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Home , Blood cell, Hemostasis, Iatrogenic anemia, Platelet

THE LIFE OF THE RBC AND THE CLINICAL /NURSING Brandy Sprunger-Helewa, CVT, RVT, AAS, VTS (ECC)

Erythrocytes and both begin their lives as hematocytoblasts, or stem cells, within the marrow. From there and within the , they become ever-maturing erythroblasts and platelets until they are released into circulation. Once there, erythrocytes become denucleated, mature red cells. Platelets are actually fragments of large nucleated ; anywhere from 1,000–3,000 platelets are formed from one . Once fragmented, platelets become capable of providing primary when an injury occurs to the blood vessels, and are also nonnucleated.

Because erythrocytes and platelets do not contain a nucleus, they cannot divide to create replacements of themselves, nor can they create to repair themselves when damaged. This is why erythrocytes only have a lifespan of 120 days, while platelets only live for about ten days. Were erythrocytes to contain mitochondria, they would use up all of the oxygen that they were designed to carry to peripheral tissues. For energy, erythrocytes anaerobically metabolize glucose within the plasma, as do platelets. This is why red cells and plasma or must be separated after being spun down in a centrifuge; blood glucose levels would be falsely decreased if we did not.

One drop of blood contains 260 million red blood cells and 7.5–15 million platelets. Erythrocytes are biconcave, which allows them to stack, bend, and fold into small capillaries, carrying oxygen to the most peripheral parts of the body. The total surface area of all the erythrocytes in the body is about 3,800 square meters; that’s almost as big as a football field, and is 2,000 times the surface area of the body itself! It takes 20 seconds for a red cell to make a complete circuit around the body, and it will do this 75,000 times during its life time. Platelets, on the other hand, are biconvex, and become more spherical in shape when being used to produce a clot. Platelets also develop long tendrils that allow them to hang on to each other, making the clot stronger. Humans create over 100 billion platelets in just one day, making them the most proliferative type in the body.

Erythrocytes Each erythrocyte contains about 280 million molecules, and each of these has four “corners” that contain a heme molecule. This heme molecule is essentially a ring around an core, which is what facilitates the binding of oxygen. Heme and iron is what gives red blood cells their “red” hue. Not all of the oxygen in the body is attached to erythrocytes; only about 98% of it is. The rest is dissolved in plasma waiting to be picked up and transported by the red blood cells. This is why the use of a pulse oximeter does not give an accurate indication of total body oxygenation. Pulse oximeters are only telling you how many erythrocytes are transporting oxygen, not how much oxygen is dissolved in plasma.

It is in the capillaries that the erythrocytes must stack, bend, and twist to be able to move along the capillary beds to deliver the oxygen to the tissues. Once the oxygen is delivered, carbon dioxide quickly attaches to the empty hemoglobin. Hypoxia and hypotension stimulate red cell production by sending messages to the in the renal cortex of the kidneys to release erythropoietin. Erythropoeitin stimulates the bone marrow to increase numbers while also decreasing the amount of time it takes for an erythrocyte to mature. As hypoxia or hypotension improve, the receives the negative feedback and reduces the amount of erythropoietin released, slowing down production.

There are many things that can affect erythrocyte life span, either directly or indirectly. These can include parasites, infectious diseases, illnesses or neoplasias, , and toxins. Some affect the erythrocyte’s ability to carry oxygen while others destroy the shape of the cell itself. Still others may demolish the erythrocyte in its entirety. A list of the common causes for are listed in Table 1.

Hemangiosarcomas of the heart, , or as well as disseminated intravascular (DIC) and vasculitis cause shearing injuries to the red blood cells seen as and acanthocytes on blood smears. Rough blood vessels damage the smooth surface of erythrocytes as they pass by, tearing off pieces of the membranes. These pieces are unable to hold hemoglobin, and, thus, cannot carry oxygen. Immune mediated (IMHA) is a very common cause of both intravascular and extravascular red cell . Red cells are inappropriately tagged with that the deems as foreign and then sets about destroying the cells. Many abnormalities of the erythrocytes can be seen when evaluating a blood smear and can help determine the source or cause of the changes themselves. In IMHA and many of the toxins, a regenerative anemia will be present and demonstrated by spherocytosis, polychromasia, anisocytosis, reticulocytosis, and nucleated red blood cells. In neoplasias, particularly of the bone marrow, a nonregenerative anemia will be present. A microcytosis and hypochromasia is present in and zinc toxicity. Howell Jolly bodies are remnants of nuclear material that were not completely cleared from the erythrocyte, and can be seen in patients with or who have a history of . Echinocytes are seen in Type B snake envenomation, and are sometimes confused with crenation seen in poor slide creation or blood sampling techniques. Nucleated red blood cells can also be a poor prognostic indicator in heatstroke patients.

Other erythrocyte changes in patients can include iatrogenic anemia caused by frequent blood draws or accidental disconnection of IV fluid lines from catheters. Heatstroke injures red blood cells through direct thermal damage; this occurs at temperatures over 107°F (42°C) and worsens when elevated temperatures are prolonged.

As red cells age, they become stiff and have more trouble moving through the capillaries. Once this happens, or when red cells become damaged, 90% of them are phagocytized within the spleen, liver, and lymph nodes. Ten percent of the red cells are removed by . Hemoglobin is then broken down into heme and globulins. The globulins are further broken down into amino acids where they are picked up and used by other cells to produce new proteins. Heme is metabolized into bilirubin and then combines with albumin. This bound bilirubin travels to the liver where it combines with glucuronic acid and becomes conjugated bilirubin. It is then secreted into the small intestines with bile and travels to the large intestines where bacteria break it down into urobilinogen. Most urobilinogen is excreted in feces, but some is reabsorbed by the colon and is excreted in the urine, making urine yellow in color.

Platelets Despite their small size, platelets have a very important job to do, which is to help prevent hemorrhage from every single and capillary in the body—they are there to keep the erythrocytes in their place! The moment a tear occurs in a vessel is the moment that platelets take action, by being attracted to the exposed of the vessel wall. Once the platelets attach to the rent in the wall (primary hemostasis), they change shape, create long tendrils to hold on to each other, and secrete proteins that signal the instigation of the coagulation cascade (secondary hemostasis). The completion of secondary hemostasis will shore up this and make it stronger.

There are many things that can affect primary hemostasis, beginning with the number of platelets available in circulation. Patients with low platelet counts are termed thrombocytopenic, while patients with high platelet counts are termed as having thrombocytosis. Thrombocytosis can be seen in inflammatory processes like Systemic Inflammatory Response Syndrome (SIRS) and as well as DIC. High platelet counts are also common in patients who have had a splenectomy, Cushing’s disease, or certain types of myleoproliferative neoplasias. Occasionally, a primary thrombocytosis is hereditary in nature. Patients with high platelet counts are at high risk for a thromboembolic event, most commonly leading to a “saddle ” or pulmonary thromboembolisms. These are also seen in patients with Cushing’s disease, IMHA, or hypertrophic cardiomyopathy, as these patients are often hypercoaguable to begin with.

Thrombocytopenia can be further categorized into decreased production, increased consumption, increased destruction or sequestration of platelets into the spleen secondary to certain types of neoplasia (most commonly ). Decreased production can be due to a decrease in , a hormone released by the kidneys and liver that stimulates the bone marrow to release and fractionate megakaryocytes. The bone marrow also may be unresponsive to thrombopoietin. Platelets can be consumed at a faster rate that they are being created in some infectious diseases (like ) or if there is a large acute hemorrhage. due to increased destruction is most commonly seen in immune mediated illnesses like IMHA and immune mediated thrombocytopenia (immune-mediated thrombocytopenia [IMT] or idiopathic thrombocytopenic [ITP]). Spontaneous occurs when platelet counts fall below 30–50,000/mm3. Thrombocytopenic patients often present with , ecchymosis, epistaxis, melena, or hematochezia. The most common causes for thrombocytopenia and thrombocytosis are listed in Table 2.

There are many other things that can affect platelet function and subsequent primary hemostasis. These include some drugs, toxins, and disease processes like sepsis and DIC. Platelet counts can be easily performed using a standard blood smear, and are often done at the same time that erythrocyte morphology is evaluated. Care must be taken that a sample of EDTA anticoagulated blood is used to ensure there are no platelet clumps, which would falsely lower the platelet count. Drugs that can alter platelet function include , which prevents platelets from sticking together, and , which reduces the ability of secondary hemostasis to occur, thus weakening the platelet plug created during primary hemostasis. Snake venom also has a direct effect on platelets, by destroying them in a manner similar to that of erythrocytes. rodenticides do not affect platelets directly, though patients who have developed hemorrhage from the toxin may have low platelet counts on blood work.

Von Willebrand factor (vWf) deficiency can be seen in Doberman pinschers and German shepherd dogs, among other breeds. Decreased levels of vWf prevent platelets from sticking together and to the exposed collagen of the blood vessels. Performing a buccal mucosal (BMBT) in house, or sending a coagulation panel to an outside laboratory before scheduling for these breeds is a good way to prevent the need for blood transfusions later. Oftentimes, these patients are not identified until an incident arises and hemorrhage is slow to stop. Patients deficient in vWf may also present with melena, hematochezia, hematemesis, hematuria, or subconjunctival hemorrhage.

For patients with thrombocytopenia, transfusion of blood products, including and/or platelets, is often the first course of treatment. (also called DDAVP) can also be used to treat patients with von Willebrand’s disease, as it helps to release vWf from the where it resides and into the blood stream where it can assist in platelet aggregation. This obviously will only work in those patients who have a supply of vWf, but are unable to release it on their own. Intravenous immune globulin (IVIG) can also be used to treat thrombocytopenia, though its use is still not quite understood and, thus, somewhat controversial. It is most effective when used in IMT patients whose platelets have been marked to be destroyed by the spleen and immune system. IVIG binds to the receptors on the platelet, thus preventing the immune system from thinking the platelet is “foreign.” This allows other treatments like immune suppressants and time to dampen the effects of the immune system and the bone marrow to catch up in releasing new platelets.

Platelet clearance must naturally occur in order to prevent thrombocytosis. This happens in a manner very similar to that of erythrocyte removal. Old, damaged platelets are marked for destruction, and are removed by macrophages as they pass through the liver and spleen. Other platelets are simply used up in the microvasculature where they are constantly plugging up small holes in the vessel walls. Unlike erythrocytes, which can cycle through the body many times, the short life-span of a platelet and its use at the site of damage prevent a long circulation pattern.

Erythrocytes and thrombocytes have very specific tasks and shapes. Despite having such short life-spans, erythrocytes manage to keep all organs and tissues fueled with oxygen, while platelets work to ensure the erythrocytes stay within the blood vessels. As some of the most numerous and proliferative cells in the body, and despite containing no nucleus, erythrocytes and platelets are amazing, busy cells. In order to best care for our patients, we should always keep in mind:

1. The process for creating new erythrocytes and platelets 2. The life cycle of the erythrocyte and platelet 3. The most common diseases related to changes in either platelet or erythrocyte counts

Table 1. Causes for Anemia REGENERATIVE NON-REGENERATIVE Acetaminophen toxicity Atypical Addison’s disease Allium sp. toxicity (onions, leeks, , etc.) Bone marrow disease or neoplasia Babesia Chloramphenicol use Disseminated Intravascular Coagulation (DIC) Early hemorrhage Hemangiosarcoma Hypothyroidism Immune Mediated Hemolytic Anemia (IMHA) Iron deficiency Late/prolonged hemorrhage Kidney injury/failure Lead toxicity Mycoplasma infection Propofol administration Sulfasalazine use Zinc toxicity (pennies minted after 1982)

Table 2. Common Platelet Disorders THROMBOCYTOPENIA THROMBOCYTOSIS Cushing’s Disease B12 deficiency Desmopressin use Bone marrow disorders Disseminated Intravascular Coagulation (DIC) Chemotherapy Immune Mediated Hemolytic Anemia (IMHA) Decreased thrombopoietin production/effectiveness Hemorrhage Dehydration Hypertrophic Cardiomyopathy Disseminated Intravascular Coagulation (DIC) Myeloproliferative neoplasias Immune mediated thrombocytopenia vera Late/prolonged hemorrhage Sepsis Sepsis Snake envenomation Snake envenomation Splenectomy borne disease (Ehrlichiosis, Lyme’s disease) Tetralogy of Fallot

References available upon request