Hemostasis and Hematopoiesis Lecture Notes PDF

Hemostasis and Hematopoiesis Marina Gharibian, PHD, RN Clinical Associate Professor NURS 210A Fall 2024-2025  Standard Laboratory Values for Red Blood Cells Test Normal Values Significance Red blood cell count (RBC) 4.2-5.4 x 10⁶/...

Hemostasis and Hematopoiesis Marina Gharibian, PHD, RN Clinical Associate Professor NURS 210A Fall 2024-2025  Standard Laboratory Values for Red Blood Cells Test Normal Values Significance Red blood cell count (RBC) 4.2-5.4 x 10⁶/μL Number of red cells in the blood Men 3.6-5.0 x 10⁶/μL Women 1.0%-1.5% of total Rate of red cell production Reticulocytes RBC Hemoglobin Hemoglobin content of the blood Men 14-16.5 g/dL Women 12-15 g/dL Hematocrit Volume of cells in 100 mL of Men 40%-50% blood Women 37%-47% Mean corpuscular volume 85-100 fL/red cells Size of the red cell Mean corpuscular 31-35 g/dL ６ Concentration of hemoglobin in hemoglobin the concentration red cell fL stands for femtoliters One femtoliter is 10-15 L. Hemostasis  The term hemostasis refers to the stoppage of blood flow.  Hemostasis is normal when: 1) it seals a blood vessel to prevent blood loss and hemorrhage.  It is abnormal when: 1) it causes inappropriate blood clotting or 2) clotting is insufficient to stop the flow of blood from the vascular compartment.  Clotting Factors Factor I Fibrinogen Factor II Prothrombin Factor III Thromboplastin Factor IV Calcium Factor V Labile factor Factor VI Is not in active use now Factor VII Stable factor Factor VIII Antihemophilic factor Factor IX Christmas factor Factor X Stuart–Prower factor Factor XI Plasma Thromboplastin antecedent Factor XII Hageman factor Factor XIII Fibrin stabilizing factor Clotting Factors  The clotting factors, except for factors III (tissue thromboplastin) and IV (calcium ion) are plasma proteins.  They circulate in the blood as inactive molecules.  The liver is the site of synthesis of all the coagulation factors except factor VIII, XI, and XIII. Hemostasis is divided into five stages: 1 Vessel spasm 2 Formation of the platelet plug 3 Blood coagulation or development of an insoluble fibrin clot 4 Clot retraction 5 Clot dissolution  1-Vessel Spasm  Vessel spasm is initiated by endothelial injury.  A spasm constricts the vessel and reduces blood flow.  It is a transient event lasting less than 1 minute. Thromboxane A2 , a substance released by the platelets, contributes to vasoconstriction. It also causes blood clotting and platelet aggregation. 2-Formation of the Platelet Plug  Is initiated as The endothelium is injured, and collagen is exposed.  Formation of the platelet plug also involves a small protein molecule called von Willebrand factor, produced by the endothelial cells of blood vessels.  Formation of a platelet plug involves adhesion and aggregation of platelets.  Platelets become activated, change from smooth disks to spiny spheres, exposing receptors on their surfaces.  These receptors bind to von Willebrand factor at the injury site. Activated platelets 2-Formation of the Platelet Plug (cont’d) The completed plug will cover the damaged components of the endothelium and will stop blood from flowing out of it, but if the wound is large enough, blood will not coagulate until the fibrin mesh from the coagulation cascade is produced, which strengthens the platelet plug. If the wound is minor, the platelet plug may be enough to stop the bleeding without the coagulation cascade. 2-Formation of the Platelet Plug (cont’d)  Then in the second stage, called secondary hemostasis, the platelet plug is reinforced by a protein mesh made up of fibrin. You can think of it like a brick wall where the platelets make up the bricks and the fibrin makes up the mortar that goes between the bricks. 3- Blood Coagulation Blood coagulation is the process by which fibrin strands create a meshwork that cements blood components together. The purpose of the coagulation process is to form an insoluble fibrin clot. It results from activation of the intrinsic or the extrinsic coagulation pathways. The intrinsic pathway (Contact activation pathway), a slow process, occurs in the vascular system; the extrinsic pathway (Tissue factor pathway), a much faster process, occurs in the tissues. Blood Coagulation Cascade The process of coagulation is a cascade of enzyme catalyzed reactions where the activation of one factor leads to the activation of another factor and so on. Cascade: a process whereby something, is successively passed on. The three main steps of the blood coagulation cascade are as follows: Formation of prothrombin activator Conversion of prothrombin to thrombin Conversion of fibrinogen into fibrin Pathway Activation Components Outcome Extrinsic Tissue factor: released due to vascular  Tissue factor Activation of factor X damage  Factor VII  Factor XII Surface contact: exposure of coagulation Factor XI  factors to negatively charged vascular  Factor IX Intrinsic subendothelial surfaces  Factor VIII Activation of factor X Thrombin: released at the end of the  Platelet membrane phospholipids common pathway (positive feedback loop) Ca2+ ions   Factor X Generation of thrombin:  Factor V  Converts fibrinogen  Prothrombin to fibrin Common Factor Xa: activation of factor X by either  Activates intrinsic the extrinsic or intrinsic pathway  Platelet membrane pathway phospholipids  Activates factor XIII Ca2+ ions  Platelet activation  Regulation of clot   Fibrinogen formation Intrinsic pathway and extrinsic pathway  The intrinsic pathway responds to spontaneous, internal damage of the vascular endothelium, whereas the extrinsic pathway becomes activated secondary to external trauma. Both intrinsic and extrinsic pathways meet at a shared point to continue coagulation, the common pathway.  Both pathways are needed for normal hemostasis. Both systems are activated when blood passes out 3-Blood of the vascular system. Coagulation The terminal steps in both pathways are the same: (cont’d) the activation of factor X and thrombin-induced formation of fibrin, the material that stabilizes a clot. Calcium (factor IV) is required in all but the first two steps of the clotting process.  Fibrin production begins with conversion of factor X to Xa, the activated form of a factor. Factor X can be activated by means of 2 reaction sequences. One, extrinsic pathway, requires tissue factor, or tissue thromboplastin which is released by the vascular endothelium at the time of injury. 3-Blood The other sequence leading to activated factor X is the intrinsic Coagulation pathway, activated by tissue injury, given that name, because it employs factors found within the vascular system of plasma. (cont’d) Factors XII, XI, IX must be activated in succession and factor VIII must be involved before factor X can be activated and calcium ion is needed. From this point coagulation proceeds along what has been called the common pathway.  The next step toward fibrin production is taken when factor Xa helped by phospholipids from activated platelets, splits prothrombin creating thrombin. 3-Blood Thrombin in turn cleaves fibrinogen to form fibrin. This fibrin, at first a soluble gel is Coagulation stabilized by factor XIIIa and polymerizes into a tight meshwork of fibrin, platelets and (cont’d) entrapped blood cells. The fibrin strands then shorten (clot retraction) bringing together the edges of the wounded vessel wall and sealing the site.  Coagulation Pathway Extrinsic pathway: tissue thromboplastin (III) Intrinsic pathway: tissue injury Extrinsic pathway: requires tissue factor or tissue thromboplastin (III) Intrinsic pathway is activated by tissue injury Coagulation studies Blood clotting molecule models 4-Clot Retraction Pulling the of the injured vessel together.  Clot retraction is the "shrinking" of a blood clot.  After 20-60 minutes of clot formation, the clot begins to contract and expresses most of the fluid (serum) from the clot.  The edges of the blood vessel wall at the point of injury are slowly brought together again to repair the damage that occurred. Clot Retraction 5-Clot Dissolution The dissolution of blood clot begins shortly after its formation, this allows blood flow to be reestablished and permanent tissue repair to take place. The process by which a blood clot dissolves is called fibrinolysis. Fibrinolysis  Plasminogen normally is present in the blood in its inactive form. It is converted to its active form, plasmin, by plasminogen activators formed in the vascular endothelium, liver, and kidneys.  The plasmin formed from plasminogen digests the fibrin strands of the clot and other clotting factors.  Circulating plasmin is rapidly inactivated by 2 - plasmin inhibitor, which limits fibrinolysis to the local clot and prevents it from occurring in the entire circulation. Fibrinolysis Interplay of enzymes in the process of fibrinolysis. Abbreviations used are FDPs, fibrin degradation products; PAI, plasminogen activator inhibitors; tPA, tissue plasminogen activator Summary of the hemostatic process  Constriction of the blood vessel: limits blood flow to the area  Formation of the platelet plug: the initial, temporary plug formed via the following steps: o Adhesion: exposed von Willebrand factor (VWF) binds to the glycoprotein (Gp) Ib receptors on platelets o Aggregation: GpIIb/IIIa receptors on platelets bind fibrinogen o Secretion: Substances are released that stimulate further platelet activation and aggregation and initiate the coagulation cascade.  Activation of the coagulation cascade: forms a more stable fibrin clot o Extrinsic pathway:  Primarily responsible for initiation of the cascade  Involves (in order): tissue factor, factor VII, and factor X o Intrinsic pathway:  Primarily involved in amplification of the cascade  Can be directly activated by vessel injury  Involves (in order): factors XII, XI, IX, VIII, and X o Common pathway:  The extrinsic and intrinsic pathways join together when factor X is activated to form the final common pathway.  Involves (in order): factors X, V, II (thrombin), I (fibrin), and XIII  Inhibition of clotting and fibrinolytic phase: o Stops clotting and breaks down the clot once it is no longer necessary o Involves:  Plasmin  Antithrombin  Proteins C and S Hematopoiesis  The production of all types of blood cells including formation, development, and differentiation of blood cells. Hematopoiesis: The Elements of Blood Hematopoiesis  Hematopoiesis Reticulocytes are immature (RBCs) produced in the bone marrow and released into the peripheral blood, where they mature into RBCs within 1 to 2 days.  Myeloblast:  Most immature stage  Large nucleus, several nucleoli  Promyelocyte:  Primary granules appear in the cytoplasm.  Myelocyte:  Cell division ceases  Specific granules appear  The size of the cell decreases  Apparent changes in nuclear morphology.  Metamyelocyte:  Nucleus begins to indent and forms a horseshoe shape-  Band cell  Mature neutrophil/segmented  Multilobulated nucleus