Describe the 5 stages of hemostasis: (Hint: See Porth pages 653- 654) 1) Vessel spasm o Constricts vessels and reduces blood flow o Transient event that lasts minutes or hours o Initiated by endothelial injury and caused by local and humoral mechanisms o Most powerful vasoconstrictor: Endothelin 1 o Prostacyclin, another prostaglandin released from the vessel endothelium, produces vasodilation and inhibits platelet aggregation 2) Formation of the platelet plug o Small breaks in the vessel wall are sealed with a platelet plug rather than a blood clot o Platelets (thrombocytes) arise from megakaryocytes within seconds of injury o Platelet has a life of 8-12 days, then it is broken down and eliminated by macrophages o Involves activation, adhesion, and aggregation of platelets o Platelets are attracted to a damaged vessel wall, become activated, and change from smooth disks to spiny spheres o Platelet adhesion requires von Willebrand factor, which binds to platelet receptors, causing adhesion of platelets to the exposed collagen fibers o Platelet membrane plays an important role in platelet adhesion and coagulation process 3) Blood coagulation or development of insoluble fibrin clot o Conversion process of the plasma protein fibrinogen (soluble) to fibrin (insoluble) o Fibrin creates meshwork that cements platelets and other blood components to form clot o Coagulation factors are proteins synthesized in the liver; Vitamin K is necessary for synthesis of factors II, VII, IX, and X (most important), prothrombin, and protein C o Deficiency of Vitamin K or liver failure will cause not enough prothrombin to be created and bleeding tendency will develop o Inactivation of calcium ion prevents clotting when removed from the body o Coagulation process results from both intrinsic—slow process, causes clotting in 1-6 mins/begins as blood comes in contact with collagen in the injured wall, aka internal trauma, initiates by activation of factor XII—and extrinsic pathways—fast process, clotting starts within 15 secs/begins with trauma to blood vessel, blood escapes from vascular system, aka external trauma— converging which form prothrombin activator (factor X) o Factor X converts prothrombin to thrombin, which then acts as an enzyme to convert fibrinogen to fibrin (meshwork) 4) Clot Retraction o Occurs within 20-30 mins after clot has formed, contributing to hemostasis by squeezing serum from the clot and joining edges of broken vessel o Large numbers of platelets contribute through their actin and myosin filaments o Failure of clot retraction indicates low platelet count 5) Clot dissolution/lysis o Clot dissolution (fibrinolysis) allows blood flow to be reestablished and permanent tissue repair to take place o The process involves the interaction of substrates, enzymes, protein cofactors, and calcium ions that circulate in the blood or are released from platelets and cells in the vessel wall o Plasminogen (inactive form) is converted into plasmin (active form) which digests the fibrin strands of the clot and certain clotting factors, causing the clot to dissolve IN SUMMARY: Hemostasis is designed to maintain the integrity of the vascular compartment. The process is divided into three phases—vessel vasoconstriction, which constricts the size of the vessel and reduces blood flow; platelet adherence and formation of the platelet plug; and formation of the fibrin clot, which cements the platelet plug together. Clot retraction, which pulls the edges of the injured vessel together, and clot dissolution, which involves the action of plasmin to dissolve the clot and allow blood flow to be reestablished and tissue healing to take place, are also important processes of hemostasis. Blood coagulation requires the stepwise activation of coagulation factors, carefully controlled by activators and inhibitors. What is hypercoagulability? - An exaggerated form of hemostasis that predisposes to thrombosis (blood clot) and blood vessel occlusion (blockage/closing of blood vessel) ========================== BASICALLY: an increased tendency of blood to thrombose (clot) - Two forms of hypercoagulability states: o Conditions that create increased platelet function o Conditions that cause accelerated activity of the coagulation system a. Hypercoagulability associated with increased platelet function: - Increased platelet function results in platelet adhesion, formation of platelet clots, and disruption of blood flow - Causes of increased platelet function are disturbances in flow, endothelial damage, and increased sensitivity of platelets to factors that cause adhesiveness and aggregation - Increases the risk of clot or thrombus formation in arterial/venous circulations o Arterial thrombi are associated with conditions that produce turbulent blood flow and platelet adherence o Venous thrombi are associated with conditions that cause stasis (slowing/stoppage) of blood flow with increased concentrations of coagulation factors - Conditions that create increased platelet function: o Atherosclerosis, Diabetes Mellitus, smoking, elevated blood lipid and cholesterol levels, and increased platelet levels o Conditions may be accelerated by: § Pregnancy causes increase of blood volume so the mom can support the growth of the fetus § Use of oral contraceptives: birth control hormones § Postsurgical state § Immobility § Obesity § Congestive heart failure allows for clots to form due to poor contraction and pumping of heart § Malignant diseases (these are examples of acquired disorders) an inherited disorder would be von Willebrand Disease b. Hypercoagulability associated with accelerated activity of the clotting system: - Thrombus formation due to the activation of the coagulation system can result from primary (genetic) or secondary (acquired) disorders affecting the coagulation components of the clotting process (an increase in procoagulation factors or a decrease in anticoagulation factors) What is the difference between atherosclerotic plaques and venous thrombi? - Atherosclerotic plaques disturb blood flow, causing endothelial damage and promoting platelet adherence o Clog and narrow arteries with plaque buildup; Preventing proper blood flow - Venous thrombi are associated with conditions that cause stasis of blood flow w/ increased concentrations of coagulation factors; results in activation of clotting cascade; Blood clot forms and blocks the vein What is thrombocytosis? What are the clinical manifestations? - Elevation in the platelet count above 1,000,000/uL can occur as a reactive process (secondary thrombocytosis) or as an essential process (primary thrombocytosis) o Primary thrombocytosis: bone marrow disorder of hematopoietic stem cells—cells that give rise to other blood cells o Secondary thrombocytosis: disease state that stimulates thrombopoietin production—hormone that produces platelet formation § Causes include tissue damage because of surgery, infection, cancer (Polycythemia Vera— bone marrow create too many RBCs = blood clots & Myelogenous Leukemia—bone marrow creates too many WBCs), and chronic inflammatory conditions such as rheumatoid arthritis and Crohn’s disease - The overstimulation of thrombopoietin production is extremely serious once levels are over 950,000 or over 1mil because it leads to random clot formation around arterial and venous system which increases risk of stroke and pulmonary embolism - Common clinical manifestations are thrombosis and hemorrhage o Thrombotic events include deep vein thrombosis, pulmonary embolism, and portal and hepatic vein thrombosis What are the bleeding disorders associated with the following? - Bleeding disorders or impairment of blood coagulation can result from defects in any of the factors that contribute to hemostasis; bleeding can occur as results of disorders associated with platelet number/function, coagulation factors, and blood vessel integrity a. Platelet Disorders – Thrombocytopenia - Thrombocytopenia refers to decreased platelet number (less than 150,000/uL) because of decreased production, increased destruction, increased sequestration of platelets in the spleen, or impaired platelet function (thrombocytopathia); greater decrease of platelet #, greater risk of bleeding o Decreased production because of loss of bone marrow function = aplastic anemia o Replacement of bone marrow by malignant cells, (such as leukemia), radiation therapy and drugs, or HIV, also decreases production Mild cutaneous vasculitis with palpable purpura and petechiae - Common sites of bleeding include mucous membranes of nose, mouth, GI tract, and uterine cavity o Cutaneous bleeding is seen as pinpoint hemorrhages (petechiae) and purple areas of bruising (purpura) in dependent areas where capillary pressure is higher
b. Coagulation Factor Deficiencies
- Results from deficiency or impaired function of 1+ clotting factors including vWF - Deficiencies can arise because of inherited disease or defective synthesis or increased consumption of clotting factors o vWF and Hemophilia (A and B) are two of the most common inherited disorders of bleeding