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

Take home points: November 2015

Immunoglobulin free light chains: A possible link between autoimmune disease and mast cell activation

  • Light chains are part of antibodies that fight infections and responds to allergens
  • Free light chains are pieces of antibodies that broke off and do not work as antibodies
  • Elevation of immunoglobulin free light chains has been linked to many diseases, including lupus, rheumatoid arthritis, inflammatory bowel disease and food allergy
  • Free light chains correlate with symptom severity and flares in some conditions
  • Free light chains may be able to activate mast cells without IgE involvement
  • Free light chains may be the link between mast cell activation and autoimmune disease

Explain the tests: Complete blood count (CB) with differential and platelets (Part One)

  • A complete blood count (CBC) counts white blood cells, red blood cells and platelets in blood
  • It also looks at the shape, size and variation in size of cells

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

  • Mature red blood cells live in the blood for 100-120 days
  • Hemolysis is when red blood cells burst and a little bit of hemolysis is normal
  • Red blood cells transport oxygen from lungs to tissues
  • Red blood cells have hemoglobin inside them
  • Hemoglobin is a protein with iron in the middle and it carries oxygen
  • Low red blood cell count or hemoglobin is called anemia
  • Red blood cell count can be low for several reasons, including nutritional deficiency and production dysregulation in bone marrow
  • Mast cell patients often suffer from anemia of chronic inflammation, which can cause low red count
  • Patients with inflammatory bowel disease can have low red count due to bleeding
  • Swelling of spleen can cause low red count

Explain the tests: Complete blood count (CBC) – Red cell indices (Part 4)

A number of red blood cell tests are performed together in a complete blood count (CBC).  These tests  (called red cell indices) are assessed together to point to specific causes of red blood cell dysfunction.  These tests include:

Red blood count: The count of all red blood cells in a volume of blood

  • Adult women: 3.9-5.0 million cells/µL
  • Adult men: 4.3-5.7 million cells/µL
  • Please refer to previous posts for detailed discussion of causes of low and high RBC.

Hemoglobin (Hb): The amount of hemoglobin in a volume of blood

  • Adult women: 12.0-15.5 grams/dL
  • Adult men: 12.5-17.5 grams/dL
  • Hemoglobin constitutes about 95% of the mass of a red blood cell.
  • Hemoglobin binds oxygen so that red cells can carry them through the blood into the tissues.
  • Common causes of low hemoglobin include vitamin or mineral deficiency, chronic inflammation, autoimmune disease, hemoglobinopathies, thalassemia, GI bleeding, surgery and blood loss.
  • Common causes of high hemoglobin include lung disease, neoplastic conditions including cancers, and dehydration.
  • If red blood cell count and hematocrit are low, usually hemoglobin is low, too. If red blood cell count and hematocrit are high, usually hemoglobin is high, too.
  • Even if red blood cell count is normal, low hemoglobin will cause symptomatic anemia.
  • Anemia is a decreased ability to carry oxygen from lungs to tissues.

Hematocrit (HCT): The portion of a volume of blood that is red blood cells

  • Adult women: 34.0-44.5%
  • Adult men: 38.8-50.0%
  • Equal to (red blood cell count)/(volume of blood measured)
  • Used to assess severity of blood loss.
  • Common causes of low hemoglobin include vitamin or mineral deficiency, chronic inflammation, autoimmune disease, hemoglobinopathies, thalassemia, GI bleeding, surgery and blood loss.
  • Common causes of high hemoglobin include lung disease, neoplastic conditions including cancers, and dehydration.
  • If red blood cell count and hemoglobin are low, usually hematocrit is low, too. If red blood cell count and hemoglobin are high, usually hematocrit is high, too.

Definitions:

  • Microcytic anemia: low MCV
  • Normocytic anemia: normal MCV
  • Macrocytic anemia: high MCV
  • Hypochromic anemia: low MCH
  • Normochromic anemia: normal MCH
  • Hyperchromic anemia: high MCH

Mean corpuscular volume (MCV): Identifies if red cells are the right size

  • 80-96 fL/cell
  • Equal to (hematocrit)/(red blood cell count)
  • The size of red cells tells you what causes anemia.
  • Low MCV with low red cell count and low hemoglobin indicates microcytic anemia.
  • Common causes of microcytic anemia (low MCV) include iron deficiency, blood loss, anemia of chronic inflammation, sideroblastic anemia, thalassemia, pyridoxine deficiency and lead poisoning.
  • High MCV with low red cell count and low hemoglobin indicates macrocytic anemia.
  • Common causes of macrocytic anemia (high MCV) include megaloblastic anemia, alcoholism, COPD, hypothyroidism, MDS, liver disease and deficiency of vitamin B12 and/or folate.

Mean corpuscular hemoglobin (MCH): The average hemoglobin in a red blood cell in a volume of blood

  • 5-33.2 pg/cell
  • Equal to (hemoglobin)/(red blood cell count)
  • MCH usually mirrors MCV. If MCV is low, MCH is usually low.  If MCV is high, MCH is usually high.
  • Common causes of low MCH include iron deficiency, blood loss, anemia of chronic inflammation, sideroblastic anemia, thalassemia, pyridoxine deficiency and lead poisoning.
  • Common causes of high MCH include megaloblastic anemia, alcoholism, COPD, hypothyroidism, MDS, liver disease and deficiency of vitamin B12 and/or folate.

Mean corpuscular hemoglobin concentration (MCHC): Determines size of red cells

  • 4-35.5 g/dL
  • Equal to (hemoglobin)/(hematocrit)
  • Low MCHC is associated with hypochromic (“too little color”) anemia. Cells with less hemoglobin have less intense red color.  Patients with hypochromic anemia often have a green tinge to their skin.
  • MCHC is usually low in microcytic anemia.
  • MCHC is sometimes normal in some macrocytic anemias. This is called normochromic anemia (“normal color”).
  • Common causes of low MCHC include thalassemia, vitamin B6 deficiency, lead poisoning, Faber’s syndrome, GI bleeding and iron deficiency.
  • Common causes of normal MCHC in the presence of anemia (normocytic anemia) include anemia of chronic inflammation, aplastic anemia, blood loss, hemolysis, and deficiency of vitamins B2 or B6.
  • High MCHC is associated with hyperchromic (“too much color”) anemia.
  • Common causes of high MCHC include sickle cell disease, hereditary spherocytosis, autoimmune hemolytic anemia and hemoglobin C disease.

Red blood cell distribution width (RDW): The amount of variation in the size of red cells

  • 5-14.5%
  • RDW is normal or high. A “low” RDW should be read as normal.
  • RDW helps to identify the cause of anemia.
  • A high RDW indicates that there are large amounts of both new and mature red cells.
  • Variation in size of red cells is called anisocytosis.
  • Common causes of high RDW include

Reticulocyte count: The amount of new red cells in a volume of blood

  • 5-1.5%
  • Elevated reticulocyte count is called reticulocytosis.
  • Common causes of reticulocytosis include hemolytic anemia, pernicious anemia, deficiency of iron, vitamin B12 or folate, anemia of chronic inflammation, cancers affecting bone marrow and chemotherapy.

In conditions with low RBC, low hemoglobin and/or low hematocrit:

  • Low MCV with high RDW: Iron deficiency anemia
  • High MCV with high RDW: Vitamin B12 and/or folate deficiency
  • Variable MCV (low, high or normal) with high RDW: Mixed deficiency (iron and B12 or folate)
  • Normal MCV with high RDW: Large blood loss (hemorrhage)
  • Normal MCV with normal MCH: chronic illness, aplastic anemia, prosthetic heart valves, sepsis or kidney failure
  • Low MCV with low MCH: iron deficiency, thalassemia, lead poisoning, long term inflammation
  • High MCV with normal or high MCH: deficiency of B12 or folate

Explain the tests: Complete blood count (CBC) – High red cell count (Part 3)

A number of conditions can cause high red blood cell count.  This is called polycythemia.  Red cells are responsible for bringing oxygen from the lungs to the tissues. If the blood is getting less oxygen than normal, the bone marrow will produce more red cells to compensate.  Excessive release of erythropoietin, a molecule that triggers red cell production, can also cause high red blood cell count.  Additionally, changes in amount of fluid in the blood stream can artificially alter red blood cell and hemoglobin levels.

Normal range for red blood count:

  • Adult women: 3.9-5.0 million cells/µL
  • Adult men: 4.3-5.7 million cells/µL

Reasons for making too many red blood cells:

  • High levels of erythropoietin, a molecule that tells the bone marrow to make red cells
  • Lower levels of oxygen in blood stream
  • Neoplastic conditions
  • Relative polycythemia, in which reduction of blood volume causes an artificial increase in red blood cells

Some conditions that cause lower oxygenation of the blood, triggering polycythemia:

  • Lung diseases, such as COPD, sleep apnea and pulmonary fibrosis.
  • Heart conditions, such as congestive heart failure.
  • Carbon monoxide poisoning.
  • Hemoglobin defects, such as 2,3-BPG deficiency, which causes hemoglobin to hold onto oxygen too tightly.
  • Lengthy stays at high altitude.

Some conditions that cause elevated erythropoietin:

  • Poor blood flow to the kidney, such as in narrowing of the renal artery, hydronephrosis and kidney cysts. The body interprets as low oxygenation.
  • Chuvash polycythemia, which causes overactivity of the erythropoietin gene.

Some neoplastic conditions that cause excessive proliferation of red cells:

  • Polycythemia vera. This myeloproliferative disorder (MPN) is strongly associated with the JAK2 V617F mutation.
  • Cancers such as renal cell carcinoma and adenocarcinoma.

Situations that cause artificially high red blood cell count:

  • Hypovolemia, from dehydration, alcoholism, obesity, smoking or third spacing.
  • Use of some diuretics.

Some medications that cause secondary polycythemia:

  • Anabolic steroids
  • Testosterone

 

Special notes on high red cell count for mast cell patients:

  • Polycythemia vera is a myeloproliferative neoplasm like systemic mastocytosis. It is a common comorbidity for patients with SM-AHNMD.  Some SM patients are positive for the JAK2 V617F mutation without having polycythemia vera.
  • Third spacing (fluid from the blood stream becoming trapped in the tissues) occurs in many mast cell patients as a regular symptom, as well as during anaphylaxis. This can cause the red cell count to appear artificially high.

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

The process of making red blood cells is called erythropoiesis.  Mature red cells live in the blood for 100-120 days before they die.  As they get older, red cells are removed from the blood stream.  A small amount of red cells burst in the blood stream before they are removed.  This is called hemolysis.  Most red cells are removed by special white cells called macrophages in the liver, spleen and lymph nodes.  When the production and destruction of red cells are not balanced, red cell count is abnormal.

Red blood cells (erythrocytes) are responsible for transporting oxygen from the lungs to the tissues.  Red blood cells have lots of hemoglobin inside their cells.  Hemoglobin is a protein that has a form of iron at its center called heme.  Hemoglobin binds oxygen so that it can be brought to other parts of the body.  When red blood cell count or hemoglobin is low, the body cannot get enough oxygen to the tissues.  This is called anemia.

A number of conditions can cause low red blood cell count.  They can be placed into three categories: not making enough red blood cells; breaking down too many red blood cells; and blood loss.  Additionally, changes in amount of fluid in the blood stream can artificially alter red blood cell and hemoglobin levels.

Normal range for red blood count:

  • Adult women: 3.9-5.0 million cells/µL
  • Adult men: 4.3-5.7 million cells/µL

Reasons for not making enough red blood cells:

  • Low levels of erythropoietin, a molecule that tells the bone marrow to make red cells
  • Deficiency or abnormality of hemoglobin
  • Nutritional deficiency
  • Damage to stem cells
  • Inability to make red cells from stem cells

Some conditions that interfere with making enough red blood cells:

  • Viral infections, such as parvovirus B19, herpes viruses and hepatitis. Some viruses induce pure red cell aplasia, which affects the cells that become red blood cells.
  • Overproliferation of white cells, such as lymphomas, leukemias, autoimmune lymphoproliferative disease. These conditions can also induce pure red cell aplasia. If too many of one cell type is in the bone marrow, it reduces the space for other cell types.  In this example, too many white cells are produced, so there is not enough space for red cells.
  • Myelodysplastic syndromes. In MDS, the stem cells that develop into blood cells are thought to harbor damaging mutations.  The process of making blood cells is very disordered in MDS.
  • Aplastic anemia. In aplastic anemia, blood stem cells are damaged.
  • Deficiency of vitamin B12, iron or folate. Iron deficiency interferes with production of hemoglobin, while B12 or folate deficiency prevents normal cell division to make new cells.
  • Chronic kidney disease. Kidney cells release erythropoietin to stimulate making new red cells.  If the kidney cells are damaged, they may release less erythropoietin.
  • Chronic inflammation. Chronic inflammation can interfere with absorption and use of iron.
  • Thalassemia causes hemoglobin to be misshapen.
  • Medications, like mycophenolate.

Reasons for increased destruction of red cells

  • Misshapen red cells
  • Abnormalities of red cell membranes
  • Hemoglobinopathies, conditions in which hemoglobin is defective
  • Attack by antibodies
  • Mechanical damage

Some conditions that cause increased destruction of red cells:

  • Hemolytic anemias. This is a general category that encompasses many conditions, including antibody mediated hemolysis, enzyme deficiencies and membrane abnormalities.
  • Membrane abnormalities, like in G6PD deficiency (favism). The membrane is weakened in this condition.
  • Hereditary spherocytosis and hereditary elliptocytosis. In these genetic conditions, red cells are misshapen.
  • Antibodies targeting red cells, such as autoimmune hemolytic anemia and transfusion reaction.
  • Hemoglobinopathies, like sickle cell disease and hemoglobin C disease. Enough hemoglobin is made, but it is structurally abnormal.
  • In this condition, there is a genetic mutation that interferes with production of hemoglobin.
  • Mechanical damage, such as in hemodialysis or malaria. In these conditions, the red cells die for physical reasons.

Reasons for blood loss

  • Trauma or surgery.
  • Gastrointestinal bleeding. This can be caused by inflammatory bowel disease, ulceration, varices or infection.
  • Excess blood loss due to menstruation or fibroids
  • Anemia of prematurity. This is caused by the need for frequent blood draws for testing coupled with low production of red cells by premature babies.

Situations that cause artificially low red blood cell count:

  • Pregnancy, due to increased blood volume.
  • Hypervolemia, from high water or sodium consumption or retention.
  • Hypervolemia, from recovery of third spaced fluids.

 

Special notes on low red cell count for mast cell patients:

  • Many mast cell patients suffer from anemia of chronic inflammation, which can result in low red cell count.
  • Some patients have inflammatory bowel disease, which can result in low red cell count.
  • Swelling of the spleen (splenomegaly) can cause low red cell count.  Splenomegaly is a B finding for SM patients.  Two B findings result in diagnosis with smoldering systemic mastocytosis (SSM).
  • Overactivity of the spleen (hypersplenism) can cause low red cell count.  Hypersplenism is a C finding for SM patients, resulting in diagnosis with aggressive systemic mastocytosis (ASM).
  • Use of some chemotherapy drugs can impair production of blood cells, including red cells.

 

Explain the tests: Complete blood count (CBC) with differential and platelets (Part One)

A complete blood count (CBC), also called full blood count (FBC) in some countries, is one of the most frequently ordered diagnostics.  A CBC quantifies and describes the types of cells found in the blood.  These cells include white blood cells (WBC, also called leukocytes), red blood cells (RBC, also called erythrocytes) and platelets (also called thrombocytes).

There are two commonly methods for counting blood cells, automated and manual.

In automated counting, the cells are counted by a machine called a flow cytometer.  Flow cytometers identify cells by shining a laser through a sample of the blood and using the way the light bounces off the cells to determine what kind of cells they are.   This bouncing of light is called scatter.  Flow cytometers measure forward scatter determines the diameter of a cell.  Side scatter determines granularity, how many granules are inside the cell. While this method is generally quite precise, if a cell is not shaped normally, the flow cytometer may count it incorrectly.

In manual counting, the blood is diluted and placed into a special chamber with grid lines called a hemocytometer.  The chamber is viewed under a microscope and the cells are counted by eye.  As someone who has counted lots of cell suspensions by eye, it can be hard to be exact.  This method works for red and white blood cells.

To evaluate abnormality in cell shape, a blood smear is made from the original blood sample.  A smear slide is made by smearing a thin layer of blood onto a glass slide.  Once the blood is dried on the slide, stains are then used to colorize the cells to make them easier to see and distinguish.  Giemsa is a commonly used stain for this purpose (fun fact: mast cells can be visualized with Giemsa stain).  Other stains can also be used. This method allows abnormalities in shape of red and white cells to visualized.

 

A CBC usually includes the following tests:

Total white blood cell count

  • The count of all white blood cells in a volume of blood;
  • Unit is cells/liter

Total red blood cell count

  • The count of all red blood cells in a volume of blood
  • Unit is cells/liter

Hemoglobin (Hb)

  • The amount of hemoglobin in a volume of blood
  • Unit is grams/deciliter

Hematocrit (Hct; also called packed cell volume, PCV)

  • The portion of a volume of blood that is red blood cells
  • Unit is percentage

Mean corpuscular volume (MCV)

  • The volume occupied by red blood cells in a volume of blood
  • Identifies if red cells are the right size
  • Unit is femtoliters/cell

Mean corpuscular hemoglobin (MCH)

  • The average hemoglobin in a red blood cell in a volume of blood; the amount of hemoglobin divided by the red blood cell count; mass of hemoglobin divided by number of red blood cells in a volume of blood; unit is picograms/cell
  • Mean corpuscular hemoglobin concentration (MCHC): the average concentration of hemoglobin in a volume of red blood cells; determines size of red cells; hemoglobin divided by hematocrit; unit is grams/liter

Red blood cell distribution width (RDW)

  • The amount of variation in the size of red cells
  • Can only be high or normal
  • High RDW means red cells show a wide range of size

Reticulocyte count

  • The amount of new red cells in a volume of blood
  • Unit is percentage

 

A CBC with differential and platelets will include the following tests:

Neutrophil count

  • The count of neutrophils in a volume of blood
  • Neutrophils are inflammatory cells that fight infections and initiate inflammatory response
  • Unit is cells/liter

Lymphocyte count

  • The count of lymphocytes in a volume of blood
  • B cells, T cells and NK cells are lymphocytes that detect pathogens in different ways
  • Unit is cells/liter

Monocyte count

  • The count of monocytes in a volume of blood
  • Monocytes respond to inflammatory signals and develop into specialized tissue cells
  • Unit is cells/liter

Eosinophil count

  • The count of eosinophils in a volume of blood
  • Eosinophils fight parasites and participate in allergic response
  • Unit is cells/liter

Basophil count

  • The count of basophils in a volume of blood
  • Basophils fight parasites and participate in allergic response
  • Unit is cells/liter

Platelet count

  • The count of plateletsin a volume of blood
  • Platelets stop bleeding
  • Unit is platelets/liter

Mean platelet volume (MPV)

  • The volume occupied by platelets in a volume of blood
  • Identifies if platelets are the right size
  • Unit is femtoliters/platelet