CV Coagulation notes PDF

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14.CV COAGULATION NOTES1. THE VASCULAR SYSTEMFunctions: A. Transport (oxygen, nutrients, waste, hormones) B. Protection (immune system - antibodies, leukocytes; clotting) C. Homeostatic regulation of fluid content and temperature2. HAEMOSTASISThe cessation of bleeding from damaged blood vessels A. C...

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14.12.18

CV COAGULATION NOTES 1. THE VASCULAR SYSTEM Functions: A. Transport (oxygen, nutrients, waste, hormones) B. Protection (immune system - antibodies, leukocytes; clotting) C. Homeostatic regulation of fluid content and temperature

2. HAEMOSTASIS The cessation of bleeding from damaged blood vessels A. Complex system of proteins and enzymes, mainly involving: i.

Adhesion & activation of platelets

ii.

Formation of fibrin

B. Platelet activation and fibrin formation are usually concurrent

3. VASCULAR ENDOTHELIUM Endothelial cells are protective against haemostasis: A. Heparan sulphate membrane glycoproteins B. Signalling molecules: Prostaglandin I2 (PGI2) & NO C. Tissue plasminogen activator (tPA) D. Converts ADP to adenosine

4. HAEMOSTATIC PLUG Platelets aggregate, activate coagulation cascade & fibrin forms: “haemostatic plug”

5. FIBRIN FORMATION To get started right away, just tap any placeholder text (such as this) and start typing. A. Thrombin is produced from prothrombin by a complex enzyme cascade initiated by signalling molecule called tissue factor B. Fibrinogen is a free-floating, soluble blood protein; thrombin cleaves the ends to form insoluble fibrin. C. Fibrin strands assemble into fibrils that bind to platelets and each other

6. PLATELET AGGREGATION

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7. PHARMACOLOGY – PROCOAGULANTS To get started right away, just tap any placeholder text (such as this) and start typing. A. Vitamin K (dietary; called Phyto menadione as medication) Vital for formation of clotting factors; may be applied with thrombin as warfarin antidote. B. Desmopressin (stimulates vWF release); for haemophilia C. Tranexamic acid (Antifibrinolytic – blocks fibrin degradation) General anti-haemorrhagic medication

8. THROMBOSIS A. Pathological coagulation within an intact blood vessel; may cause blockage (thrombus) B. May detach from the vessel wall – embolus. Embolisms are often life-threatening if they become stuck in a smaller blood vessel. C. Differ by blood vessel: i.

Venous thrombi are high in fibrin

ii.

Arterial thrombi are high in platelets

9. MAJOR CAUSES OF THROMBOSIS

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i.

Myocardial infarction

ii.

Atherosclerosis

iii.

Vasculitis

iv.

Hypertension

v.

Smoking

vi.

Radiation

vii.

Chemical irritation

viii.

Inflammation

ix.

Hypoxia

x.

Infection

10.

ANTITHROMBOSIS DRUGS & STRATEGIES Note: all antithrombotic increase risk of bleeding / haemorrhage A. Anticoagulants: i. B.

Anti-platelet drugs: i.

C.

Inhibit amplification by restricting platelet thrombin production Fibrinolytics (thrombolytics)

i.

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Inhibit initiation by limiting small scale production of thrombin

Promotes degradation of fibrin strands – “clot buster”

COAGULATION PATHWAY

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i.

Tissue damage or contact with external bodies sets off signalling and enzyme cascade

ii.

End result is conversion of prothrombin to thrombin (factor IIa)

12.

ANTICOAGULANTS - WARFARIN Warfarin is the most used anticoagulant (UK): “Vitamin K antagonist”.

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i.

Inhibits VKORC1 enzyme, blocks production of active form of Vit K

ii.

Gene polymorphisms – wide variations in effectiveness

iii.

Side effects: haemorrhage, teratogen, hepatotoxicity, soft tissue necrosis

iv.

Low therapeutic index: requires heavy monitoring

13.

OTHER ANTICOAGULANTS To get started right away, just tap any placeholder text (such as this) and start typing. A. Heparin: Useful in acute situations; injection only. Activates the thrombin inhibiting enzyme antithrombin III B. Hirudins: (e.g. Lepirudin, Bivalirudin) thrombin inhibitors; injection only C. Dabigatran: thrombin inhibitor, orally active. Increasingly popular D. Rivaroxaban, Apixaban: factor Xa inhibitors, orally active

14.

ANTI-PLATELET DRUGS: P2Y & PAR A. Giα GPCR activation by ADP and thrombin B. Release of Ca2+ from internal stores C. Ca2+ triggers release of procoagulative molecules from granules (e.g. ADP)

15.

ANTIPLATELET DRUGS – P2Y ANTAGONITS To get started right away, just tap any placeholder text (such as this) and start typing. A. Clopidogrel – pro-drug; irreversible Side effects: dyspepsia, rash, diarrhoea B.

Prasugrel – irreversible Side effects: rash, hypersensitivity, angioedema

C.

Ticagrelor – reversible Side effects: dyspnea, GI disturbances

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16.

ANTIPLATELET DRUGS – PAR ANTAGONISTS PAR = Protease Activated Receptor A. Vorapaxar: Licensed by FDA in USA (2014) B. Side effects of easy bleeding, bruising, hypersensitivity, GL disturbances C. Others (e.g. atopaxar) in clinical trials.

17.

ANTI-PLATELET DRUGS: TXA 2 & GPIIB To get started right away, just tap any placeholder text (such as this) and start typing. A. Arachidonic acid (AA) produced downstream of PAR activation B. AA converted to thromboxane A2 (TXA2) by cyclooxygenase C. TXA2 activates glycoprotein IIb (GPIIb) receptor D. GPIIb & GPIIIa combine to form fibrinogen-binding complex

18.

ANTI-PLATELET DRUGS: TXA 2 & GPIIB A. Aspirin: Cyclooxygenase inhibitor (COX-1 in platelets) i. B.

Aspirin resistance; GI side effects very rare due to low dose. Often administered with other drugs e.g. clopidogrel. Abciximab: GPIIb receptor inhibitor

i.

Antibody used during or after coronary surgery; side effects of immunogenicity

C. Also, eptifibatide, tirofiban: peptides, not available orally.

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SUMMARY: ANTI-PLATELET DRUGS

20.

FIBRINOLYTICS (THROMBOLYTICS)

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i.

Fibrinolytic pathway also initiated with coagulation system

ii.

Plasminogen activated to protease plasmin, which degrades fibrin

iii.

Coagulation v. fibrinolysis controlled by competing signalling

21.

FIBRINOLYTICS A. Streptokinase: i.

Bacterial plasminogen-activating enzyme

ii.

Acute thrombotic / embolic events such as deep vein thrombosis; post-MI

B. Recombinant tPA:

22.

i.

Alteplase (some others e.g. duoplase)

ii.

Only recommended stroke medication; also, other acute thrombotic / embolic events, post-MI

iii.

All fibrinolytics administered IV, usually in acute cases for occluded arteries. Haemorrhage due to fibrinolytics can be treated with tranexamic acid

STROKE A. Complex and frequently devastating cerebrovascular disorder B. Loss of blood flow to brain (ischaemia) caused by thrombosis / embolism (~85%), cardiac arrest; haemorrhage (~15%). C. Major cause of physical and mental impairment worldwide:

23.

i.

Most common cause of disability

ii.

2nd most common cause of dementia

iii.

2nd most common cause of death (WHO)

TREATMENT SUMMARY

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HYPERLIPIDAEMIA A. Abnormally high levels of lipids & lipoproteins (generally, or specific) in the blood B. Cholesterol C. Lipids circulate in the blood as lipoproteins i.

Chylomicrons

ii.

High density lipoprotein (HDL)

iii.

Low density lipoprotein (LDL)

25.

LIPOPROTEINS Bundles of lipids and proteins – “cargo crates” for lipids

26.

ATHEROSCLEROSIS Oxidised LDL cholesterol ↑ = atheroma formation in arteries A. Atherogenic cholesterol from LDL B. Normally, HDL is able to mop up cholesterol C. Causes inflammatory response and cell necrosis D. Clot forms over damaged artery = atherosclerosis

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