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TACO: Transfusion Associated Circulatory Overload TRALI: Transfusion Related Acute Lung Injury Transfusion debate: Risks of transfusion: Increased mortality Increased length of stay...

TACO: Transfusion Associated Circulatory Overload TRALI: Transfusion Related Acute Lung Injury Transfusion debate: Risks of transfusion: Increased mortality Increased length of stay Increased cost of stay Increased infection Increased in ammation Increased mechanical ventilation Decreased survival Transfusion Overuse: Modi able Risks Correctable anemia Excessive surgical blood loss Excessive blood loss due to unnecessary testing Poor transfusion practice Process Techniques Ultra ltration Acute Normovolemic hemodilution Perioperative Cell Salvage Miniaturized Corporeal Circuits Retrograde Autologous Priming Techniques help reduce hemodilution, excess plasma, water removal, red cell recovery. Normal Values: Adult HCT: male: 41.4% - 51.6% ; female: 36.3%- 45.3% RBC: male: 4.5 -5.9 x10^6/microliter ; female: 4.1 -5.1 x10^6/microliter fi fi fl  Platelets: 150,000 - 400,000 /microliter WBC: 4,500 - 10,000 /microliter Newborn HCT: 42 - 72 ; Infant HCT: 28.5 - 39 Hemoglobin: male: 14 - 17; female: 12 - 15; newborn: 14 -24; infant: 10 - 13 History: Landsteiner: 1900s, de ned A, B, AB, O Composition of whole blood: Functions of blood: Transportation: free in plasma, bound to plasma protein, bound to blood cells. Regulation: electrolyte balance, pH regulation. Protection: clotting, immunity Plasma: 55% - proteins 7% (albumin, globulin, brinogen); water 91%; other solutes 2% (ions, nutrients, waste products, gas, regulatory substances). Formed elements: 45% - WBC (neutrophils, leukocytes, monocytes, eosinophils, basophils), RBC, Platelets. Blood Smears Examines morphology; indicates percent of each cell type present. Fixated by methanol - stabilize the cell Stained with Romanowsky stains Anisocytosis: varying RBC sizes Poikilocytosis: abnormal shapes Hematopoisesis: formation of blood cells and blood plasma. Occurs in the bone marrow, liver, spleen, thymus, lymph nodes. Across di erent phases of life: Adults: mainly bone marrow; infancy- childhood: long bones; gestation: 2 months: yoke sac, 2-7 months liver and spleen, late stages of fetus and birth - bone marrow, fat shi s to long bones at 4. ff fi fi ft  Asymmetric division: some are self renewing so they don’t become depleted. Development of each cell type: Basic family tree of cells Pluripotent -> progenitors (2) -> blast cells (4) -> mature cells Iron Located: in heme, circulation - attached to transferrin, stored in liver and reticuloendothelial system - ferritin and hemosiderin. 3500-4000 mg, 2/3 is hemoglobin iron, 1/3 is tissue iron (90% of tissue iron is made up of ferritin / hemosiderin). 1 - 3 mg is metabolized. Movement: absorption (regulated by intestines), reuptake (transferrin, iron is released from hemoglobin and back into plasma), storage (liver, spleen, reticuloendothelial cells), transportation (transferrin- from cells to tissues). Erythrocytes (RBC) Bioconcave, central portion is thinnest, no nucleus, 120 day lifespan - ruptures in spleen and macrophages take them. Volume = 90 Erythropoietin (EPO) Released in kidney, peptide hormone. A release of EPO is released in bone marrow. Signals growth factors in bone marrow to release stem cells for RBC formation. Takes about 5 days to develop mature erythrocytes. Requires: Globin, Iron, Protoporphyrin (combines with iron and heme, binds O2 with CO2). Hemoglobin A 95%: 2 alpha / 2 beta Hemoglobin A2 3.95%: 2 alpha / 2 delta Hemoglobin F 1-2%: 2 alpha / 2 gamma Reticulocytes: immature RBCs No nucleus, contain RNA and loose it a er reaching blood stream. Anemia will increase reticulocytes and bone marrow activity. ft fl  Erythrocyte: No nucleus, can carry oxygen and carbon dioxide due to having hemoglobin. Eventually rupture in spleen. WBC Formation Lymphopoiesis: formation of lymphocytes Lymphocytes - 20-44% of adult white blood cells, 2nd most numerous cell in the blood. T cells - thymus B cells - bone marrow (antibodies) Natural Killer Cells - toxicity Monopoiesis: formation of monocytes Monocytes: commit to myeloid and monocyte stage. In response to macrophages stimulating factor - monoblast. Lifespan = 12 hours Granulopoiesis: formation of granulocytes Neutrophils: rst in line of defense of innate immune system, kill and digest bacteria and fungi. Lifespan = 10 hours, turns into pus and dies Secretes products to attract monocytes Eosinophils: granules, 0-4% in blood, destruction of tumor cells. Basophils: 0-2% in blood, release histamine, helps reduce prostaglandin. Megakaryocytopoisesis: formation of platelets Megakaryocytes: rst in line of defense for clotting, 7-10 day life span. How are platelets formed? Descend from same stem cell. fi fi  TPO = Thrombopoietin Produced in liver; signal bone marrow to start production of platelets. Responsible for platelet development from megakaryocytes. Interleukins: cause stem cells to produce precursors to mature blood cells, respond to tissue injury and foreign matter in in ammatory response. Colony Stimulating Factors: glycoproteins that produce white blood cells (granules) for infections. Binds to receptor proteins of hemopoietic stem cells. Lab measurements Complete Blood Count (CBC) WBC (leukocytes) = infection RBC (erythrocytes) = oxygen transport MCH - mean corpuscular hemoglobin (content and weight of hemoglobin) MCV - mean corpuscular volume (average size of hemoglobin) MCHC - MHC Concentration (amount of hemoglobin per unit volume, %Hgb) MCV: normal: normocytic (80-100), < normal: microcytic (72-79), > normal: macrocytic (95-160). MCH & MCHC: normal: normochromic, < normal: hypochromic, > normal: hyperchromic. Fishbone diagram fl  Automated methods for RBC and HCT measurement Electrical impedance (Coutler Principle) - produces cell count and measure of volume. Split into three: Hemoglobinometry, RBC counting, Plasma carries a charge, RBC is insulator. Light Scatter (Co-oximetry) - newer, low-angle light scatter Lab evaluations of Iron Serum: amount of iron in blood Serum ferritin: how much of body’s stored iron has been used Transferrin: total iron binding capacity Anemia WHO grades of anemia Grade 0: > 11 g/dl Grade 1 (mild): 9.5-10.9 g/dl Grade 2 (moderate): 8.0-9.4 g/dl Grade 3 (serious): 6.5-7.9 Grade 4 (life threatening): < 6.5 g/dl Causes of anemia: Blood loss Accelerated destruction of RBCs Nutritional de ciency Infection Toxicity Hematopoietic stem cell de ciency Heredity vs acquired Hemoglobinopathy Qualitative disorders: structure - sickle cell Quantitative disorders: numbers - thalassemia fi fi  Microcytic anemias: iron overload, sideroblastic, iron overload Iron de cient: most common, decreased in hemoglobin, MCV, and HCT; decreased in total body stores of iron. Depletion of iron stores, iron-de cient erythropoiesis, iron-de cient anemia. Sideroblastic: ine ective erythropoiesis; increased level of tissue and serum iron. Normal hemoglobin; can be congenital or acquired. Iron overload: increased iron absorption, transfusion overload. 3rd and 4th stage lead to cirrhosis and organ damage; there is no mechanism to reverse it. Macrocytic anemias: Megaloblastic Megaloblastic: mega (large) , plastic (immature cells) Causes: folic acid, B12 Increased hemolysis, increased EPO Normocytic anemias: aplastic, hemolytic, immune mediated hemolytic Aplastic: loss of bone marrow cellularity; decreased in production or erythrocytes, leukocytes, and platelets. Hemolytic: hemolysis, increased in reticulocytes, increased red blood cell destruction, increased EPO, decreased oxygen, and decreased life span. Can be inherited or acquired, intrinsic or extrinsic, acute or chronic. Autoimmune: body loses recognition of it’s own RBC antigens; patient produces antibodies against its own RBCs. Cold agglutinins: reactivity at 4-22 C; IgM activates complement; hemolysis occurs. Alloimune: Transfusion: IgM and ABO incompatibility; Pregnancy: maternal fetal blood group incompatibility, hemolytic disease of newborns; Organ transplants: antibodies produced. fi ff fi fi Sickle cell anemia Point mutation: Hemoglobin S in the mutation for the 6th amino acid in Beta chain; Valine is substituted for glutamic acid. Sickle cell disease: homozygous; 0.15% African Americans; 80-98% hemoglobin S present; Sickle starts at oxygen saturation 85% with complete sickling at 38%. Sickle cell trait: heterozygous; 8% African Americans; 20-45% hemoglobin S present; Sickle starts at oxygenation of 40%. Degree of Sickling depends on: dehydration, pH, oxygenation, irreversible/ reversible. Coagulation Hemostasis involves which major systems? Vascular system, fybrinolytic system, platelets, coagulation system. Stages of Hemostasis Primary: platelet plug forms; platelet adhesion. Secondary: enzyme activation of coagulation proteins to produce brin. Fibrinolysis: clot dissolves; plasmin digests brinogen and brin. How does the endothelium activate thrombus formation? Coagulation cascade Intrinsic Pathway: X, VIII, IX, XI, XII Extrinsic Pathway: III, VII, X Common Pathway: X, V, II, I fi fi fi  Primary hemostasis Platelets characteristics: 150,000-400,000; originates in bone marrow; develops 5-7 days a er release of thrombopoietin. 70% circulating and 30% in microvasculature of spleen Survives 7-0 days in circulation and active for hemostasis. For adequate hemostasis, >50,000 platelet count. 3 zones: peripheral, sol-gel, organelle Peripheral: platelet membrane, glycocalyx; exterior glycoprotein coat, phospholipid plasma membrane. Sol-Gel: cytoskeleton, responsible for metabolic activity, allow for shape change. Consists of microtubules, micro laments (actin and myosin), sub- membranous laments. Organelle: responsible for metabolic activity, contains granules/ Contains dense granules (ADP, ATP, ionic calcium, serotonin, and phosphate), alpha granules, and lysosomes. Platelet plug formation: Vasoconstriction, platelet shape change, platelet aggregation, platelet secretion, stabilization. Vasoconstriction: regulates blood ow to damaged cells; adhesion. 3 components: Von Willebrand factor: links platelet to sub endothelial binding sites; GP1B; Collagen: collagen is released, binds to Von W. Factor, then to GP1B receptor sites bind to GP1B bridge to start forming platelet plug. Shape change: interaction of platelet and agonist (collagen, ADP, thrombi, thromboxane II) alter cytosolic calcium and change shape of platelet. Both TXA2 and ADP bind to membrane receptor surface and expose it to platelet membrane phospholipids, which cause aggregation. Aggregation: Platelet to platelet interaction Usually begins 10-20 sec following vascular injury and platelet adhesion; Requires 4 elements: ATP - energy, lonized calcium, Fibrinogen, GPIlb/ Illa complex. fi ft fi fl  The brinogen binds to the activated platelet membrane GPIlb/Illa complex. Calcium/ brinogen bridges form and promote platelet aggregation. Will not produce clot without brinogen Secretion: Liberate ADP and calcium from the dense granules Release of ADP makes other platelets sticky; Stickiness of platelets causes them to adhere to the originally activated platelets Serotonin and thromboxane A2 function as vasoconstrictors Contracts vascular smooth muscle; Decreases blood ow through then injured vessel. Stabilization: last stage in arresting bleeding Activation of coagulation cascade and brin on platelet aggregates. Fibrin interweaves through initial platelet, compressing into site of injury. Secondary hemostasis Clotting factors: roman numerals and name; listed in order of discovery; a means it is activated. I to Ia: brinogen to brin II to IIa: prothrombin to thrombin Clotting factors: I - brinogen II - prothrombin III - Tissue factor IV - Calcium V - Labile factor VI - doesn’t exist anymore VII - Proconvertin, stable factor VIII - AHF, AHG IX - PTC, AHB, Christmas X - Stuart-Prower factor, autoprothrombin III XI - PTA fi fi fi  fi fi fi  fi fl  XII - Hageman XIII - brin stabilizing factor Intrinsic: exposure to negatively charged foreign substances or activation of factor XII involving, initiates the intrinsic pathway. Requires factors: YII, IX, XI, XII; Prekallikrein and HMWK; Calcium and PF3. Extrinsic: Initiated when factor III, enters the vascular system; Factor VII is activated to VIIa in the presence of calcium and tissue factor (factor III); Only VIIa, Ca+, and Factor Ill are needed to activate Factor X to Xa. Common: composed of factors X, II, V, and I; thrombin activates VII and V, converting brinogen to brin; factor XII. Know clotting cascade: Fibrinogen/thrombin interaction to form crosslinked brin clot: brinogen is a protein produced by the liver; Thrombin cleaves brinogen into short fragments of brin -> Fibrin monomer links to form insoluble brin polymer. What is the Cell Model Theory for coagulation? How is it di erent than the coagulation cascade: A er injury, tissue factor (TF) becomes exposed to blood and combines with free circulating FVII. This complex activates FX, Which with FV can form small amounts of thrombin, enough to activate local platelets; The surface of the activated platlet becomes the catalytic center for a larger amount of thrombin production which produces  fi fi ff fi fi  fi ft fi fi  fi  enough brin to stabilize the clot; Thrombin has both pro-coagulatory as well as anti brinolytic e ects; Tissue factor pathway inhibitor (TFPI); Protein C and S will inactivate FVa and FVIlla Antithrombin will inactivate thrombin as well as FXa, FIXa, FXIa, FXIla. Stages: Initiation, Ampli cation, Propagation. Natural anticoagulants in blood: Antithrombin (ATIII), Protein C Antithrombin (ATIII): main physiologic inhibitor of thrombin; In presence of heparin → ATIll consumed and inhibits thrombin. Protein C: Activated Protein C exerts an anticoagulant e ect by inactivating factors Va and VIlla and slowing thrombin formation. Fibrinolysis How does clot breakdown: Activation of coagulation also activates brinolytic system; Re-establishes blood ow in vessels a er thrombus and facilitates healing; Plasminogen is activated by t-PA. Plasmin: Has very strong a nity for brin; breaks down brin. Thrombopoiesis: platelet production; 30% in spleen; liver: coagulation factors. Thrombocytopenia: < 100,000; De cient platelet production; Increased destruction. Thrombocytosis/Thrombocythemia: >400,000; High platelet number; Bone marrow overproduces megakaryocytes. fi fi fi ff fi ffi fi fi fl ff ft fi