D’YOUVILLE COLLEGE BIOLOGY 307/607 - PATHOPHYSIOLOGY Lecture 9 - BLOOD & BLOOD DISORDERS II Chapter 7 1. White Cell Disorders: • leukopenia (mostly neutropenias - fig. 7 - 26 & ppt. 1): • neutropenia - deficiency of neutrophils -- two patterns of causes - impaired production in marrow, e.g., marrow tumor (produces non functional cells), drugs or radiation used in tumor therapy (suppression of marrow), other drugs (table 7 - 7), or nutrient deficiencies, e.g., vitamin B12 - excessive destruction of neutrophils, e.g., hypersplenism (entrapment in spleen), drug-induced immune attacks, or autoimmune attacks • leukocytosis - increased white cell levels (usually associated with inflammations that stimulate marrow) (table 7 - 8) - neutrophilia (response to acute inflammation) & eosinophilia (allergies or parasitic infections) are most frequently encountered • leukemias - tumors of leukopoietic cell lines in marrow - neoplastic takeover of marrow results in neutropenia, anemia, bleeding disorders due to thrombocytopenia - invasion of adjacent bone tissue leads to bone destruction and pain in bone & joints - metastasis usually targets liver (hepatomegaly), spleen (splenomegaly), and lymph nodes (lymphadenopathy) (fig. 7 - 28 & ppt. 2) - four main types: acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), & chronic lymphocytic leukemia (CLL); acute forms are usually more severe (fig.7 - 29 & ppt. 3) Bio 307/607 lec 9 - p. 2 - • lymphomas - neoplasias of lymphoid tissues that generally do not freely circulate Bio 307/607 lec 9 - p. 3 - • Hodgkin's disease (lymphoma) - neoplasias that arise usually in cervical node and follow a predictable pattern of growth and spread; four stages are identified, based on the stage of progress through this pattern (table 7 - 9): I - single lymph node involvement; II- several lymph nodes on same side of diaphragm; III lymph node involvement on both sides of diaphragm; IV - involvement of non lymphoid organs - probable cause: genetic vulnerability to Epstein-Barr virus infection - Reed-Sternberg cells (fig. 7 - 30) are important diagnostic feature of biopsies - splenomegaly and lymphadenopathy are generally present as well as depressed immune function and vulnerability to infections • non-Hodgkin's lymphomas - also lymphoid neoplasms; growth and spread pattern is less systematic • bone marrow transplants: usual treatment strategy; proper matching of HLA (MHC) between donor & recipient + suppression of recipient immune response is required 2. Hemostasis: prevention of blood loss • three main steps: vascular spasm (vasoconstriction), platelet plug formation, & coagulation • vasoconstriction: stressed smooth muscle in wall of small artery or arteriole responds with contraction • platelet activation: (von Willebrand factor - factor VIII complex) - vWF-VIII from circulating blood contacts collagen at wound site & activates platelets - platelet plug formation: platelet activation causes aggregation to occur, forming platelet plug (figs. 7 - 3, 7 - 8 & ppts. 4 & 5) - platelet degranulation: platelets secrete substances (ADP, serotonin & thromboxane) that perpetuate activation and degranulation (positive feedback), provoke inflammation, & intensify vasoconstriction, (reduces blood loss by reducing flow to wound site) Bio 307/607 lec 9 - p. 4 - - these substances collaborate with thrombin from coagulation cascade to consolidate the clot that forms concurrently; contractile proteins in platelets participate in clot retraction (shrinkage or consolidation of clot) (fig. 7 - 9 & ppt. 6) - other substances from platelets assist in coagulation (platelet factor 3 PF3) and in tissue repair (platelet derived growth factor - PDGF) Bio 307/607 lec 9 - p. 5 - • coagulation: third step of hemostasis involves three steps of its own (in reverse order): - formation of fibrin from fibrinogen (plasma protein; factor I); catalyzed by powerful clotting enzyme thrombin, which also activates fibrin stabilizing factor (XIII), cross linking fibrin polymers to stabilize meshwork of fibrin (fig. 7 - 4 & ppt. 7) - formation of thrombin from prothrombin (plasma protein; factor II) - formation of prothrombin activator from reaction cascade involving numerous additional clotting factors (mostly plasma proteins from liver {table 7 -1}, Ca2+, PF3, & tissue factor III {TF} - aka thromboplastin) - two pathways are involved for prothrombin activator formation: - extrinsic (triggered by TF) is faster, involving fewer steps (fig. 7 - 5 & ppt. 8) - intrinsic is slower, with more steps, but produces more fibrin (fig. 7 6 & ppt. 9); intrinsic pathway is triggered by thrombin, formed via extrinsic pathway {fig. 7 - 7 & ppt. 10}, & assisted by factor VII, or alternatively triggered by Hageman factor {XII}) - recall that Hageman factor is involved in plasma-derived mediation of inflammation (fig. 2 - 16 & ppt. 11) - thrombin is virtually ubiquitous in its stimulatory effects in coagulation cascade (fibrin formation, autocatalysis of thrombin activation, activation of platelets, & stimulation of clot retraction) (fig. 7 - 10 & ppt. 12) Bio 307/607 lec 9 3. - p. 6 - Control of Hemostasis: • anticoagulant processes: flowing blood washes away many uninvolved clotting factors, diluting them and sending them to the liver for inactivation (hemodynamic control) - healthy endothelium releases several substances that inhibit platelet aggregation (& degranulation), inhibit both extrinsic and intrinsic pathways (fig. 7 11 & ppt. 13); endothelial secretions notably include heparin that activates an antithrombin present in plasma • fibrinolysis: degrades clot, preparing way for healing - mainly involves plasmin formed from inactive plasma protein, plasminogen (fig. 7 - 12 & ppt. 15); various checks and balances in the system promote enough coagulation to stem the blood loss (fig. 7 - 13 & ppt. 16) 4. Bleeding Disorders: • terms for blood loss: petechiae (minute pinpoint losses), purpura (somewhat larger, more widespread patches of blood loss), ecchymoses (also known as bruises), & hematoma (large mass of entrapped blood loss) • thrombocytopenia: platelet deficiency resulting from impaired marrow function (e.g. tumors, antitumor therapy) or excessive rate of platelet clearance from blood (DIC, hemangiomas, immune destruction of platelets, & hypersplenism) (fig. 7 - 15 & ppt. 17) • clotting factor disorders: may be genetically determined, or acquired - genetic deficiencies include vWF (von Willebrand's disease), factors IX and/or VIII (hemophilias) - acquired deficiencies (fig. 7 - 16) are largely determined by some impairment of liver function or inadequate supply of vitamin K; excessive clotting in the body (disseminated intravascular coagulopathy - DIC) is also a known cause Bio 307/607 lec 9 - p. 7 - • anticoagulant therapy: overuse of heparin or warfarin (coumadin) may cause dangerous internal bleeding, making it necessary to monitor such treatments closely