Clotting

Question 1

Mechanisms of haemostasis

Answer 1

Vascular spasm
Platelet plug
Clot formation

Question 2

Pathways of clotting cascade

Answer 2

Intrinsic pathway (contact activation)
Extrinsic pathway (tissue factor)
Common pathway

Question 3

Activation of intrinsic pathway

Answer 3

Damage to vessel wall
Negatively charged collagen exposed from damaged endothelium
Activates factor XII

Question 4

Intrinsic pathway

Answer 4

XIIa: XI –> XIa
XIa: IX –> IXa

VIII circulates in complex with vWF. Thrombin (IIa) = VIIIa + vWF

IXa + VIIIa = enzyme complex: X –> Xa

Question 5

Activation of extrinsic pathway

Answer 5

Damage to blood vessel
Tissue factor (Factor III) is released into circulation. VII exits circulation into tissues
III + VII = TF-VIIa complex
TF-VIIa complex activates X

Question 6

Factor Xa

Answer 6

Produced in final step of both intrinsic and extrinsic pathways.
Xa + Va = prothrombinase complex: Converts prothrombin (II) to thrombin (IIa)

Question 7

Thrombin

Answer 7

Produced by Factor Xa from prothrombin
Converts soluble fibrinogen (Factor I) into insoluble fibrin strand.
Activates V and VIII to generate additional Xa
Activates XIII to stabilise fibrin strands
Negative feedback: works with thrombomodulin to activate protein C

Question 8

Fibrin

Answer 8

Forms long strands of insoluble protein that are bound to platelets
Factor XIII completes cross-linking of Fibrin to form mesh and complete clot

Question 9

Von Willibrand Factor

Answer 9

Stabilises XIII to stabilise fibrin clot

Question 10

Steps of platelet plug formation

Answer 10

Platelet activation
Platelet adhesion
Platelet aggregation

Question 11

Platelet activation

Answer 11

Platelets bind to exposed collagen on damaged tissues.
Additional activation by thrombin.
Platelets will degranulate (releasing: serotonin, ATP, platelet-derived growth factor, fibrinogen, vWF).
Change in shape to increase surface area (covers more exposed issue and increased space of additional platelet binding)

Question 12

Platelet adhesion

Answer 12

vWF and fibrinogen act as anchors for platelets to adhere to vessel wall
Glycoprotein Ib + vWF allows platelet to bind to vessel wall.

Question 13

Platelet aggregation

Answer 13

Mediated by vWF, fibrinogen and B3 integrin.

Thrombin triggers binding of adhesive platelets with vWF and fibrinogen.

Question 14

Regulate/inhibit clotting cascade

Answer 14

Protein C + S
Tissue factor pathway inhibitor (TFPI)
C1 esterase inhibitor
Antithrombin

Question 15

Protein C

Answer 15

Thrombomodulin is endothelial membrane protein
Thrombin + thrombomodulin: activates protein C
Cofactor: Protein S
inhibits V and VIII activation

Question 16

Tissue factor pathway inhibitor (TFPI)

Answer 16

Circulates in plasma
Directly inhibits Xa
Inhibits activation of VII

Question 17

C1 esterase inhibitor

Answer 17

Inhibits factor XIIa and XIa

Question 18

Antithrombin

Answer 18

Inhibits X activation and Thrombin

Question 19

Fibrinolysis

Answer 19

tPAs (tissue plasminogen activators) released slowly by endothelial cells
Plasminogen + tPAs = plasmin
Plasmin breaks down fibrin to fibrin degradation products (incl. d-dimer)

Thrombin actives: Thrombin activatable fibrinolysis inhibitor (TAFI), which inhibits plasmin.
Activated platelets release Plasmin activator inhibitor (PAI1) inhibits tPA and aplha2-antiplasmin, which inhibits plasmin

TXA inhibits tPA/plasminogen producing less plasmin
Alteplase is synthetic form of tPA

Question 20

Liver dependent clotting factors

Answer 20

I, II, V, VII, VIII, IX, X, XIII

Question 21

Vitamin K dependent clotting factors

Answer 21

II, VII, IX, X

Protein C/S/Z

Question 22

Heamophilia A

Answer 22

Factor VIII deficiency

X-linked recessive

Question 23

Haemophilia B

Answer 23

Factor IX deficiency

X-linked recessive

Question 24

von Willibrand Disease

Answer 24

vWF deficiency
(Excess VIII broken down, clots aren't stabilised)
Autosomal dominant

Question 25

Disseminated Intravascular Coagulation (DIC) - pathophysiology

Answer 25

Dysregulation of coagulation vs fibrinolysis. Large release of Tissue factor initiates activation of coagulation cascade. Thrombin activates fibrinogen to fibrin creating widespread microvascular and macrovascular thrombosis. Coagulation cascade proteins depleted, including inhibitor proteins creating more clotting. Fibrinolysis of clots creates large amounts of fibrin in circulation, further interferes with platelet aggregation/clot formation. Fibrin breakdown to FDP increases anti thrombosis and results in bleeding.

Question 26

DIC - Symptoms

Answer 26

``` Bleeding from unrelated sites Confusion Fever ARDS Petechial/purpuric rash --> skin necrosis ```

Question 27

DIC - investigations

Answer 27

Prolonged PT & APTT Low fibrinogen Raised D-Dimer Low platelets

Question 28

DIC causes

Answer 28

V: aortic aneurysm I: sepsis (E coli 0157) T: any massive tissue injury: trauma/burns/rhabdo/surgery A: allergic reaction, ABO incompatibility M: I: N: leukaemia, solid tumours, haemangiomas C: Pregnancy: placental abruption, pre-eclampsia/eclampsia, amniotic fluid embolus, post-partum haemorrhage

Question 29

DIC - treatment

Answer 29

Treat underlying condition FFP + TXA if active bleeding Unfractionated heparin infusion/LMWH Recombinant human activated protein C

Question 30

PT - prothrombin time/INR

Answer 30

Measure of extrinsic pathway | Causes of raised PT/INR: Warfarin, liver disease, DIC, deficiency of II/V/VII or X

Question 31

APTT - activated partial thromboplastin time

Answer 31

Measure of intrinsic pathway | Causes of raised APTT: haemophilia A/B, vWF disease, deficiency of II/V/VII/IX/X/XII, liver disease, warfarin

Question 32

Warfarin

Answer 32

MoA: inhibits vitamin K epoxide reductase inhibits production of: II/VII/IX/X and Protein C/S/Z Initial paradoxical increase in coagulability as antithrombotic protein production decreases. Reversed by Vit K/prothrombin complex concentrate

Question 33

Heparin

Answer 33

Binds to enzyme inactivator antithrombin III increasing inactivation of Xa and thrombin Can lead to heparin induced thrombocytopenia

Question 34

Novel oral anti-coagulants

Answer 34

Apixaban/rivaroxaban: Direct Xa inhibitor | Dabigatran: direct thrombin inhibitor