Hello, my name is Dr. Bill Dill-Jones. I'm a professor in the Faculty of Health Disciplines at Athabasca University. Welcome to this second hematology review. What we'll principally talk about today is the pathophysiology of the hematologic system with a focus on specific disorders affecting red blood cells, white blood cells, and platelets. And it's important to keep in mind as we go through this unit that most of these blood cell abnormalities are not diseases per se, rather they reflect or manifest other dysfunctions.
The most common disorder or hematologic disorder that you'll likely encounter in primary care practice is anemia. And anemia, of course, affects red blood cells. focus on two specific types of anemias as well as ways of diagnosing anemia.
White blood cell disorders include leukemias and lymphomas and we'll not focus on these. in this particular chapter too much. And finally, we'll cover in this module and in discussion formats platelet disorders, including thrombocytopenias and coagulation disorders. So classically, when we think of an anemia, we think of it as being a decrease in red blood cell number.
And this is actually only part of the story. Nevertheless, most anemones do manifest as a decrease in red blood cell number, and aside from loss due to hemorrhage, there are two means by which red blood cell numbers may decrease. There may be defective or decreased erythrocyte production, as is the case in certain anemias, carcinomas, lymphomas, and leukemias.
Or there may be increased erythrocyte destruction, as is the case with infections and hemolytic urinary syndromes. The flip side of anemia is polycythemia, which is an excess of red blood cells, and we'll only mention this in passing later on. So how do we classify anemia? Well there are a few different schemes but one that I find particularly helpful is to base it on erythrocyte size and also hemoglobin content. And there are some useful suffixes to remember here.
If you see cytic at the end of a word it usually implies something about cell size and chromic tells you about color and therefore hemoglobin content. So based on mean corpuscular volume, or MCV, we can classify three types of red blood cell disorders, beginning with macrocytic red blood cells, which are manifested during folic acid B12. deficiencies, liver disease, and also can be caused by alcoholic disorders and certain drugs. Normocytic red blood cells can be found in disorders such as aplastic anemia, chronic renal failure, and hemolytic anemia, and microcytic red blood cells, wherein there's a decrease in mean corpuscular volume, and this is typical of iron deficiency and thalassemia.
With respect to color, we can think of there being three classifications here. And we'll use the term MCHC, which is mean corpuscular hemoglobin concentration. And we can refer to blood cells as being hyperchromic, in which case MCHC is increased, normochromic, no increase or decrease, and hypochromic, where there's a decrease in mean corpuscular hemoglobin concentration. And on the basis of MCHC and cell size, we can discuss anemias in the following way. First of all, anemias in which red blood cells are typically macrocytic but normochromic include pernicious anemia and folate deficiencies.
Microcytic, hypochromic red blood cells are typical of iron deficiency and sideroblastic anemia as well as thalassemia. Now we're not going to talk too much about sideroblastic anemia and thalassemia in this particular review. Normocytic, normochromic red blood cells can be found in anemia such as a Plastic anemia or post-hemorrhagic anemia and certain early stages of hemolytic anemias, as well as sickle cell and anemia of chronic illness.
So how do we treat anemias? Well, this will depend really on the type of anemia, of course, and we'll focus on the two most common ones you're likely to encounter, which are iron deficiency and pernicious anemia. Iron deficiency anemia is worldwide the most common anemia and the etiologies depend on what part of the world we're talking about.
In the developed world pregnancy and chronic blood loss are the most common causes. of IDA and aside from pregnancy some chronic causes of blood loss include gastrointestinal bleeds or inflammation and women are are at greater risk than men, as are women of childbearing age, kids, and people living in poverty. In the developing world, it is more likely that you'll see more dietary insufficiencies playing a role in iron deficiency anemia. Before we go further, it's useful to talk about the way iron is handled in the body.
In the top left corner you'll see a red blood cell which upon lysis releases its hemoglobin. broken down into the globin, polypeptide, the heme portion, and iron. Now, plasma iron is really taken from two sources, the breakdown of red blood cells, as well.
dietary intake. So plasma iron itself is not particularly soluble, therefore to transport iron we need iron transport proteins, and two primary iron transport proteins are transferrin and ferritin. So transferrin can cycle iron back to the liver, spleen, and marrow. And ferritin can transport iron within plasma and into cells.
Both of these iron-binding proteins help transport the ferric form, or Fe3+, form of iron, and help prevent it from becoming the more toxic ferrous, or Fe2+, form. And to keep in your head straight the difference between ferric and ferrous, just think that there are two of us, ferrous. And because of the oxidation potential of Fe2 plus iron, it is more prone to be involved in the formation of free radicals. Ferritin is the storage compound for iron that's not typically incorporated in hemoglobin, and its level is linked directly to the amount of iron stored. So it's a very useful measure of stored iron.
However, it's also an acute phase reactant, meaning that the levels of ferritin, serum ferritin, can go up during chronic infection or inflammation, quite independent of iron state. So, it's important to interpret ferritin levels according to whether or not there is an ongoing infection or inflammation. Regardless of these complications, ferritin is the most sensitive test for iron deficiency, and I'm going to give you some numbers which are really fairly approximate numbers. Normal serum ferritin levels are 30 grams per deciliter. A patient may be considered to have borderline iron deficiency if ferritin levels are 13 to 20 grams per deciliter.
And iron deficiency can be diagnosed if you have two successive readings wherein serum ferritin is between 0 and 12 grams per deciliter. So the main take-home point is ferritin is the most sensitive test for iron deficiency. The pathophysiology of iron deficiency anemia essentially follows three stages.
In stage 1, iron stores may be depleted, but erythropoiesis in the bone marrow occurs normally. In stage 2, there's a further decrease of iron to the marrow, and at this point, iron-deficient red blood cells are not present. blood cell production occurs, although you may still get RBC indices with the normal limits. Finally, in stage 3, the iron deficiency is such that microcytic hypochromic red blood cells are produced in enterocirculation.
The signs and symptoms of iron deficiency anemia are classic. They usually start to appear when iron is approximately... Some of the first signs and symptoms of iron deficiency anemia include fatigue and weakness, as well as shortness of breath.
Poor skin color is also one of the signs. And with chronic iron deficiency anemia, brittle ridge nails, sometimes... Spoon-shaped nails, a condition called quilinichia, are also manifest.
And as you can note from the picture at the side of the panel here, glossitis, or a red, beefy, inflamed tongue, is very typical of iron deficiency anemia. So how do you diagnose it? Well, we look at low serum iron.
Although low serum iron is not always a good sign because iron levels can vary during the day. Low ferritin remains. remains one of the best diagnostic tests. Also, high total iron binding capacity, or TIBC, is typical of iron deficiency anemia. And this makes sense because if there's low iron, then there will be unoccupied iron binding proteins, therefore a high capacity.
Microcytic red blood cells, thrombocytosis, and another sign is elevated RDW, or red cell distribution width. And the problem clinically is that in the early stages of iron deficiency anemia, hemoglobin levels, hematocrit, and red blood cell indices are largely unchanged. In later stages, transferrin saturation, which is the ratio of serum iron to TIBC, can be diagnostic, and low values indicate iron deficiency anemia.
If the total iron binding capacity is greater than 71.6 micromoles per liter, that's another good indication of iron deficiency anemia. Whereas if the total iron binding capacity is 35.8 micromoles per liter or less, it's typically indicative of an inflammatory process. In terms of treatment, as with any pathological disorder, it's best to fix the cause, whether it's secondary to GI bleed or inflammatory conditions such as colitis or Crohn's disease.
Until that time can be fixed, it's usually a good measure to start iron supplementation. And iron supplementation can be used both as a diagnostic, a treatment measure, and a diagnostic measure. So if an increase in hemoglobin of 10 to 20 grams per liter after iron therapy occurs, it's usually taken as confirmatory of iron deficiency anemia.
However, one also has to be careful. consider that if there's no response to treatment, compliance might be an issue. So iron supplements are the rule, and what do we supplement with? Well, dietary supplements are best, provided we have...
a non-inflamed gastrointestinal tract. Meat, fish, poultry are the best forms of iron. Beverages such as orange juice are also recommended in that vitamin C is an important co-factor in the uptake of iron from the gut. On the flip side, tea and dairy impede uptake.
Iron supplements may be needed. Iron sulfate is the most commonly used form, largely because of cost. However, it is not the most bioavailable form of iron.
Other forms include iron succinate, gluconate, and fumarates. If oral iron supplements do not give a satisfactory response, parenteral iron may be required, particularly if absorption is impaired through an inflamed gut. And in this case, iron dextrans may be given either intravenously or intramuscularly. So some of the macrocytic anemias include B12 and folate deficiency. anemia secondary to alcoholism, medication induced, and so on.
And we'll not spend much time about any of these. I encourage you, however, to read specifically more about B12 and folate deficiencies. Pernicious anemia is another common anemia which is caused mainly by vitamin B12 deficiency. And it's rare in individuals less than 30 years old, but the symptoms typically start earlier and develop very slowly.
And some of the signs and symptoms are initially fairly vague. It can include mood swings and or some of the more classic symptoms such as weakness, fatigue, paresthesia, and so on. And the neuronal manifestations are a result of nerve demyelination, and this is particularly troubling, and for this reason, if an anemia is suspected, B12 levels should always be tested, as well as folate levels. Pallor, glossitis, things we've seen with IDA. are also typical manifestations, as is liver enlargement. Diagnosis is based on a few measures.
It's a macrocytic anemia, so if there's an elevated mean corpuscular volume, it's heading you towards pernicious anemia. And we see elevated mean corpuscular volume because B12 is needed for DNA synthesis. and the rate of RNA and cytoplasm synthesis in these cells exceeds DNA production if B12 is low.
So the cells don't grow normally and releases large, immature red blood cells. Low B12 titers can also indicate pernicious anemia, and these are usually due to a lack of intrinsic factor, which is an enzyme required for B12 absorption across the gut. And this may be the result of autoantibodies to gastric cells.
Treatment, of course, is fairly straightforward. You want to give foods which are rich in vitamin B12, which include liver, cereals, fish, and dairy. Oral replacement may be necessary, usually 1 to 2 milligrams daily for 2 weeks and 1 milligram per week.
And in more advanced cases, a parenteral regime may be used in which daily injections of 1,000 micrograms grams of cyanocobalbumin for one week are given. This leads us next to white blood cell disorders, and we will not spend a lot of time on these other than talk about the fact that white blood cell disorders are common. Abnormalities in function are rare.
Most frequently, you'll see white blood cell disorders reflected as changes in neutrophil counts, neutrophils being the most abundant white blood cell. So if there's an increase in white count or leukocytosis, this may be the result of a normal adaptation to a physiological stress like infection, or neutropenia, and neutropenia is never a typical response or a normal response. Lymphocyte numbers can be affected by a variety of parameters.
Lymphocytosis can occur, or an increase in lymphocyte number, can occur as a result of viral infections, whereas lymphopenia is commonly associated with steroid therapy, HIV, or Cushing syndrome. And I'll leave you with these e-medicine... topics to read more about leukemias and lymphomas if you wish.
And there are a variety of handy websites which can be accessed by the primary care practitioner. We'll finish with platelet disorders. And they can be either qualitative or quantitative.
Qualitative meaning there are intrinsic abnormalities to the cell or abnormalities, for example, which prevent platelet adhesion. and there can be quantitative disorders of platelets in which you can have either thrombocytopenia or thrombocytosis. And thrombocytopenia is typically due to decreased production or decreased survival. Thrombocytosis is seen in a variety of myeloproliferative disorders, malignancies, and also post-splenectomy. So, iron deficiency.
The anemia also can be manifested by thrombocytosis, and thrombocytopenia can be a reflection of aplastic anemia. And in this case, thrombocytopenia, that is, systemic lupus, can also cause thrombocytopenia by decreasing. platelet survival. Thrombocytopathy or improper platelet function can be the result of liver failure where many of the clotting factors are made, uremia or importantly NSAIDs.
Bone marrow depression of course can affect platelet RBC or white blood cell levels. And in cases where there are decreased platelets, red blood cells and granulocytes, we refer to this condition as pancytopenia. And I'll leave you with a few therapeutic questions. Tissue plasminogen activator, or TPA, and streptokinase are drugs you're likely familiar with.
My question is, when are these indicated, and how do they work? Vitamin K, also known as VITAMIN K, is sometimes used in clinical practice. Again, my question is, when is VITAMIN K given, to what population that is, and why?
And DIC, or disseminated intravascular coagulation, is another disorder which I'd like you to think about. And the question is, how does it present? What are some causes?
And how is it managed? With that, we'll conclude our brief overview of pathologies of the hematologic system. We've gone over fairly lightly and generally some of the key hematologic disorders you're likely to see, and I encourage you to participate in class. conversations and to read your fellow classmates' posts to learn more about these.