Fibrinolysis and Coagulation Regulation PDF

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Summary

- Primary Hemostasis, involves your blood vessels constricting and your platelets aggregating. Platelets adhere to constricted blood vessel and trigger secondary hemostasis. - Secondary Hemostasis, triggered by primary hemostasis and involves your coagulation system generating a fibrin clot.Cascade ...

Description

MLSC-3121U, Clinical Hematology II -

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Primary Hemostasis, involves your blood vessels constricting and your platelets aggregating. Platelets adhere to constricted blood vessel and trigger secondary hemostasis. Secondary Hemostasis, triggered by primary hemostasis and involves your coagulation system generating a fibrin clot.

Cascade Theory -

Series of enzyme-catalyzed reactions ultimately converting soluble fibrinogen into an insoluble fibrin clot. The clot is stabilized by factor XIII. First Complex, activates FIX and FX. Also known as the extrinsic Tenase complex. Second Complex, activates/cleaves FX. Also known as intrinsic Tenase complex. Third Complex, activates/cleaves prothrombin. Also known as the prothrombinase complex. These complexes work together in secondary hemostasis to form the fibrin clot. INR, a ratio used to standardize the measurement of clotting times across different countries. Uses an ISI number and is calculated using the PT patient results. The closer the result is to the lab mean, the closer the INR will be to one. People with prolonged PT will have higher INR and are at higher risk of random bleeding.

Clot Dissolution -

The body has a built-in feedback mechanism to stop and control fibrin clot formation. Plasma proteins that interfere with clotting factors regulate clotting.

Antithrombin (AT) -

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A serine protease inhibitor known as a seprine. AT inhibits thrombin, FXa, FIXa, FXIa and FXIIa. In the presence of heparin, inactivation of thrombin and FXa by AT is greatly increased. Heparin is given after operation to help inhibit unwanted clotting from trauma. Heparin increases AT inhibition by 1000-fold and is recyclable. Antithrombin however is consumed in the reaction through Thrombin-Antithrombin complexes. Low molecular weight heparins inhibit only FXa and do not act on thrombin but are used in disorder where unfractionated heparin cannot be used (home use).

Heparin Cofactor II (HC-II) -

Only inhibits thrombin and a lot more heparin is needed to accelerate thrombin inhibition compared to AT.

MLSC-3121U, Clinical Hematology II Protein C (PC) -

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Vitamin K-dependant and is produced in the liver. Activated by thrombin and thrombomodulin to activated PC (APC). APC inactivates FVa and FVIIIa to turn off the coagulation system. Protein S, also vitamin K-dependant, enhances the inactivation of FVa and FvIIIa to shut off the coagulation system. Thrombin/TM complex activates Protein C to APC. APC binds to protein S which goes back and inactivates FVa and FVIIIa to turn of the coagulation system. Congenital protein C or S deficiency is associated with recurrent venous thrombosis.

Tissue Factor Pathway Inhibitor (TFPI) -

Binds to FX and/or FIX to inhibit their actions. When bound to TFPI, FX/TFPI or FIX/TFPI binds to the FVII-tissue factor complex on a membrane. Competitively inhibits further activation of FX or FIX. TFPI inactivates FVIIa and limits the FVIIa:TF activity.

Thrombin -

Promotes clot formation by converting fibrinogen into fibrin. Activates and aggregates platelets and activates cofactors FV and FVIII to FVa and FVIIIa. Converts PC to APC which inactivates FVa and FVIIIa. Also activates thrombin activated fibrinolysis inhibitor (TAFI) which inhibits fibrinolysis.

Thrombomodulin (TM) -

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Found on the surface of epithelial cells and complexes with thrombin. Thrombin bound to TM no longer converts fibrinogen into fibrin. Instead, it converts PC into APC on the endothelial PC receptor. The thrombin/TM complex will indirectly cause to the formation of TAFI.

Fibrinolytic System -

Components include: o Plasminogen, the inactive form of plasmin. Made in the liver. Fibrin bound to this is converted to plasmin by TPA or urokinase (UPA) o Active Protease, allows plasmin to degrade the fibrin clot. o Plasminogen Activators, include tissue plasminogen activator (TPA) and converts plasminogen into plasmin. o Plasmin Inhibitor, include alpha-2-antitrypsin and alpha-2-macroglobulin which inhibit plasmin activity. o Thrombomodulin o TAFI

MLSC-3121U, Clinical Hematology II

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o Fibrin/Fibrinogen, substrate for plasmin Fibrinolysis, the dissolution of a fibrin clot by plasmin. TPA and urokinase activate fibrin bound plasminogen to plasmin 2-3 hours after fibrin clot formation. Fibrin clot breakdown will restore blood flow during blood vessel repair. Plasmin, active form of plasminogen that degrades fibrin in clots and circulation. Alpha2-antiplasmin will inactivate free plasmin. The end products are fibrin/fibrinogen degradation products (FDPs that include d-dimer). Plasmin cleavage of cross-linked fibrin (trans-aminated fibrin via action of FXIIIa and Ca2+) generates d2e with generation of fragment e or d-d (d dimer).

Plasminogen Activators -

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Primarily include tissue plasminogen activator (T-PA) and urokinase plasminogen activator (U-PA). Tissue Plasminogen Activator, secreted by endothelial cells. Recombinant TPA mimic TPA from endothelium and is used therapeutically to dissolve pathologic clots forming during venous and arterial disease. Thrombin from coagulation pathway most important inducer of endothelial cell secretion of TPA, UPA and PAI-1. Converts fibrin bound plasminogen to plasmin 2-3 hours after fibrin clot formation. Urokinase, secrete by urinary tract endothelial cells and is always bound close to the plasminogen in the clot to ensure that fibrinolysis happens where it should. Purified urokinase can be used to stop stroke/heart attack causing clots and deep vein thrombosis clots but is very expensive. Converts fibrin bound plasminogen to plasmin 23 hours after fibrin clot formation. Streptokinase, used in thrombolysis medication for heart attacks and embolism. In the event of a stroke, the medication is to be given quickly after the attack to have an effect. Secreted from streptococci and harnessed for medicinal use. May induce an immune response and cause the body to make antibodies against streptokinase, rendering it ineffective.

Plasminogen Inactivators -

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Plasmin is formed in the vicinity of the clot and without control of free plasmin, fibrinogen is digested, and the blood becomes unclottable. Plasminogen Activator Inhibitor-1 (PAI-1), prevents TPA and urokinase from activating the fluid phase of plasminogen. Stored in platelets for secretion where it is needed. Alpha-2-Antiplasmin, primary plasmin inhibitor in vivo. Rapidly and irreversibly binds free plasmin and inactivates it to limit clot break down. Clot bound plasmin cleaves fibrin and restores blood flow in the vessels. TAFI, activated TAFI blocks the conversion of plasminogen to plasmin. Some act on plasmin itself while some act on plasminogen.

MLSC-3121U, Clinical Hematology II

Disseminated Intravascular Coagulation (DIC) -

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Consumption of coagulation factors and platelets with fibrin formation at site of endothelial damage and throughout the microcirculation. Coagulation response is accentuated throughout the circulation. Triggered by… o Activation of the Extrinsic Pathway, from tissue factor release. o Direct Activation of FX or FII, snake venom can cause this. o Activation of the Intrinsic Pathway DIC is secondary to an underlying cause/condition. Severity depends on how well the body can compensate with DIC. Fragments or RBCs are seen (RBCs rip as they pass clots/blockages in the vessels) and leads to the development of microangiopathic hemolytic anemia. Lab diagnosis is based on several test results since it is a secondary disorder. Decreased platelet count, elevated PT and APTT (factors used up, low fibrinogen (used up) and elevated levels of fibrin degradation products are seen. Therapy is directed at treated the underlying condition causing the DIC and then maintaining the blood volume and hemostasis after the primary condition is solved.

Fibrin Degradation Products (FDP) and D-Dimer -

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d-d fragments are generated from plasmin action on cross linked fibrin (d-dimer). Fragments inhibit platelet activation and fibrin polymerization, contributing to hemorrhaging. D-dimer is quantified by monoclonal antibody based on immunoassay. D-dimer is a specific marker for venous thrombosis. It means that fibrin was deposited in the venous system. D-Dimer, a breakdown product from the action of plasmin on fibrin. Used to diagnosis thrombosis, deep vein thrombosis (DVT) or DIC. D-Dimer is tested using ELISA techniques. The D-dimer test has no interference from fibrinogen unlike other FDP tests. Can use citrated plasma instead of another special tube. Specific and only tests for fibrin breakdown products.

Fibrinogen Level Testing -

A high concentration of bovine thrombin is added to platelet poor plasma. Causes the reaction of fibrinogen to fibrin. It is a clot-based method of the Clauss method and a modification of the thrombin clotting time test. A dilution is needed because the conversion of fibrinogen to fibrin happens to fast to analyze in an undiluted sample.

MLSC-3121U, Clinical Hematology II -

Hypofibrinogenemia, may be observed in patients with DIC or severe liver disease. Patients have prolonged fibrinogen conversion times....