The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 76

I get asked a lot about how mast cell disease can affect common blood test results. I have broken this question up into several more manageable pieces so I can thoroughly discuss the reasons for this. The next few 107 series posts will cover how mast cell disease can affect red blood cell count; white blood cell count, including the counts of specific types of white blood cells; platelet counts; liver function tests; kidney function tests; electrolytes; clotting tests; and a few miscellaneous tests.

89. How does mast cell disease affect platelet counts?

Before I continue, I want to explain one basic fact. Even though they are often included in the term “blood cells”, platelets are not actually cells. They are actually pieces of an original large cell called a megakaryocyte that lives in the bone marrow. Even though platelets are not really cells, they more or less act like they are.

An unusual thing about platelets is that sometimes a specific trigger can cause platelets to become lower or higher.

There are several ways in which mast cell disease can make platelet counts lower.

  • Swelling of the spleen. This can happen in some forms of systemic mastocytosis, and may also happen in some patients with mast cell activation syndrome, although the reason why it happens in MCAS is not as clear. Swelling of the spleen can damage blood cells and platelets, causing lower platelet counts. If the spleen is very stressed and working much too hard, a condition called hypersplenism, the damage to blood cells and platelets is much more pronounced. This may further lower platelet counts. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
  • Medications. Some medications that are used to manage mast cell disease can cause low red blood cell count. Chemotherapies, including targeted chemotherapies like tyrosine kinase inhibitors, can cause low platelet counts. Non steroidal anti-inflammatory drugs (NSAIDs) are used by some mast cell patients to decrease production of prostaglandins. They can interfere with platelet production in the bone marrow. Proton pump inhibitors, often used by mast cell patients to help with GI symptoms like heart burn, can decrease platelet coun Some H2 antihistamines can also lower platelet production. However, none of these H2 antihistamines are currently used in medicine.
  • Heparin induced thrombocytopenia. Mast cells make and release large amounts of heparin, a powerful blood thinner. When there is an excessive amount of heparin circulating, it can cause your body to incorrectly produce antibodies that cause an immune response to heparin. A side effect of this situation is that platelets are activated incorrectly, which can lead to the formation of blood clots and low platelet counts. Heparin induced thrombocytopenia has only been definitively described in patients who receive medicinal heparin as a blood thinner. However, it is reasonable to assume that this situation can also affect mast cell patients who have higher than normal levels of platelets circulating in the blood.
  • Liver damage. Liver damage is associated with malignant forms of systemic mastocytosis such as aggressive systemic mastocytosis and mast cell leukemia. Liver damage can also occur as the result of IV nutrition, which is sometimes needed by patients with mastocytosis or mast cell activation syndrome. When the liver is damaged enough, it may not make enough of the molecules that tell the bone marrow to make platelets.
  • Excessive production of blood cells. In very aggressive forms of systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia, the bone marrow is making huge amounts of mast cells. As a result, the bone marrow makes fewer platelets and cells of other types.
  • Vitamin and mineral deficiencies. Chronic inflammation can affect the way your body absorbs vitamins and minerals through the GI tract, and the way it uses vitamins and minerals that it does absorb. Deficiency of vitamin B12 or folate can decrease platelet production.
  • Excess fluid in the bloodstream (hypervolemia). In this situation, the body doesn’t actually have too few platelets, it just looks like it. If your body loses a lot of fluid to swelling (third spacing) and that fluid is mostly reabsorbed at once, the extra fluid in the bloodstream can make it look like there are too few platelets if they do a blood test. This can also happen if a patient receives a lot of IV fluids.

There are also reasons why mast cell disease can cause the body to make too many platelets.

  • Anemia of chronic inflammation. This is when chronic inflammation in the body affects the way the body absorbs and uses iron. It can result in iron deficiency. Iron deficiency can increase platelet counts.
  • Hemolytic anemia. In hemolytic anemia, the body destroys red blood cells. This can happen for several reasons that may be present in mast cell patients. Hemolytic anemia can increase platelet counts.
  • Iron deficiency. Iron deficiency for any reason can elevate platelet counts.
  • Excessive bleeding. Mast cell disease can cause excessive bleeding in several ways. Mast cells release lots of heparin, a very potent blood thinner that decreases clotting. This makes it easier for the body to bleed. It is not unusual for mast cell patients to have unusual bruising. Bleeding in the GI tract can also occur. Mast cell disease can cause ulceration, fissures, and hemorrhoids, among other things. Mast cell disease can contribute to dysregulation of the menstrual cycle, causing excessive bleeding in this way. It is not unusual for mast cell patients to have GI bleeding, as well as ulceration, fissures, and hemorrhoids.
  • Sustained GI inflammation. Sustained GI inflammatory disease can cause elevated levels of platelets. Given what we know about mast cell driven GI inflammation, it is reasonable to infer that mast cell GI effects and damage may also elevate platelet levels.
  • Clot formation. If a large clot forms, it can affect the amount of platelets circulating in the blood. Some mast cell patients require central lines for regular use of IV therapies or to preserve IV access in the event of an emergency. Blood clots can form on the outside surface of the line, inside the line, or between the line and the wall of the blood vessel it is in.
  • General inflammation. Platelets are activated by a variety of molecules released when the body is inflamed for any reason. This can translate to increased levels of platelet production.
  • Allergic reactions. Platelets can be directly activated by mast cell degranulation through molecules like platelet activating factor (PAF).
  • Heparin. Heparin can cause platelet levels to increase. As I mentioned above, it can also cause platelet levels to decrease.
  • Removal of the spleen. The spleen can become very stressed and work too hard, a condition called This situation is remedied by removing the spleen. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
  • Glucocorticoids. In particular, prednisone is known to increase platelet counts. Prednisone and other glucocorticoids can be used for several reasons in mast cell patients.
  • Third spacing. If a lot of fluid from the bloodstream becomes trapped in tissues (third spacing), there is less fluid in the bloodstream so it makes it look like there are too many cells. As I mentioned above, this is not really a scenario where you are making too many red blood cells, it just looks like that on a blood test.

For additional reading, please visit the following posts:

Anemia of chronic inflammation

Effect of anemia on mast cells

Mast cell disease and the spleen

MCAS: Anemia and deficiencies

Mast cells, heparin and bradykinin: The effects of mast cells on the kinin-kallikrein system

MCAS: Blood, bone marrow and clotting

Third spacing

Gastrointestinal manifestations of SM: Part 1

Gastrointestinal manifestations of SM: Part 2

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 72

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 73

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 74

I get asked a lot about how mast cell disease can affect common blood test results. I have broken this question up into several more manageable pieces so I can thoroughly discuss the reasons for this. The next few 107 series posts will cover how mast cell disease can affect red blood cell count; white blood cell count, including the counts of specific types of white blood cells; platelet counts; liver function tests; kidney function tests; electrolytes; clotting tests; and a few miscellaneous tests.

  1. How does mast cell disease affect red blood cell counts?

There are several ways in which mast cell disease can make red blood cell count lower.

  • Anemia of chronic inflammation. This is when chronic inflammation in the body affects the way the body absorbs and uses iron. It can result in iron deficiency. Iron is used to make hemoglobin, the molecule used by red blood cells to carry around oxygen to all the places in the body that need it. If there’s not enough iron to make hemoglobin, the body will not make a normal amount of red blood cells.
  • Vitamin and mineral deficiencies. Like I mentioned above, chronic inflammation can affect the way your body absorbs vitamins and minerals through the GI tract, and the way it uses vitamins and minerals that it does absorb. While iron deficiency is the most obvious example of this, deficiency of vitamin B12 or folate can also slow red cell production.
  • Swelling of the spleen. This can happen in some forms of systemic mastocytosis, and may also happen in some patients with mast cell activation syndrome, although the reason why it happens in MCAS is not as clear. Swelling of the spleen can damage blood cells, including red blood cells, causing lower red blood cell counts. If the spleen is very stressed and working much too hard, a condition called hypersplenism, the damage to blood cells is much more pronounced. This may further lower the red blood cell count. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
  • Medications. Some medications that are used to manage mast cell disease can cause low red blood cell count. Chemotherapies, including targeted chemotherapies like tyrosine kinase inhibitors, can cause low red blood cell count. Medications that specifically interfere with the immune system can do the same thing, including medications for autoimmune diseases like mycophenolate. Non steroidal anti-inflammatory drugs (NSAIDs) are used by some mast cell patients to decrease production of prostaglandins. They can interfere with red blood cell production in the bone marrow and also cause hemolytic anemia, when the immune system attacks red blood cells after they are made and damages them.
  • Excessive bleeding. Mast cell disease can cause excessive bleeding in several ways. Mast cells release lots of heparin, a very potent blood thinner that decreases clotting. This makes it easier for the body to bleed. It is not unusual for mast cell patients to have unusual bruising. Bleeding in the GI tract can also occur. Mast cell disease can cause ulceration, fissures, and hemorrhoids, among other things. Mast cell disease can contribute to dysregulation of the menstrual cycle, causing excessive bleeding in this way.
  • Excessive production of other types of blood cells. In very aggressive forms of systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia, the bone marrow is making huge amounts of mast cells. As a result, the bone marrow makes fewer cells of other types, including red blood cells. Some medications can also increase production of other blood types, causing less production of red cells. Corticosteroids can do this.
  • Excess fluid in the bloodstream (hypervolemia). In this situation, the body doesn’t actually have too few red blood cells, it just looks like it. If your body loses a lot of fluid to swelling (third spacing) and that fluid is mostly reabsorbed at once, the extra fluid in the bloodstream can make it look like there are too few red cells if they do a blood test. This can also happen if a patient receives a lot of IV fluids.

There are also a couple of scenarios where mast cell disease can make the red blood cell count higher. This is much less common.

  • Chronically low oxygen. If a person is not getting enough oxygen for a long period of time, the body will make more red blood cells in an effort to compensate for the low oxygen. This could happen in mast cell patients with poor oxygenation.
  • Third spacing. If a lot of fluid from the bloodstream becomes trapped in tissues (third spacing), there is less fluid in the bloodstream so it makes it look like there are too many cells. As I mentioned above, this is not really a scenario where you are making too many red blood cells, it just looks like that on a blood test.

For additional reading, please visit the following posts:

Anemia of chronic inflammation

Effect of anemia on mast cells

Effects of estrogen and progesterone and the role of mast cells in pregnancy

Explain the tests: Complete blood cell count (CBC) – Low red cell count

Explain the tests: Complete blood cell count (CBC) – High red cell count

Explain the tests: Complete blood cell count (CBC) – Red cell indices

Gastrointestinal manifestations of SM: Part 1

Gastrointestinal manifestations of SM: Part 2

Mast cell disease and the spleen

Mast cells, heparin and bradykinin: The effects of mast cells on the kinin-kallikrein system

MCAS: Anemia and deficiencies

MCAS: Blood, bone marrow and clotting

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 3

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 12

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 19

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 20

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 45

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 72

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 73

Third spacing

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 45

54. How does mast cell disease affect clotting?

Heparin is a very potent blood thinner and inhibits the body’s ability to form clots.  Mast cells are full of heparin. Mast cells stores chemicals like heparin in little pouches inside them called granules. In the granules, histamine is stuck to heparin. This means that when mast cells open their granules and release histamine, heparin comes out with it. This can contribute to things like bruising or bleeding more than expected.

Mast cells release other chemicals that can affect clotting. Platelet activation factor and thromboxane A2 both encourage the body to make clots. Some chemicals that help to regulate when to make a clot can activate mast cells, like complement C3a and C5a.

55. How many people have mast cell disease?

It is hard to know exactly how many people have a rare disease because they are not reported if they are recognized and correctly diagnosed. As recognition and diagnosis improves, rare diseases are often found to be more prevalent than previously thought. The numbers below are current estimates.

Systemic mastocytosis is thought to affect around 0.3-13/100000 people. In one large study, indolent systemic mastocytosis (ISM) makes up 47% of cases. Aggressive systemic mastocytosis (ASM) has been described in various places as comprising 3-10%. Systemic mastocytosis with associated hematologic disease could count for as many of 40% of cases of SM. Mast cell leukemia is extremely rare and accounts for less than 1% of SM cases.

Systemic mastocytosis accounts for about 10% of total mastocytosis cases. This means that total mastocytosis cases come in at around 3-130/100000 people. The remaining 90% of mastocytosis cases are cutaneous with incidence roughly around 2.7-117/100000 people.

We do not have yet have a great grasp upon how many people have mast cell activation syndrome (MCAS) but from where I am sitting, it’s a lot and that number is likely to grow. We know that genetic studies have found mutations that might be linked to MCAS in up to 9% of the people in some groups. However, having a mutation is not the same thing as having a disease. As we learn more about MCAS, we will gain some clarity around how many people have it.

For more detailed reading, please visit the following posts:

Progression of mast cell diseases: Part 2

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Natural history of SM-AHD, MCL and MCS

The Provider Primer Series: Cutaneous mastocytosis/Mastocytosis in the skin

 

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 6

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

12. What do these blood and urine tests look for?

• There are a lot of tests ordered for mast cell disease. How they are interpreted can depend upon a lot of factors. Some of the tests are unreliable, a fact that will be addressed in detail later in this series. (And has been addressed in detail elsewhere on this blog). Please keep in mind when reading this post that I am being VERY general and assumed the test was performed correctly on a correctly stored sample.
• The most common test ordered for mast cell disease is serum tryptase. Tryptase is a molecule that mast cells release. While it has lots of functions in the body, and is especially important in healing wounds and tissue growth, the amount present in your body at a given moment should be low.
• Tryptase is special because mast cells release it in two ways. Firstly, they make and release a little bit steadily. This is not related to activation. Mast cells just normally release a little tryptase as they go about their work. So the idea is that if you have more mast cells than you should, and each of those mast cells releases a little tryptase all the time, that you will have a higher than normal serum tryptase.
• Patients with a clonal mast cell disease, in which they have too many broken mast cells, usually have elevated baseline tryptase. This means tryptase that is elevated at least two times when you are NOT having a big reaction or anaphylaxis.
• Mast cells also store lots of tryptase in their pockets. When the mast cell is activated and it empties out its pockets, lots of tryptase comes out at once. This is why tryptase can be higher after a reaction or anaphylaxis, because mast cells release a bunch at once.
• Patients with mast cell activation syndrome or cutaneous mastocytosis do not always have elevated tryptase even with a big reaction or anaphylaxis.
• Mast cells have huge amounts of histamine stored in their pockets inside their cells. Histamine has lots of functions inside the body and is required for normal body functions. In particular, it is important to our nervous system. Smaller amounts are released as a normal function of the body.
• A lot of histamine is released when mast cells are activated. The idea is that if your mast cells are more activated than they should be that your histamine level will be higher. However, the test recommended for us to consider the histamine level in mast cell patients is not for histamine. It is for n-methylhistamine. This is a molecule that is formed when the body breaks down histamine, which happens very quickly (within minutes of release). n-methylhistamine is more stable, which is why we look at it.
• The test for n-methylhistamine is most reliable when performed in a 24 hour urine sample. This is because the level in urine can fluctuate throughout the day.
• Mast cells make a lot of prostaglandin D2 (abbreviated PGD2). PGD2 is very important for cell communicating. It can carry a message from one cell to another, allowing cells to work together. Unlike histamine and tryptase, mast cells do not keep PGD2 stored in their pockets. They make it only when they need it and then release it.
• PGD2 is released in large amounts when mast cells are activated. However, because it is not stored in the pockets, it is not always elevated right away when you have a big activation event or anaphylaxis. Prostaglandin D2 is broken down quickly. While we do test directly for PGD2 for mast cell disease, we also test for 9a,11-PGF2, a molecule formed when PGD2 breaks down.
• The tests for PGD2 and 9a,11b-PGF2 are most reliable when performed in 24 hour urine samples. This is because the levels in urine can fluctuate throughout the day.
• Heparin is a blood thinning molecule that is stored in pockets inside mast cells. Mast cells are the only cells that release significant amounts of histamine. When the mast cell is activated and it releases histamine, the histamine comes out stuck to heparin. Heparin is broken down very quickly so it is hard to measure accurately.
• The test to assess heparin level actually looks for a molecule called anti-factor Xa that can interact with heparin. This test is performed in serum.
• Chromogranin A is released by mast cells. It is also released by a lot of other cells. The level of this molecule can be affected by many things, including common medications. It is sometimes tested for and considered a sign of mast cell disease if elevated when all other possible reasons can be excluded.
• Chromogranin A levels are most reliable in serum.

 

For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The Provider Primer Series: Mediator testing

Evidence of mediator release

  • Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[i].
  • Objective evidence of mast cell mediator release is required for diagnosis of MCAS (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in MCAS testing recommendations (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[v]; plasma heparin[ix]; serum chromogranin A[ix]; and leukotriene E4[ix].

Tryptase

  • Tryptase is extremely specific for mast cell activation in the absence of hematologic malignancy or advanced kidney disease. Of note, rheumatoid factor can cause false elevation of tryptase[ix].
  • Serum tryptase levels peak 15-120 minutes after release with an estimated half-life of two hours[vi].
  • Per key opinion leaders, tryptase levels should be drawn 15 minutes to 4 hours after onset of anaphylaxis or activation event (Castells 2013[ii]), (Akin 2010[iii]), (Valent 2012)[iv]). Phadia, the manufacturer of the ImmunoCap® test to quantify tryptase, recommends that blood be drawn 15 minutes to 3 hours after event onset[vii].
  • Serum tryptase >11.4 ng/mL is elevated[i]. In addition to measuring tryptase level during the event, another sample should be drawn 24-48 hours after the event, and a third sample drawn two weeks later. This allows comparison of event tryptase level to baseline[vi].
  • An increase in serum tryptase level during an event by 20% + 2 ng/mL above patient baseline is often accepted as evidence of mast cell activation[v],[i].
  • Absent elevation of tryptase level from baseline during an event does not exclude mast cell activation[viii].
  • Sensitivity for serum tryptase assay in MCAS patients was assessed as 10% in a 2014 paper[ix].
  • A recent retrospective study of almost 200 patients found serum was elevated in 8.8% of MCAS patients[x].
  • Baseline tryptase >20.0 ng/mL is a minor criterion for diagnosis of systemic mastocytosis. 77-85% of SM patients have baseline tryptase >20.0 ng/mL[ix].

Histamine and degradation product n-methylhistamine

  • N-methylhistamine is the breakdown product of histamine.
  • Histamine is degraded quickly. Samples should be drawn within 15 minutes of episode onset[vii].
  • Serum histamine levels peak 5 minutes after release and return to baseline in 15-30 minutes[vii].
  • Sample (urine or serum) must be kept chilled[xi].
  • In addition to mast cells, histamine is also released by basophils. Consumption of foods or liquids that contain histamine can also inflate the level when tested[ix].
  • A recent retrospective study of almost 200 patients found that n-methylhistamine was elevated in 7.4% of MCAS patients in random spot urine and 5.4% in 24-hour urine[xi].
  • Sensitivity of 24-hour n-methylhistamine for MCAS was assessed as 22% in 24-hour urine[ix].
  • Plasma histamine was elevated in 29.3% of MCAS patients[xi].
  • 50-81% of systemic mastocytosis patients demonstrate elevated n-methylhistamine in 24-hour urine[ix].

Prostaglandin D2 and degradation product prostaglandin 9a,11b-F2

  • 9a,11b-prostaglandin F2 is the breakdown product of prostaglandin D2.
  • Prostaglandin D2 is only produced in large quantities by mast cells. Basophils, eosinophils and other cells produce minute amounts[ix].
  • A recent retrospective study of almost 200 patients found that PGD2 was elevated in 9.8% of MCAS patients in random spot urines and 38.3% in 24-hour urine[xi].
  • PGD2 was elevated in 13.2% of MCAS patients in plasma[xi].
  • 9a,11b-PGF2 was elevated in 36.8% in 24-hour urine[xi].
  • 62-100% of systemic mastocytosis patients demonstrate elevated prostaglandin D2 or 9a,11b-PGF2 in urine[ix].
  • Prostaglandins are thermolabile and begin to break down in a minutes. This can contribute to false negative results[xi].
  • Medications that inhibit COX-1 and COX-2, such as NSAIDs, decrease prostaglandin production[xi].

Leukotriene E4

  • Leukotriene E4 is produced by mast cells and several other cell types[ix] including eosinophils, basophils and macrophages.
  • A recent retrospective study of almost 200 patients found that LTE4 was elevated in 4.4 % of MCAS patients in random spot urines and 8.3% in 24-hour urine[xi].
  • 44-50% of systemic mastocytosis patients demonstrate elevated leukotriene E4 in urine[ix].
  • Medications that inhibit 5-LO, such as lipoxygenase inhibitors, decrease leukotriene production[xii].

Chromogranin A

  • Chromogranin A is produced by mast cells and several other cell types including chromaffin cells and beta cells.
  • Proton pump inhibitors can cause increased values during testing[xi].
  • A 2014 paper reported chromogranin A was elevated in 12% of MCAS patients and 63% of systemic mastocytosis patients tested[ix].

Heparin

  • Heparin is a very specific mediator for mast cell activation[ix].
  • Heparin is extremely heat sensitive. The sample must be kept on ice or refrigerated at all times[ix].
  • Venous occlusion of upper arm for ten minutes has been successful in provoking mast cell activation leading to heparin release[ix].
  • A 2014 paper reported plasma heparin was elevated in 59% of MCAS patients and 47% of systemic mastocytosis patients tested[ix].
  • A recent retrospective study of almost 200 patients found that plasma heparin was elevated in 28.9% tested[ix].

 

References

[i] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[ii] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.

[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[iv] Valent P, et al. (2012). Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol, 157(3), 215-225.

[v] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.

[vi] Payne V, Kam PCA. (2004). Mast cell tryptase: a review of its physiology and clinical significance. Anaesthesia, 59(7), 695-703.

[vii] Phadia AB. ImmunoCAP® Tryptase in anaphylaxis. Retrieved from: http://www.phadia.com/Global/Market%20Companies/Sweden/Best%C3%A4ll%20information/Filer%20(pdf)/ImmunoCAP_Tryptase_anafylaxi.pdf

[viii] Sprung J, et al. (2015). Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. Anesthesiology, 122(3), 713-717.

[ix] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912

[x] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).

[xi] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.”  Mast Cells, edited by David B. Murray, Nova Science Publishers, Inc., 2013, 155-231.

[xii] Hui KP, et al. (1991). Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax, 46, 184-189.

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

Symptoms, mediators and mechanisms: A general review (Part 1 of 2)

Skin symptoms    
Symptom Mediators Mechanism
Flushing Histamine (H1), PGD2 Increased vasodilation and permeability of blood vessels

Blood is closer to the skin and redness is seen

Itching Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria Histamine (H1), PAF, heparin, bradykinin Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of skin

Angioedema Histamine (H1), heparin, bradykinin, PAF Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of tissue

 

Respiratory symptoms    
Symptom Mediators Mechanism
Nasal congestion Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Sneezing Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Airway constriction/ difficulty breathing Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Increased mucus production

Smooth muscle constriction

 

Cardiovascular symptoms    
Symptom Mediators Mechanism
Low blood pressure Histamine (H1), PAF,  PGD2, bradykinin Decreased force of heart contraction

Increased vasodilation and permeability of blood vessels

Impact on norepinephrine signaling

Change in heart rate

Presyncope/syncope (fainting) Histamine (H1), histamine (H3), PAF, bradykinin Increased vasodilation and permeability of blood vessels

Decrease in blood pressure

Dysfunctional release of neurotransmitters

High blood pressure Chymase,  9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

Tightening and decreased permeability of blood vessels

Tachycardia Histamine (H2), PGD2 Increasing heart rate

Increasing force of heart contraction

Impact on norepinephrine signaling

Arrhythmias Chymase, PAF, renin Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

 

Gastrointestinal symptoms    
Symptom Mediators Mechanism
Diarrhea Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Gas Histamine (H1), histamine (H2), bradykinin Smooth muscle constriction

Increased gastric acid secretion

Abdominal pain Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Nausea/vomiting Histamine (H3), serotonin Dysfunctional release of neurotransmitters
Constipation Histamine (H2), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

Master table of stored mast cell mediators

Mediator Symptoms Pathophysiology
Angiogenin Tissue damage Formation of new blood vessels, degradation of basement membrane and local matrix
Arylsulfatases Breaks down molecules to produce building blocks for nerve and muscle cells
Bradykinin Angioedema, swelling of airway, swelling of GI tract, inflammation, pain, hypotension Vasodilation, induces release of nitric oxide and prostacyclin
Carboxypeptidase A Muscle damage Tissue remodeling
Cathepsin G Pain, muscle damage Converts angiotensin I to II, activates TGF-b, muscle damage, pain, fibrosis, activates platelets, vasodilation
Chondroitin sulfate Cartilage synthesis
Chymase Cardiac arrhythmia, hypertension, myocardial infarction Tissue remodeling, conversion of angiotensin I to II, cleaves lipoproteins, activates TGF-b, tissue damage, pain, fibrosis
Corticotropin-releasing hormone Dysregulation has wide reaching and severe effects Stimulates secretion of ACTH to form cortisol and steroids
Endorphins Numbness Pain relief
Endothelin Hypertension, cardiac hypertrophy, type II diabetes, Hirschsprung disease Vasoconstriction
Eotaxin (CCL11) Cognitive deficits Attracts eosinophils, decreases nerve growth
Heparin Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers Cofactor for nerve growth factor, anticoagulant, prevents platelet aggregation, angiogenesis
Histamine Headache, hypotension, pruritis, urticaria, angioedema, diarrhea, anaphylaxis Vasodilation of vessels, vasoconstriction of atherosclerotic coronary arteries, action of endothelium, formation of new blood vessels cell proliferation, pain
Hyaluronic acid Degradation contributes to skin damage Tissue repair, cartilage synthesis, activation of white blood cells
IL-8 (CXCL8) Mast cell degranulation Attracts white blood cells (mostly neutrophils) to site of infection, activates mast cells, promotes degranulation
Kininogenases Angioedema, pain, low blood pressure Synthesis of bradykinin
Leptin Obesity Regulates food intake
Matrix metalloproteinases Irregular menses (MMP-2) Tissue damage, modification of cytokines and chemokines (modifies molecules to make them useful)
MCP-1 (CCL2) Nerve pain Attracts white blood cells to site of injury or infection, neuroinflammation, infiltration of monocytes (seen in some autoimmune diseases)
MCP-3 (CCL7) Increases activity of white blood cells in inflamed spaces
MCP-4 (CCL13) Shortness of breath, tightness of airway, cough Attracts white blood cells to inflamed spaces, induces mast cell release of TNFa and IL-1, asthma symptoms
Phospholipase A2 Vascular inflammation, acute coronary syndrome Generates precursor molecule for prostaglandins and leukotrienes
RANTES (CCL5) Osteoarthritis Attracts white cells to inflamed spaces, causes proliferation of some white cells
Renin Cardiac arrhythmias, myocardial infarction, blood pressure abnormalities Angiotensin synthesis, controls volume of blood plasma,lymph and interstitial fluid, regulates blood pressure
Serotonin/5-HT Nausea, vomiting, diarrhea, headache, GI pain Vasoconstriction, pain
Somatostatin Low stomach acid symptoms, low blood sugar Regulates endocrine system, cell growth and nerve signals, inhibits release of glucagon and insulin, decreases release of gastrin, secretin and histamine
Substance P Neurologic pain, inflammation, nausea, vomiting, mood disorders, anxiety Transmits sensory nerve signals, including pain, mood disorders, stress perception, nerve growth and respiration
Tissue plasminogen activator Blood clots Activates plasminogen, clotting
Tryptase Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers; inflammation Activation of endothelium, triggers smooth muscle proliferation, activates degradation of fibrinogen, activates MMP molecules,tissue damage, activation of PAR, inflammation, pain
Urocortin Increased appetite when stressed, inflammation, low blood pressure Vasodilation, increases coronary blood flow
Vasoactive intestinal peptide Decreased absorption, low blood pressure, low stomach acid symptoms Vasodilation, mast cell activation, lowers blood pressure, relaxes muscles of trachea, stomach and gall bladder, inhibits gastric acid secretion, inhibits absorption
VEGF Diseases of blood vessels Formation of new blood vessels, vasodilation and permeability of smaller vessels

Mast cells, heparin and bradykinin: The effects of mast cells on the kinin-kallikrein system

The kinin-kallikrein system is a hormonal system with effects on inflammation, blood pressure, coagulation and pain perception. This system is known to have a significant role on the cardiovascular system, including cardiac failure, ischemia and left ventricular hypertrophy. Despite significant research, it is not entirely understood.

Kininogens are proteins that have extra pieces on them. Kininogenases cut off those extra pieces. Active kinins that can act on the body are the result of this action. So kininogenases change kininogens to form kinins.

There are two types of kininogens: low molecular weight (smaller) and high molecular weight (larger.) We are going to focus on HMW, which circulates in the blood.

Also circulating in the blood are two other components called prekallikrein (sometimes called Fletcher factor) and Hageman factor (Factor XII.) When Hageman factor lands on a negatively charged surface, it changes shape and becomes Factor XIIa. Factor XIIa changes the prekallikrein to kallikrein. Kallikrein is a kininogenase.

When kallikrein finds a kininogen, it cuts off the extra piece to release bradykinin. Bradykinin is a kinin and is ready to act on the body.

Bradykinin has several functions in the body. It contributes to contractility of duodenum, ileum and cecum. In the lungs, it can cause chloride secretion and bronchoconstriction. It can cause smooth muscle contraction in the uterus, bladder and vas deferens. It contributes to rheumatoid arthritis, inflammation, pain sensation and hyperalgesia. It also induces cell proliferation, collagen synthesis, and release of nitric oxide, prostacyclin, TNF-a and interleukins. It can also cause release of glutamate by nerve cells. Glutamate has a variety of actions in the body and excessive release can cause epileptic seizures, ALS, lathyrism, autism and stroke.

Bradykinin acts on the endothelium, the cells that line the inner surface of blood and lymphatic vessels, to cause the blood vessels to dilate. This decreases blood pressure. It also regulates sodium excretion from the kidneys, which can further decrease blood pressure. Kininogen levels are reduced in hypertensive patients. Kinins, including bradykinin, oppose the action of angiotensin II, a hypertensive agent.

So how are mast cells related to this system? A couple of ways. The first way is that they release kininogenases and bradykinin. Tryptase can actually behave as a kininogenase. The second way is by being the exclusive producers of heparin.

As I mentioned above, Factor XII needs to change to Factor XIIa to initiate the formation of bradykinin. It does this when it contacts a negatively charged surface. In the lab, you can use a surface like glass for this. But in the body, it often happens on the surfaces of large, negatively charged proteins like heparin. (Side note: Factor XII is part of the clotting cascade. It can be activated by medical devices like PICC lines and that is why they carry a risk of clot formation.) So by releasing heparin, mast cells cause the formation of bradykinin. When the mast cells release heparin in inappropriate amounts, too much bradykinin is formed.

Overproduction of bradykinin is one of the principal causes of angioedema. In hereditary angioedema, the body is deficient in a component that regulates bradykinin. One of the reasons that physical trauma can cause mast cell degranulation is because it causes formation of bradykinin. Bradykinin in turn causes mast cell degranulation with release of histamine and serotonin, among other contents.

Bradykinin antagonists are being researched as possible therapies for hereditary angioedema. Icatibant is one such medication. Bromelain, found in the stems and leaves of pineapples, are known to suppress swelling caused by bradykinin. Aloe and polyphenols, like those in green tea, are also known to suppress bradykinin activity.

References:

Kaplan AP, Ghebrehiwet B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol. 2010 Aug; 47(13):2161-9

Oschatz C, et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011 Feb 25; 34(2):258-68.

 

Brunnée T, et al. Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions. Clin Exp Allergy. 1997 Jun;27(6):653-63.