MLAB 1227- Coagulation Keri Brophy-Martinez

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Thrombosis. Imbalances between clotting activity and fibrinolytic processes Causes increased tendency to form thrombiInvolves the naturally occurring inhibitors of coagulation (those that control the amount of clotting); allowing uncontrolled thrombus formationMore than one hemostatic defect or a

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MLAB 1227- Coagulation Keri Brophy-Martinez

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1. MLAB 1227- Coagulation Keri Brophy-Martinez Chapter 33: Thrombosis

2. Thrombosis Imbalances between clotting activity and fibrinolytic processes Causes increased tendency to form thrombi Involves the naturally occurring inhibitors of coagulation (those that control the amount of clotting); allowing uncontrolled thrombus formation More than one hemostatic defect or abnormality increases risk

3. Terms Hypercoagulation: more clotting activity than normal Thrombosis: formation of platelet and/or fibrin mass in a vessel Thrombus: fibrin mass consisting of fibrin, platelets and trapped cells Embolus: piece of thrombotic material Embolism: obstruction in circulatory system caused by embolus Blood Clot: a mass that forms extravascularly, either in vitro or in tissue

4. Terms con’t Plaque: consists of lipids, fibrous connective tissue, macrophages and smooth muscle cells Thrombophlebitis: thrombus of superficial veins of legs; self-limiting and benign Deep vein thrombosis: involvement of deep veins of legs Thrombophilia: any disorder associated with an increased tendency to cause venous thromboembolism Ischemia: Local obstruction of a blood vessel by a thrombus

5. Atherosclerosis in Artery

6. Thrombus Formation Two types Arterial—white thrombi Venous—red thrombi

7. Arterial Thrombus Formation Occurs when activation of blood coagulation exceeds ability of the anticoagulant/inhibitors and fibrinolytic system to prevent the formation of fibrin. White thrombi composed of platelets, fibrin and a few WBC’s and RBC’s Form at areas where the flow has been disturbed via damage to endothelium, especially atherosclerotic plaques

8. Arterial Thrombus Formation Thrombosis initiated by rupture of the plaque, exposing material to subendothelium in the blood Causes platelet plasma coagulation factor activation which results in fibrin formation. The end result is a thrombus that can obstruct the artery or an embolus breaks off and lodges in the heart or brain, causing tissue death

9. Arterial Thrombus Risk Factors Hypercholesterolemia Hypertension Smoking Physical inactivity Obesity Diabetes Inflammatory processes related to atherosclerosis

10. Venous Thrombi Occurs when activation of blood coagulation exceeds ability of the anticoagulant/inhibitors and fibrinolytic system to prevent the formation of fibrin. Most occur in veins in lower limbs Thrombophlebitis= thrombosis of superficial veins Deep Vein Thrombosis (DVT)=deep veins in limbs and more serious

11. Venous Thromboembolism Venous Thromboembolism (VTE) Pulmonary embolism (PE) Embolization of lung circulation Deep vein thrombosis (DVT)

12. Venous Thrombi Red thrombi Form in veins Composed of rbc’s trapped in fibrin mesh with few platelets and WBC’s Form in areas of slow or disturbed blood flow, where venous segments have been exposed to direct trauma

13. Venous Thrombosis Risk Factors Venous stasis Vessel wall damage Factor V leiden and protein C resistance Deficiency of AT, Protein C, Protein S, heparin cofactor II Increased PT levels Antiphospholipid antibodies Hyperhomocysteinemia Decreased fibrinolytic activity Malingnancy Misc( those associated with plaque formation, pregnancy and oral contraceptive use)

14. Thrombosis Most common cause of death in the United States Inherited or acquired

15. Inherited Predisposing genetic defect that results in a tendency to thrombosis Usually associated with venous thrombosis Caused by: Increased activation of coagulation cascade Defect or decrease in natural inhibitors Abnormalities of fibrinolysis Abnormalities in platelet activation

16. Inherited: Clinical Presentation Venous thromboembolis prior to age 45 Recurrent VTE Family history of VTE Thrombosis in an unusual site (cervical/ visceral veins)

17. Inherited States Associated with Thrombosis Antithrombin (AT) deficiency AT binds thrombin to inhibit coagulation. When deficient thrombin may uncontrollably convert fibrinogen to fibrin clots. Observe DVT in the leg Rare, but has severe clinical manifestations

18. Inherited States Associated with Thrombosis Deficiency of Protein C or S Protein C and S work together to inactivate factors Va and VIIIa Lack of Protein C or S will result in increased production of thrombin, which generates fibrin Protein C deficiency=common DVT Protein S deficiency=risk of ARTERIAL thrombosis

19. Inherited States Associated with Thrombosis Factor V Leiden or Activated protein C resistance (FVL) Genetic mutation of factor V which causes resistance to the action of Protein C Factor II (Prothrombin) 20210 mutation Causes increased thrombin generation Often seen with FVL mutation

20. Acquired States Antiphospholipid Antibody Syndrome Includes the lupus anticoagulant, anticardiolipin antibodies and others are antibodies that prolong phospholipid dependent clotting assays in vitro Patients show no bleeding disorder Most common acquired thrombophilia Antibodies made after certain infections, after exposure to certain medications, and in patients with autoimmune disorders

21. Acquired States Heparin-Induced Thrombocytopenia(HIT) Autoantibody directed against heparin complexed with platelet factor 4. Induces platelet activation and aggregation Patients presents with a thrombocytopenia of < 150 x 109/L 5-14 days after starting heparin therapy

22. Acquired States Thrombotic Microangiopathies (TMA) Characterized by: Microangiopathic hemolytic anemia Thrombocytopenia Microvascular thrombotic lesions Examples include: DIC, TTP, HUS Activation of platelets without the cascade activating, platelets aggregate in vasculature

23. Acquired States Malignancy Stasis, activation of blood coagulation and vascular injury play a role Chemotherapy increases risk Pregnancy & Oral Contraceptives Postoperative States Hematologic Disorders MPD: Polycythemia Vera, idiopathic myelofibrosis, essential thrombocythemia

24. Antithrombotic Therapy: 3 Categories Antiplatelet Drugs Aspirin Inhibits the formation of thromboxane A2 Anticoagulant Drugs Heparin binds to AT to produce an anticoagulant effect Oral Anticoagulant Coumadin drugs interfere with vitamin K action of the liver Thrombolytic Drugs Plasminogen activators are used to lyse thrombi in vivo

25. Therapeutic Anticoagulants Heparin and Low Molecular Weight Heparin (LMWH) Administered IV Causes immediate inhibition of blood clotting Accelerates the action of AT to inactivate Thrombin Ia Heparin will not work if AT levels are low, thus AT called heparin co-factor Monitored using the APTT test Heparin can be neutralized by protamine sulfate Low molecular weight heparin (LMWH) has less risk and is replacing traditional heparin

26. Therapeutic Anticoagulants Coumadin (Warfarin, Dicoumarol) Oral anticoagulant Takes couple days for effects to show Inhibits production of vitamin K dependent factors (II, VII, IX, X) (Protein C & S) Monitored using the PT test (since factor VII has the shortest ˝ life and becomes deficient first)

27. Antiplatelet Therapy Aspirin Administration results in irreversible inhibition of the platelet enzyme cyclooxygenase, which is needed for proper platelet aggregation This reduces the “stickiness” of platelets Affects last for the lifetime of the platelets – 7-10 days Patients undergoing certain platelet function tests should avoid aspirin ingestion for at least seven days NSAID drugs such as ibuprofen compete for cycloxygenase and may be used in conjunction with aspirin

28. References McKenzie, Shirlyn B., and J. Lynne. Williams. "Chapter 33." Clinical Laboratory Hematology. 2nd ed. Boston: Pearson, 2010. Print.

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