Hematopoietic Function PDF

Hematopoietic Function Blood Composition Summary of Blood Cells RBC production is stimulated by bleeding and hypoxemia WBCs and Lymphocytes are stimulated by infection 1 Hemostasis Hemostasis: drives from the Greek meaning “The stoppage of blood flow” Regulated by activators and inhibitors that main...

Hematopoietic Function Blood Composition Summary of Blood Cells RBC production is stimulated by bleeding and hypoxemia WBCs and Lymphocytes are stimulated by infection 1 Hemostasis Hemostasis: drives from the Greek meaning “The stoppage of blood flow” Regulated by activators and inhibitors that maintain blood fluidity Disorders of hemostasis: 1. Inappropriate formation of clots within the vascular system (thrombus). 2. Failure of blood to clot in response to an appropriate stimulus (bleeding). RBCs are stimulated by hypoxia and excessive bleeding Platelets are triggered in a similar way Three Stages Vascular Constriction Vasospastic stage in inflammation overlaps with this cascade! Reflective vasospasm Formation of the Platelet Plug Primary hemostasis Blood Coagulation Secondary hemostasis because it requires the activation of the coagulation cascade to be triggered. Steps of Hemostasis After the clot is formed then the clot tries to approximate the area and decreased bleeding Dissolution comes after 2 Vascular Constriction Vessel spasm constricts the vessel and reduces blood flow Transient- minutes to hours Vessel spasm is initiated by endothelial injury Endothelin- vasoconstrict Release endothelin-smooth muscle contraction Vessel narrow-less bleeding Local nervous reflexes and local humoral factors such as Thromboxane (TXA2) (from the arachidonic acid cascade) contribute to the vasoconstriction Nitric Oxide and Prostacycline help keep vessels open and the later prevents them from sticking together Formation of Platelet Plug Release of Thromboxane A2- a major enzymatic product of platelet activation, which cause vessel wall contraction Von Willebrand factor is secreted by endothelial cells and binds to expose collagen fiber to the wound surface Platelet through the interaction with bound Von Willebrand factor (Platelet adhesion) vWF released from the endothelium, binds to platelets receptors (1B receptor) Platelets adhere to the collagen fibers on the damaged vessel wall Platelets become activated and release ADP and Thromboxane (TXA2) ADP and TXA2 increase platelet aggregation Von Willebrand is like the glue that keeps the platelets on the wound Platelets will be partially activated and send out chemicals that attract more platelets, thromboxane, and ADP (this increases platelet aggregation 23BA helps keep binding platelets they stack on top of each other Initially VonWillebrand help platelets to stick to the wound then since there is circulating fibrinogen this will bind to 2B3A receptors is going to create a “plug” the next stage is that the cell is going to excrete tissue factor (clotting factor #3) and this will trigger the extrinsic cascade. Extrinsic and then intrinsic is triggered. Blood Clotting (Coagulation) Coagulation cascades from Fibrin which wraps and strengthens platelet plug. Form a “clot” or “Thrombus” 3 Involves a number of plasma proteins called “Clotting Factors” Requirements for Blood Clotting Process Presence of platelets produced in the bone marrow Von Willebrand factor generated by the vessel endothelium Clotting factors synthesized in the liver using vitamin K 2,7,9,10 are vitamin K dependent factors Babies need this shot because they don’t make it yet in their gut Calcium also important Clotting Cascades Factor X is a common factor between the Extrinsic and Intrinsic pathways Factor 3 is going to activate factor 7 and make it Factor 7a(activated) Factor 7a is going to activate factor X and factor X is activated by Ca. Factor X is going to activate prothrombin into fibrinogen and activate that into Fibrin (the one that SEALS the deal!) When Thrombin is activated, the INTRINSIC system is activated and then the numbers work backwards! Factor 8-9-11-12. Since those are activated then more factor X is activated and more prothrombin and then more fibrinogen and then more fibrin! Lovenox BLOCKs factor X Heparin BLOCKS antithrombin III Warfarin BLOCKS factors 2,7,9,10 o PROTEIN C & S are our own natural anti-coags (Warfarin blocks these) Fibrin then traps RBCs making a red insoluble clot and plasminogen is also in there waiting for it to be activated in order to break down the clot at whatever point it is necessary Terminal Steps in both pathways are the same: Activation of factor X Prothrombin activator converts prothrombin to thrombin This interaction causes conversion of fibrinogen in fibrin stands that create the insoluble blood clot. MVP is factor 10! 4 Primary vs Secondary Hemostasis AKA Factor 3 Regulation of Blood Coagulation (Antithrombin III, Protein C&S, Tissue Factor inhibitor) Antithrombin III inactivates coagulation factors and neutralizes thrombin When antithrombin III is complexed with naturally occurring heparin in, its action is accelerated, and provides protection against uncontrolled thrombus formation on the endothelial surface. Protein C, a plasma protein, acts as an anticoagulant by inactivating factors V and VIII. Protein S, another plasma protein, accelerates the action of protein C. Clot Retraction 20-60 minutes after clot formation “Squeezing” serum from clot to bring edges of the broken blood vessel together Approximation of injury to help stop bleeding Clot shrink Clot Dissolution Plasma protein Plasminogen is trapped in the clot Tissue Plasminogen Activator (tPA) is released from uninjured cells tPA converts inactive Plasminogen (trapped in the clot) to active “Plasmin” , which dissolves fibrin and allows platelet plug to dissolve. Think of tPA as acetone and Plasminogen is the nail polish We need to give exogenous tPA to patients because we can’t wait 72 hours for the body to wake up and do that on its own. In Endothelum linning disfunction patients will have problems with clotting Triggers abnormal platele aggregation Fritction (Plaques) HTN Low amount of Nitric Oxide and so vessels stick together 5 Summary Slide of Cascades Hypercoagulability States Increase the risk of clot formation in the arterial or venous circulations Arterial thrombi are associated with conditions that produce turbulent blood flow and platelet adherence. HTN, diabetes, hyperlipidemia, smoking Venous thrombi are associated with conditions that cause stasis of blood flow with increased concentrations of coagulation factors. Virchow’s Triade- Protein C&S deficiency, Sickle Cell, endothelial injury (surgery, factors, hitting your toe LOL, women on B.C. and smoking) Hypercoagulability Associated with Increased Platelet Function 6 Thrombocytosis Platelet count: 150,000-400,000 Reactive (Secondary): due to other conditions Surgery, trauma, infections Essential Process (Primary): bone marrow disorder of the hematopoietic stem cells Negative Feedback Mechanism Thrombopoietin-key hormone in the regulation of Megakaryocyte and platelet formation In Plasma Attached to receptors of platelets Unbound-promote megakaryocyte proliferation Reactive (Secondary Thrombocytosis) A disease state that stimulates thrombopoietin production Common Causes (tissue damage) Surgery Infection Cancer Prolonged stress Clinical Manifestations Those of underlying disease In primary thrombocytosis the patient is referred to a hematologist because the bone marrow is overproducing, and the body has NO need for the new cells Hypercoagulability Associated with Increased Clotting Activity Primary (Genetic) vs Secondary (Acquired) Either create veno-stasis state or increase coagulation or a result of endothelial injury Arterial- HTN, Diabetes, hyperlipidemia, smoking Venous- Virchow’s Triade, è 7 Bleeding Disorders Platelets Defects Coagulation Defects Platelet Defects Thrombocytopenia Circulating platelets < 150,000/ul Most concern is for bleeding YOU MUST move fast with treatment when the platelets are less than 15 Causes Decreased in platelet production Aplastic anemia Leukemia Radiation therapy and some drugs (sulfa) There are some drugs like Heparin that can cause destruction of RBCs Viral illness can trigger thrombocytopenia Increased sequestration in the spleen Decreased platelet survival Immune Thrombocytopenic Purpura (ITP) (MOST COMMON) The only thing on the CBC that is abnormal is the platelets Autoimmune disorder This issue is associated with the IgG antibody they attack the 2B3A receptor. Mostly seen in the spleen where they are destroyed or phagocytized. Platelet antibody formation and excess destruction of platelets Primary or Idiopathic Sometimes it can have an acute phase Sometimes it can be chronic, and it lasts more than 12 months followed by a HemOnc specialist Secondary—due to an underlying disorder AIDS/HIV SLE-Lupus Chronic Lymphocytic Leukemia Vaccines can cause this too! The J&J covid vaccine was causing them when they were being administered (ITP) Isolated low platelet lab level and there is an increased risk of bleeding because of this 8 Pathophysiology of ITP Acute Vs Chronic Acute ITP Occurs in young children Usually follows a viral infection Sudden onset of petechiae Self-limited disorder requiring no treatment Usually self-limiting and resolves in 6 months Chronic ITP Occurs in adults Insidious onset Rarely follows a viral infection This is a primary form of ITP Immune Thrombocytopenic Purpura or Idiopathic Clinical Manifestations Hx of bruising Bleeding from gums Epistaxis Melena Splenic enlargement may occur Diagnosis Severe Thrombocytopenia, platelets count