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Megakaryocyte Information and Courses from MediaLab, Inc.

These are the MediaLab courses that cover Megakaryocyte and links to relevant pages within the course.

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Authentic and Spurious Causes of Thrombocytopenia
Diseases and Disorders That Affect the Bone Marrow and Decrease Platelet Production

Conditions that affect the bone marrow can also lead to thrombocytopenia. It may be necessary to examine bone marrow smears and sections to diagnose the primary condition that is causing the decrease in circulating platelets. In leukemia, the platelet count is diminished as a result of displacement in the bone marrow of normal hematopoietic cells (including megakaryocytes and their precursor cells) by leukemic cells. If megakaryocytes are reduced in the bone marrow, the number of circulating platelets will be reduced. Chemotherapy can lead to transient thrombocytopenia since it interferes with the cell cycle of normal as well as tumor cells. In patients with aplastic anemia, where the stem cells are not functioning properly, thrombocytopenia occurs as the bone marrow becomes more and more hypoproliferative. Pancytopenia is often seen with megaloblastic anemias that are caused by folic acid or vitamin B12 deficiency. Thrombopoiesis (as well as erythropoiesis and granulopoiesis) is ineffective. The bone marrow contains a normal, or even increased number of megakaryocytes, but the number of platelets entering the peripheral circulation is decreased.

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Treatment of TTP

Currently, the most effective treatment for TTP is therapeutic plasma exchange (TPE). Fresh frozen plasma (FFP), preferably cryoprecipitate-poor plasma (that lacks von Willebrand factor), is used as the replacement fluid in the treatment. The exchange takes place over several days until the patient's platelet count stabilizes above 100 x 109/L.The logic of TPE is to rid the circulation of plasma containing ultra-large vonWillebrand factor (vWF) multimers. vWF is a large multimeric protein that is made by megakaryocytes and endothelial cells. It is is a key factor in platelet adhesion and also is responsible for carrying Factor VIII into the circulation. vWF binds glycoproteins Ib, IIb, and IIIa. The largest multimer is called ultra-large vWF and in normal plasma, it is cleaved into smaller fractions (necessary for balanced coagulation activity) by an enzyme processed by the gene, ADAMTS13. In patients with TTP, the enzyme activity is < 5% of normal and therefore, these ultra-large vWF molecules get into circulation, resulting in excessive platelet aggregation and microvascular thrombus formation.Therapeutic plasma exchange has decreased TTP mortality rate from 90% to 15% since the treatment first came into use as the standard primary treatment of TTP in the 1970's. TPE does not cure TTP, but it arrests the manifestations of the disease until spontaneous remission occurs.

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Idiopathic Thrombocytopenic Purpura (ITP)

ITP is an immune-mediated disorder in which platelets are coated with autoantibodies; the antibody-coated platelets are subsequently removed by the spleen. The autoantibodies are directed against glycoproteins IIb/IIIa (fibrinogen receptor) and the complex GPIb/IX (von Willebrand factor receptor). These glycoproteins are located on the platelet membrane and play an important role in platelet aggregation, in creating a bridge with fibrinogen, and in platelet adhesion. The pathophysiology for this disorder is unclear. There is speculation that the autoantibodies arise as a result of a common viral or bacterial infection. Another speculation is that there may be a failure of T-regulatory cells. In addition to increased platelet destruction, platelet production may also be impaired or disrupted to some extent, possibly as a result of megakaryocyte injury by the autoantibodies. ITP can be acute or chronic.

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Bone Marrow Aspiration Part I: Normal Hematopoiesis and Basic Interpretive Procedures
Megakaryocyte: Immature

The megakaryocyte lineage is the cell line responsible for the production of platelets found in the peripheral blood. Unlike the other bone marrow lineages that decrease in size as they mature, the megakaryocyte starts smaller and increases in size as it matures. The megakaryocyte begins as a mononuclear cell that has the same physical size and nuclear/cytoplasmic proportions as a lymphoblast. Eventually the megakaryocyte matures into a multinucleated giant cell with vast amounts of cytoplasm. As this cell matures, it can actually increase to more than ten times the size of other nucleated cells found in the bone marrow.In the early stages of development, the cytoplasm of a megkaryocyte is basophilic without any obvious platelet granules. The cytoplasm will be darker near the edges of the cell and may have a "foamy" look in the golgi area adjacent to the nucleus. Cytoplasmic granule development is not usually noticeable until the cell's cytoplasm color begins to lighten.Notice the sizes of the early-intermediate stage megakaryocytes (red arrows) in comparison to the background bone marrow cells present in the two images to the right. The megakaryocyte nucleus makes up the largest part of the cell at this early stage. Notice the increasing lobulation as the cell increases in size and how the cytoplasm becomes more foamy and slightly more granular as well.

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Megakaryocyte: Mature

The mature megakaryocyte is the largest cell found in the bone marrow. It can easily reach more than ten times the size of the other cells and usually has as much, if not more, cytoplasmic volume than it has nucleus.Once nuclear/DNA replication found in the early megakaryocyte has halted, the amount of cytoplasm will begin to increase until the megakaryocyte reaches its maximum mature size. As platelet granule production increases, the cytoplasm color will shift from basophilic to the grainy pink texture and light lavender color we are familiar with in peripheral platelets. When the cytoplasm has matured enough to produce platelet granules, the process of shedding platelets can begin. This can occur either as an ongoing continuous process or as a single complete release leaving a naked megakaryocyte nucleus.Notice the extremely large sizes of the megakaryocytes in the images to the right. The megakaryocytes tend to be found in the heart of the bone marrow fragments rather than loosely scattered throughout the smear. Observe the proportion of nucleus to cytoplasm. Notice the foamy, shaggy, irregular cytoplasmic border of the single megakaryocyte that is circled in the bottom image. This megakaryocyte is in the process of releasing platelets and small clusters of platelets can be seen in its vicinity.

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Osteoclast

Osteoclasts are the cells responsible for bone resorption. They work in conjunction with osteoblasts. Both cells under normal circumstances are constantly in the process of rebuilding/reshaping/repairing bone to ensure strength and function. Osteoclasts are only infrequently seen in bone marrow aspirates. They become more obvious when the cellularity is depressed.Osteoclasts are large multinucleate cells somewhat similar in appearance to megakaryocytes, which can cause confusion. Notice in the images to the right that the nuclei of the osteoclasts are flat, even in number, oval or round, uniform in size, and well separated in the cytoplasm. In contrast, megakaryocyte nuclei are segmented and clump in three dimensional clusters. The cytoplasm of an osteoclast is grainy and paler in color than a megakaryocyte. Observe how fluid and irregular the cytoplasmic borders are in the osteoclast.

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Fundamentals of Hemostasis
Which of the following is not true in terms of platelet characteristics?View Page
Primary Hemostasis: Platelet Production

Platelets are produced in the bone marrow by highly specialized cells called megakaryocytes. The arrow in the image on the right points to a megakaryocyte. The area enclosed by the red circle contains platelets that are created within the megakaryocyte cytoplasm and eventually released. The average lifespan of a platelet is 9-12 days.About 70-80% of a person's total platelets are circulating in the vasculature at any given time. Approximately 20-30% of the total platelets are pooled in the spleen.

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Hematology / Hemostasis Question Bank - Review Mode (no CE)
The cell indicated by the arrow in this illustration is called:View Page
The precursor of the platelet which is commonly only found in the bone marrow is:View Page

Introduction to Bone Marrow
Which of the following cell types would be considered a rare finding in a direct bone marrow smear?View Page
The M:E ratio represents the ratio of:View Page
Match each of the following:View Page
These cells tend to occur in tight clusters. They may have prominent nucleoli, immature chromatin, and scant cytoplasm.View Page
Location of Cells within Cord

Within the hematopoietic cords each cell line has a specific location for development. Erythroid precursors are located near a venous sinusoid and cluster around a macrophage. This is referred to as an erythroblastic island. Developing red cells obtain iron needed for hemoglobin production from macrophages. Megakaryocytes are also located close to a venous sinus. They extend their cytoplasm in fingerlike projections through the sinus wall in order to release their platelets directly into the blood in the sinus. Immature granulocytes lie within the hematopoietic cords. The metamyelocyte stage is the first stage of the granulocyte series that is motile and able to move toward the sinus area. Mature neutrophils, eosinophils and basophils enter the sinusoidal blood through the basement membrane. As maturing erythrocytes also move toward the sinus wall any remaining nuclei are lost as the red cells move through small openings in the cells lining the sinus wall.

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Promegakaryocyte

The next stage after the megakaryoblast is the promegakaryocyte. It is intermediate in maturity between a megakaryoblasts and mature megakaryocytes. It may have multiple nuclei, coarse chromatin, and more cytoplasm than a megakaryoblast.

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Examination of Wright-Giemsa Stained Bone Marrow

Examination of Wright-Giemsa stained bone marrow preparation involves examination under low power (10X objective) high power (40-50X objective )and oil immersion (100X objective). Low power examination: Assess quality of smear, assess number of megakaryocytes.Assess myeloid to erythroid ratio.Evaluate morphology and do differential count.

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Low Power Magnification

This smear is shown under low power (10x objective) magnification. The reddish cells in the background are mature red blood cells. The dark dots are nucleated erythroid and myeloid precursors. The large dark dot in the middle is a megakaryocyte. Normally, about 5 to 10 megakaryocytes are seen per microscopic field at low power magnification. Clusters of megakaryocytes usually indicate megakaryocytic hyperplasia. Less than 2 megakaryocytes per low power field may mean megakaryocytic hypoplasia.

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High Power Magnification

This field under high magnification shows an increased number of megakaryocytes (megakaryocytic hyperplasia). This patient had thrombotic thrombocytopenic purpura. He was therefore consuming increased numbers of platelets, and his bone marrow was responding by increasing the number of megakaryocytes, which of course break up into platelets.

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Megakaryoblast

This slide shows an example of the youngest cell in the megakaryocyte series, the megakaryoblast. Megakaryoblasts have a fine chromatin structure with multiple nucleoli, and scant basophilic cytoplasm. Cytoplasmic tags are frequently seen. It may vary 20-50 microns in diameter.

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Megakaryocyte

The next stage is the fully developed megakaryocyte. It typically shows nuclear divisions and abundant very granular cytoplasm. Megakaryocytes are the largest cell found in normal bone marrow and can range in size from 30-100 microns. The nuclear chromatin pattern is coarse. Nucleoli are absent.

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Meta Megakaryocyte Stage

The next stage is the meta megakaryocyte. By this point, platelets are actually breaking away from the meta megakaryocyte cytoplasm. The example shown in this slide illustrates the platelets forming and breaking away near the arrow.

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Other Large Cells

It is also important to scan the slide for the presence of other large cells which are not usually seen in normal marrow. An osteoclast is an example of this type of cell. Osteoclasts are large multiinucleated cells (up to 100 microns) which may be confused with megakaryocytes. One striking difference is that an osteoclast has multiple nuclei which are separate from each other. The multiple nuclei in the megakaryocyte are joined together. The cytoplasm, although somewhat finer in texture, could be mistaken for platelets.

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Please identify the cell in this image.View Page
Please identify the cells present in this image?View Page
Megakaryocyte Morphology

It is also important to examine the morphology of platelets. One megakaryocyte shows a single nucleus surrounded by cytoplasm which will eventually break off to form platelets. The other one at the arrow shows a lobated nucleus which has divided several times; the large amount of cytoplasm surrounding this nucleus means that this cell will be able to produce more platelets. In general, as the megakaryocyte gets older, it forms more nuclear lobes, more cytoplasm and therefore is able to produce more platelets.

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Bare Nucleus Megakaryocyte.

Rarely, the bare nucleus is visible after the platelets have been shed. It is referred to as a bare nucleus megakaryocyte.

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Please identify the cell in this image?View Page
Nuclear Division in Megakaryocytes

Megakaryocytes differ from other cell lines because the nucleus divides during mitosis but the cytoplasm does not.

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Normal Peripheral Blood Cells
Glossary of Terms A through M.

Antibody - A modified type of serum globulin synthesized by lymphoid tissue in response to antigenic stimulus. By virtue of specific combining sites each antibody reacts with only one antigen. Anucleate - Having no nucleus. Azurophilic granules - The well-defined large reddish granules (lysosomes) which may be present in large lymphocytes. They are called "azurophilic granules" because they stain blue with the azure stains which were originally used. Basophilic granules - Specific granules present in the cytoplasm of basophils. These granules are large and stain purple-black due to their strong affinity for basic stain. B-cell - Bone marrow derived lymphocytes which produce humoral antibodies. Biconcave - Having two concave surfaces. Cellular Immunity - The capacity of a small proportion of lymphoid population to exhibit response to a specific antigen. Chromomere - The centrally located granular portion of the platelet. Clone - A population of cells descended from a single cell. Delayed Hypersensitivity - (part of cellular immunity) that develops slowly over a period of 24-72 hours after an antigenic stimulus. It consists of an accumulation of cells around small vessels and/or nerves. Example: Tuberculin skin test reaction. Digestive Enzyme - A substance that catalyzes or accelerates the process of digestion. Eosinophilic Granules - Specific granules present in the cytoplasm of eosinophils. These granules are large, refractile spheres which stain reddish-orange due to their strong affinity for acid stain. Erythrocyte (red blood cell, RBC) - One of the elements found in peripheral blood. Normally the mature form is a non-nucleated, circular, biconcave disk adapted to transport respiratory gases. Fixed Macrophage - A phagocyte that is non-motile. Free Macrophage - An ameboid phagocyte present at the site of inflammation. Graft Rejection - A transplanted tissue that is rejected by the body's antibodies. Graft vs. Host Reaction - A complication that occurs when an implanted piece of tissue, which contains antibodies, rejects the host's tissue. Granulocyte - A leukocyte which contains granules in its cytoplasm, i.e., neutrophilic, eosinophilic, or basophilic granules. Half-life - is the length of time it takes for half of the cells circulating at a given time to leave the blood for the tissues. Hemocyte - Any blood cell or formed element of the blood. Hemostasis - A mechanism of the vascular system to arrest an escape of blood. It involves an interaction between blood vessels, platelets, and coagulation. Heparin - A mucopolysaccharide acid which, when present in sufficient amounts, functions as an anticoagulant by inhibiting thrombin. Histamine - A powerful dilator of capillaries and a stimulator of gastric secretions. Humoral Immunity - Acquired immunity produced after response to an antigenic stimulus in which B cells produce circulating antibodies. Hyalomere - the clear, blue non-granular zone surrounding the chromomere of a platelet. Immune Response - The interaction of a cell and an antigen that results in a proliferation of the cell and a capacity to produce antibodies. Isotonic Fluid - A fluid whose elements have an equal osmotic pressure. Leukocyte (white blood cell, WBC) - One of the formed elements of the blood; involved primarily with the body's defense. Lysosome - A microscopic body within cell cytoplasm; contains various enzymes, mainly hydrolytic, which are released upon injury to the cell. Megakaryocyte - A giant cell of the bone marrow from which platelets are derived. Mononuclear - A cell having a single nucleus.

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Normal Peripheral Blood Cells (retired 6/20/2012)
Platelet Kinetics

Platelets are derived from the cytoplasm of megakaryocytes, giant cells in the bone marrow. At any given time, two thirds of the total platelets are in the circulation and one third are present in the spleen. In persons with enlarged spleens 80-90% of the platelets are in the spleen resulting in a decreased concentration of circulating platelets. In individuals who have had a splenectomy all of the platelets will be in the circulating blood. The life span of the platelet is 8-10 days.

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Glossary of Terms A through M.

Antibody - A modified type of serum globulin synthesized by lymphoid tissue in response to antigenic stimulus. By virtue of specific combining sites each antibody reacts with only one antigen. Anucleate - Having no nucleus. Azurophilic granules - The well-defined large reddish granules (lysosomes) which may be present in large lymphocytes. They are called "azurophilic granules" because they stain blue with the azure stains which were originally used. Basophilic granules - Specific granules present in the cytoplasm of basophils. These granules are large and stain purple-black due to their strong affinity for basic stain. B-cell - Bone marrow derived lymphocytes which produce humoral antibodies. Biconcave - Having two concave surfaces. Cellular Immunity - The capacity of a small proportion of lymphoid population to exhibit response to a specific antigen. Chromomere - The centrally located granular portion of the platelet. Clone - A population of cells descended from a single cell. Delayed Hypersensitivity - (part of cellular immunity) that develops slowly over a period of 24-72 hours after an antigenic stimulus. It consists of an accumulation of cells around small vessels and/or nerves. Example: Tuberculin skin test reaction. Digestive Enzyme - A substance that catalyzes or accelerates the process of digestion. Eosinophilic Granules - Specific granules present in the cytoplasm of eosinophils. These granules are large, refractile spheres which stain reddish-orange due to their strong affinity for acid stain. Erythrocyte (red blood cell, RBC) - One of the elements found in peripheral blood. Normally the mature form is a non-nucleated, circular, biconcave disk adapted to transport respiratory gases. Fixed Macrophage - A phagocyte that is non-motile. Free Macrophage - An ameboid phagocyte present at the site of inflammation. Graft Rejection - A transplanted tissue that is rejected by the body's antibodies. Graft vs. Host Reaction - A complication that occurs when an implanted piece of tissue, which contains antibodies, rejects the host's tissue. Granulocyte - A leukocyte which contains granules in its cytoplasm, i.e., neutrophilic, eosinophilic, or basophilic granules. Half-life - is the length of time it takes for half of the cells circulating at a given time to leave the blood for the tissues. Hemocyte - Any blood cell or formed element of the blood. Hemostasis - A mechanism of the vascular system to arrest an escape of blood. It involves an interaction between blood vessels, platelets, and coagulation. Heparin - A mucopolysaccharide acid which, when present in sufficient amounts, functions as an anticoagulant by inhibiting thrombin. Histamine - A powerful dilator of capillaries and a stimulator of gastric secretions. Humoral Immunity - Acquired immunity produced after response to an antigenic stimulus in which B cells produce circulating antibodies. Hyalomere - the clear, blue non-granular zone surrounding the chromomere of a platelet. Immune Response - The interaction of a cell and an antigen that results in a proliferation of the cell and a capacity to produce antibodies. Isotonic Fluid - A fluid whose elements have an equal osmotic pressure. Leukocyte (white blood cell, WBC) - One of the formed elements of the blood; involved primarily with the body's defense. Lysosome - A microscopic body within cell cytoplasm; contains various enzymes, mainly hydrolytic, which are released upon injury to the cell. Megakaryocyte - A giant cell of the bone marrow from which platelets are derived. Mononuclear - A cell having a single nucleus.

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White Cell and Platelet Disorders: Peripheral Blood Clues to Nonneoplastic Conditions
Normal Bone Marrow Cells

A normal bone marrow smear stained with Wright/Giemsa stain is captured in this photograph.Note the normal maturation sequence beginning with myelocytes (the two large cells in the left upper corner)through metamyelocytes, band neutrophils,and multi-lobed segmented neutrophils.The small cells with darkly staining, centrally placed nuclei are normoblasts (three are clustered in the left lower field).Absent in this field are eosinophils, basophils and megakaryocytes.A normal M:E ratio of 2.4:1 is calculated from the twelve myeloid cells and five normoblasts. Two lymphocytes are identified, one left center, the other left upper.

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Megakaryocyte in Bone Marrow

The large cell illustrated in this photograph of a Wright/Giemsa-stained bone marrow smear is a megakaryocyte. This megakaryocyte appears mature. The nucleus has at least 8 lobes and the nuclear chromatin is coarse and distinct. Clusters of young platelets are being released from distinct platelet territories at the periphery of the cytoplasm (blue arrows). When mature, each megakaryocyte produces approximately 4000 platelets/day. Production can expand by 8-fold during times of increased demand and under the stimulus of thrombopoietin.

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