WHAT ARE THE COMPONENTS OF THE BLOOD, AND WHERE ARE THEY MADE? Plasma: proteins made mainly in liver Serum is the fluid that remains after blood clots Red cells, neutrophils and platelets made in bone marrow lymphocytes made in bone marrow, lymph nodes, spleen

BONE MARROW

1.Neutrophils, red cells and megakaryocytes all descended from common precursor cell called myeloid stem cell 2.Stem cells differentiate into primitive cells called blasts, which are precursors of each cell type 3.Blasts divide and mature under the influence of proteins called growth factors; as they mature they lose the ability to divide 4.Mature neutrophils and red cells enter the blood 5.Megakaryocytes break into small fragments (platelets), which enter blood WHAT HAPPENS IN BONE MARROW?

What is a stem cell? A cell that can reproduce itself indefinitely –Other cells eventually stop dividing and die A cell that can differentiate into one or more types of functional mature cells –Other cells are “locked in” to a certain differentiation pathway –For example, hematopoietic stem cells can differentiate into red cells, neutrophils, megakaryocytes, or lymphocytes There are many types of stem cells –Usually they exist in small numbers compared to other cell types In theory a single hematopoietic stem cell could re- constitute an entire bone marrow

B T NK BlastsStem cellsMature cells U L M rbc pmn megakaryocyte E N M L lymphocytes Differentiation

B T NK BlastsStem cellsMature cells U L M rbc pmn megakaryocyte E N M L lymphocytes Differentiation

DIFFERENTIATION OF NEUTROPHILS AND RED CELLS

A megakaryocyte releasing platelets Blood 2005;106:9 Platelets

HEMATOPOIETIC GROWTH FACTORS CONTROL PRODUCTION OF BLOOD CELLS Growth factors regulate the growth, differentiation and function of cells of the hematopoietic and immune systems Examples –Erythropoietin: stimulates red cell production –Thrombopoietin: stimulates platelet production –G-CSF: stimulates granulocyte (neutrophil) production, activates neutrophil function These can be manufactured and given to patients to boost production of specific blood cells

NORMAL BLOOD COUNTS MenWomen White cells (thousands) Red cells (millions) Hemoglobin (grams/dl) Hematocrit (%) Platelets (thousands) 150, ,000 White cell, red cell and platelet numbers are per microliter of blood

HEMATOCRIT TUBES Anemia normal polycythemia

Functions of blood transport oxygen, nutrients & waste products fight infection prevent bleeding

little bags of hemoglobin function: carry 0 2 to tissues, CO 2 to lungs hematocrit: proportion of blood volume occupied by red cells RED BLOOD CELLS (ERYTHROCYTES) top side

Red blood cells RBC in small blood vessel

Red cells must be very flexible

WHITE BLOOD CELLS (LEUKOCYTES) Neutrophils eat bacteria produce inflammatory molecules Lymphocytes make antibodies kill foreign or infected cells regulate immune system Monocytes eat bacteria and other unwanted things regulate immune system

PLATELETS Smallest formed elements in blood Not really cells (no nuclei) but fragments of large cells called megakaryocytes found mainly in bone marrow Function: help blood clot, prevent bleeding

 B lymphocytes and plasma cells  T lymphocytes  Natural killer (NK) lymphocytes  Monocytes and macrophages CELLS OF THE IMMUNE SYSTEM

MONOCYTES

LYMPHATIC TISSUE LYMPH NODESPLEEN

THE LYMPHATIC SYSTEM

WHERE LYMPHOMAS COME FROM or, why good lymphocytes go bad  Lymphocytes must undergo extensive rearrangement of their DNA to create a repertoire of cells capable of responding to many different antigens  Occasionally this rearrangement is not accomplished properly and the cell gains a growth advantage over its neighbors  Lymphocytes (especially B-cells) must undergo programmed cell death (apoptosis) when they are no longer needed  Occasionally this program is faulty and the cells continue to divide indefinitely

ANEMIA Definition: reduced total red cell mass Hematocrit and hemoglobin concentration usually low (exception: acute blood loss) Causes: 1.blood loss 2.red cell destruction (hemolysis) 3.decreased red cell production

 Macrocytic: big red cells  Normocytic: normal size red cells  Microcytic: small red cells  Reticulocytes: newly made red cells; number in blood proportional to rate of red cell production ANEMIA

VARIATION IN RED CELL SHAPE IN ANEMIA

1.Decreased red cell production a.Stem cell damage - neutrophils, platelets often affected also b.Defective red cell maturation 2.Increased red cell destruction (hemolysis) a.Intrinsic defect in red cell leading to shortened lifespan b.External factors in blood or blood vessels destroy red cells 3.Blood loss ANEMIA Classified by cause

B T NK BlastsStem cellsMature cells U L M rbc pmn megakaryocyte E N M L lymphocytes Differentiation Stem cell damage

B T NK BlastsStem cellsMature cells U L M rbc pmn megakaryocyte E N M L lymphocytes Differentiation Defective red cell maturation

 Decreased numbers of pluripotent stem cells cytotoxic chemicals ionizing radiation virus infection "idiopathic" - probably autoimmune  Marrow empty or hypocellular  Anemia, neutropenia, thrombocytopenia  Treatment: supportive (transfusions, antibiotics etc) immune suppression bone marrow/stem cell transplantation APLASTIC ANEMIA: a stem cell disorder

APLASTIC ANEMIA Bone marrow biopsy NormalAplastic

ANEMIA SECONDARY TO OTHER DISEASES “Anemia of chronic disease”  Inflammation: infection, rheumatoid arthritis, etc  Kidney failure (kidneys make erythropoietin)  Cancer  Malnutrition  All associated with decreased stimulus for red cell production  Nothing intrinsically wrong with bone marrow  Anemia resolves if causative disorder cured  May be treatable with synthetic erythropoietin

 Most common cause of anemia worldwide  Decreased red cell production  Microcytic: small cells due to decreased hemoglobin production (need iron to make hemoglobin)  Causes: chronic blood loss, pregnancy, poor diet Premenopausal women: Menstrual blood loss, pregnancy All others: Gastrointestinal bleeding (eg, ulcer, cancer) (Young children): diet of cow's milk  Treatment: replace iron, rule out/treat bleeding IRON DEFICIENCY ANEMIA NormalIron deficient (small, pale cells)

 Vitamin B-12 Deficiency Macrocytic (big cells): B-12 needed for DNA synthesis, so cells grow but can’t divide normally Usually due to poor absorption of vitamin rather than poor diet Pernicious Anemia = stomach disorder causing lack of factor which aids B-12 absorption (intrinsic factor) May be associated with serious neurologic disorder Treatment: B-12 injections  Folic Acid deficiency Macrocytic (folic acid also needed for DNA synthesis) Causes: poor diet, alcohol abuse, certain medications Treatment: oral folic acid supplements ANEMIA DUE TO VITAMIN DEFICIENCY NormalMacrocytic

 Inherited disorder of hemoglobin production  Caused by defect in gene(s) for either of the protein chains in hemoglobin alpha beta  Microcytic anemia Severe = thalassemia major  Most patients depend on red cell transfusion to survive Mild or moderate = thalassemia minor THALASSEMIA Normal Thalassemia minor