Ch_14_Alterations_in_Hemostasis.docx

Chapter 14 – Alterations in Hemostasis PA Pathophysiology Objectives: Chapter 14: Alterations in Hemostasis What are the general consequences of too much or too little clotting? What are the steps in hemostasis? What factors released from platelets contribute to hemostasis? How do they work...

Chapter 14 – Alterations in Hemostasis PA Pathophysiology Objectives: Chapter 14: Alterations in Hemostasis What are the general consequences of too much or too little clotting? What are the steps in hemostasis? What factors released from platelets contribute to hemostasis? How do they work? What are the roles of the intrinsic and extrinsic pathways in clotting? What are the specific clotting factors that result in enzymatic cleavage of fibrinogen? Why does initiation of fibrinolysis occur simultaneously with clot formation and what are the mediators of fibrinolysis? What is the role of the liver in clotting? What proteins/cells/vitamins are needed for proper clotting? Where do they come from? How do they get into the body and where they need to go? if a person has low or high PT/PTT and/or INR what cells are increased/decreased in the blood - same as above with HCT- same as above with WBC What are the symptoms of abnormal bleeding? What are normal laboratory tests that are used to diagnose bleeding disorders. What does each reveal? What are the expected lab findings of the more common coagulopathies What are the causes and consequences of an insufficient quantity of platelet)? What are the causes and symptoms of thrombocytopenia? What are the causes and symptoms of an excessive quantity of? Why does a normal platelet count not ensure adequate platelet function? What treatments or disease states lead to coagulation disorders? What are the causes and symptoms of hemophilia? What are the causes and symptoms of Vitamin K deficiency and how does it affect coagulation? What is disseminated intravascular coagulation (DIC)? What are the pathophysiological processes, symptoms, and lab findings? Process of Hemostasis Intro- Hemostasis is process of clotting involves interactions of vessel walls, platelets, and coagulation proteins Pathologies Too much = thrombosis (vascular blockage, or emboli –CVA) Too little = bleeding. Stages Immediate stage – vasoconstriction Can last hours mediated by local vasoactive mechanisms more vasospasm with blunt vs. sharp injuries (intact muscles in vasculature???) Primary Hemostasis - Platelet plug formation Aggregation of platelets that attach to damaged endothelium Platelets attract other clotting factors to area. Onset in minutes Secondary hemostasis - Fibrin clot formation Intrinsic or extrinsic pathway activated to recruit clotting factors to injury Production of fibrin from fibrinogen 3-10 min to accomplish this Clot retraction clot hardens and is compressed takes about an hour Platelets (aka thrombocytes) – major players in hemostasis. They are fragments made from megakaryocytes Life span = 7-10 days (M’phage digestion after that) First cell on the scene of an injury Normally inhibited from aggregating by endothelial secretion of nitric oxide (NO) and Prostaglandin I2. Primary hemostasis actions (fig 14-2) bind to subendothelial collagen that is exposed with injury. Degranulation – Alpha granules - coagulation factors (fibrinogen, fibronectin, von Willebrand factor, etc). Dense granules – release ADP, ATP, and serotonin (5HT) All of these factors released help platelets aggregate. Secondary hemostasis actions Coagulation cascade help convert prothrombin to thrombin which eventually activates ______________ helps eventually in clot retraction (via plasmin activation) Coagulation Cascade. Blood Coagulation factors (table 14-1) Circulate in blood in inactive form Most are synthesized by liver (not factor 8) Many need vit K to be made Cascade is a complex meshwork of factors that activate fibrin formation (fig 14-4) Cascade is activated by extrinsic or intrinsic pathways both are Vit K dependent (have specific proteins that are Vit K dependant) both converge on activation of factor X. both are Ca2+ dependent. Intrinsic Pathway Activated when blood comes into contact with damaged vascular endothelium Collagen exposure and Factor XII are starting points. Extrinsic pathway Activated when vascular wall is damaged (especially if crushed) Vascular factor III is starting point. Important reactions: Factor X – start of final pathway – convergence point of extrinsic and intrinsic paths. Fibrinongen to fibrin – mediated by thrombin (IIa) Process inhibited by antithrombin III (ATIII) Heparin – anticoagulant. Stimulates ATIII to block thrombin’s effects on fibrin production. (fig 14-3) And blocks some of intrinsic paths proteins so PTT test is good to use with heparin Tx. Factor Va and factor VIIIa key points in cascade Inhibited by Protein C Fibrinolysis (fig 14-5) Process of clot breakdown. Activated shortly after (if not during) clot formation Thrombin (and other factors) activates plasminogen conversion to plasmin. Plasmin inside the clot starts to digest fibrin and initiate clot breakdown. Cascade offers many points of amplification and regulation Role of the liver in clotting Kind of like the janitor of the clotting cascade. – cleans up all the factors left behind and prevents ‘overdoing’ clotting and fibrinolysis. Makes anti-plasmins to prevent inappropriate fibrinolysis Clears clotting factors from blood to prevent over-clotting. Evaluation of Hemostasis and Coagulation Clinical Assessment Many coagulopathies are inherited so an accurate family history is often needed for diagnosis. (table 14-2). Hemophilia (mostly in males) Personal history is very useful as well. bleeding after a trauma – usually a platelet dysfunction more chronic bleeding – usually a coagulopathy. onset of bleeding after change in medications (especially aspirin, NSAIDS, intake of alcohol (ETOH), chemotherapeutics, etc.) Skin assessment Petechiae (p-tk-) – (Fig 14-6) – pinpoint red spots due to capillary hemorrhages- especially in legs. Not always a bleeding problem – sometimes due to localized trauma Purpura (pûrp-r) A condition characterized by hemorrhages in the skin and mucous membranes that result in the appearance of purplish spots or patches (= petechiae in localized areas). Fig 14-7 ecchymosis – (k-mss) bruise in skin caused by blood escaping capillaries (hematoma = raised ecchymosis) . Usually occurs after localized trauma. Telangiectasia (tl-nj-k-tzh) - Chronic dilation of groups of capillaries causing elevated dark red blotches on the skin. (fig 14-9) Lab Findings Platelet count – good for diagnosis of ability to initiate clotting. Prothrombin time (PT) – extrinsic pathway evaluation The PT test evaluates how well all of the coagulation factors in the extrinsic and common pathways of the coagulation cascade work together. Included are: factors I (Fibrinogen), II (Prothrombin), V, VII and X. INR (international normalized ratio) – similar to PT time except it controls for variation due to reagents used in the test from one lab to the next. When used (almost always) it is listed alongside PT values. The PT/INR may be done at the same time and evaluates the clotting factors that are part of the extrinsic and common pathways: XII, XI, IX, VIII, X, V, II (prothrombin), and I (fibrinogen) as well as prekallikrein (PK) and high molecular weight kininogen (HK). Activated partial thromboplastin time (PTT) – evaluates factor IX function thereby evaluating intrinsic pathway and common pathway. The aPTT is functional determination of the intrinsic pathway of coagulation (factors XII, XI, IX, VIII, X, V, II (prothrombin), and I (fibrinogen) as well as prekallikrein (PK) and high molecular weight kininogen (HK). Measures many factors in the intrinsic and common pathways of clotting. Plasma D dimer – assesses fibrinolysis ability. indicates the presence of an abnormally high level of fibrin degradation products in your body for lab test explanations - http://www.labtestsonline.org/understanding/analytes/d_dimer/test.html https://labtestsonline.org/tests/partial-thromboplastin-time-ptt-aptt Interpretation of PT and PTT in Patients with a Bleeding or Clotting Syndrome PT result ptt result Examples of conditions that may be present Prolonged Normal Liver disease, decreased vitamin K, decreased or defective factor VII, chronic low-grade disseminated intravascular coagulation (DIC), anticoagulation drug (warfarin) therapy Normal Prolonged Decreased or defective factor VIII, IX, or XI, von Willebrand disease (severe type), presence of lupus anticoagulant Prolonged Prolonged Decreased or defective factor I, II, V or X, severe liver disease, acute DIC Normal Normal or slightly prolonged May indicate normal hemostasis; however, PT and PTT can be normal in conditions such as mild deficiencies in other factors and mild form of von Willebrand disease. Further testing may be required to diagnose these conditions. Vascular and Platelet Disorders Vascular Vascular Purpura (fig 14-7) Etiology Normally drug induced (allergic). Especially blood thinners Autoimmune response to drug causes vascular inflammation Can also be caused by connective tissue disorders Scurvy (lack of Vit C) etc. Possibly causes structural abnormalities of vasculature (elastin and or collagen) => leaky vessels Sx – specific to cause. Generally purpura appear and disappear in groups. Allergic purpura often on proximal extremities and may be accompanied by other allergic responses or localized paresis. Drug induced purpura illustrates more generalized outbreaks on skin Scurvy –lesions on medial thighs and hair follicles Tx Remove drug/allergen or restore vitamin levels and prognosis is good Hereditary Hemorrhagic Telangiectasia Etiology Telangiectasia (tl-nj-k-tzh) - Chronic dilation of groups of capillaries causing sometimes elevated, dark red blotches on the skin. (fig 14-9) Also known as ‘skin spot’ resulting from vascular lesion. Due to abnormal vascular development (poor contractile or support fibers) => leaking vessel Genetic link Sx Localized red or purple lesion Recurrent episodes with increased incidents with age (especially after puberty). Tx Topical hemostatic agents (vasoconstrict local tissue) Skin laser treatments. Cauterization (especially if in nasal mucosa) Blood transfusions and hemostasis if very severe. Platelet Disorders Thrombocytopenia (lack of platelets) Etiology (see box 14-1) Decreased production – usually due to drug induced damage to marrow stem cells Decreased survival - usually due to autoimmune destruction or exhaustion of platelet supplies (see “DIC” later) Pooling in the spleen (sequestered from system) – due to splenomegaly Platelet dilution – due to large blood transfusions without platelets. Sx Reduced ability to clot - increased bleeding time Bruising, petechiae and purpura Tx Based on the cause (remove the stimulus) Corticosteroids can increase platelet production Platelet transfusion Splenectomy Thrombocytosis (excessive platelets) Etiology Can be due to exercise Transient thrombocytosis Can be a temporary response to trauma Secondary thrombocytosis Can be due to a chronic response (polycythemia) Primary thrombocytosis Sx Primary – can lead to hemorrhage in skin, mucus membranes, and GI tract. Occlusion of vessels leads to necrosis of tissue If in GI tract: sloughing off of GI layers (duodenum especially) ➔ ulceration of GI tract. Can also lead to thrombosis and embolism. Tx Primary – hydroxyurea can be used to decrease platelet production. Mutagenic drug - Inhibits DNA synthesis (RNA reductase inhibitor), reducing all 3 blood cell counts Aspirin therapy to prevent platelet aggregation. (inhib thromboxane A2) Transient and Secondary forms will usually resolve themselves. Qualitative platelet Disorders Etiology – platelets don’t aggregate well enough (numbers are ok, function isn’t) rare cases von Willebrand disease -abnormal platelet adhesion due to lack of this factor (von Willibrand factor) in the vasculature Bernard-Soulier syndrome – abnormal platelet adhesion because VWF can’t activate Platelets thrombasthenia – fibrinogen receptor defect Sx Bleeding (Petechiae, purpura, etc) Bleeding time is increased b/c platelet function is decreased. Tx Transfusion with normal platelets Desmopressin for von Willibrand disease Increase production of VWF and Factor 8 Coagulation Disorders Hemophilia Etiology Two types Hemophilia A – More common (X linked – mostly males affected) Factor VIII deficiency = end of __________ path Hemophilia B Less common Factor IX disease= late __________path Largest concern is intracranial bleeding Sx Hard to distinguish between Hemophilia A and B Bleeding (especially after injury) is major sign. Can be superficial or internal Hemearthrosis (blood in the joints) Can lead to joint deformity Tx Injury prevention Bleeding treatments (ice on joints after injury) Administration of deficient factor (factor VIII or IX) or synthetic drugs that stimulate the intrinsic pathway. Pharmacologically inhibit fibrinolysis Aminocaproic acid (Amicar) - Inhibits fibrinolysis by inhibiting plasminogen activator substances and antiplasmin activity. Desmopressin (IV or intranasal spray) mimics ADH action at renal tubules – increases blood volume also increases Factor VIII levels (Hemophilia A Tx) DIC – Disseminated Intravascular Coagulation Etiology widespread clotting and fibrinolysis (don’t know why) Can be caused by: snakebites, malignancy, transfusion reactions, shock, etc uses most of platelet stores (especially if acute DIC) – liver and bone marrow can keep up with loss of clotting factors if it is a mild and chronic case. The main problem is bleeding due to depleted platelet stores although coagulation is always the initial event. Sx thrombi at first then and widespread bleeding. Petechiae and ecchymosis on skin bleeding at wound sites cynosis at skin (due to thrombosis at capillaries) Dyspnea (due to thrombosis at pulmonary capillaries) Renal failure and hematuria (due to thrombosis at kidney) Tx remove the cause (if known) treat symptoms fibrolytics if clotting in lungs or kidney (or brain) replacement of clotting factors if going into hemorrhagic shock (hypotensive). Hepatic Disease. Etiology liver is responsible for making most of clotting factors. Liver disease => poor clotting. Can be poor bile production – Vit K absorption Poor production of clotting factors – Factor II, VII, IX, X, etc Sx bleeding Tx supplement with missing clotting factor (plasma transfusion) treat liver disease.