Clotting Flashcards
Mechanisms of haemostasis
Vascular spasm
Platelet plug
Clot formation
Pathways of clotting cascade
Intrinsic pathway (contact activation) Extrinsic pathway (tissue factor) Common pathway
Activation of intrinsic pathway
Damage to vessel wall
Negatively charged collagen exposed from damaged endothelium
Activates factor XII
Intrinsic pathway
XIIa: XI –> XIa
XIa: IX –> IXa
VIII circulates in complex with vWF. Thrombin (IIa) = VIIIa + vWF
IXa + VIIIa = enzyme complex: X –> Xa
Activation of extrinsic pathway
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
Factor Xa
Produced in final step of both intrinsic and extrinsic pathways.
Xa + Va = prothrombinase complex: Converts prothrombin (II) to thrombin (IIa)
Thrombin
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
Fibrin
Forms long strands of insoluble protein that are bound to platelets
Factor XIII completes cross-linking of Fibrin to form mesh and complete clot
Von Willibrand Factor
Stabilises XIII to stabilise fibrin clot
Steps of platelet plug formation
Platelet activation
Platelet adhesion
Platelet aggregation
Platelet activation
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)
Platelet adhesion
vWF and fibrinogen act as anchors for platelets to adhere to vessel wall
Glycoprotein Ib + vWF allows platelet to bind to vessel wall.
Platelet aggregation
Mediated by vWF, fibrinogen and B3 integrin.
Thrombin triggers binding of adhesive platelets with vWF and fibrinogen.
Regulate/inhibit clotting cascade
Protein C + S
Tissue factor pathway inhibitor (TFPI)
C1 esterase inhibitor
Antithrombin
Protein C
Thrombomodulin is endothelial membrane protein
Thrombin + thrombomodulin: activates protein C
Cofactor: Protein S
inhibits V and VIII activation
Tissue factor pathway inhibitor (TFPI)
Circulates in plasma
Directly inhibits Xa
Inhibits activation of VII
C1 esterase inhibitor
Inhibits factor XIIa and XIa
Antithrombin
Inhibits X activation and Thrombin
Fibrinolysis
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
Liver dependent clotting factors
I, II, V, VII, VIII, IX, X, XIII
Vitamin K dependent clotting factors
II, VII, IX, X
Protein C/S/Z
Heamophilia A
Factor VIII deficiency
X-linked recessive
Haemophilia B
Factor IX deficiency
X-linked recessive
von Willibrand Disease
vWF deficiency (Excess VIII broken down, clots aren't stabilised) Autosomal dominant
Disseminated Intravascular Coagulation (DIC) - pathophysiology
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.
DIC - Symptoms
Bleeding from unrelated sites Confusion Fever ARDS Petechial/purpuric rash --> skin necrosis
DIC - investigations
Prolonged PT & APTT
Low fibrinogen
Raised D-Dimer
Low platelets
DIC causes
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
DIC - treatment
Treat underlying condition
FFP + TXA if active bleeding
Unfractionated heparin infusion/LMWH
Recombinant human activated protein C
PT - prothrombin time/INR
Measure of extrinsic pathway
Causes of raised PT/INR: Warfarin, liver disease, DIC, deficiency of II/V/VII or X
APTT - activated partial thromboplastin time
Measure of intrinsic pathway
Causes of raised APTT: haemophilia A/B, vWF disease, deficiency of II/V/VII/IX/X/XII, liver disease, warfarin
Warfarin
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
Heparin
Binds to enzyme inactivator antithrombin III increasing inactivation of Xa and thrombin
Can lead to heparin induced thrombocytopenia
Novel oral anti-coagulants
Apixaban/rivaroxaban: Direct Xa inhibitor
Dabigatran: direct thrombin inhibitor
