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Haemostasis & Vascular Pathology Flashcards

1
Q

Define haemostasis.

A

Precisely orchestrated series of regulatory processes that culminate in the formation of a blood clot that limits bleeding from an injured vessel

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2
Q

Why does haemostasis occur in the body?

A

So blood is in fluid state in normal vessels

To form a localised haemostatic clot at sites of vascular injury

To prevent haemorrhage

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3
Q

What are the 3 components of haemostasis?

A
  1. Vascular wall
  2. Platelets
  3. Coagulation/clotting cascade
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4
Q

What are the 3 layers of the blood vessel and what is present in each layer?

A
  1. Intima: endothelium, basement membrane, connective tissue + internal elastic lamina
  2. Media: circumferentially arranged smooth muscle
  3. Adventitia (subendothelium): connective tissue containing vascular + neural supply
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5
Q

Do all blood vessel types have the same layers with the same composition of tissue?

A

No, different vessel types contain differing amounts of these layers if present at all

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6
Q

What is the role of endothelium?

A

Normal endothelial cells are antiplatelet, anticoagulant + fibrinolytic

Act as a barrier between thrombogenic subendothelium + coagulation factors in blood

Express factors which prevent thrombosis in undamaged vessels + limit clot formation to site of vascular injury

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7
Q

What are the roles of platelets?

A

Form initial haemostatic plug

Provide surface for recruitment + concentration of coagulation factors

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8
Q

What are the 3 stages in which platelets carry out their function?

A
  1. Adhesion to ECM at site of vascular injury
  2. Activation by secretion of granules
  3. Aggregation of platelets
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9
Q

What are the 4 steps of haemostasis?

A
  1. Arterial vasoconstriction
  2. Primary haemostasis
  3. Secondary haemostasis
  4. Clot stabilisation + resorption
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10
Q

Explain what occurs in step 1 of haemostasis.

A

Arterial vasoconstriction mediated by reflex neurogenic mechanisms + release of endothelin to:

  • Minimise blood loss
  • Maximise interaction between platelets, clotting factors + vessel wall
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11
Q

What releases endothelin?

A

Endothelial cells adjacent to site of injury

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12
Q

Explain what occurs in step 2 of haemostasis.

A

AKA primary haemostasis

Damage to vessel wall exposes subendothelial vWF + collagen causing platelet binding + activation

Platelets change shape to promote platelet-platelet interactions + release secretory granules causing further platelet recruitment/aggregation -> formation of platelet plug

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13
Q

Explain what occurs in step 3 of haemostasis.

A

AKA secondary haemostasis

Damage to vessel wall exposes TF on subendothelial cells (SMCs + fibroblasts) -> TF binds + activates factor VII instigating the coagulation/clotting cascade

Thrombin generated which cleaves fibrinogen -> fibrin (insoluble) -> fibrin meshwork formed around primary platelet plug reinforcing it

Fibrin also binds more platelets + consolidates initial platelet plug

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14
Q

What is the coagulation/clotting cascade? What is its role?

A

A cascade involving proteolytic cleavage of pro-enzymes to activate enzymes (proteins involved called coagulation/clotting factors)

Amplification system: allows formation of clot from activation of very small amounts of initial factor

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15
Q

What are the 4 categories of molecules the coagulation/clotting cascade requires?

A
  1. Coagulation factors (pro-enzymes) -> activated coagulation factors (enzymes) e.g. factors XII, XI, IX, X, VII + prothrombin
  2. Cofactors (reaction accelerators) e.g. factor V + VIII
  3. Ca2+ ions
  4. Vitamin K (factors VII, IX, X + prothrombin dependent on this for correct production)
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16
Q

What is the ultimate goal of the coagulation/clotting cascade?

A

To produce thrombin which converts fibrinogen to fibrin stabilising the clot

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17
Q

What are the 2 pathways of the coagulation/clotting cascade?

A
  1. Extrinsic
  2. Intrinsic

Both lead to final common pathway

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18
Q

What occurs in the extrinsic pathway of the coagulation/clotting cascade?

A

Initiated by TF -> activates FVII -> FVIIa-Ca2+ complex formed -> complex activates FX + FIX -> final common pathway

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19
Q

What measures the extrinsic pathway of the coagulation/clotting cascade?

A

Prothrombin time assay: TF, phospholipids + Ca2+ added to plasma + time taken for fibrin clot to form recorded

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20
Q

What occurs in the intrinsic pathway of the coagulation/clotting cascade?

A

Initiated by FXII coming into contact with negatively charged surface e.g. activated platelet -> FXII activated to FXIIa -> converts FXI to FXIa -> converts FVIII to FVIIIa -> FIXa, FVIIIa + Ca2+ form complex to activate FX -> downstream products include FXa + thrombin amplify process -> final common pathway

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21
Q

What measures the intrinsic pathway of the coagulation/clotting cascade?

A

Partial Thromboplastin Time (PTT) assay: clotting initiated by adding negatively charged particle e.g. ground glass to activate factor XII - time for fibrin clot to form is recorded.

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22
Q

What occurs in the final common pathway of the coagulation/clotting cascade?

A

FXa, FVa + Ca2+ form prothrobinase complex -> activates prothrombin + converts it to thrombin -> converts fibrinogen (soluble plasma protein) -> fibrin (small monomers) -> fibrin polymerises to form long fibres to form a insoluble network around primary platelet plug -> clot further stabilised by FXIIIa which forms stronger cross-links between fibrin polymers

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23
Q

What are the actions of thrombin?

A
  • Converts fibrinogen to fibrin
  • Amplifies coagulation upstream products by activation FXI, FV + FVIII
  • Stabilises secondary haemostatic plug by activating FXIII
  • Further platelet activation
  • Proinflammatory effects (tissue repair + angiogenesis)
  • Anticoagulant effects (limits clot to site of injury when interacting with normal endothelium)
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24
Q

What is the problem with the Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) assays?

A

Useful for evaluation coagulation factor function but do not accurately represent the events in vivo as in vivo, the 2 separate pathways of the coagulation cascade are closely linked

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25
What happens in coagulation (in vivo)?
Initially TF forms complex with FVIIa -> activates FIX + FX Activated platelet membrane catalyses prothrombin conversion to thrombin by FXa on its own -> thrombin activates FV, FVIII + FXI -> FIXa forms complex with FVIIIa + Ca2+ on surface of activated platelets -> potent activator of FX (more than TF-FVIIa complex) FXa forms complex with FVa + Ca2+ -> potent at converting prothrombin to thrombin (more than FXa alone) = lots more thrombin produced
26
Coagulation must be restricted to injury site so it must be controlled. What factors limit coagulation?
- Dilution - Need for negatively charged surface (via activated platelets) - Anticoagulation factors expressed by intact endothelium - Circulating inhibitors e.g. antithrombin III (augmented by heparin-like molecules on intact endothelium) -> inhibit thrombin, FIXa, FXa, FXIa + FXIIa - Fibrinolytic cascade
27
How does heparin affect coagulation?
Binds reversibly to anti-thrombin III + enhances inactivation of thrombin + FXa (unfractionated heparin) OR primarily inactivates FXa (LMWH) Inhibits thrombosis (low dose) + prevents progression of existing clots (higher dose) so used in prophylaxis + treatment of VTE
28
How does warfarin affect coagulation?
Affects metabolism of vitamin K but inhibiting synthesis of vitamin-K dependent coagulation factors (FVII, IX, X + prothrombin) Used for prophylaxis + treatment of VTE + prevention of ischaemic stroke in AF
29
How do New Oral Anticoagulants (NOACs) affect coagulation?
Competitively + reversibly inhibits thrombin E.G. Dabigatran
30
Explain what occurs in step 4 of haemostasis.
AKA clot stabilisation + resorption Fibrin + platelet aggregates undergo contraction to form a permanent plug Counterregulatory mechanisms limit clotting to site of injury Clot reabsorption+ tissue repair Involves fibrinolytic system
31
What happens in the fibrinolytic system?
Inactive circulating plasminogen converted to plasmin by either FXII-dependent pathway or plasminogen activates (e.g. t-PA released by ECs adjacent to site of injury) Plasmin breaks down fibrin -> limits size of clot + contributes to later dissolution
32
What can be used a marker for hypercoagulability?
D-dimers as they are degradation products of fibrin detectable in the blood
33
Define haemorrhage.
Extravasation of blood into extravascular space (tissues, body cavities or out of body)
34
What 4 factors affect the clinical significance of a haemorrhage?
1. Volume of blood lost: significant ability to compensate 2. Rate blood is lost: compensation can occur if over a long period of time 3. Medical fitness pre blood loss 4. Site of bleeding e.g. small volumes in intra-cranial bleeds significant
35
What is thrombosis?
A pathological process where there is formation of a solid mass of blood products in a vessel lumen (thrombus) -> can lead to vascular occlusion, ischaemia + infarction
36
What is Virchow's Triad?
Factors which predispose to thrombosis Includes: - Endothelial injury - Abnormal blood flow - Hypercoagulability
37
What factor is the most important in Virchow's Triad?
Endothelial injury
38
How can abnormal blood flow occur?
Static blood e.g. in DVT Turbulent blood e.g. in AF Directly or indirectly via endothelial injury
39
How can hypercoagulability occur?
Abnormalities of balance of procoagulants + anticoagulants -> can tip balance towards thrombosis
40
What are the causes of endothelial injury?
Hypertension Smoking Turbulent blood flow Bacterial endotoxins
41
What is endothelial injury?
Physical endothelial damage or endothelial cell dysfunction promote thrombi rich in platelets (treated with antiplatelet drugs e.g. aspirin) via gene expression Main cause of arterial or intracardiac thrombi because high rates of blood flow impede normal clot formation
42
What is relative stasis of blood?
Slow flowing blood in veins e.g. DVT Loss of lamina low Endothelial dysfunction
43
What is turbulent blood flow?
Endothelial injury/dysfunction Creation of eddy currents with focal stasis + loss of lamina flow Occurs in arterial vessels + heart e.g. AF
44
What are the 2 ways in which a patient can acquire hypercoagulability?
1. Inherited disorders e.g. abnormalities in FV or prothrombin genes 2. Acquired disorders e.g. dehydration, disseminated carcinoma, postoperatively, heparin-induced thrombocytopenia syndrome, anti-phospholipid Ab syndrome etc.
45
What are the clinical consequences of thrombi?
Obstruction to blood flow - venous (congestion + oedema) or arterial (ischaemia + infarction of tissues) Embolism + infarction to distal tissues
46
List the 4 fates of thrombi.
1. Propagation 2. Embolisation 3. Resolution/dissolution 4. Organisation
47
What is thrombi propagation?
Enlargement + growth along vessel due to further platelet + fibrin deposition -> can lead to vascular occlusion/embolism
48
What is thrombi embolization?
Detachment of part/all of thrombus from one site of origin to lodge at a distant site (thromboembolism) -> can cause occlusion + infarction
49
What is thrombi resolution/dissolution?
Fibrinolysis + autolytic degeneration of cellular components of thrombus -> restoration of blood flow
50
What is thrombi organisation?
Ingrowth of granulation tissue + fibrous repair -> recanalization (new channel forms in organising thrombus)
51
Define embolism.
A detached intravascular solid, liquid or gas that is carried by the blood to a site distant from its point of origin
52
How can embolisms be classified?
Site: pulmonary vs systemic Material embolising: dislodged thrombus (thromboembolism), fat (e.g. via fractures, massive soft tissue injury or orthopaedic procedures), air/N2 (e.g. decompression sickness) or amniotic fluid (rare complication of delivery) Assume it is a thromboembolism unless otherwise specified
53
What is the most common type of embolism?
Thromboembolism
54
What is an arterial thrombosis?
Usually due to rupture of plaque of atheroma -> endothelial injury + turbulent flow (source of emboli too) Occludes blood supply -> ischaemic necrosis (infarction) E.G. thrombosis in coronary artery -> MI
55
What are common sites of an arterial thromboembolism?
Heart (left ventricle/atrium commonly): ventricular thrombus 2ndary to MI, AF or infected heart valve Arterials vessels: atheromatous plaque or aortic aneurysms
56
What do the effects of an arterial thromboembolism depend upon?
Size of embolism | Vessel affected
57
What are common embolization sites of an arterial thromboembolism i.e. places that clot may move too?
- Lower extremities -> limb ischaemia - CNS -> stroke - Intestines -> bowel ischaemia - Kidney/spleen -> may be relatively asymptomatic
58
What is a Deep Vein Thrombosis (DVT)?
Venous thrombus forming in deep veins of leg or pelvis (iliac veins)
59
What do venous thrombosis tend to be associated with?
Stasis + hypercoagulable states for example: - Bed rest/immobilisation (reduced muscle action + slow venous return causing stasis) - Pregnancy (stasis due to enlarging uterus + hypercoagulability) - Post-surgical (stasis due to immobilisation, vascular injury + procoagulant factor release) ETC...
60
What are the symptoms of venous thrombosis?
Asymptomatic in 50% of cases Swelling, pain, tenderness, erythema + increased temperature
61
What is a Pulmonary (thrombo) Embolism (PE)?
Due to embolism from DVT (VTE often used to cover both conditions as closely linked) Embolism goes from DVT -> right side of heart -> pulmonary circulation
62
What are the typical effects of a Pulmonary (thrombo) Embolism (PE)?
Effects depend on size Asymptomatic - multiple tiny emboli over long period -> pulmonary hypertension Occlusion of small/medium pulmonary vessels -> respiratory/cardiac symptoms + tissue infarction (SOB, pleuritic chest pain, cough + haemoptysis, tachycardia, tachypnoea, hypoxia etc.) Massive PE affecting major pulmonary arteries (saddle embolus) -> sudden death
63
Define infarction.
Area of ischaemic necrosis caused by inadequate blood supply
64
What are the causes of infarction?
MI Cerebral infarction Bowel infarction Ischaemic necrosis of distal extremities (gangrene) Other e.g. vasospasm, expansion of atheroma due to intraplaque haemorrhage, dissection aortic aneurysm, extrinsic compression of vessel (tumour), oedema within confined space (compartment syndrome) or vessel twisting (testicular torsion)
65
When can an infarction be caused as a result of a venous thrombosis?
Most commonly causes congestion as bypass channels typically open rapidly to restore outflow however, infarction secondary to venous thrombosis can occur if there is only 1 efferent vein e.g. testis or ovary
66
Define ischaemia.
Inadequate flow of blood to part of body caused by constriction or blockage of the blood vessels supplying it

Block 2 (45 decks)

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