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X. MRCS: Physiology > Clotting > Flashcards

Clotting Flashcards

1
Q

Mechanisms of haemostasis

A

Vascular spasm
Platelet plug
Clot formation

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2
Q

Pathways of clotting cascade

A 
Intrinsic pathway (contact activation)
Extrinsic pathway (tissue factor)
Common pathway
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3
Q

Activation of intrinsic pathway

A

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

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4
Q

Intrinsic pathway

A

XIIa: XI –> XIa
XIa: IX –> IXa

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

IXa + VIIIa = enzyme complex: X –> Xa

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5
Q

Activation of extrinsic pathway

A

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

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6
Q

Factor Xa

A

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

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7
Q

Thrombin

A

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

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8
Q

Fibrin

A

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

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9
Q

Von Willibrand Factor

A

Stabilises XIII to stabilise fibrin clot

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10
Q

Steps of platelet plug formation

A

Platelet activation
Platelet adhesion
Platelet aggregation

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11
Q

Platelet activation

A

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)

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12
Q

Platelet adhesion

A

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

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13
Q

Platelet aggregation

A

Mediated by vWF, fibrinogen and B3 integrin.

Thrombin triggers binding of adhesive platelets with vWF and fibrinogen.

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14
Q

Regulate/inhibit clotting cascade

A

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

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15
Q

Protein C

A

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

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16
Q

Tissue factor pathway inhibitor (TFPI)

A

Circulates in plasma
Directly inhibits Xa
Inhibits activation of VII

17
Q

C1 esterase inhibitor

A

Inhibits factor XIIa and XIa

18
Q

Antithrombin

A

Inhibits X activation and Thrombin

19
Q

Fibrinolysis

A

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

20
Q

Liver dependent clotting factors

A

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

21
Q

Vitamin K dependent clotting factors

A

II, VII, IX, X

Protein C/S/Z

22
Q

Heamophilia A

A

Factor VIII deficiency

X-linked recessive

23
Q

Haemophilia B

A

Factor IX deficiency

X-linked recessive

24
Q

von Willibrand Disease

A 
vWF deficiency
(Excess VIII broken down, clots aren't stabilised)
Autosomal dominant
25
Q

Disseminated Intravascular Coagulation (DIC) - pathophysiology

A

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.

26
Q

DIC - Symptoms

A 
Bleeding from unrelated sites
Confusion
Fever
ARDS
Petechial/purpuric rash --> skin necrosis
27
Q

DIC - investigations

A

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

28
Q

DIC causes

A

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

29
Q

DIC - treatment

A

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

30
Q

PT - prothrombin time/INR

A

Measure of extrinsic pathway

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

31
Q

APTT - activated partial thromboplastin time

A

Measure of intrinsic pathway

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

32
Q

Warfarin

A

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

33
Q

Heparin

A

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

34
Q

Novel oral anti-coagulants

A

Apixaban/rivaroxaban: Direct Xa inhibitor

Dabigatran: direct thrombin inhibitor

X. MRCS: Physiology (4 decks)

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