5 Hem(at)opoiesis = Blood Cell Formation Few uncommitted stem cells in red bone marrow throughout life time (Fig 16-2)Controlled by cytokines. Examples:ErythropoietinCSFs and ILs: e.g. M-CSF, IL- 3 (= multi CSF)ThrombopoietinLeukemia vs. leukocytosis vs. leukopeniaAny of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen.Leukemias (“white blood”) group of cancerous conditions of WBCs. Named according to the abnormal WBC type primarily involved (e.g. lymphocytic leukemia, myelocytic leukemia). Leukemia is acute (quickly advancing - mostly in children) if it derives from blast-type cells like lymphoblasts, and chronic (slowly advancing - mostly in adults) if it involves proliferation of later cell stages like myelocytes.Leukemia, lymphoma and myeloma are cancers that originate in the bone marrow (in the case of leukemia and myeloma) or in lymphatic tissues (in the case of lymphoma). Leukemia, lymphoma and myeloma are considered to be related cancers because they involve the uncontrolled growth of cells with similar functions and origins. The diseases result from an acquired (not inherited) genetic injury to the DNA of a single cell, which becomes abnormal (malignant) and multiplies continuously. The accumulation of malignant cells interferes with the body's production of healthy blood cells and makes the body unable to protect itself against infections. Leukemia - Leukemia is a malignant disease (cancer) that originates in a cell in the marrow Non-Hodgkin Lymphoma - Lymphoma is a general term for a group of cancers that originate in the lymphatic systemHodgkin Lymphoma - Hodgkin lymphoma (also known as Hodgkin's disease) is a specialized form of lymphoma and represents about 8 percent of all lymphomas diagnosed each yearMyeloma - Myeloma is a cancer of plasma cells, a type of white blood cell found in many tissues of the body, but mainly in the marrowMyelodysplastic Syndromes - Myelodysplastic syndromes are a group of diseases that originate in an early blood-forming cell in the marrowLeukopenia at
6 Controlled by ____________,specifically CSFs and ILs colony-forming unitCFU-GEMM, multipotent progenitor cells, give rise to erythroid, granulocyte-macrophage and megakaryoCompare to Fig 16-2
7 EPO Regulates RBC Production “Hormone” synthesized by kidneys in response to hypoxemiaEPO gene cloned in Recombinant EPO now available (Epogen, Procrit)Use in therapy, abuse in sportEPO is not stored, only produced upon demand.
8 Erythropoiesis lifespan ~ 120 days Reticulocytes EPO releaseMitotic rate Tissue O2 Maturation speed RBC bag of Hb for carrying O2lifespan ~ 120 dayssource of ATP for RBC? Tissue O2 Reticulocytesentercirculation
9 Hemoglobin (Hb) Requires iron (Fe) + Vit. B12 (cobalamin) p.698/Ch21 Quaternary protein structure ?Reversible binding between Fe & O2CO: a toxic gas (not in book)Bilirubin to bile. HyperbilirubinemiaHbA vs. HbFHbF is designed to steal oxygen from maternal blood in placenta. Replaced shortly after birth.CO is a product of incomplete combustion (complete combustion producesCO2 and H2O.) This obviously includes exposures to fires by victims and fire fighters but also includes smokers (cigars produce more CO than cigarettes - up to 20% CO Hb possible). Exhaust fumes are a common source of CO exposure. A recent report detailed high levels of CO exposure in enclosed pickup truck beds from a backdraft of exhaust fumes into the back of the truck.Carbon monoxide also binds coordinately to heme iron atoms in a manner similar to that of oxygen, but the binding of carbon monoxide to heme is much stronger than that of oxygen. The preferential binding of carbon monoxide to heme iron is largely responsible for the asphyxiation that results from carbon monoxide poisoning.
10 Hb Structure Porphyrin ring with Fe in center How many O2 can 1Hb carry?
11 RBC Disorders Anemias (O2 carrying capacity too low) Polycythemia vera (PCV ~ 60-70%)Anemias (O2 carrying capacity too low)Hemorrhagic anemia Fe deficiency anemiaHemolytic anemia, due to genetic diseases (e.g. Hereditary spherocytosis) or infectionsPernicious anemiaRenal anemiaPolycythemia vera most commonly due to bone marrow cancer. Hematocrit can become as high as 80%. Secondary poycytemia when less oxygen is available (high altitudes) or EPO production increased. Polycythemia vera is a clonal stem cell disorder characterized by excessive erythrocyte production. Its etiology is not fully established, but hypersensitivity to interleukin-3 may play a role in the sustained erythrocytosis observed in this disease. Polycythemia vera usually occurs within the age range of 20-80, with 60 being the mean age of onset. The disease is slightly more common in males than in females. Clinical features include headaches, weakness, weight loss, and pruritus (itching without visible eruption on the skin). Major Criteriatotal RBC vol men > 36 mg/kg; women >32 mg/kgarterial 02 saturation > 92%SplenomegalyFe deficiency anemia USUALLY A SECONDARY RESULT OF HEMORRHAGIC ANEMIAS. But also due to inadequate intake of iron containing foods or impaired absorption. Results in microcytes (pale small RBCs)Pernicious anemia (p.621) leads to large pale cells due to developing RBCs not dividing.Aplastic anemia due to some toxic chemicals and drugs and ionizing radiation. E.g.: arsenic, chloramphenicol. Fallout from nuclear bomb, excessive exposure to X-rays. Cancer and cancer chemotherapy. Marrow destruction of course affects all formed elements, anemia is just one symptom.
12 Sickle Cell Anemia 1st genetic illness traced to a specific mutation: Sickle cell anemia HbS instead of normal HbA. One in 100 black newborns in US. Malaria connection: RBCs loose potassium which is essential for survival of parasite (plasmodium)DNA: CAC CTCaa: glutamic acid valine (aa #6 of 146)HbA HbS crystallizes under low oxygen conditions
13 Platelets = Thrombocytes Megakaryocytes (MKs) are polyploid. Mechanism?MK produces ~ 4,000 platelets which live an average of 10 days.Platelets contain gra- nules filled with clotting proteins & cytokinesActivated when blood vessel wall damaged
14 Hemostasis Vasoconstriction Platelet plug (temporary blockage of hole) = Opposite of hemorrhage stops bleedingToo little hemostasis too much bleedingToo much hemostasis thrombi / emboliThree major steps:VasoconstrictionPlatelet plug (temporary blockage of hole)Coagulation (clot formation seals hole until tissues repaired)
17 Steps of Hemostasis cont. Two coagulation pathways converge onto common pathwayIntrinsic Pathway. Collagen exposure. All necessary factors present in blood. Slower.Extrinsic Pathway. Uses TF released by injured cells and a shortcut.Usually both pathways are triggered by same tissue damaging events.Fig 16-12
18 The Coagulation Cascade “Cascade” is complicated network!Numbering of coagulation factors according to time of discoveryFig 16-12
20 Structure of Blood Clot Plasmin, trapped in clot,will dissolve clot by fibrinolysisClot formation limited to area of injury: Intact endothelial cells release anticoagulants (heparin, antithrombin III, protein C).SEM x 4625
21 Clot Busters & Anticoagulants Dissolve inappropriate clotsEnhance fibrinolysisExamples: Urokinase, Streptokinase & t-PAPrevent coagulation by blocking one or more steps in fibrin forming cascade Inhibit platelet adhesion plug prevention Examples:Coumarin and warfarin block Vit K action (Vitamin K is cofactor in synthesis of several coagulation factors.Ca chelators (EDTA and citrate) only in vitroHeparin inhibits activity of thrombin (produced by basophils)Aspirin prevents platelet plug fomation
22 HemophiliaIt is sometimes called Christmas disease after Stephen Christmas, the first patient described with this disease. In addition, the first report of its identification was published in the Christmas edition of the British Medical Journal.In more recent history, royal watchers know that Queen Victoria of Britain's son Leopold had hemophilia, and that two of her daughters, Alice and Beatrice, were carriers of the gene. Through them, hemophilia was passed to the royal families in Spain and Russia, leading to one of the most famous young men with the disease, Tsar Nicholas II's only son Alekei.
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