W10 Haemostasis Flashcards
Haemostasis
Protective process evolved in order to maintain a stable physiology
“An explosive reaction designed to curtail blood loss, restore vascular integrity and ultimately preserve life”
DIC
disseminated intravascular coagulation
The Horseshoe Crab
Limulus Polyphemus
‘A primitive coagulation pathway can be initiated by endotoxin’
The Haemolymph contains amebocytes:
Proteins of the coagulation system
Proteins & peptides of the immune system
Life preserving processes designed to maintain blood flow
Respond to tissue injury
Curtail blood loss
Restore vascular integrity & promote healing
Limit infection
Four Key Components
Endothelium
Coagulation
Platelets
Fibrinolysis
What makes a Blood Clot?
Fibrin mesh
Platelets
Red blood cells
Haemostasis simplified steps
Tissue injury Vasoconstriction Platelet activation Haemostatic plug Coagulation Stable clot formation Clot dissolution
Primary haemostasis:
Vasoconstriction (immediate) Platelet adhesion (within seconds) Platelet aggregation and contraction (within minutes)
Secondary haemostasis:
Activation of coagulation factors (within seconds)
Formation of fibrin (within minutes)
Fibrinolysis:
Activation of fibrinolysis (within minutes)
Lysis of the plug (within hours)
The vessel Wall
Normal Endothelium: - inhibits coagulation - prevents platelet aggregation Provides a barrier to reactive elements in the subendothelium - collagen fibronectin - tissue factor
Haemostasis at rest
triggers and cofactors separated
Von Willebrand Factor: functions
Forms a bridge between damaged vessel wall (collagen) and platelets
(primary haemostasis)
Stabilises and protects Factor VIII from rapid clearance
Loss of VWF function
results in a bleeding disorder
VWF synthesis and storage
Synthesis
Endothelial cells
Weibel Palade bodies
Megakaryocytes
Platelet a granules
Plasma VWF entirely derived from endothelial cells
Distribution of VWF
Constitutive path (95%) Regulated path (5%)
Weibel-Palade bodies (storage granules of endothelial cells)
Platelet activation
Resting Platelet
Activation
Adhesion + spreading
When a vessel wall is damaged
various signalling molecules are expressed / exposed, including tissue factor and collagen
Initiation of coagulation
The TF leads to the production of a small local amount of thrombin, which is the initiation step of the coagulation process
Adhesion
The exposed signalling molecules attract circulating platelets, which attach themselves to the exposed sub-endothelial tissue
secretion
These platelets become activated – principally through the presence of the thrombin – and release further attractant chemicals, which attract more platelets
Aggregation
These new platelets bind to the adhered platelets and themselves become activated
contraction
Through the conformational changes inherent in activation, the loose platelet plug contracts to form a dense, adherent plug
activated platelets also present a substantial area of…
of negatively-charged phospholipid membrane at the site of the injury, upon which the subsequent processes of coagulation (secondary haemostasis) can occur, if needed
Fibrin mesh
Fibrin mesh binds and stabilises platelet plug and other cells
Fibrinogen (I)
Forms clot (fibrin)
Prothrombin (II)
Its active form (IIa) activates I, V, VII, XIII, protein C, platelets
Tissue factor (III)
Co-factor of VIIa
Calcium
Required for coagulation factors to bind to phospholipid (formerly known as factor IV)
V (proaccelerin, labile factor)
Co-factor of X with which it forms the prothrombinase complex
VI
Unassigned - old name of Factor Va
VII (stable factor)
Activates IX, X
VIII (antihaemophilic factor)
Co-factor of IX with which it forms the tenase complex
IX (Christmas factor)
Activates X: forms tenase complex with factor VIII
X (Stuart-Prower factor)
Activates II: forms prothrombinase complex with factor V
XI (plasma thromboplastin antecedent)
Activates XII, IX and prekallikrein
XII (Hageman factor)
Activates prekallikrein and fibrinolysis
XIII (fibrin-stabilizing factor)
Crosslinks fibrin
von Willebrand factor
Binds to VIII, mediates platelet adhesion
FVII deficiency
FVII deficiency causes bleeding
FXII deficiency
FXII deficiency not associated with bleeding
Tissue Factor drives coagulation
TF is outside the lumen
Formation of TF-FVIIa complex
Recruitment of FX and formation of thrombin
Initiation of coagulation occurs when
occurs when sub-endothelial tissue is exposed to the circulation at a site of injury. These tissues express tissue factor at their surface, which binds to endogenous activated FVII
This complex binds
complex binds small amounts of FX and FV to the exposed endothelial surface, which produce small quantities of thrombin
The thrombin activates
activates platelets that are attracted to the site by the process, as well as other plasma-borne clotting factors
The activated factors (among them FVIII and FIX) enable the binding of ?
enable the binding of activated FX and FV to the surface of platelets whose activation has produce conformational changes in their surface membranes to expose the ‘reaction sites’ necessary for continuation of the process
the ‘thrombin burst’
This leads to the ‘thrombin burst’ that is necessary for the large-scale production of fibrin and so the development of an effective clot
coagulation phases
These three stages are called the initiation, amplification and propagation phases of coagulation
Fibrinolysis
Main function
clot limiting mechanism
repair and healing mechanism
Series of tightly regulated enzymatic steps
Feedback potentiation & inhibition
Main Key players
Plasminogen
Tissue plasminogen activator (t-PA) & urokinase (u-PA)
Plasminogen activator inhibitor -1 and -2
α2-plasmin inhibitor
Plamin formation
Plasminogen to plasmin through tPA (tissue plasminogen activator)
D dimers
D dimers are generated when cross-linked fibrin is degraded.
FDP (Fibrin degradation products)
FDP (Fibrin degradation products) are generated if non-cross linked fibrin or fibrinogen is broken down
tPA and a bacterial activator used for..
tPA and a bacterial activator, streptokinase, are
used in therapeutic thrombolysis for myocardial
infarction (Clot busters) and stroke
During thrombosis what increases/decreases
Coagulation factors + platelets increase
Fibrinolytic factors, anticoagulant proteins decrease
Chronic venous insufficiency
Atrophic changes
Hyperpigmentation
Ulceration
Infection
During bleeding what increases/decreases
Coagulation factors + platelets decrease
Fibrinolytic factors, anticoagulant proteins increase
Easy bruising
ecchymosis
Virtually all bleeding disorders and often in normals
