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Coagulation and Clot Breakdown

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Coagulation and Clot Breakdown Coagul ation Simplified … Published by ACKNOWLEDGEMENTS CONTENTS We gratefully acknowledge the support and funding provided by the Ontario Ministry of 1. The Basics of Coagulation and Clot Breakdown . 4–7 Health and Long-Term Care. 2. Routine Coagulation Tests . 8–17 Special thanks to the past contributors and material reviewers of the first edition. Evaluating coagulation in the laboratory . 8 Sample collection for coagulation testing . 9 Prothrombin Time (PT) . 10 Thanks also to: International Normalized Ratio (INR) . 11 s Dale Roddick, photographer, Sunnybrook Health Sciences Centre Activated Partial Thromboplastin Time (APTT) . 12 Thrombin Time (TT) . 13 s Doug Nicholson, photographer, Sunnybrook Health Sciences Centre Fibrinogen . 14 s Reena Manohar, graphic artist, Sunnybrook Health Sciences Centre D-dimer . 15 s The ECAT Foundation Anti-Xa assay . 16 Summary . 17 CLOT-ED Images used or modified with permission from the ECAT Foundation, The Netherlands. 3. Anticoagulant Drugs . 18–25 Unfractionated Heparin (UFH) . 18 We hope you enjoy the second edition of Bloody Easy: Coagulation Simplified . Like the first Low Molecular Weight Heparins (LMWHs) . 19 edition we hope to provide basic foundational learning in coagulation and the assessment Fondaparinux . 20 of bleeding disorders and coagulopathies. Updates include, new direct oral anticoagulants Warfarin . 21 and reversal strategies for these drugs, in elective and urgent situations, in Chapter 3. New Direct Thrombin Inhibitors (DTI) . 23 extended half-life replacement products for hemophilia are now included in Chapter 6. Direct Xa Inhibitors . 25 4. Evaluating Abnormal Coagulation Tests . 26–29 First Edition, March 2013 Prolonged PT / INR with normal APTT . 26 Second Edition, February 2019 Prolonged APTT with normal PT / INR . 27 Prolonged APTT and PT / INR . 28 Prolonged Thrombin Time (TT) with normal or prolonged APTT and PT / INR . 29 General Disclaimer: While the advice and information in this handbook are believed to be true and accurate at 5. Approach to the Evaluation of the Bleeding Patient . 30–35 the time of publishing, neither the authors nor the publishers accept any legal responsibility or liability for any errors or omissions in the information provided, or for any of the 6. Diagnosis and Emergency Management of recommendations made. Any decision involving patient care must be based on the judgement Common Bleeding Disorders . 36–45 of the attending physician according to the needs and condition of each individual patient. von Willebrand disease (VWD) . 36 Disorders of platelet function . 38 Hemophilia A and B (Factor VIII and IX deficiency) . 40 Factor XI deficiency . 43 Key References . 45-47 2 3 t 1. ThE BASiCS Of COAGuLATiON AND CLOT BrEAKDOWN o l C & Lesley Black & rita Selby n n w o o i d t k a l a u e r g a B o C . Hemostasis is a complex process in which multiple components of the blood clotting system 2. Secondary hemostasis = activation of coagulation factors and generation 1 are activated in response to vessel injury to control bleeding. of thrombin: Hemostasis is composed of four major events: initiation of coagulation 1. Primary hemostasis s Tissue factor (TF) is released from injured tissue cells, endothelial cells and monocytes. 2. Secondary hemostasis s TF and Factor VIIa form the TF / Factor VIIa complex. 3. Fibrin clot formation and stabilization s TF / Factor VIIa activates a small amount of Factor IX and X to generate a small amount 4. Inhibition of coagulation of thrombin. s Factor XII (and other “contact” factors) play a minor role in the activation of Factor XI. 1. Primary hemostasis = vasoconstriction and platelet plug formation: s The key component of primary hemostasis is the platelet. Amplification phase s Primary hemostasis is triggered by injury to the vessel wall, exposing subendothelial s Thrombin activates Factor V to Va, Factor VIII to VIIIa and activates more platelets. collagen. s Thrombin also activates FXI to FXIa. s Vasoconstriction occurs at the site of injury to reduce blood flow. s Adhesion: von Willebrand factor GPllb / llla Propagation phase adheres platelets to exposed s Additional Factor Xa is produced when TF / Factor VIIa complex activates Factor IX. The subendothelial collagen via Dense granules Platelet resultant Factor IXa along with Factor VIIIa forms the tenase complex which then converts the platelet receptor more Factor X to Xa. glycoprotein Ib / IX (GPIb / IX). Platelets also adhere directly to Alpha granules s Factor Xa and Va along with calcium and a phospholipid (PL) surface (activated platelets) GPlb / IX Endothelium form the prothrombinase complex which converts prothrombin (Factor II) to large amounts collagen via other receptors. Collagen VWF Injury site of thrombin (Factor IIa). s Aggregation: Platelets aggregate collagen exposed with each other with the help of fibrinogen that binds to activated glycoprotein IIb / IIIa (GPIIb / IIIa), 3. Fibrin clot formation and stabilization: forming a platelet plug. Platelet s Thrombin converts fibrinogen to fibrin monomers which polymerize to form a soluble clot. aggregates also provide the Thrombin then activates Factor XIII which cross-links the fibrin monomers and stabilizes phospholipid surface necessary the clot. for coagulation factor activation. GPllb / IIIa Activated Fibrinogen Platelet Collagen GPlb / IX VWF 4 5 t o l C 1. ThE BASiCS Of COAGuLATiON AND CLOT BrEAKDOWN & n n w o o i d t k a l a u e r g a B o C . Secondary hemostasis, fibrin clot formation and stabilization: 4. Inhibition of coagulation = inhibition of thrombin generation and fibrin 1 clot breakdown (fibrinolysis): Contact Factors (HMWK, Prekallikrein) inhibition of thrombin generation INITIATION s At the same time that a clot is being formed, the clotting process also starts to shut itself off to limit the extent of the thrombus formed. FXII FXIIa Tissue Factor s PROPAGATION FVIIa Thrombin binds to the membrane receptor thrombomodulin and activates Protein C to FXI FXIa Activated Protein C (APC). Ca 2+ TF - VIIa complex s APC combines with its cofactor Protein S which then inhibits Factors Va and VIIIa, slowing FIX FIXa down the coagulation process. FVIII FVIIIa Ca2 + +PL s Thrombin bound to thrombomodulin becomes inactive and can no longer activate procoagulant factors or platelets. FX FXa s The endogenous anticoagulant, antithrombin inhibits the activity of thrombin as well 2+ FV FVa Ca +PL as several of the other activated factors, primarily Factor Xa. Prothrombin Thrombin (FII) (FIIa) fibrinolysis AMPLIFICATION s Tissue plasminogen activator (t-PA) converts plasminogen to plasmin which breaks down cross-linked fibrin to several fibrin degradation products, the smallest of which is D-dimer. Soluble Fibrinogen s Thrombin activatable fibrinolysis inhibitor (TAFI) inhibits the formation of plasmin and Fibrin suppresses fibrinolysis. s Fibrin Clot Formation FXIIIa Anti-plasmin and plasminogen activator inhibitor-1 (PAI-1) inhibit plasmin and t-PA and Stabilization respectively. Insoluble TAFI Cross-Linked Fibrin Plasminogen Antiplasmin t-PA PAI-1 Plasmin Fibrin(ogen) Fibrin Clot Degradation Products D-dimer 6 7 2. rOuTiNE COAGuLATiON TESTS Elena Brnjac & rita Selby Sodium Citrate Tube Evaluating coagulation in the laboratory Sample collection for coagulation testing (Blue Top) s In the coagulation laboratory, the coagulation factors are divided into: s To assess coagulation “in vitro,” the laboratory measures the time • Extrinsic pathway factors (Factor VII) taken to form a clot. s t s s Blood is collected into a blue top tube containing sodium citrate e e T • Intrinsic pathway factors (Factors XII, XI, IX, VIII) n i n t anticoagulant (which chelates calcium) to prevent blood clotting o i u t o • Common Pathway factors (Factors X, V, II, Fibrinogen) a l r in the tube during transport. u . 2 g a o ATTENTION C s Memorizing which factors belong to the extrinsic, intrinsic and common pathways Sodium Citrate Tube Coagulation testing respectively will make evaluating the causes of abnormal coagulation tests easier. (Blue Top) MUST only be sent in a sodium citrate Centrifugation (blue top) tube. Intrinsic Pathway Extrinsic Pathway ! XII XI VII IX Tissue Factor s Plasma (the liquid component of blood that contains the clotting VIII factors) is then separated from the platelets (phospholipid source) APTT X PT Intrinsic Extrinsic by centrifugation. + Common V Pathway + s Common II Common Later we will see how adding back phospholipids and calcium is important in standardizing routine coagulation tests. Fibrinogen Fibrin Clot s Some common problems that may result in spurious coagulation Plasma test results are: Buy C oat • Blood collected into incorrect type of tube (not a sodium citrate Red s Here is another picture to help with memorizing the coagulation cascade without the tube) Cells Roman numerals: • Incorrect plasma to citrate ratio (e.g., underfilling of tube or 8 5 patient’s hematocrit > 0.55 L / L) 12 11 9 10 2 1 • Heparin contamination of sample (e.g., incorrect order of Thrombin Fibrinogen PTT sample collection or sample collected from central lines) • Clotting in tube from traumatic venipuncture or inadequate 7 INR mixing • Hemodilution of sample • The common pathway factors can be memorized by thinking of the denominations of dollars in Canada: factors 10, 5, 2 and 1 • The PT / INR pathway starts with factor 7 and includes the common pathway factors • The APTT pathway starts from the left at factor 12, counts backwards to factor 8 (skipping factor 10) and includes the common pathway factors 8 9 2. rOuTiNE COAGuLATiON TESTS Prothrombin Time (PT) International Normalized Ratio (INR) s The PT is used to assess deficiencies or Extrinsic s The International Normalized Ratio (INR) was developed to standardize the PT to allow inhibitors of the extrinsic pathway Pathway for monitoring of oral vitamin K antagonist therapy (e.g., warfarin) across different labs. s t factors (Factor VII) and common s s The PT in seconds is used to calculate the INR. e e T n i pathway factors (Factors X, V, II, VII n t s o i u Each lot of PT reagent needs to have an International Sensitivity Index (ISI) determined / t o Fibrinogen).
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