Lesson 4.3 Disorders of Hemostasis PDF

## Lesson 4.3 Disorders of Hemostasis ### Learning Outcomes - Identify different etiologies of hemorrhage and thrombosis. - Discuss the mechanism of the development of disoders of hemostasis. - Describe the morphologic appearance (gross & microscopic) of hemorrhage and thrombosis. - Discuss the seq...

## Lesson 4.3 Disorders of Hemostasis ### Learning Outcomes - Identify different etiologies of hemorrhage and thrombosis. - Discuss the mechanism of the development of disoders of hemostasis. - Describe the morphologic appearance (gross & microscopic) of hemorrhage and thrombosis. - Discuss the sequelae of hemorrhage and thrombosis. ## Hemostasis - The arrest of bleeding. - An immediate reparative response to vascular injury to prevent blood loss. - Interdependent interactions - Endothelium - Platelets - Coagulation factors ## Hemostasis 1. Transient vasoconstriction. 2. Primary hemostasis (platelet plug). 3. Secondary hemostasis (fibrin-platelet aggregate). 4. Hemostasis localization and dissolution (thrombolysis/fibrinolysis). ## Hemostasis **A. Injury:** Illustration of the site of injury with ECM (collagen), arteriole smooth muscle, basement membrane, and endothelium. Endothelin and other molecules with similar effects are also present. **B. Primary Hemostasis:** Illustration of primary hemostasis showing platelet adhesion and activation, platelet granule release, platelet recruitment, and platelet aggregation. **C. Secondary Hemostasis:** Illustration of secondary hemostasis showing coagulation factor activation and fibrin polymerization. **D. Hemostasis Localization:** Illustration of hemostasis localization showing release of tPA (fibrinolysis), thrombomodulin (anticoagulant), trapped neutrophils and red blood cells, and polymerized fibrin. - An illustration of the process with endothelial cells, platelets, Von Willebrand factor (vWF), tissue factor (TF), and collagen. Shows the prothrombotic activity of these factors ## Extrinsic Pathway vs. Intrinsic Pathway - An illustration of the classic (Intrinsic, Extrinsic, and Common) Coagulation Cascades, showing the process in detail. - Phospholipid surface is shown as a yellow square, active components as red filled squares and inactive components as empty squares. ## Cell Based Model of Coagulation - An illustration of the Cell Based Model of Coagulation, showing the initiation, amplification and propagation stages/reactions, in detail. ## Fibrinolytic System - An illustration of the fibrinolytic system showing: - Fibrin degradation products - Plasminogen, Plasmin, and Platelet - Urokinase and tPA - PAI-1 and TAFI - Thrombin and Thrombin/thrombomodulin - Illustration of the antifibrinolytic system showing: - Antiplasmins - Antiplasmin/plasmin complexes - Urokinase, tPA and PAI-1 - TAFI and Thrombin ## Antithrombotic and Prothrombotic Events - An illustration shows the antithrombotic events: - Thrombin - Inactivates thrombin - Inactivates Xa and IXa - Proteolysis of Va and VIIla - **(Protein S)** - Active Protein C - Inactivates tissue factor Vila complexes - **(ATIII)** - **(Thrombin receptor)** - **(TFPI)** - Heparin-like molecule - Thrombomodulin receptor - **(Protein C)** - **(Inhibit platelet aggregation)** - **(Activates fibrinolysis)** - **(PGI_2_, NO, and adenosine diphosphatase)** - **tPA** - An illustration of the prothrombotic events: - Endothelial cell - Platelet adhesion - Platelet - vWF - TF - Fibrinogen - **(TF)** - **(Extrinsic coagulation)** - **(Collagen)** ## Hemostasis - Failure= hemorrhage or thrombosis - Hemorrhage - Extravascular blood loss - Thrombosis - Inappropriate formation of intravascular clots ## Hemorrhage - 2 forms - Rhexis - Breaking forth - Diapedesis - Dia= through, pedian= leap (intact vessels) - Inherited or acquired - An illustration of blood vessel adhesion molecules and ligands, showing: - Leukocytes - Blood vessel - *Capture and rolling* - *Floating* - *Adhesion* - *Crawling* - *Diapedesis (paracellular and transcellular)* - Endothelial cells - Pericytes - Basement membrane - Tissue ## Hemorrhage - Occurs when there is abnormality - Endothelium & blood vessels - physical disruption - Platelets - Thrombocytopenia - Decreased platelet function - Coagulation factors - Decreased concentrations or function - Inherited or acquired ## Hemorrhage (etiology) - Damage to blood vessels - Trauma - Vascular erosion (neoplasm or inflammatory reactions) - Fungi (e.g., internal carotid artery erosion secondary to guttural pouch mycosis in horses) - Infectious agents (e.g., canine adenovirus-1) - Immune complexes- entrapped in endothelium> complement activation & neutrophil influx (e.g., type III hypersensitivity) - Developmental collagen disorders (e.g,. Ehlers-Danlos syndrome) - Endotoxemia - Chemicals (e.g., uremic toxins) ## Hemorrhage (etiology) **Thrombocytopenia** - Decreased production - Increased destruction - Increased use of platelets - An illustration shows the causes and mechanisms leading to thrombocytopenia. ## Hemorrhage (etiology) **Thrombocytopenia (decreased production)** - Megakaryocyte damage or destruction - Radiation injury - Estrogen toxicity - Cytotoxic drugs - Myelophthisis (myelofibrosis or bone marrow neoplasia w/c displaces normal b. marrow) - Viral & other infectious disorders (e.g., feline & canine parvovirus) - An illustration shows the causes and mechanisms leading to thrombocytopenia. ## Hemorrhage (etiology) **Thrombocytopenia (increased destruction)** - Often autoimmune (immune dysregulation) - Ab against platelet membrane components such as GPIIb and GPIIIa - e.g., systemic lupus erythematosus - Alteration of platelet membranes - infectious agents or drugs - Isoimmune destruction of platelets in neonatal pigs - Ingestion of colostrum containing antiplatelet Ab - Increased removal by the spleen - Viral disss (e.g., EIA, FIS) - Arthropod-borne agents - An illustration shows the causes and mechanisms leading to thrombocytopenia. ## Hemorrhage (etiology) **Thrombocytopenia (increased use of platelets)** - DIC or disseminated intravascular coagulation - Widespread intravascular coagulation and platelet activation - Progressive thrombocytopenia, widespread hemorrhage **Thrombotic thrombocytopenic purpura** - Not accompanied by coagulation - Platelet aggregates form in the microvasculature - An illustration showing the mechanism of DIC with: - Procoagulant/Endothelial damage - Tissue Factor activation - Thrombi formation in microvasculature - Consumption of clotting factors, fibrin & platelets - Widespread deposition of fibrin thrombi - Fibrinolytic system activation - Bleeding - Plasmin generation - FDP (potent anticoagulant & antiplatelet effect) ## Hemorrhage (etiology) **Decreased platelet function** - Inability to adhere to or aggregate at a site of vascular injury - Bernard-Soulier syndrome (man) - Deficiency of GPIb on platelet surface - Glanzmann's thrombasthenia (man) - Deficiency of GPIIb on platelet surface - Reported in otterhound and Great Pyrenees dogs and horses - Prolonged bleeding and hematoma from minor injuries - Spontaneous epistaxis - mutation affecting a Ca2+-binding domain of the extracellular portion of GPIlb ## Hemorrhage (etiology) **Decreased platelet function** - “storage pool disease” - Deficient release of platelet granule content - calcium diacylglycerol guanine nucleotide exchange factor I platelet disorders - Simmental cattle, dogs (spitz, basset hound, and American foxhounds), cats, and fawn-hooded rats - Defective platelet storage of ADP - Chedia-Higashi syndrome (Aleutian mink, cattle, Persians cats, killer whales) ## Hemorrhage (etiology) **Decreased platelet function** - Acquired platelet inhibition and dysfunction - Ass. w/ NSAID (e.g., aspirin) administration - Inhibition of COX pathway> decreased thromboxane prod'n=reduced platelet aggregation - Uremia (renal failure) - Secondary platelet dysfunction - e.g., von Willebrand dss, autimmune or myeloproliferative disorders - AutoAb against vWF= decreased platelet adhesion ## Hemorrhage (etiology) - Decreased conc. or functions of coagulation factors - Inherited - Acquired - An illustration of Inherited Coagulation Deficiency Disorders with details on each factor. ## Hemorrhage (etiology) - Decreased conc. or functions of coagulation factors (Acquired) - Decreased prod'n or increased use - Severe liver dss - decreased synthesis - Vitamin K deficiency (prod'n, absorption or fxn) - reduce conversion of glutamic acid residues into y-carboxyglutamic acid (II, VII, IX, X and prot. C & S) - Dicumarol in moldy sweet clover (Melilotus alba) - warfarin-containing rodenticides - Sulfaquinoxaline - Increased consumption ass. w/ DIC - An illustration showing hemorrhage, Anticoagulant (Warfarin-Containing) Rodenticide Toxicosis, Skin and Subcutis, Medial Aspect of the Right Hind Leg, Dog. ## Hemorrhage (morphologic appearance) - Depends on its cause, location, and severity ## Hemorrhage (morphologic appearance) - Petechia (pl. petechiae) - Pinpoint (~1-2mm); diapedesis ass. w/ minor vascular damage - Ecchymosis (pl. ecchymoses) - Larger (~2-3 cm in dm); more extensive vascular damage - An Illustration shows Hemorrhage, Endotoxemia, Heart, Cow. - An Illustration shows Ecchymotic Hemorrhages (Ecchymoses), Subcutis, Rabbit. ## Hemorrhage (morphologic appearance) - Suffusion - Affects larger contiguous area - An illustration showing Suffusive Hemorrhage, Serosa, Stomach, Dog. ## Hemorrhage (morphologic appearance) - Hematoma - occurs in a focal, confined space - Grows in size until P exerted by the extravascular blood matches that w/n the vessel - Most common in long-eared dogs or pigs; spleen after trauma to vasculature - An illustration showing Organizing Hematoma, Spleen, Horse. - Illustrations showing Hematoma in different animals. ## Hemorrhage (morphologic appearance) - Hemorrhage into body cavities - Hemoperitoneum- peritoneal cavity - Hemothorax- thoracic cavity - Hemopericardium- pericardial sac - An illustration showing Hemopericardium, Pericardial Sac, Dog. ## Hemorrhage (morphologic appearance) - According to location - Epistaxis- nose bleed - Hemoptysis- spitting of blood - Hematamesis- vomiting of blood - Enterorhaggia- intestinal hemorrhage - Metorrhagia- uterine bleeding - Hematuria- bloody urine - Hemopericardium, hemothorax, hemoperitoneum - An illustration showing Hemorrhage in different animals. ## Hemorrhage (sequelae) - Depends on the amount, rate, and location of blood loss ## Hemorrhage (sequelae) - Local blood loss - Resolves by hemostasis - Severe blood loss - Hematoma (or) hemorrhage to body cavities - Slow rates of blood loss - Gastric ulceration and hemorrhage - Compensated by increased hematopoiesis - Rapid loss of substantial amt of blood - Hypovolemia, decreased tissue perfusion, and hypovolemic shock ## Thrombosis - the formation of an excessive or inappropriate fibrin-platelet aggregate in an injured blood vessel - Thrombus (pl. thrombi) - aggregate of platelets and other blood elements (e.g., RBCs and neutrophils) ## Thrombosis - Mural thrombus - on the endothelium of a blood or lymphatic vessel - Cardiac thrombus - within the heart - Thromboembolus - free in the lumina of blood or lymphatic vessels ## Thrombosis (etiology) - Injury to the endothelium and blood vessels - Excessive activity of coagulation factors and platelets (hypercoagulability) - Dynamics of blood flow (stasis or turbulence) - An illustration showing Virchow's Triad in Thrombosis ## Thrombosis (etiology) - Endothelial injury - Exposure of blood to TF and subendothelial components (e.g., collagen, laminin)> potent stimulus for platelet aggregation and coagulation - loss of anticoagulant properties of normal endothelium - enhanced expression of procoagulant substances to promote fibrin formation. - An illustration showing Thrombus (Mural), Artery. ## Thrombosis (etiology) - Endothelial injury - Trauma - Vasculitis caused by infection or immunologic reactions (resulting in release of TNF and IL-1) - Metabolic disorders - Neoplasia - Toxins (e.g., endotoxin) ## Thrombosis (etiology) - Abnormal blood flow (stasis) - Occur systemically with heart failure or in a local region of congestion caused by vascular obstruction or vascular dilation - Most important in veins - Slow flow rate favors accumulation of activated coagulation factors and contact of platelets with the endothelium - Areas predisposed to thrombus - Dilated heart chambers (e.g., dilatative cardiomyopathy) - Dilated vessels (e.g., aneurysm) - Venous thrombosis - Common in horses w/ occlusion of intestinal veins secondary to intestinal torsion - An illustration showing Venous Thrombus. ## Thrombosis (etiology) - Abnormal blood flow (turbulence) - disrupts laminar blood flow> disrupts thin layer of plasma - platelets interact more readily with the endothelium - Physically damage endothelium - Stimulus for platelet adhesion and coagulation ## Thrombosis (etiology) - Abnormal blood flow (turbulence) - Turbulence + increased risk for thrombosis - Greatest in areas where vessels branch, there is narrowing of the vessel lumen, or at sites of venous or lymphatic drainage ## Thrombosis (etiology) - Hypercoagulability - caused by enhanced activation or decreased degradation of these proteins - Or an alteration in hemostatis protein fxn (less often) - ~reflects an increase or decrease in the concentration of activated hemostatic proteins (e.g., coagulation factors and coagulation or fibrinolytic inhibitors) ## Thrombosis (etiology) - Hypercoagulability - Increased activity of coagulation and fibrinolytic proteins - Inflammation- most common cause> results in increased - TF, platelet activation, fibrinogen concentration, concentrations of membrane phospholipids (e.g., phosphatidylserine), conc. of PAI-1, and decreased thrombomodulin concentration - End products of complement activation - increase coagulability of blood by inducing procoagulant and antifibrinolytic proteins (e.g., complement membrane attack complex induces TF expression). ## Thrombosis (etiology) - Hypercoagulability - Increased activity of coagulation and fibrinolytic proteins - Stress & tissue necrosis - Transient increase in fibrinogen conc. - Surgery - Elevated conc. Of factors I & VIII - Renal disease (e.g., the nephrotic syndrome) - Deficiency of AT (major inhibitor of thrombin)> increased loss thru damaged glomeruli ## Thrombosis (morphologic appearance) - Depends on the: - underlying cause - location (artery, vein, or microcirculation) - Composition (relative proportions of platelets, fibrin, and erythrocytes) ## Thrombosis (morphologic appearance) - Cardiac and arterial thrombi - ~initiated by endothelial damage> provides site for firm platelet attachment + fibrin - Rapid flow- x passive incorporation of RBC - Laminated appearance - Alternating layers of platelets, interspersed by fibrin, intermixed w/ erythrocytes and leukocytes (lines of Zahn) - An illustration showing Arterial Thrombus, Lines of Zahn, Cranial Mesenteric Artery, Horse. ## Thrombosis (morphologic appearance) - Cardiac and arterial thrombi - Dull, usually firmly attached to the vessel wall, red-gray (pale thrombi) - May or may not occlude vessel lumen - Large thrombi tend to have tails - Extend downstream from point of endothelial attachment - An illustration showing Thrombi, Cardiac and Arterial, Dogs. ## Thrombosis (morphologic appearance) - Venous thrombi - Occur in areas of stasis - Result: increased activation of coagulation element and reduced clearance rate of activated clotting factors - Increased erythrocytes - Increased blood viscosity - Enhanced margination of platelets and leukocytes - Gelatinous, soft, glistening, and dark red w/ point of vascular attachment (red thrombi) - An illustration showing Venous Thrombi, Pulmonary Vein, Lung, Horse. ## Thrombosis (morphologic appearance) - Microvascular thrombi (microthrombosis) - ~due to systemic infection, neoplasia, response to emboli, oc DIC - Physiologic microthrombosis/immunothrombosis - Host defense against systemic infection to localize pathogens and host products (e.g., antimrobial peptides and neutrophil products) - EXCESSIVE and widespread microthrombosis or immunothrombosis> DIC ## Thrombosis (sequelae) - Determined by its location and its ability to disrupt perfusion in independent tissue ## Thrombosis (sequelae) - Disruption of tissue perfusion - Size of thrombus - Small vs. large - Occlusion - Rate of formation - Slow vs.rapid - Method of resolution or repair - thrombolysis - Number of vessels affected - An illustration showing Thrombus Resolution. ## Thrombosis (sequelae) - reestablishment of blood flow increases tissue perfusion - permanent vascular narrowing and altered, more turbulent blood flow at the site of a healed thrombus result in an increased risk for subsequent thrombosis at the site - An illustration showing Occlusive Mural Thrombus, Recanalization, Cat. ## Thrombosis (sequelae) - Embolus (pl. emboli) - Thrombus break loose and enter the circulation - Venous thromboemboli - Typically lodge in pulmonary circulation> infarct/ RS-HF - Arterial thromboemboli - Typically lodge in smaller arteries downstream - Cardiac thromboemboli> lodge at the bifurcation of the iliac external arteries> saddle thrombus ## Thrombosis (sequelae) - Embolus (pl. emboli) - Fat emboli - Fibrocartilaginous emboli - Bacterial emboli (e.g., vegetative valvular endocarditis) - Parasitic emboli (e.g., Dirofilaria) - Neoplastic emboli - Gas embolus ## Thrombosis (sequelae) - Embolus (pl. emboli) - Thrombus break loose and enter the circulation - Venous thromboemboli - Typically lodge in pulmonary circulation> infarct/ RS-HF - Arterial thromboemboli - Typically lodge in smaller arteries downstream - Cardiac thromboemboli> lodge at the bifurcation of the iliac external arteries> saddle thrombus ## Thrombosis (sequelae) - Disseminated intravascular coagulation - caused by the loss of localization of the coagulation process and generation of excess thrombin - widespread endothelial activation or injury - excessive concentrations of circulating TF - extensive trauma or tissue damage - Shock, systemic inflammation - Vasculitis, Sepsis, Burns, heat stroke - Neoplasia, Surgery - immunothrombosis w/c is unable to confine pathogens or damaged cells. ## Thrombosis (sequelae) - Disseminated intravascular coagulation - Serious manifestation of abnormal coagulation - imbalance between procoagulant and anticoagulant, and profibrinolytic and antifibrinolytic pathways - Fibrinolytic form= widespread hemorrhage - Thrombotic form= widespread microthrombosis ## References - Runnells, R.A., Monlux, W.S., & Monlux, A.W. (1960). Principles of veterinary pathology. - Zachary, J.F. (2022). Pathologic Basis of Veterinary Disease (7th ed). Elsevier. ## Coagulation Factors - A table showing the coagulation factors with their names. - An illustration of the coagulation factors with an easy-to-remember mnemonic.