Lecture 12 CH14 Abnormalities of Blood Coagulation PDF

Abnormalities of Blood Coagulation Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com. Learning Objectives Contrast hemorrhage with thrombosis and describe functions and processes. 2. Describe the functions of blood vessels and platelets in control...

Abnormalities of Blood Coagulation Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com. Learning Objectives Contrast hemorrhage with thrombosis and describe functions and processes. 2. Describe the functions of blood vessels and platelets in controlling bleeding. 3. Explain primary hemostasis and secondary hemostasis, and list the coagulation factors involved. 5. Describe the clotting cascade, including the extrinsic and intrinsic pathways. Describe how to stop clotting using drug therapy. 6. List the most common clinically significant disturbances of hemostasis and describe their clinical manifestations and therapy. 7. Describe the laboratory tests used to evaluate hemostasis. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com 1. Hemostasis Arrest of bleeding (blood clotting) caused by activation of the blood coagulation mechanism Balance: maintain blood fluidity/stop flow rapidly when system is compromised to prevent blood loss Factors concerned with proper function of hemostasis ▪ Integrity of small blood vessels (and lining: endothelium) ▪ Adequate numbers of platelets ▪ Normal amounts of coagulation factors (proteins and factors (Ca ions) in blood) ▪ Normal amounts of coagulation inhibitors Malfunction can lead to life threatening hemorrhagic or clotting disorders Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Causes: Trauma, inflammatory or neoplastic damage, vessel erosion, congenital malformations Factors Concerned with Hemostasis ▪ Adequate number of platelets to accumulate and adhere to injury area Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Small blood vessel integrity ▪ Small vessels are first line of defense in the body ▪ Constrict on injury to facilitate closure by a clot (vasoconstriction) ▪ Endothelium secrete factors that prevent coagulation – injury leads to loss of these factors ▪ Exposure of underlying connective tissue of the endothelium (subendothelial collagen) allows platelet adhesion, activates coagulation mechanism (release of vasoconstriction and coagulation factors) Factors That can compromise hemostasis Absence of one factor will stop the cascade ▪ Injury or disease of bone marrow damaging the megakaryocytes (precursors of platelets) Infiltration of bone marrow by leukemic cells or cancer cells that have spread to the bone marrow, crowding out the megakaryocytes fewerr stimulatory hormones reaching them ▪ Liver/kidney damage: Platelet production is stimulated by thrombopoietin (from kidneys and liver) which stimulates production and differentiation on megakaryocytes ▪ Overconsumption of coagulation factors (Disseminated Intravascular Coagulation- DIC) Widespread several lots being formed in the body at the same time • also lots of haemorrhages and bleeding since you lose ability to control Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Abnormality of small blood vessels ▪ Abnormal bleeding resulting from failure of small blood vessels to constrict after tissue injury ▪ Abnormality of platelet formation ▪ Thrombocytopenia ▪ Failure/absence of coagulation factor(s) (Von Willebrand disease, hemophilia) Platelets ▪ Platelets: Small fragments of cytoplasm from large precursor cells called megakaryocytes Once they get to the site they become sticky and intertwine to form platelet plug ▪ Average survival in the circulation is 10 days; removed by macrophages in the spleen Three important platelet functions – activated by adherence to collagen (increase size, stickiness and degranulation) ▪ Plug defect in the vessel wall ▪ Liberate vasoconstrictors from granules (serotonin, ADP, thromboxane A2) and compounds causing platelets to aggregate (ADP, thromboxane A2) ▪ Contain granules that release factors that initiate and promote coagulation upon activation Physically plug up damage in endothelium to emphasize and increase the concentration of these factors to get a hemostasis reaction quickly Platelet plug – primary hemostasis in seconds Secondary hemostasis: coagulation factors (present in inactive state in blood) culminates in the production of fibrin mesh to stabilize platelet plug. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com buds of membranes of megakarocyte Abnormal Platelets Thrombocytopenia or abnormal platelet function As soon as you don’t have platlets you have these red dots • Leukemia, bone marrow injury, cancer treatment Overconsumption (DIC/TTP) • Autoimmune destruction (ITP) DEVELOPS ANTIBODIES AND DECIDES TO ATTACK PLATLETS Petechiae (less than 2mm diameter) Small red or red-blue spots about 1–5 mm Pinpoint-sized hemorrhages of small capillaries in skin or mucous membranes Indicative of defective or inadequate platelets Do not blanch when pressed Petechiae with fever: In infections such as meningococcemia; dengue hemorrhagic disease Purpura (2-10mm)- Ecchymoses (>10mm) FIGURE 14-1 Characteristics of bleeding in patients with disturbed hemostatic function. (A) Petechial hemorrhages indicative of thrombocytopenia or defective platelet function. Courtesy of Leonard V. Crowley, MD, Century College. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com • Additional Causes of Coagulation Disturbances ▪ Insufficient supply of calcium ions (required for Primary and secondary hemostasis) ▪ Liberation of thromboplastic material into circulation ▪ Vitamin K deficiency causes increased clots • can happen in tumours Required for synthesis of coagulation factors from the liver • any GI diseases or liver disease that inhibit vitamin K will cause problems in producing these CF ▪ Drugs (NSAIDS– blocks thromboxane synthesis, Heparin (decreases platelets) • Genetic disease (Von Willebrand, Hemophilia) Since production of factor gets affected as well as thromboxane • Liver/kidney disease Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Deficiency of one or more plasma coagulation factors Blood Coagulation Factors Highly complex chain reaction slow homeostatic maintenance pathway Intrinsic pathway (slow, 1-6 minutes maintenance): coagulation factors in blood (platelets and plasma factors) induced by injury to blood vessels and platelet binding to collagen Extrinsic pathway (fast – 10-15 seconds, explosiveemergency): factors from components outside circulatory system: vascular endothelial (in cells) cancer tissue expresses these and damage releases tissue factor some inappropriately activate this pathway Extreme tissue damage Phase 2: Conversion of prothrombin into thrombin by activated factor X (Prothrombin activator) Goal of both of these pathways is to activate this thromboplastin interacts with other factors to form prothrombin activator fibrin is the final product to form these clots Usually soluble need to make it insoluble Figure 14-4 A simplified view of the clotting cascade. Note that Factors VIII and V are not shown although critical for normal hemostasis. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Phase 1: Blood Coagulation Factors Phase 3: Conversion of fibrinogen into fibrin by thrombin Fibrin monomers join end to end into long strands of fibrin and are linked side to side Fibrin stabilizing factor strengthens bonds between fibrin molecules to increase strength of fibrin clot Blood clot: End stage of clotting process Made up of an interlacing meshwork of fibrin threads with plasma, RBC, WBC, and platelets Figure 14-4 A simplified view of the clotting cascade. Note that Factors VIII and V are not shown although critical for normal hemostasis. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Thrombin splits off a part of the fibrinogen (soluble) and forms smaller molecules, fibrin monomers (insoluble) Blood Coagulation Factors • Plasminogen is incorporated into clot – binds to fibrin • As clot is formed and clotting factors dissipate, fibrinolytic system takes over • tPA (tissu plasminogen activator) present on vascular endothelium • Plasminogen-plasmin dissolves clots by breaking down fibrin into degradation products (FDP) – can be used to measure deep vein thrombosis, embolism, DIC • Recombinant tPA Figure 14-4 A simplified view of the clotting cascade. Note that Factors VIII and V are not shown although critical for normal hemostasis. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Fibrinolytic system is activated slowly at same time as clotting system: Coagulation Inhibitors ▪Antithrombin III – inhibits factor 2a in cascade Early factors in the pathway ▪Protein C and S ▪ Inactivates factors V and VIII keep this in check until you have damage - massive increase in factors to overcome this inhibition Both circulate in blood plasma, produced by liver Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Are necessary to counterbalance coagulation factors and Restrict clotting process to limited area Disturbances of Blood Coagulation Most serious ones - fetus won’t come into conception —> miscarriage more predominant in males Hemophilia: X-linked hereditary disease ▪ Most common and best known ▪ Episodes of hemorrhage in joints and internal organs after minor injury von Willebrand disease: von Willebrand factor (vWF) ▪ Large protein molecule produced by endothelial cells required for platelets to adhere to vessel wall at site of injury “glue” ▪ vWF adheres to the damaged vessel wall, forms a framework that allows platelets and coagulation factors to adhere, interact, form clot ▪ Forms a complex with factor VIII and maintains normal level of factor VIII Without this, platelets can’t interact with the collagen Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Relatively rare ▪ Hemophilia A – more common(factor VIII deficiency) ▪ Hemophilia B – less common (factor IX deficiency) ▪ von Willebrand disease Large Hemorrhage Associated with Deficiency in Coagulation Factors Courtesy of Leonard V. Crowley, MD, Century College. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com FIGURE 14-1 Characteristics of bleeding in patients with disturbed hemostatic function. (B) A large hemorrhage (hematoma) associated with a deficiency of plasma coagulation factors. Disturbances of Blood Coagulation Additional causes of coagulation disturbance ▪ Coagulation factors produced in liver ▪ Vitamin K required for synthesis of most factors ▪ Vitamin K synthesized by intestinal bacteria ▪ Calcium ions required for all stages of hemostasis • even more rare- autoimmune, acquired forms of clotting disorders, Ab mediated Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Can also be caused by deficiency of prothrombin or factors required for the conversion of prothrombin into thrombin Disturbances of Blood Coagulation Administration of anticoagulant drugs (Heparin, coumadin) ▪ Inhibits synthesis of biochemically active vitamin K–dependent factors Inadequate synthesis of vitamin K ▪ Occurs if the intestinal bacteria have been eradicated with prolonged use of antibiotics Inadequate absorption of vitamin K ▪ Occurs in blockage of common bile duct by a gallstone or tumor, preventing bile from entering the intestine to promote absorption of vitamin Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Severe liver disease ▪ Impairs synthesis of adequate amounts of coagulation factors ▪ Vitamin K, Ca2+ required for factor production Liberation of Thromboplastic Material into Circulation • • provide coagulation factors instead Provide heparin if too much clotting is an issue Can express tissue factor It enters the mother’s blood stream half mother, half fetus • if tearing off, it can enter mother’s bloodstream and cause coagulation and inflammation widespread Leads to activation of coagulation system and abnormal bleeding state at multiple sites Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Products of the following events have thromboplastic activity, liberated into circulation - result in intravascular coagulation ▪ Diseases associated with systemic shock and tissue necrosis ▪ Overwhelming bacterial infections – circulating toxins (gram –ve) sepsis –antibiotic tx can cause initial exacerbation from increased toxins as bacteria are destroyed (meningococcemia) ▪ Other causes of tissue necrosis (trauma, cancer) ▪ Pregnancy – amniotic fluid embolism, placental abruption Pathogenesis of DIC (Disseminated Intravascular Coagulation) Activation of fibrinolysin to defend body from widespread intravascular clotting Clots are dissolved to prevent lethal obstruction of the circulatory system Net effect: Disseminated intravascular coagulation (DIC) Hemolysis In other places - clotting and bleeding at the same time Condition where clotting and fibrinolysis are occurring, consumption of factors results in widespread failure of hemostasis Results in widespread bleeding, clotting- Multi organ failure once you treat cause, it will treat itself Tx: Treat cause !! Supportive : blood products or anticoagulation treatment as required Figure 14-6 Pathogenesis of disseminated intravascular coagulation syndrome. In cancer, it will form more clotting - provide heparin to break down these clots Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Clotting: Platelets and plasma coagulation factors are utilized, causing the levels to drop rapidly in the blood Thrombotic Thrombocytopenic purpura (TTP) • Deficiency of VWF cleaving protein ADAMTS1 Autoantibody, mutation, deregulation of endothelial function/expression (tumour, autoimmune disease, drugs, infection, BMT - most are idiopathic) • Deficiency results in formation of large VWF multimer chains that criss-cross blood vessels – hyper adhesive to platelets • results in platelet aggregation and damage leading to clotting and multi organ thrombosis, fragmentation of RBC (schistocytes) causing anemia and thrombocytopenia • Neurologic damage (almost like mini-strokes happening in the brain) and renal failure are also common • Inherited/Congenital, infection (HIV), cancer, autoimmune, pregnancy, transplant or drug associated – most cases are idiopathic • Tx: plasma exchange (remove VWF fragments), immune suppressive therapy/ corticosteroids, Splenectomy to remove cells creating antibodies against ADAMTS1 if spleen is sequestering and removing cells Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com • VWF is secreted by endothelial cell in large multimers that are cleaved by ADAMTS1 ITP (Immune thrombocytopenic Pupura) development if autoimmune antibody against platelets Children tend to recover spontaneously – Adult onset tends to lead to chronic disease with periods of flare ups an remission Autoimmune therapies : • corticosteroids/immune suppressive agents • IVIG – non- specific biding to macrophage receptors • IV Anti-D IG – targets RBC as well • splenectomy Provide antibodies that are anti-RBC • occupy macrophages Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Targeted destruction of platelets by splenic macrophages Infectious causes of clotting disorders • Bacterial: Not specific to a particular bacteria, but relates to systemic spread potential • Gram –ve sepsis (meningococcemia): endotoxin release, widespread damage and cytokine cascade activation Viral causes: • non –specific :CMV (Vasculitis), HIV (DIC/Vasculitis) , HCV (clotting factor loss) • Viruses that can infect endothelial cells: induce procoagulant state due to endothelial damage inducing TF (Parainfluenza, Mumps, Adenovirus) • Specific – hemorrhagic viruses Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com • Systemic infections – DIC (platelet and clotting factor consumption), TTP (platelet consumption), Vasculitis https://en.wikipedia.org/wiki/Ebola Very beginin vary widely in fatality • places that don’t have access to medical care —> increased fatality Vanishes between outbreaks Marburg – clinically indistinguishable from Ebola, much worse prognosis (no tx or vaccine) • 90% fatality, even survivors have sever long term effects from wide spread organ damage Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Ebola • Spread by direct contact with bodily fluids (2-20 inc phase) • Initial symptoms: sore throat, fever, muscle pain • Virus infects and destroys monocytes/macrophages/DC, spreads to LN – lymphocyte apoptosis • Can spread to circulatory endothelium cause wide spread damage and bleeding (40-50% of cases) • Vaccine, hydration, supportive, limited antivirals • Outbreaks: 25-90% fatality • Reservoir – unconfirmed (fruit bats) Hemorrhagic viruses • • most are rare self-limiting Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com November 2016Future Microbiology 12(2) DOI:10.2217/fmb-2016-0147 Laboratory Tests to Evaluate Hemostasis ▪ ▪ ▪ ▪ CBC - Platelet count: Examination of blood smear or cell counter for platelet numbers Fibrinogen levels in blood Kidney/liver function Schistocytes: damaged blood cells (DIC / TTP) D-dimers: fibrinolytic activity (Fibrin Degradation Product) Bleeding time: Time it takes for a small skin lesion to stop bleeding; used to evaluate the function of capillaries in the hemostatic process ( and test vWF) Clotting time: Time it takes for blood to clot in a test tube Partial thromboplastin time (PTT): Time it takes for blood plasma to clot after a lipid substance and calcium is added to the plasma sample; measures time of first phase coagulation (extrinsic) Prothrombin time (PT): Measures time it takes for blood to clot after adding thromboplastin; prolonged time indicates abnormality in second or third phases of coagulation; used to measure effects of warfarin (intrinsic, common) Thrombin time (TT): Bypasses the first two phases of blood coagulation, primarily measures the level of fibrinogen Or fibrin - ability to clot Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ ▪ ▪ ▪ ▪ ▪ Look at RBC and even WBC Treatments Provide specifically what they require Blood products: if anemic ▪ RBC (if loosing too much blood) ▪ Fresh Frozen Plasma: contains clotting factors ▪ Cryoprecipitate : enriched in fibrinogen , factor VIII and VWF (concentrated from FFP) ▪ Platelet transfusion for clotting issues Heparin – slow evolving DIC Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Treat Cause (bacterial infection, liver/kidney disease, cancer, nutritional deficiency)