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Block 2 > Haemostasis & Vascular Pathology > Flashcards

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
Q

What happens in coagulation (in vivo)?

A

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

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26
Q

Coagulation must be restricted to injury site so it must be controlled. What factors limit coagulation?

A
  • 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
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27
Q

How does heparin affect coagulation?

A

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
Q

How does warfarin affect coagulation?

A

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
Q

How do New Oral Anticoagulants (NOACs) affect coagulation?

A

Competitively + reversibly inhibits thrombin

E.G. Dabigatran

30
Q

Explain what occurs in step 4 of haemostasis.

A

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
Q

What happens in the fibrinolytic system?

A

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
Q

What can be used a marker for hypercoagulability?

A

D-dimers as they are degradation products of fibrin detectable in the blood

33
Q

Define haemorrhage.

A

Extravasation of blood into extravascular space (tissues, body cavities or out of body)

34
Q

What 4 factors affect the clinical significance of a haemorrhage?

A
  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
Q

What is thrombosis?

A

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
Q

What is Virchow’s Triad?

A

Factors which predispose to thrombosis

Includes:

  • Endothelial injury
  • Abnormal blood flow
  • Hypercoagulability
37
Q

What factor is the most important in Virchow’s Triad?

A

Endothelial injury

38
Q

How can abnormal blood flow occur?

A

Static blood e.g. in DVT

Turbulent blood e.g. in AF

Directly or indirectly via endothelial injury

39
Q

How can hypercoagulability occur?

A

Abnormalities of balance of procoagulants + anticoagulants -> can tip balance towards thrombosis

40
Q

What are the causes of endothelial injury?

A

Hypertension
Smoking
Turbulent blood flow
Bacterial endotoxins

41
Q

What is endothelial injury?

A

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
Q

What is relative stasis of blood?

A

Slow flowing blood in veins e.g. DVT

Loss of lamina low

Endothelial dysfunction

43
Q

What is turbulent blood flow?

A

Endothelial injury/dysfunction

Creation of eddy currents with focal stasis + loss of lamina flow

Occurs in arterial vessels + heart e.g. AF

44
Q

What are the 2 ways in which a patient can acquire hypercoagulability?

A
  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
Q

What are the clinical consequences of thrombi?

A

Obstruction to blood flow - venous (congestion + oedema) or arterial (ischaemia + infarction of tissues)

Embolism + infarction to distal tissues

46
Q

List the 4 fates of thrombi.

A
  1. Propagation
  2. Embolisation
  3. Resolution/dissolution
  4. Organisation
47
Q

What is thrombi propagation?

A

Enlargement + growth along vessel due to further platelet + fibrin deposition -> can lead to vascular occlusion/embolism

48
Q

What is thrombi embolization?

A

Detachment of part/all of thrombus from one site of origin to lodge at a distant site (thromboembolism) -> can cause occlusion + infarction

49
Q

What is thrombi resolution/dissolution?

A

Fibrinolysis + autolytic degeneration of cellular components of thrombus -> restoration of blood flow

50
Q

What is thrombi organisation?

A

Ingrowth of granulation tissue + fibrous repair -> recanalization (new channel forms in organising thrombus)

51
Q

Define embolism.

A

A detached intravascular solid, liquid or gas that is carried by the blood to a site distant from its point of origin

52
Q

How can embolisms be classified?

A

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
Q

What is the most common type of embolism?

A

Thromboembolism

54
Q

What is an arterial thrombosis?

A

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
Q

What are common sites of an arterial thromboembolism?

A

Heart (left ventricle/atrium commonly): ventricular thrombus 2ndary to MI, AF or infected heart valve

Arterials vessels: atheromatous plaque or aortic aneurysms

56
Q

What do the effects of an arterial thromboembolism depend upon?

A

Size of embolism

Vessel affected

57
Q

What are common embolization sites of an arterial thromboembolism i.e. places that clot may move too?

A
  • Lower extremities -> limb ischaemia
  • CNS -> stroke
  • Intestines -> bowel ischaemia
  • Kidney/spleen -> may be relatively asymptomatic
58
Q

What is a Deep Vein Thrombosis (DVT)?

A

Venous thrombus forming in deep veins of leg or pelvis (iliac veins)

59
Q

What do venous thrombosis tend to be associated with?

A

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
Q

What are the symptoms of venous thrombosis?

A

Asymptomatic in 50% of cases

Swelling, pain, tenderness, erythema + increased temperature

61
Q

What is a Pulmonary (thrombo) Embolism (PE)?

A

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
Q

What are the typical effects of a Pulmonary (thrombo) Embolism (PE)?

A

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
Q

Define infarction.

A

Area of ischaemic necrosis caused by inadequate blood supply

64
Q

What are the causes of infarction?

A

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
Q

When can an infarction be caused as a result of a venous thrombosis?

A

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
Q

Define ischaemia.

A

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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