Hemopoietic System PDF

# Hemopoietic System ## Introduction * Total body water (TBW) → 60% of the body weight, in adult male. * In infants → 75% * In adult female & obese → less than 60% (high fat content). * Total blood volume → 8% of body weight → plasma + blood cells ## Distribution of water in the body Compartments...

# Hemopoietic System ## Introduction * Total body water (TBW) → 60% of the body weight, in adult male. * In infants → 75% * In adult female & obese → less than 60% (high fat content). * Total blood volume → 8% of body weight → plasma + blood cells ## Distribution of water in the body Compartments: | Compartment | Water inside the cells | Water outside the cells | |---|---|---| | Intracellular fluid (ICF) | 2/3 of the TBW | 1/3 of the TBW | | | 40% of body weight | 20% of body weight | | | | Intravascular fluid (IVF) | | | | 5% in vessels → plasma | Interstitial fluid (ISF) | | | | | 15% outside the vessels | | | | | → between cells | | Main cations | Potassium (K) | Sodium (Na); Calcium (Ca) | | Main anions | Protein; Phosphate (PO4) | Chloride (CI); Bicarbonate (HCO3) | ## Measurement of volume of water in different compartments: * **Fick's principle:** Volume of compartment = Amount of the indicator injected / Concentration of indicator in plasma * The indicator used is inert, non-toxic and not utilized by the tissues: | Compartment | Indicator used | |---|---| | TBW volume | Heavy water (D₂O) | | ECF volume | Inulin | | plasma volume | Evan's blue | | Indicator is distributed | In all compartments | in extracellular water | in plasma only | * ICF volume: Can’t be determined directly. ICF = TBW - ECF * ISF volume: Can’t be determined directly. It is calculated by: ISF = ECF - plasma ## Homeostasis * Keeping the internal environment constant in spite of external or internal changes. * The internal environment is the interstitial fluid. * Most of the body systems work to maintain homeostasis. ## Importance of homeostasis: * Homeostasis is Essential for life. * Failure of homeostasis → diseases and death * Cells are capable of living within a narrow change in O2, CO2, glucose, temperature, pH, arterial blood pressure. ## Homeostasis is maintained by control systems ### Components of control system: 1. Stimulus 2. Receptor 3. Control center 4. Effector organ(s). 5. Feedback mechanism ### Negative feedback mechanisms * Almost all homeostatic control mechanisms are negative feedback. * They change the variable back to its original state or "ideal value". ### Positive feedback * The stimulus progressively increases the response. * Accelerate the processes that must be completed rapidly = (Blood clotting & Uterine contractions during childbirth) ## Blood * The total blood volume is about 5600 ml in a 70 Kg man. ### The main functions of Blood: 1. Transport Function: 2. Defensive Function 3. Hemostatic Function 4. Homeostatic Function ### The composition of the Blood: * **a. Plasma**: 55% of total blood volume. * **b. Cellular elements**: 45% of total blood [RBC's, WBC's & platelets]. ### Plasma * Plasma is a yellow clear fluid * The normal plasma volume is about 3000-3500 ml. ### Components of Blood: | Component | Description | |---|---| | **Plasma** | 55% | | **Water** | | | **lons**| | | **Proteins** | | | **Nutrients** | | | **Wastes** | | | **Gases** | | | **Platelets** | 1% | | **White blood cells** | | | **Red blood cells** | 44% | ## Difference between the plasma and the serum: * When blood is left in glass tube, a clot is formed and the remaining fluid is the serum; so, serum is plasma minus the elements consumed in the clot. ## The constituents of plasma: | Component | Description | |---|---| | **Water** | 90% of plasma volume | | **Inorganic substances** | | | **Chief cation** | Sodium (Na*) | | **Chief anions** | Chloride (CI) & bicarbonate (HCO3) | | **Organic substances** | | | **Plasma proteins** | | | **Plasma Lipids** | Carried in blood as lipoproteins. | | **Glucose** | | | **Amino acids** | | | **Vitamins** | | | **Enzymes** | | | **Uric acid & urea** | | | **Gases** | | | **Soluble O2 & CO2** | | ## The Plasma Proteins 7.2-7.4 gm/dl. * Albumin, globulins (α1, α2; β1, B2 and r), fibrinogen & other coagulation factors. ## Site of Formation of Plasma Proteins 1. The liver is the main site for synthesis of Albumin, fibrinogen, prothrombin and 50% of globulins. 2. Gamma globulins are formed in the plasma cells in the lymphoid tissue. ## Ratio between albumin & globulin concentration in plasma: * This ratio is called the Albumin-Globulin Ratio (A/G Ratio) * The normal value for the A/G ratio ranges between 1.2-1.6 * This ratio decreases in: 1. Liver diseases: decrease the synthesis of albumin (liver cirrhosis, hepatitis) 2. Renal diseases: increase the loss of albumin in urine (small size) 3. Infections: due to increase formation of immunoglobulins. ## The main functions of Plasma Proteins: 1. **Osmotic Function:** * The total osmotic pressure of plasma is 5000 mmHg = 290 mmol/L. * Most of this osmotic pressure is due to crystalloids (Na*, CI, HCO3) * Plasma proteins mainly albumin (greatest concentration), are responsible for only 25-28 mmHg. * Plasma proteins are kept inside the plasma & exert an effective (colloidal) osmotic pressure to draw tissue fluid to the blood. * Hypoalbuminemia decreases the colloidal osmotic pressure of plasma. * This can result in: Edema 2. **Buffer function:** * They are responsible for 15% of the buffering power of the blood. * They are negatively charged at normal plasma pH (alkaline pH 7.4) 3. **Defensive function:** * Gamma globulins → antibodies → humoral immunity. 4. **Blood clotting:** * Fibrinogen and prothrombin are essential for the coagulation of the blood. 5. **Blood viscosity:** * RBC's and plasma proteins are responsible for the viscosity of the blood. * Blood is 3 times, while plasma is 1.5 times as viscous as water. * Fibrinogen has an elongated shape → contributes more than other proteins to blood viscosity. * Viscosity is important in maintenance of normal arterial blood pressure.&#x20; * Viscosity of blood: * a. increases in polycythemia (+++ RBC's) * b. decreases in anemia (---- RBC's). 6. **Capillary function:** * Plasma proteins close the pores in the capillary walls thus limiting their permeability. 7. **Transport and conservation of important elements:** * albumin, a and ẞ globulins ... act as carriers for hormones, vitamins, ... * Binding to plasma proteins: * a. prevents their rapid loss in urine * b. provides a reservoir that can be used when needed. 8. **Use of plasma proteins as a source of amino acids:** for rapid replacement of tissue proteins ## Red Blood Corpuscles (Erythrocytes/RBC'S) * The red blood corpuscles are the main cellular constituents of the blood. * They are not true cells (corpuscles) because they have no nuclei. * 5.4 million/mm³ in males and 4.8 million/mm³ in females. * high count in newly born infants, people living at high altitudes & athletes. * lower count in growing children and old age. ## Main characters of RBCs: ### Shape and Size * circular, biconcave, non-nucleated discs. * contain hemoglobin (red respiratory pigment). * lack mitochondria and ribosomes. ### The biconcave shape of erythrocytes has several advantages: * a. It produces a larger surface area than a spherical cell of the same volume. * b. It enhances cell flexibility → RBCs squeezed in small capillaries without rupture. * c. Minimal tension on the membrane when RBCs volume increases. ## Hemoglobin 34% of RBC's weight ## Types of Hemoglobin: 1. **Adult hemoglobin:** * HbA: 2 alpha & 2 beta polypeptide chains. 2. **Fetal hemoglobin HbF:** * 2 alpha and 2 y chains. HbF has more affinity to O2 than HbA → extraction of O2 from maternal blood. * After birth, HbF is changed to HbA → completed by the age of 4 months. ## Hemoglobin content: * 15-16gm/dL in adult males * 13-14 gm/dl in adult female. * 19 gm/dl in normal newly born (relative intrauterine O2 hypoxia). ## Hematocrit value or packed cell volume (PCV) * It is the percentage ratio of RBC's volume to the total blood volume. * Normally it is 46% in males, 42% in females. ## Chemical Reactions of Hemoglobin 1. **Hb unites loosely with oxygen (02)** → oxyhemoglobin. * O2 is attached to the iron → remains in Fe2+ state (oxygenation not oxidation) 2. **Hb combines with carbon dioxide (CO2)** → carbaminohemoglobin. 3. **Hb reacts with carbon monoxide (CO)** → carboxyhemoglobin. 4. **Fe2+ iron of Hb strong oxidizing agents** → Fe3+ iron (ferric) → dark methemoglobin & can't carry 02. * Small amounts of met-Hb are normally formed but are reduced by NADH-met-Hb reductase back to Hb. * Hereditary methemoglobinemia: congenital deficiency of this enzyme leads to increased met-Hb in the RBC's. ## Functions of RBC's: ### A. Functions of Hemoglobin: 1. O₂ & CO2 transport. 2. Buffering function: is 6 times that of plasma proteins. ### B. Function of the membrane of the RBC's: * The membrane of erythrocytes keeps hemoglobin inside the cell.&#x20; ### Hazards of free hemoglobin in the plasma: * Hb blocks the renal tubules. * Hb increases the viscosity of the blood → +++ the work load on the heart. * Increase the osmotic pressure of the plasma → +++ the work of the heart. ## Life Span and fate of Erythrocytes: * average of 120 days. * Cells become fragile → rupture in spleen. * The released hemoglobin is picked up by macrophages → goblin & heme. * The heme is broken into iron and protoporphyrin. * Iron is reused in formation of new RBC. * The protoporphyrin → bilirubin, → secreted by the liver in the bile. ## Role of spleen: 1. Site of erythropoeisis during fetal life 2. Blood filter → removes aged or abnormal RBCs 3. Blood storage → add blood volume into circulation in hemorrhage (in animals) 4. Stores platelets (30%) 5. Hypersplenism= over functioning spleen (excessive destruction of blood cells). 6. Splenectomy is associated with increased number of RBCs & platelet count ## Erythropoiesis ### Definition * It is the process of formation of new erythrocytes. ### Site 1. In the fetus, erythrocytes are formed in the liver and spleen. 2. In children, erythrocytes are formed in active red marrow of all bones. 3. By age 20 years, the marrow in long bones except upper humerus and femur become inactive. 4. After the age of 20, only the membranous bones such as vertebrae, skull, ribs and pelvis produce erythrocytes. ## Factors affecting Erythropoiesis: ### A. Oxygen supply to the tissues and role of erythropoietin: * Decrease the O2 supply to the tissues (hypoxia) → +++ erythrocytes → provide sufficient tissue oxygenation. ### Some examples of hypoxia: 1. High altitudes. 2. Increased demand for oxygen as in athletes. 3. Loss of erythrocytes in hemorrhage. 4. Lung diseases and prolonged heart failure. * Hypoxia → +++ erythropoietin hormone → +++ erythropoiesis. ## Erythropoietin hormone: * **Nature**: glycoprotein; * **Sources:** * During fetal life: erythropoietin is formed by the liver. * In adults: 85% formed by the kidneys, while 15% is formed by the liver. * NB: Patients with renal failure develop severe anemia. ### Mechanism of action: * Erythropoietin combines with specific receptors on stem cells → stimulate all steps of erythropoiesis, mitosis & inhibit apoptosis. * Recombinant DNA → Erythropoietin → treatment of anemia due to renal failure. ### Stimulation of Secretion: 1. Hypoxia is the main stimulus for erythropoietin secretion by the kidneys. 2. Alkalosis present at high altitudes. 3. Cobalt salts and androgens. 4. ẞ-adrenergic stimulants & adenosine → facilitate erythropoietin secretion. * Adenosine antagonists (theophylline) → inhibit its secretion ### B. Healthy Bone Marrow * Destruction of bone marrow → aplastic anemia. Bone marrow is destroyed by: 1. X-ray 2. Atomic radiation 3. Drugs as chloramphenicol 4. Malignant tumors. * **C. Healthy Liver: it is the site of:** * Formation of 15% of erythropoietin hormone. * Storage of iron and vitamin B12. * **D. Healthy kidney: Kidney → formation of 85% of erythropoietin** * **E. Hormones: Other hormones → +++ erythropoiesis:** * a. Thyroid hormones, * b. Androgens * c. Glucocorticoids * **F. Diet:** 1. Proteins: Proteins → globin part of hemoglobin 2. Iron: Iron → hemoglobin synthesis 3. Vitamin B12 and Folic acid → division and maturation of RBCs 4. Trace elements. ## Iron ### Forms of iron in the body: * Average human body contains 3-5 grams of iron distributed as follows: * a. 70% of body iron in hemoglobin of RBCs. * b. 25% of body iron → stored as ferritin mainly in liver, spleen, enterocytes of the intestinal mucosa, and bone marrow * c. 3% of body iron in muscle myoglobin. * d. 2% of body iron in enzymes ### Iron requirements and iron balance in the body: * About 30 mg of iron are needed daily for hemoglobin synthesis. * Most of this amount is obtained from recycled iron of Hb of aged RBCs in macrophages in liver and spleen. * Adult male loses 0.5-1.0 mg of iron daily (in sloughed epithelium, hair, sweat & any blood loss). Adult female loses 2.0 mg/day in menses & others as male. * Normal person needs to absorb, from diet, an amount of iron equal to the daily iron loss. ### Iron in diet is present in two main forms: | Form | Description | |---|---| | **Heme (Fe2+) iron** | In meat & meat products, 10% of total dietary iron, more readily absorbable | | **Non-heme (Fe3+) iron** | In cereals, vegetables, beans, fruits (plant origin), 90% of dietary iron, less absorbable | * Ferric iron (Fe3+) should be reduced to the ferrous (Fe2+) form to be absorbed. * Ascorbic acid in diet can reduce Fe3+ to Fe2+. * Gastric HCl helps dissolving iron & facilitates iron reduction. * Reduced HCI secretion (achlorhydria) → iron deficiency. * Oxalates, and phosphates react with iron → insoluble non-absorbable compounds → decrease iron absorption. ### Mechanism of Iron absorption: 1. Iron is absorbed in duodenum. 2. Ferric Iron (Fe³*) is reduced to ferrous (Fe2+) in stomach or in duodenum helped by reductase enzyme. 3. Divalent metal transporter 1 (DMT1) transport Fe** into the cell. 4. Heme carrier protein (HCP1) transport heme into the cell. 5. Depending on body requirements, iron inside the enterocyte will be: * a. If no demand for iron → iron will be stored as ferritin inside the enterocytes. * b. If +++ demand for iron → iron will be transported through ferroportin, → into blood. 6. Iron (Fe3+) in plasma is transported by transferrin (plasma protein). Normally, transferrin in plasma is 35% saturated with iron. 7. Transferrin delivers iron to bone marrow, liver, muscle cells.... ### Iron Homeostasis * Iron deficiency causes microcytic anemia; * iron overload causes hemosiderosis. * Human body does not have mechanisms to regulate iron excretion. * We depend on regulation of iron absorption to maintain normal blood iron level. ## Factors that regulate iron absorption: 1. **Dietary iron:**&#x20; * +++ iron in food → -- the number of DMT1→ --- iron absorption. 2. **Hepcidin:** * Hepcidin is secreted by the liver. * Hepcidin is a major regulator of iron intestinal absorption. * Hepcidin promotes iron storage and lowers iron plasma level. ### Actions of hepcidin: * Hepcidin binds to ferroportin in enterocytes, macrophages & liver cells; followed by degradation of ferroportin molecules. This leads to: * Inhibition of intestinal absorption of iron. * Inhibition of release of recycled iron from macrophages. * Inhibition of release of iron from liver and other store sites. ### Factors affecting hepcidin secretion: * a- Hypoxia and erythropoietin decrease hepcidin secretion. * b- Iron loading increases hepcidin & iron deficiency decreases its secretion. * c- Inflammation increases hepcidin secretion. This explains why anemia is a common complication of many inflammatory diseases. ## Hemosiderosis = Hemochromatosis * +++ hemosiderin (ferritin deposits) in tissues due to +++ iron absorption → iron overload. * Excess deposits may lead to: * a. Pigmentation of the skin, * b. Pancreatic damage leading to diabetes (bronze diabetes), * c. Liver cirrhosis * d. High incidence of hepatic carcinoma. * Can be treated by venesection (withdraw 500ml blood / time). * Repeated blood transfusion in hemolytic anemia → hemochromatosis (treated by iron-chelating substances) ## Vitamins * All vitamins are needed for erythropoiesis: vitamin C, vitamin B₁₂, & folic acid... ### Vitamin B12 * **A. Sources and daily requirements:** * animal origin: liver, meat, chicken.... * daily requirements: 5µg. * stored in liver in big amounts (5 mg). * **B. Importance of Vitamin B12:** * Essential for DNA synthesis (required for TTP). * Important for division & maturation of RBCs. * Important for the myelination of nerves. ### C. Deficiency of Vitamin B12: * Usually due to failure of absorption & not due to deficiency in the diet. * **Deficiency of vitamin B12 results in:** * Macrocytic anemia due to decreased DNA, failure of nuclear maturation & cell division in bone marrow. * Cells are bigger in size, irregular in shape & fragile. * Neurological manifestations ### D. Absorption of Vitamin B12: 1. The parietal cells of the gastric glands secrete a glycoprotein called **intrinsic factor** which protect vitamin B12 from digestion. 2. Intrinsic factor helps vitamin B12 to bind to a **receptor** in lower ileum. 3. **Trypsin** from pancreas is needed for vitamin B12 absorption. Pancreatic deficiency → vitamin B12 absorption. 4. Vitamin B12 & intrinsic factor enter the cell by **pinocytosis**. 5. Inside the cell the vitamin is set free & is absorbed to the blood. 6. In blood, it is carried by **transcobalamine II** → distributed to the tissues; excess vitamin is stored in liver. ## Folic Acid: * **A. Sources:** * It is present in green vegetables, some fruits, liver and meat. * It is easily destroyed by cooking. * **B. Importance:** * Essential for DNA synthesis. * Therefore, it is important for division and final maturation of red cells. * **C. Deficiency:** * Causes; deficiency in diet, GIT disease (----absorption) or antifolate cytotoxic drugs (methotrexate). * Leads to macrocytic anemia. ## Trace Elements * Copper and cobalt act as cofactor for Hb formation. * Cobalt is part of vitamin B12 and a stimulator of erythropoietin secretion. ## Blood Indices 1. **Mean corpuscular hemoglobin "MCH"** * It is the amount of hemoglobin in a single RBC. * MCH = Hb content / RBC's count x 10 * = 25-32 picograms; less than 25 pg → hypochromic. 2. **Mean Corpuscular Volume MCV** * It is the volume of a single RBC. * MCV = Hematocrite Value X 10 / RBC's count * = 80-95 µ³; less than 80 microcytes; more than 95 → macrocytes. 3. **Mean Corpuscular Hb Concentration (MCHC)** * It is measure of Hb in 100 ml of packed red cells. * MCHC = Hb content / Hematocrite value x 100 * = 32-38 g/dl; normal values → normochromic; below normal → hypochromic. ## Anemia ### Definition * Decrease in the oxygen carrying power of the blood either due to decrease number of RBC's or a decrease in hemoglobin content of the blood. * Anemia is the most common blood disorder affecting about a quarter of people globally. * The highest prevalence is in preschool age children (47%) and the lowest prevalence is in men (12%). * Nearly 50% of women of the reproductive age are anemic. * Pregnant women are the most affected. * Anemia goes undetected in many people, and symptoms can be minor or vague, however in women it may become the underlying cause of maternal & perinatal mortality. ### Anemia is considered when: * RBC's count less than 4.5 million/µL in adult males or 3.9/ µl in adult female. * Hb content is less than 13.5 g/dl in men or 11.5 g/dl in women. ### Symptoms: * shortness of breath & fatigue, * tachycardia & palpitation, * intolerance to exercise * dizziness. ### Types of Anemia * **A. Microcytic hypochromic anemia (iron deficiency anemia):**&#x20; * Decrease in RBC's mass and Hb content with MCV< 80 µ³ and MCH<25 pg. Microcytic hypochromic anemia = iron deficiency anemia (most common type). ### Causes of Iron Deficiency Anemia: 1. **Deficiency of iron in diet:** iron intake than needed, more common in growing children & pregnancy. 2. **Deficient iron absorption:** * partial gastrectomy; * vitamin C deficiency; * much intake of phytic acid oxalates and phosphates * diseases of the small intestine. 3. **Chronic blood loss:** * ankylostoma parasitic infestation, * bleeding from peptic ulcer or piles * excess bleeding during menstruation in females. ### Specific features of Iron Deficiency Anemia: * Brittle Spoon-shaped nails * Brittle hairs * Atrophy of papilla in tongue * Angular stomatitis * Pallor * **NB: Other causes of microcytic hypochromic anemia:** Spherocytosis & Thalassemia. * **B. Macrocytic Anemia (Megaloblastic anemia):** * The RBC's mass and Hb content are decreased with MCV > 95µ3. ### Causes of Macrocytic anemia (Megaloblastic anemia): 1. **Folic acid deficiency:** * low intake in diet. * +++ need as in pregnancy, * failure of absorption. * antifolate cytotoxic drugs (methotrexate). * Pregnant woman should take folic acid daily: * important for the fetal development of brain & spinal cord. * ↓folic acid in pregnancy → fetal anencephaly & spina-bifida 2. **Vitamin B12 deficiency (accompanied with nervous manifestations):** * defective absorption (after gastrectomy), * absence of intrinsic factor (pernicious anemia) * distal small intestine diseases. ### Pernicious anemia * Familial disease of elderly women. * Cause: antibodies against the parietal cells of the stomach → absence of HCL & intrinsic factor. * Result: defective absorption of vitamin B12 → macrocytic anemia & nervous manifestations. * If a patient has both, vitamin B12 and folic acid deficiency, we correct vitamin B12 first as correction of folic acid deficiency first will mask neurological manifestations of B12 deficiency. ### NB: Polycythemia: * Polycythemia means increased number of RBC's (may reach 6-8 millions/mm³). * **Primary polycythemia (Polycythemia Vera):** * Uncontrolled division of stem cells in bone marrow → +++ RBC's & WBC's & platelets. * **Secondary Polycythemia:** * Tissue hypoxia (obstructive lung diseases and at high altitudes) →↑ n= RBCs. ### Manifestations: * Red flushed skin * Palpable spleen * Erythema & warm hand & feet * Swollen bleeding gingiva ### Management: * Venesection (phlebotomy) at periodic intervals to remove 500-600 ml of blood. * Aspirin * **C- Normocytic normochromic anemia:** * There is decrease in RBC's mass & Hb content but MCH & MCV are within normal value. ### It occurs in: 1. **Anemia of chronic disease:** * chronic inflammatory disorders, * kidney disease, * autoimmune disease, * cancer 2. **Anemia due to Hemorrhage:** * Acute blood loss as in hemorrhage, * the liver can replace the plasma loss in 2 days, * while the bone marrow can't compensate for RBCs loss simultaneously, * thus, RBCs become diluted in the plasma. 3. **Aplastic anemia:** * Bone marrow failure; hemopoietic cells disorder → all types of cells: anemia, leucopenia, thrombocytopenia (pancytopenia) * **Causes:** * drugs, * toxins, * radiation, * tumors * **Manifestations:** * Rare disorder commonly seen in young adults. * Anemia: headache, pallor, dyspnea. * Leucopenia: bacterial & fungal infections are common. * Thrombocytopenia: bruises, bleeding, cerebral hemorrhages. ### Management * Bone marrow transplantation. * Antibiotics & transfusion. * Stimulation of hemopoiesis: androgens & corticosteroids 4. **Hemolytic anemia:** * Premature destruction of RBCs due to intrinsic or extrinsic disorders; * Jaundice is usually present. ### Extrinsic disorders include: usually acquired * a. Antibodies against RBC as in Incompatible blood transfusion * b. Infections (malaria) * c. Toxins * d. Drugs ### Intrinsic disorders (usually inherited) include: * Defect in cell membrane → spherocytosis * Defect in cell metabolism → G6PD deficiency * Defect in Hb structure → sickle cell anemia & thalassemia * **a. G6PD enzyme (glucose-6-phosphate dehydrogenase) deficiency:** * X-linked recessive gene → mostly affects males. * Deficiency of G6PD → +++ RBCs hemolysis by oxidizing agents. * Infections, oxidative drugs, food (fava beans (favism) → acute hemolytic crisis * **b. Sickle cell anemia:** * Hereditary disease (autosomal dominant). * Normal Hb is replaced by HbS (abnormal ẞ-chain) → precipitates inside the RBC'S at low O2 tension → sickle shape cell. ### Manifestations: * Periods of latency interrupted by periods of acute crisis: * RBCs stick together → occlusion of blood vessels → severe pain, heart attack. * Severe anemia * **c. Hereditary spherocytosis:** * Due to mutations in structural proteins of membrane of RBC. * RBCs are spherocytes & fragile → hemolyze in spleen easily → microcytic anemia. * **d. Thalassemias:** * Also known as Cooley's anemia or Mediterranean anemia. * Hereditary disease due to decreased or absent alpha or beta chains of Hb → precipitation of polypeptide chains in immature RBCs → microcytic anemia. * There is a high carrier rate of thalassemia in Egypt (9-10%). * Most severe form → Thalassemias maior = Cooley’s anemia:&#x20; * Overgrowth of maxilla * Spacing between teeth * jaundice * saddle nose, retracted upper lip * **NB: Spherocytosis & Thalassemia → microcytic anemia** ## Platelets * The platelets are small, granulated, non-nucleated round or oval bodies. * The normal platelet count is about 300,000/mm³ blood. ### Production of platelets: * Platelets are produced in the bone marrow from giant **megakaryocytes** under effect of **Thrombopoietin** (produced by the liver and kidneys).&#x20; * 70% released into blood & 30% stored in spleen. * Splenectomy → +++ the platelet count (thrombocytosis). * Their lifespan is about 8 days. ## Hemostasis prevention of blood loss after injury ### Steps in hemostasis: 1. Constriction of the blood vessel, 2. Formation of temporary hemostatic plug (1ry hemostasis) 3. Formation of definitive blood clot (2ry hemostasis) 4. Lysis of the clot. ### I. Constriction of the Blood Vessel: * The constriction of injured blood vessel occurs immediately after injury and may be so marked that the lumen is completely closed. ### Causes of vasoconstriction: * a. Local myogenic contraction due to direct trauma. * b. Nervous reflexes initiated by pain receptors from the traumatized vessel. * c. Local humoral factors liberated from platelets (ADP, serotonin, TXA2.) * d. Endothelin: vasoconstrictor secreted from injured endothelium. ### II. Formation of Temporary Hemostatic Plug: (1ry hemostasis) * Small cut → platelet plug can stop blood loss. * Large cut → blood clot (platelet plug within fibrin threads) is required to stop bleeding. ### Steps of Platelet reactions & formation of temporary plug: 1. **Platelet adhesion:** * Platelets adhere by their membrane receptors for collagen & von-Willebrand Factor to the exposed subendothelial collagen & vWF. 2. **Platelet activation:** * Adhesion → intracellular signaling → platelet activation * Platelets swell, * change their shape, * put out pseudopodia, and * discharge the contents of the granules. * Activation is enhanced by ADP and thrombin. 3. **Platelet Release reaction: (Ca++ dependent reaction)** * Released contents of dense granules: * a. Calcium → more release of granules * b. ADP → activation, aggregation and fusion of platelets * c. Serotonin → reinforce & maintain vasoconstriction of injured blood vessel. 4. **Platelet aggregation:** * Released ADP & TxA₂, cause more platelets to bind each other at site of injury. * Fibrinogen acts as a bridge between 2 receptor molecules on adjacent platelets. * This leads to further release reactions → more ADP & TxA2 → more aggregation, Self-propagating process of platelet aggregation → formation of a platelet plug. * Aggregation is also stimulated by platelet activating factor (PAF). 5. **Platelet pro-coagulant activity:** * Platelet membrane phospholipid (platelet factor 3) is exposed providing an ideal surface for concentration & activation of coagulation factors. 6. **Platelet fusion:** * Irreversible fusion of aggregated platelets at the site of injury is caused by:- * High concentration of ADP and thrombin. * Enzymes liberated during the platelet release reaction. ### III. Blood coagulation: * **Coagulation factors:** * Coagulation factors are plasma proteins mainly ẞ-globulins synthesized by liver. * They are inactive enzymes which when activated lead to a chain of proteolytic reactions activating other factors.&#x20; * **The coagulation factors are classified into 3 groups:** | Group | Description | |---|---| | **Fibrinogen group** | factor I (fibrinogen), V. VIII and XIII, activated by thrombin | | **Prothrombin group** | factor II (Prothrombin), VII, IX and X, need vitamin K for their synthesis in the liver. | | **Contact Group** | factors XI and XII, activated by contact to electro-negatively charged surface | ### Mechanism of Coagulation: cascade of reactions * Blood clot is formed of fibrin threads entrapping RBCs, platelets & plasma. * **A- Intrinsic pathway:** * This pathway occurs both in vivo and in vitro. * It is initiated when blood is exposed to: * **In Vivo:** subendothelial collagen & catalyzed by high-molecular weight (HMW) kininogen & kallikrein. * **In Vitro:** electro-negatively charged wettable surfaces as glass.&#x20; * Inactive factor XII will be activated to active factor XIIa. * **2- Active factor XII then activates factor XI, and active XI activates factor IX.** * **3- Activated factor IX forms a complex with active factor VIII (F VIII is activated when separated from von Willebrand factor by thrombin)** * **4- The complex of IXa-VIIIa, phospholipids (PL) of aggregated platelets and Ca++ activates factor X.** * **5- Active factor X, in the presence of PL, Ca++ and av, converts prothrombin to thrombin.** * **B- Extrinsic pathway:** * **The Extrinsic system occurs only in vivo.** * **1- Tissue trauma either vascular or extravascular will release thromboplastin (tissue phospholipid TPL) which activates factor VII.**&#x20; * **2- TPL and factor VII, activate factor IX and X.** * **3- Active factor X, in presence of PL, Ca++ and active factor V, converts prothrombin to thrombin.** * **C- Common Pathway** * **1. Thrombin then catalyzes the conversion of soluble fibrinogen polymer to insoluble fibrin monomer threads arranged spontaneously into a loose mesh.** * **2. Fibrin stabilizing factor (XIII) of platelets converts the loose fibrin threads into tight strands. Factor XIII is activated by thrombin in presence of Ca** ions.**&#x20; * **3. Formation of clot entrapping blood cells, platelets, and plasma & closes and adheres to the injured vessel wall.** ### D- Interactions between Extrinsic and Intrinsic pathways: 1. When a blood vessel is injured blood clotting is initiated by both systems simultaneously.&#x20; 2