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Year 1 - PoM > 3.9 - Haemostasis > Flashcards

3.9 - Haemostasis Flashcards

1
Q

What is haemostasis?

A
  • haemostasis describes the ‘halting of blood’ following trauma to blood vessels
  • haemostasis results from three intertwined processes: vasoconstriction, primary haemostasis, secondary haemostasis/coagulation
  • important to understand haemostatic mechanisms in order to: diagnose and treat bleeding disorders, identify risk factors for thrombosis, treat thrombotic disorders, monitor drugs used to treat bleeding and thrombotic disorders, control bleeding
  • overview of response to injury: vasoconstriction –> formation of unstable platelet plug (platelet adhesion and aggregation, primary haemostasis) –> stabilisation of plug with fibrin (coagulation, secondary haemostasis) –> dissolution of clot and vessel repair (fibrinolysis)
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2
Q

Primary haemostasis overview

A
  1. endothelial injury
  2. exposure
  3. adhesion
  4. activation
  5. aggregation
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3
Q

Primary haemostasis - endothelial injury

A
  • nerves attached to endothelial cells and smooth muscle cells detect injury
  • they trigger reflexive contraction of smooth muscles near the injury site - vascular spasm
  • vascular spasm narrows vessels –> vasoconstriction
  • vasoconstriction reduces blood flow, and therefore reduces blood loss
  • endothelial cells usually secrete nitric oxide and prostaglandins, causing nearby smooth muscle to relax
  • endothelial injury causes reduced secretion of NO and prostaglandins, and instead endothelin is secreted, causing smooth muscle to contract
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4
Q

Primary haemostasis - exposure

A
  • damage to endothelial cells exposes the collagen below
  • damaged endothelial cells release a protein called Von Willebrand’s Factor, that binds to exposed collagen
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5
Q

Primary haemostasis - adhesion

A
  • platelets are discoid, non-nucleated, granule-containing cells, derived from myeloid stem cells
  • they are formed in the bone marrow by the fragmentation of megakaryocyte cytoplasm
  • platelets circulate and come into contact with VWF bound to collagen –> platelets have a surface protein called GPIb that allows them to bind to the VWF proteins (indirect)
  • or, platelets can directly bind to collagen via the platelet GPIa receptor
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6
Q

Primary haemostasis - activation

A
  • platelets bind to collagen –> platelet activated –> releases contents of storage granules (alpha granules and dense granules) through invagination of membrane forming surface tunnel network through which contents are released
  • changes shape from a disc to more rounded with spicules - membrane forms tentacle-like arms which allows it to interact with other platelets
  • release more VWF
  • releases serotonin - attracts more platelets to the area and maintains vasoconstriction
  • releases Ca2+ - involved in secondary haemostasis
  • releases ADP - helps additional platelets stick to the injury site
  • releases thromboxane A2 - when ADP and thromboxane A2 bind to platelets it expresses a new surface protein: GPIIb/IIIa = fully activated
  • snowball effect - more and more platelets activated - positive feedback loop (limited to injury site so not all platelets are used by NO and prostaglandins secreted from undamaged endothelial cells bind to platelets and prevent activation)
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7
Q

Thromboxane A2 synthesis

A
  • platelets are stimulated to produce the prostaglandin thromboxane A2 from arachidonic acid, that is derived from the cell membrane
  • ADP binds to the P2Y12 receptor
  • thromboxane A2 binds to the thromboxane A2 receptor
  • these result in further platelet recruitment, activation and aggregation
  • thromboxane A2 has a key role in linking the platelets together to form the plug
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8
Q

Primary haemostasis - aggregation

A
  • ADP + thromboxane A2 cause platelets to stick to collagen and cause free floating platelets to express GPIIb/IIIa
  • platelet activation causes a conformational change in GPIIb/IIIa = fibrinogen (circulating blood protein which links two platelets together) binds to GPIIb/IIIa receptors causing ‘outside-in’ signalling which further activates the platelets
  • each platelet has many GPIIb/IIIa receptors –> allows platelets to rapidly aggregate at site of injury –> forms platelet plug to stop bleeding
  • effects counterbalanced by active flow of blood and release of prostacyclin (PGI2) from endothelial cells - vasodilator, suppresses platelet activation = prevents inappropriate platelet aggregation
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9
Q

Anti-platelet drugs

A
  • prevention and treatment of cardiovascular and cerebrovascular disease
  • aspirin inhibits the production of thromboxane A2 by irreversibly blocking the action of cyclo-oxygenase (COX), resulting in reduction in platelet aggregation
  • prostacyclin production is also inhibited by COX, but endothelial cells can synthesise more COX whereas non-nuclear platelets cannot
  • clopidogrel - irreversibly blocks ADP receptor P2Y12 on platelet cell membrane
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10
Q

Von Willebrand Factor

A
  • glycoprotein synthesised by endothelial cells and megakaryocytes
  • circulates in plasma in different sizes of multimer
  • mediates adhesion of platelets to sites of injury
  • promotes platelet-platelet aggregation
  • specific carrier for factor VIII
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11
Q

Coagulation (secondary haemostasis)

A
  • primary platelet plug is sufficient for small vessel injury, but larger vessels would fall apart
  • fibrin formation stabilises the platelet plug
  • blood coagulation pathways centre on the generation of thrombin, which cleaves fibrinogen to generate a fibrin clot that stabilises the platelet plug at sites of vascular injury
  • enzymes circulating the blood (clotting factors) are proteolytically activated (small fragment chopped off = activated)
  • these factors activate one another eventually leading to activation of fibrin (factor Ia) –> fibrin mesh around platelet plug to reinforce and hold together
  • each step is characterised by the conversion of an inactive zymogen (proenzyme) into an active clotting factor by the splitting of one or more peptide bonds and exposure of the active enzyme site
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12
Q

Extrinsic and intrinsic pathway overview

A
  • extrinsic pathway - activated by tissue factor found outside of blood
  • intrinsic pathway - activated by factors in the blood
  • both pathways activate independently
  • this leads to the activation of factor X –> Xa
  • pathways merge into common pathway and coagulation cascade
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13
Q

Extrinsic pathway

A
  • trauma exposes the cells below the endothelial layer e.g. smooth muscle cells
  • these cells have tissue factor (factor III) in their membrane
  • factor VII is floating in the blood - some is already active (VIIa) so is set to proteolytically cleave other proteins
  • factor VIIa binds to a TF and Ca2+ –> VIIa-TF complex on surface of smooth muscle cells
  • TF and Ca2+ (released by nearby activated platelets) are cofactors - must bind to VIIa for it to function
  • VIIa-TF complex cleaves factor X –> factor Xa
  • factor Xa cleaves factor V –> factor Va
  • factor Xa uses factor Va and Ca2+ as cofactors to form the prothrombinase complex (one can activate thousands of thrombins = enormous amplification)
  • activates prothrombin (factor II) –> thrombin (factor IIa)
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14
Q

Thrombin

A
  • thrombin uses Ca2+ as a cofactor and has many procoagulative effects:
    1. thrombin binds to receptors on platelets and activates them
    2. activates three cofactors: factor V (common pathway), factor VIII, fabin - cleaves soluble fibrinogen (I) –> insoluble fibrin (Ia) - fibrin precipitates out of plasma and forms long rope-like protein chains
    3. proteolytically cleaves stabilising factor (XIII) –> XIIIa - combines with Ca2+ cofactor to form cross links between fibrin chains –> further reinforcing the fibrin mesh
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15
Q

Intrinsic pathway

A
  • circulating factor XII comes into contact with negatively charged phosphates on membranes of activated platelets or subendothelial collagen exposed by trauma
  • undergoes conformational change –> activated into factor XIIa
  • factor XIIa proteolytically cleaves factor XI –> factor XIa
  • factor XIa combines with Ca2+ –> proteolytically cleaves factor IX –> IXa
  • factor IXa forms a complex with Ca2+ and factor VIIIa –> proteolytically cleaves factor X –> factor Xa
  • (factor VIII degrades rapidly in blood unless bound to VWF)
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16
Q

Synthesis of clotting factors

A
  • most clotting factors are synthesised in the liver except factor VIII + VWF (endothelial cells, VWF also made in megakaryocytes and incorporated into platelet granules)
  • factors II (prothrombin), VII, IX and X are dependent on vitamin K for carboxylation of their glutamic acid residues (essential for functioning)
  • factors V and VIII = cofactors
  • many clotting factors work on exposed phospholipid surface of platelets = helps localise and accelerate reactions
  • Ca2+ important role in binding of activated clotting factors to phospholipid surfaces of platelets
  • tissue factor triggers coagulation - not usually exposed to blood under normal conditions, blood only encounters TF at sites of vascular injury
17
Q

Natural anticoagulants

A
  • a number of inhibitory mechanisms prevent blood from clotting completely whenever clotting is initiated by vessel injury
  • ensures coagulation is confined to the site of injury and prevents spontaneous activation of coagulation
  • most important natural anticoagulants: protein C, protein S and antithrombin
  • thrombin binds to thrombomodulin on the endothelial cell surface –> activated protein C (APC) –> inactivates factors Va and VIIIa in the presence of cofactor protein S
  • thrombin and factor Xa are inactivated by antithrombin - this action is potentiated by heparin, occurs physiologically by binding of antithrombin to endothelial cell-associated heparins
18
Q

Anticoagulant drugs

A
  • used in the prevention and treatment of thrombosis
    Heparin:
  • increases action of antithrombin leading to inactivation of factors Xa and IIa (thrombin)
  • administered intravenously / by subcutaneous injection
    Warfarin:
  • vitamin K antagonist - interferes with protein carboxylation
  • reduces synthesis of functional factors II, VII, IX and X by the liver
  • oral tablet, effects need to be monitored by regular blood testing
    Direct oral anticoagulants (DOACs):
  • directly inhibits thrombin or factor Xa (without involvement of antithrombin)
  • orally available, usually does not require monitoring
19
Q

Fibrinolysis

A
  • following haemostasis, the body has a mechanism to break down clots
  • principal fibrinolytic enzyme = plasmin
  • plasmin circulates in an inactive zymogen form - plasminogen
  • tissue plasminogen activator (t-Pa) activates plasmin when it binds with plasminogen to lysine residues on fibrin
  • fibrin breakdown leads to generation of fibrin degradation products (FDPs)
  • plasmin is not specific to fibrin - can also break down other protein components of the plasma e.g. fibrinogen and clotting factors Va and VIIIa
  • plasmin is inhibited by antiplasmin which circulates in the blood and alpha 2 microglobulin
20
Q

Thrombolytic therapy

A
  • thrombolytic agents e.g. recombinant t-Pa generate plasmin to lyse clots
  • administered intravenously to selected patients with ischaemic stroke
  • benefit is time-dependent so t-Pa needs to be given to eligible patients preferably within an hour of symptoms
  • high risk of bleeding associated with its use
  • can also be given to life threatening pulmonary emboli
21
Q

Antifibrinolytic drugs

A
  • tranexamic acid is a synthetic derivative of lysine that works by binding to plasminogen, stopping it from binding to lysine residues of fibrin
  • competitive inhibition
  • this prevents activation of plasminogen to plasmin, which would otherwise result in fibrinolysis
  • used widely to treat bleeding in trauma and surgical patients as well as in patients with inherited bleeding disorders
22
Q

Tests of coagulation - prothrombin time (PT)

A
  • measures integrity of extrinsic pathway (think T =tennis = outside)
    1. blood collected into a bottle containing sodium citrate, which chelates calcium thus preventing the blood from clotting in the bottle
    2. sample spun to produce platelet-poor plasma
    3. a source of TF and phospholipid is added to the citrated plasma sample, together with calcium to start the reaction
    4. the length of time taken for the mixture to clot is recorded
  • PT may be prolonged if there is a reduction in activity in factors VII, X, V, prothrombin or fibrinogen
23
Q

Tests of coagulation - activated partial thromboplastin time (APTT)

A
  • measures integrity of intrinsic pathway (think TT = table tennis = inside)
  • performed by contact activation of factor XII by a surface e.g. glass, or using a contact activator e.g. silica / kaolin
    1. contact activator, together with phospholipid, is added to the citrated plasma sample followed by calcium
    2. the time taken for this mixture to clot is measured
  • prolongation of APTT can be seen in a variety of situations where there is a reduction in one or more clotting factors
  • isolated prolonged APTT (normal PT) is seen in factor VIII (haemophilia A), IX (haemophilia B) or XI deficiency
24
Q

Bleeding

A
  • normal haemostasis - state of equilibrium between fibrinolytic factors + anticoagulants, and coagulation factors + platelets
  • loss of balance can lead to bleeding - can be caused by:
  • reduction in platelet number (failure of production, shortened lifespan, increased splenic pooling) / function (antiplatelet drugs, inherited causes)
  • reduction in coagulation factors - congenital or acquired
  • increased fibrinolysis - seen in DIC / administration of thrombolytic therapy
25
Q

Thrombosis

A
  • thrombosis: formation of a blood clot in an intact blood vessel (where it is not needed)
  • usually results in obstruction of blood flow with serious consequences
  • Virchow’s triad (three contributory factors to pathological clotting / thrombosis):
  • blood - dominant in venous thrombosis
  • vessel wall - dominant in arterial thrombosis
  • blood flow - complex, contributes to both thromboses

Changes in blood that increase the risk of venous thrombosis include:
- reduced levels of anticoagulant proteins (usually genetic)
- reduced fibrinolytic activity (e.g. in pregnancy)
- increased levels of clotting factors or platelets (e.g. increased factor VIII in pregnancy)
- hyperviscosity (e.g. due to polycythaemia)

26
Q

Summary of clotting factors (number - type of molecule - source - pathways)

A
  • I - fibrinogen - plasma protein - liver - common (converted to fibrin)
  • II - prothrombin - plasma protein - liver - common (converted to thrombin)
  • III - tissue factor - lipoprotein mixture - damaged cells and platelets - extrinsic
  • IV - calcium ions - inorganic ions - diet, platelets, bone matrix - entire process
  • V - proaccelerin - plasma protein - liver, platelets - extrinsic and intrinsic
  • VI
  • VII - plasma protein - liver - extrinsic
  • VIII - plasma protein factor - platelets and endothelial cells - intrinsic (deficiency = haemophilia A)
  • IX - plasma protein - liver - intrinsic (deficiency = haemophilia B)
  • X - protein - liver, extrinsic and intrinsic
  • XI - plasma protein - liver - intrinsic (deficiency = haemophilia C)
  • XII - plasma protein - liver - intrinsic
  • XIII - plasma protein - liver, platelets - stabilises fibrin and slow fibrinolysis
27
Q

A deficiency of which factor does not cause bleeding?

A

Factor XII

28
Q

What happens in the initiation stage?

A
  • TF combines with factor VIIa (and Ca2+)
  • IX –> XIa
  • X –> Xa
  • II –> IIa (small amount of thrombin generated)
29
Q

What happens in the amplification stage?

A
  • the small amount of thrombin generated:
  • cofactor V –> Va
  • cofactor VIII –> VIIIa
  • IX –> IXa
  • platelet activation
  • the factor XIa increases the activation of IX –> IXa
  • IXa in concert with VIIIa (and Ca2+) amplifies the conversion of X –> Xa
30
Q

What happens in the propagation stage?

A
  • the amplified conversion of X –> Xa causes a rapid burst in thrombin production
  • cleaves fibrinogen (I) –> fibrin (Ia) = clot formed

Year 1 - PoM (41 decks)

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