control patients, and the enzyme that degrades PAF, called PAF acetylhydrolase, is much lower. It is important to note that binding at the IgE receptor can also produce PAF, but that also causes degranulation and release of histamine and tryptase, which seems to be absent in some patients.

To induce IgG mediated anaphylaxis, you need more allergen than for IgE anaphylaxis.  A lot more. 100-1000x more.  So in mice that have both IgE and IgG for peanut (not really peanut), doesn’t it seem like the IgE would react first to the peanut, and you would have IgE anaphylaxis?  But that’s not what happens.  What happens is that the IgG scoops up the peanut faster than the IgE can.  The IgG can block IgE anaphylaxis.  (WHAT UP MAST CELL PATIENTS DOING WAY BETTER ON IVIG?!?!)

IgG anaphylaxis in mice has been exclusively isolated to triggers administered intravenously.  The reason this fact matters is because of the frequency with which people (who don’t always have mast cell disease) have anaphylaxis to intravenous antibody treats, like IVIG, monoclonal antibodies for treating various diseases, or transfusions (which contain IgG antibodies). Treatments of this kind provide a huge influx of allergen. This pathway favors IgG anaphylaxis over IgE anaphylaxis because of how the IgG will scoop the allergen up (see previous paragraph).

As a final aside, there is also the curious fact that a group of patients with CVID (common variable immunodeficiency, a primary immunodeficiency disease) have a mutation that makes one of the IgG receptors found on cells like mast cells WAY more active.  The CVID patients with this mutation also have antibodies to IgA and experience anaphylaxis after IVIG.

I know I have gone on and on but this is the most exciting thing to happen to tryptase and histamine normal anaphylaxis patients in the last decade, at least.  There is SO much work that needs to be done.  Mouse and human mast cells are different.  Mouse and human IgG antibodies are different.  They could not induce food allergy in mice with an IgG dependent mechanism.  We need to pursue research on the role of PAF specifically in anaphylaxis patients with normal tryptase and histamine.

But now, when you tell your doctor that anaphylaxis is not always IgE dependent, you can give them a reference to a solid paper that fairly describes the findings, the caveats and the strengths of the current research on IgE independent anaphylaxis.  And it’s not just speculation. PEOPLE OUTSIDE OF MAST CELL DISEASE RESEARCH GROUPS ACKNOWLEDGE THAT THIS IS REAL.  IGE INDEPENDENT ANAPHYLAXIS IS REAL.

Boom.

Someone hold my Epipens while I make my dog dance with me.

Reference:

Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol 2016.

 

Cardiovascular manifestations of mast cell disease: Part 4 of 5

Heart failure is uncommon in mast cell patients, but is noteworthy as a condition that involves mast cell activation.  One study of adults with SM found 12 patients out of 548 had congestive heart failure.  A small study with 18 MCAS patients found that persistent mast cell activation did not affect such parameters as systolic left ventricular function, systolic and diastolic left ventricular diameter, or shortening fraction.  These markers are often tied to heart failure. In that same study, 12/18 MCAS patients did exhibit a diastolic left ventricular dysfunction.  This defect is a sensitive indicator of changes to the myocardium, muscle around the heart and can be found using Doppler imaging. Five of those MCAS patients also showed hypertrophy in the left ventricle, a thickening of tissue that can be linked to heart damage.

Importantly, these findings were not linked to chronic heart failure in this population.  Mast cell patients should be aware that while these anatomical changes of the left ventricle may be present, there is not currently any indication that their increase the frequency of symptomatic heart failure in this population.  Mast cells are heavily involved in tissue remodeling and it is possible that local mast cell activation can lead to laying of additional tissue or scarring.  Tryptase, chymase and matrix metalloproteinases, all released by mast cells, participate in tissue remodeling and fibrosis.

Tryptase has been associated with both heart failure and atherosclerosis, involved in coronary disease and syndromes.  A number of other mediators can also contribute to heart failure, including histamine, platelet activating factor, IL-4, IL-6, IL-10, TNF, fibroblast growth factor (FGF) and transforming growth factor beta (TGFB).

Treatment of heart failure in mast cell patients is not terribly different from that of the general population.  Diuretics are often used first, including furosemide. Angiotensin receptor antagonists like losartan are good choices for mast cell patients since ACE inhibitors and beta blockers should be avoided wherever possible.  Calcium channel blockers like verapamil can be used. Spironolactone or similar medications may provide additional benefit. Ivabradine, a newer medication that works by affecting the funny current (Author’s note: Not a joke!  My favorite pathway name), is also a consideration.  Digoxin is appropriate for atrial fibrillation (afib) where other attempts to correct rhythm have failed.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

Cardiovascular manifestations of mast cell disease: Part 3 of 5

Recurrent or perpetual elevation in blood pressure has been observed in multiple studies and may affect up to 31% of patients with mast cell activation disease (systemic mastocytosis, mast cell activation syndrome/disorder, monoclonal mast cell activation syndrome). Despite this high prevalence, many providers continue to believe that this symptom cannot be inherently from mast cell activation.

A number of mast cell mediators are vasoconstrictors, narrowing the blood vessels and elevating blood pressure. Histamine can both increase and lower blood pressure depending on which receptor it acts upon (H1: hypotension; H2: hypertension).

Several mediators participate in the angiotensin-renin pathway. Angiotensin II, the level of which is largely determined by mast cell mediators like renin, strongly elevates blood pressure. Chymase, involved in the angiotensin-renin pathway, can also either increase or lower blood pressure depending on concentration relative to other mediators present. Carboxypeptidase A can also affect angiotensin II level as well. Renin regulates the level of a molecule that becomes angiotensin II and can increase blood pressure this way.

Phospholipases, which help produce the molecule needed to make prostaglandins, leukotrienes and thromboxanes can contribute to either high or low blood pressure depending upon which molecule is made. Prostaglandin D2 (PGD2) is a vasodilator, lowering blood pressure; but its metabolite, 9a,11b-PGF2, increases blood pressure. (Author’s note: I personally believe this to be the reason for the rapid blood pressure fluctuations in mast cell patients, but do not have evidence to directly support this.) Thromboxane A2, a molecule related to prostaglandins and leukotrienes, increases blood pressure, as do leukotrienes.

Management of high blood pressure is complicated in mast cell patients by the interaction of common antihypertensives with mast cell activation. Beta blockers are contraindicated in mast cell patients because they interfere with epinephrine, both naturally produced and medicinally.  Use of beta blockers is a risk factor for fatal anaphylaxis.  Any patient on beta blockers that carries an epipen should also carry a glucagon pen, which can be administered prior to the epipen to increase efficacy.

ACE inhibitors interfere with angiotensin converting enzyme, which increases blood pressure through the angiotensin II pathway.  ACE inhibitors affect bradykinin levels, a mast cell mediator that is also mast cell activating.  For this reason, ACE inhibitors can increase mast cell reactivity and symptoms like angioedema.

Author’s note:  I extended this series to four posts to discuss heart failure in mast cell patients.  Following this series, I will be posting a series dedicated exclusively to Kounis Syndrome, including diagnosis and treatment.  Sit tight!

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

 

Mast cells in vascular disease: Part 3

Aneurysms are formed when elastic tissue is degraded by proteases and MMPs; the vessel is thinned due to smooth muscle loss; and the endothelium is broken down, resulting in inflammation. There is a significant body of evidence linking aneurysm formation and growth to mast cell activity.

A number of studies have found that mast cells are present in larger numbers in vasculature near aneurysms. Mast cells are increased in cerebral arteries of patients who died from subarachnoid hemorrhage. In particular, mast cell number is higher in arteries close to the rupture site. Mast cell count has been linked previously to aneurysm instability. Another study found that activated mast cells were increased in the aortas of patients who died from abdominal aortic aneurysms. Increased mast cells are also found in ascending aortic aneurysms. Mast cell density is a predictor for occurrence of ascending aortic aneurysm.

Chymase activity has been heavily implicated in aneurysm physiology. One study found that levels of angiotensin II were unlikely to induce development of aneurysm, but that degradation of the vessel by chymase may weaken the aneurysm and increase risk of rupture. Increased chymase activity was found in an additional fourteen patients having aortic aneurysms repaired. In thoracic aortic aneurysm patients, chymase positive mast cells were found in inflamed areas. Chymase may participate in the generation of reactive oxygen species. In abdominal aortic aneurysm samples, most players in the renin-angiotensin system, including chymase and cathepsins, are increased.

Serpin A3, a protease inhibitor, normally regulates activity of elastase, chymase and cathepsin G. It is thought that deficiency of this molecule may worsen damage caused by chymase.

Mast cell proteases, like tryptase and chymase, may be involved in the formation of aneurysms. Erosion of the endothelium occurred in the thrombosed region of the vessel, followed by decreased oxygen supply to the underlying vessel. Tryptase and chymase may participate in rupture of the vessel and intravascular hemorrhage. Adrenomedullin, a mast cell mediator, is found to be strongly expressed in mast cells to local to aneurysms. Adrenomedullin suppresses formation of the extracellular matrix.

Serum tryptase levels in abdominal aortic aneurysms correlated well with growth of aneurysm as well as risk of complications during repair. Tryptase deficient mice were completely protected against developing this type of aneurysm. Tryptase deficiency reduced expression of cathepsins, as well as activation of endothelial cells and movement of monocytes. Tryptase induces release of cathepsins that trigger apoptosis, so this may be a mechanism.

5-lipoxygenase is the enzyme that drives leukotriene formation. Mice deficient in this molecule were protected against aneurysm formation. They also had less inflammation and apoptosis, lower IL-6 and IFN-γ. Mast cell degranulation augmented aneurysm formation while mast cell stabilizer cromolyn decreased it. Another study found that treatment with tranilast, another mast cell stabilizer, decreased the diameter of the aorta.

Leukotriene C4 and 5-lipoxygenase are increased in patients with abdominal aortic aneurysms, but leukotriene B4 is not. Leukotrienes increase release of MMPs and encourage matrix degradation. Leukotrienes may be a therapeutic target to slow aneurysm progression.

References:

Kennedy, Simon, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53-65.

Bot, Ilze, et al. Mast cells: Pivotal players in cardiovascular diseases. Current Cardiology Reviews, 2008, 4, 170-178.

 

Progression of mast cell diseases (Part 3)

What causes aberrant mediator release in mast cell activation diseases (including MCAS and SM)?

“Selective release of mediators during mast cell activation may be accomplished in three important and possibly interrelated ways. One is by activation via one of the mast cell’s non-IgE receptors, for instance, through the activation of the IL-1 receptor… Another way in which mast cells may selectively activate is through ‘piecemeal’ release of mediators stored in the secretory granules (such as histamine and serotonin)… Lastly, downstream signaling pathways may affect mast cell activation… Differential activation of mast cells in any of these ways may clinically manifest as nc-MCAS.” (Cardet 2013)

“It is also conceivable that mast cells in this group of patients may aberrantly possess a lower threshold to release mediators… It is also conceivable that patients with nc-MCAS are symptomatic because of an abnormal tissue response to physiologically appropriate release of MC mediators.” (Cardet 2013)

“The mutations underlying systemic MCAD drive aberrant mediator production/release with or without readily histologically detectable mast cell accumulation. Mast cell accumulation is due predominantly to a decrease in mast cell apoptosis (refs 30,31 and further references therein). On a limited scale, it is also due to an increase in proliferation.” (Haenisch 2012)

 

Do all SM patients have elevated n-methylhistamine and prostaglandin F2a?

71% had elevated urinary histamine in 24 hr test; 81% had elevated urinary n-methylhistamine in 24 hr test; 75% had elevated urinary PGF2a in 24 hr test. (Lim 2009)

 

If my tryptase is normal, does that mean I don’t have SM?

In patients tested, 96% had elevated tryptase over 11.5 ng/ml. (Lim 2009)

“20% to 30% of SM patients have serum tryptase levels below the WHO-defined threshold of 20 ng/mL (sensitivity 80%, specificity 98%).” (Pardanini 2013)

 

If my blood test for the D816V mutation is negative, I definitely don’t have it, right?

“The sensitivity of KITD816V detection in peripheral blood is suboptimal, and tests for non-KITD816V mutation screening may not be readily available.” (Pardanini 2013)

“I prefer using DNA from BM aspirate for KITD816V screening given the low sensitivity of peripheral blood in this regard… Using this approach, we found 78% of ISM patients to harbor KITD816V.” (Pardanini 2013)

“Although, the sensitivity of KITD816V detection may be higher when using sorted or purified mast cells, this option is not routinely available. Consequently, the inability to detect KITD816V in peripheral blood does not exclude SM [].” (Pardanini 2013)

 

How often do SM patients not meet the major diagnostic criteria (mast cell aggregates)?

“Attempts at validating the WHO diagnostic criteria reveal that approximately 20% of ISM patients lack mast cell clusters in the BM and approximately 30% exhibit a serum tryptase level < 20 ng/mL.” (Sanchez 2011)

 

Is MCAS the same as HIT (histamine intolerance)?

“[S]ome have proposed that a deficiency in the enzymes responsible for histamine metabolism, diamine oxidase (DAO) and histamine N-methyltransferase, leads to excess levels of histamine and therefore histamine intolerance, with clinical manifestations not unlike those described for nc-MCAS… There is no scientific literature to support their relevance to nc-MCAS.” (Cardet 2013)

 

Are MCAS patients usually positive for the three most commonly tested mediators (tryptase, n-methylhistamine, PGD2?)

“Although all of our patients with MCAS had a positive test result for at least 1 MC mediator, only 33%, 56%, and 44% of the patients had positive test results for tryptase, histamine, and PGD2, respectively.” (Hamilton 2011)

 

Will my MCAS symptoms ever get better?

“Most patients with MCAS in our cohort who were treated with anti-MC mediator medications responded dramatically. After an average of 4.6 years of MC-related symptoms, 66% of the patients with MCAS achieved a complete or major regression in symptoms to MCAS treatment.” (Hamilton 2011)

“It is important to mention that no defining characteristics (eg, presence of allergies or history of anaphylaxis) could be identified that distinguished those who had a complete regression in symptoms versus those who did not.” (Hamilton 2011)

“The most impressive treatment responses were for abdominal pain (14/17 of the patients who initially had the symptom responded), headache (12/15), poor concentration and memory (7/12), and diarrhea (9/12); there was a more modest response to flushing (6/16). We also found that all but 1 of our patients with MCAS had a sustained response to anti-MC mediator medications. Patients in our cohort were followed for an average of 2.8 years (range, 1-4 years).” (Hamilton 2011)

“In patients with MCAS the rate of response to antimediator therapy is rather good, with 33% showing complete response, 33% a major response, and 33% a minor response after 1 year of treatment.” (Picard 2013)

 

How prevalent is MCAS?

“MCAS seems to be a more common disorder. Evidence has been presented that MCAS may be an underlying cause of various clinical presentations, e.g. in subsets of patients with fibromyalgia and irritable bowel syndrome. Hence, the prevalence of MCAS is likely to lie within the single-digit percentage range.” (Haenisch 2012)

“Mast cell activation disease in general has long been thought to be rare. However, although SM and MCL as defined by the WHO criteria are truly rare, recent findings suggest MCAS is a fairly common disorder. Evidence has been presented for a causal involvement of pathologically active mast cells not only in the pathogenesis of SM and MCAS but also in the etiology of idiopathic anaphylaxis, interstitial cystitis, some subsets of fibromyalgia and some subsets of irritable bowel syndrome.” (Molderings 2011)

 

References:

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

LimKH, TefferiA, LashoTL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113(23): 5727-5736.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Animesh Pardanani. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) April 18, 2013; Blood: 121 (16).

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.

 

MCAS: Blood, bone marrow and clotting

One of the reasons MCAS is so difficult to diagnose is because it often has no effect on routine blood work.  Mast cells leave the bone marrow early in their lives, circulate in the blood stream very briefly, and then live in peripheral tissues for life spans of several months to about three years.  The reason many MCAS patients have no obvious hematologic abnormalities is that mediator release in these peripheral tissues usually doesn’t affect generation of blood cells or the blood cells already circulating. 
Hematologic issues are more commonly found in proliferative disease, like SM.  Still, one study found that in SM patients, random bone marrow biopsies missed the diagnosis 1/6 of the time.  For patients in whom SM is suspected, a second BMB can be helpful and bilateral biopsies are being ordered more frequently. 
MCAS patients very rarely have increased numbers of mast cells, spindled cells, CD2/25 receptor expression or the CKIT D816V mutation.  On examination of marrow, when irregularities are found, they are off a mild “myeloproliferative/myelodysplastic” nature, which sometimes leads to a diagnosis of MDS.  These patients do not respond to MDS treatments.
When serum tryptase is less than twice the upper limit of normal, BMB is not recommended due to how infrequently abnormalities are found.  Even during reactions, MCAS patients usually have normal tryptase values.  In recent years, a tryptase of 20% + 2 ng/ml above baseline has become regarded as evidence of activation, but this is not universally accepted.
MCAS patients often have normal blood counts, white blood cell differentials and bone marrow findings.  But there is now a growing population of MCAS patients with evident abnormalities.  Elevation of monocytes is the most common irregularity, followed by elevation of eosinophils, and then elevation of basophils.  High reactive lymphocytes are often identified in these patients on manual differential.  White blood counts can be high or low, often for no clear reason, and usually mild, but sometimes severe.  Likewise, platelets can be high or low, which sometimes garners patients a diagnosis of essential thrombocytosis or immune thrombocytopenia. 
Overproduction of red blood cells can occur to excessive release by mast cells or other cells of mediators stimulating production.  Sometimes patients are originally diagnosed with and treated for polycythemia vera, but do not improve. 
Poor clotting and easy bruising is found in a lot of MCAS patients due to activation that releases heparin.  By itself, it does not typically require treatment.  The bleeding is often localized, such as excessive bleeding from a surgical site but clotting correctly elsewhere.  Antihistamines typically help, with protamine being reserved for severe cases and transexamic acid and aminocaproic acid being reserved for the most severe.
Thromboembolism, formation of a clot in one vessel that breaks away and impedes blood flow in another vessel, is not rare in MCAS patients, even those with normal coagulation labs.  Some patients have low or high PT or PTT values.  Antiphospholipid syndrome should be excluded. 
Heparin released by mast cells activates anti-thrombin III and factor XII, which activate the rest of the intrinsic clotting cascade.  Heparin also stimulates the formation of bradykinin, which in turn causes vascular dilation and loss of fluid volume from the vessels into the tissues.  This is notable as a non-histamine route that can cause angioedema, low blood pressure and fainting in MCAS patients.

References:
Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
Sur R. Cavender D. Malaviya R. Different approaches to study mast cell functions. Int. Immunopharmacol. 2007 May; 7(5):555-567.
Butterfield JH, Li C-Y. Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient? Am. J. Clin. Pathol. 2004; 121:264-267.

Mast cell mediators: Recommended testing for MCAS diagnosis

Lab tests specific to mast cell activation for suspected MCAS patients should include serum tryptase, serum chromogranin A, plasma histamine, chilled plasma PGD2, stat chilled plasma heparin, chilled urine for PGD2, PGF2a and n-methylhistamine. 
Tryptase is the most famous mast cell mediator.  It is a complex molecule with many functions in the body.  It is easily damaged by heat and has a short half-life in the body (6-8 minutes in health subjects, 1.5-2.3 hours in patients with hypersensitivity reactions.  In separated serum, it can last approximately four days.  Serum tryptase value is usually normal in MCAS patients, but sometimes it is elevated.  Tryptase values that show an increase of 20% + 2 ng/ml above the baseline level are considered diagnostic for MCAS.
Chromogranin A is a heat-stable mast cell mediator.  High levels can suggest MCAS, but other sources must first be ruled out, such as heart failure, renal insufficiency, neuroendocrine tumors and proton pump inhibitor (PPI) use.  Starting or stopping PPI therapy will generally cause a change in value within five days.  Once other causes have been excluded, serum chromogranin A can be considered a reliable marker of mast cell activity. 
Heparin is a very sensitive and specific marker of mast cell activation.  However, due to its quick metabolism in the body, it is very difficult to measure reliably.  It has a very short half life and quickly deteriorates, even when refrigerated.  Values above 0.02 anti-Factor Xa units/ml are abnormal, but many commercial tests cannot test that low.  Elevated plasma heparin is sometimes found in MCAS patients. 
Histamine is also released by basophils, but the majority is released by mast cells.  It is heat stable and has a short half life in the body.  Serum histamine peaks at about 5 minutes after release and returns to baseline within 15-30 minutes in most patients.  In separated plasma, it is stable at room temperature for at least 48 hours.  It is broken down to n-methylhistamine, which is more stable and can be measured accurately longer.  N-methylhistamine is usually measured in a 24 hour urine test to account for the variability in release over the course of the day. 
Prostaglandin D2 is produced by several other cell types, but mast cell release is responsible for the dominant amount found in the body.  MCAS patients typically produce much higher levels of PGD2 than n-methylhistamine.  PGD2 is less stable than histamine, being metabolized completely in an estimated 30 minutes.  Its metabolite, PGF2a, is the preferred compound for detection due to its superior stability.    Accurate prostaglandin testing relies upon refrigeration of the sample from the start of collection through testing.  NSAIDs inhibit prostaglandin production and can lower PGD2 in blood and urine.  Renal insufficiency may produce an inaccurately low test value, but elevated prostaglandins are sometime seen in patients with renal disease.  Prostaglandins D2 and F2a can be tested in serum, but 24 hour urine samples are considered more accurate.

Leukotriene B4 and cysteinyl leukotrienes C4, D4 and E4 have been noted to be elevated in SM patients and during acute asthma attacks.  Though commercial testing for these compounds is not easily accessible, but they may be elevated in MCAS patients as well.  Other less specific mast cell mediators that are sometimes abnormal in MCAS patients include Factor VIII, plasma free norepinephrine, tumor necrosis factor alpha, and interleukin-6.

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