MLAB 1227- Coagulation Keri Brophy -Martinez

1. MLAB 1227- CoagulationKeri Brophy-Martinez 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: stationary fibrin mass consisting of fibrin, platelets and trapped cells • Embolus: piece of thrombotic material that moves • 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 for 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. 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

26. 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

27. 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 ½ life and becomes deficient first)

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