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Pathology > 1.02 - Thrombosis, Embolism & Atherosclerosis > Flashcards

1.02 - Thrombosis, Embolism & Atherosclerosis Flashcards

1
Q

Define: Haemostasis

A

The balance between excessive ‘fluidity’ (haemorrhage) and excess ‘stickiness’ (clotting).
It is essential to maintain blood flow within the organisms but prevent excess blood loss at sites of injury & prevent inappropriate clot formation

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2
Q

What is thrombosis?

A

The pathological occlusion of blood vessels in response to endothelial damage, stasis, procoagulants

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3
Q

What are the key components of Haemostasis?

A 
Endothelium
Platelets
Coagulation Proteins
Coagulation Inhibitors
Fibrinolytic and antifibrinolytic pathways
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4
Q

Describe the Endothelium and how it relates to haemostasis

A

The epithelial layer within blood vessels.
Vesses usually maintain blood flow via fibrinolytic, anticoagulant effects and an environment not conducive to platelet activation or adhesions.

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5
Q

List the types of injury to vessels that can alter haemostats

A 
Trauma
Plaque rupture
Plasma mediators/cytokines (TNF, IL-1)
Haemodynamic factors (high shear stress)
Infectious agents
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6
Q

Describe Platelets and how they relate to haemostasis

A

Small a nuclear cells with a primary role in haemostats
Initial platelet aggregation at sites of vessel injury, forming a platelet plug.
Also serve as a cofactor for coagulation cascade, which requires negatively charged phospholipid

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7
Q

Describe the plasma membrane of the platelet as it relates to Haemostasis

A

Consists of a phospholipid bilayer
Phospholipids are located on the inner membrane and are exposed only when the platelet is activated.
Has redundant folds under the outer-membrane so that upon activation the platelet can flatten and expand rapidly –> forms somewhat of a mesh.
Glycoproteins in the membrane act as receptors

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8
Q

Describe the function of glycoproteins found in platelets

A

They are receptors for a host of platelet agonists

Receptors for cell-cell interations

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9
Q

Describe Glycoprotein Ib/IX/V

A

Major receptor for initial platelet adhesion
Major ligand is von Willebrand factor, which is exposed from subendothelial tissues –> can therefore hook the platelet to the endothelium

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10
Q

Describe Glycoprotein IIb/IIIa

A

The dominant platelet surface receptor

Undergoes conformational change leading to string fibrinogen and vWF binding –> leads to platelet aggregation

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11
Q

What types of granules are located in platelets?

A

Alpha granules

Dense bodies

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12
Q

What compounds are found in Alpha Granules in platelets?

A 
Fibrinogen
Fibronectin
Factor V
vWF
Platelet Factor 4
Platelet derived growth factor
Transforming growth gator beta
Express P selection on the membrane surface
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13
Q

What is found in dense bodies in platelets?

A 
Contain ADP
Calcium
Serotonin
Histamine
Adrenaline
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14
Q

Describe the steps involved in platelet function

A

Like leukocytes, platelets roll across the endothelium
In response to soluble agonists and outside in signalling, platelets:
- Adhere to vWF (via GP-Ib/IX/V) and collagen on subendothelial surfaces (Adhesion) –> Become activated –> Conformational change of GP IIb/IIIa –> release of granules and production of thromobxane A2 (activates themselves and other platelets) via the action of cyclooxygenase (release/secretion) –> activate further platelets leading to platelet activation via fibrinogen and GP IIb/IIIa (aggregation)

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15
Q

What substances can activate platelets?

A

vWF
Collagen
Fibrinogen
Fibronectin

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16
Q

Describe The Coagulation Cascade

A

A series of zymogens (enzymes that are not active but can be activated)
Produced by the liver and circulate in the plasma
End result is cleaving fibrinogen to fibrin, which cross-links to form a solid clot
Cellular based (i.e. occurring on the surface of cells)

17
Q

What are the two pathways in the coagulation cascade?

A

Extrinsic: the dominant pathway in vivo
Intrinsic: Serves as a positive feedback / amplification loop

18
Q

Explain the Initiation phase of the coagulation cascade

A

Tissue factor is a membrane bound procoagulant on endothelial cells
It becomes exposed at site of vessel injury on endothelial cells, macrophages
Binds to VIIa –> this complex cleaves X to Xa –> Xa cleaves prothrombin to thrombin –> Thrombin feeds back to activate the intrinsic pathway.

19
Q

Describe the amplification of the coagulation cascade via positive feedback

A

Extrinsic pathway produces very little amounts of thrombin
Thrombin feeds back to activate V, III and XI (Positive Feedback)
XIa activates IX –> IXa and VIIIa activate X, then Xa/Va activate thrombin

20
Q

What is the end product of the coagulation cascade

A

Clot Formation
Thrombin cleaves fibrinogen to fibrin
Fibrin monomers bind to each other and become permanently cross linked with the aid of factor XIIIa (also activated by thrombin)

21
Q

What are the key features of the coagulation cascade?

A

TF/VIIa are important for initiation –> creating a small local thrombin burst
Thrombin feedback activation of XIa, VIIIa and Va –> leads to amplification of response and much larger thrombin formation
Thrombin cleaves fibrinogen to fibrin
Fibrin monomers combine and cross-link with the aid of XIIa, which is also activated by thrombin
Thrombin also activates platelets, coagulation inhibitors and fibrinolysis

22
Q

Describe The inhibition of the Coagulation Cascade

A

Inhibition is essential in any positive feedback loop
Thrombin activates Protein C and its co-factor Protein S
Protein C together with Protein S cleaves the activated factors V and VIII, switching them off
Antithrombin binds to thrombin in the presence of heparin
Tissue factor pathway inhibitor binds to tissue factor and Xa

23
Q

Define: Atherosclerosis

A

The formation of inflammatory intimal fibrous plaques with a central lipid core
It primarily affects elastic arteries and medium to large muscular arteries

24
Q

List the stages in the development of atherosclerosis

A

Local endothelial injury –>Expression of adhesion molecules and leakage of lipids
Monocytes & T cells are recruited
Chronic inflammation and accumulation of oxidised LDL
Oxidised LDL is a potent chemo-attractant for monocytes (positive feedback loop)
Migration of monocytes in to the vessel wall, which develop in foamy (lipid laden) macrophages, engulfing lipid via scavenging receptors (rather than LDL receptors) –> FATTY STREAK
Lipid accumulation and intimal thickening
Cytokines lead to migration of smooth muscle cells in to the intima from the media
Proliferation of smooth muscles in the intima and accumulation of collagen and proteoglycans –> FIBROUS PLAQUE OVER THE SURFACE
CALCIFICATION in connective tissue elements and weakening of vessel wall
Connective tissue on the intimal surface forms a fibrous cap
Advanced lesions develop neovascularisation with a central lipid rich, often necrotic core

25
Q

Describe Plaque rupture and its consequences

A

A plaque is vulnerable to rupture due to structural instability (having a thin, collagen poor fibrous cap), lacks of smooth muscle cells, impaired synthesis or enhanced breakdown of matrix, outward vascular remodelling.

On rupture, there is exposure of sub endothelial structures and lipids, including tissue factor.
This leads to platelet aggregation, clot formation, clot propagation that can possibly occlude the artery. Embolism from the site of the plaque to distal sites can also occur.

26
Q

What are some common risk factors for Atherosclerosis

A 
Hypercholesterolaemia (LDL)
Hypertension
Diabetes Mellitus
Cigarettes
Family History
Male
Post Menopausal
Obesity
27
Q

Describe Thromboembolic disease

A

Intravascular thrombosis due to a breakdown in normal haemostatic mechanisms.
May occur in arterial or venous systems
Arterial thromboses are largely predisposed to atherosclerosis, plaque rupture and platelet activation under high shear stress
Venous thromboembolism is predisposed to by venous stasis and changes in coagulation constituents of blood

28
Q

What are the three components of Thrombosis

A

Vessel wall injury
Blood Flow
Blood constituents

29
Q

Compare the three components of thrombosis as they relate to arterial and venous thrombosis.

A

Vessel Wall Injury

  • Arterial: Atherosclerosis
  • Venous: Trauma

Blood Flow

  • Arterial: Turbulence
  • Venous: Stasis

Blood Factors

  • Arterial: Qualitative platelet abnormalities
  • Venous: Hypercoaguability (Deficiency of Inhibitors)
30
Q

Define And Describe Embolism

A

A detached intravascular mass (gas, liquid or solid) carried by the blood to a site distant from the point of origin
Usually thrombosis, but air, amniotic fluid or fat embolism can also occur
Occlusions of small vessels leads to infarction of distal tissue
Arterial: Peripheral vascular disease –> lower limbs leading to gangue
Cardiac: Stroke or peripheral. Atrial fibrillation leads to relative stress.
Venous: Pulmonary Emboli (from peripheral veins through the heart to pulmonary arteries)

31
Q

Describe Acute Myocardial Infarction

A

Thrombus occurs locally, leading to occlusion of coronary artery
Distal loss of circulation leads to infarction of cardiac muscles

32
Q

Describe Stroke as it relates to thrombosis

A

Rupture of an unstable atherosclerotic plaque in large proximal arteries, such as the carotids, leads to embolisation distally
Ebolus lodges in smaller arteries leading to infarction of area supplied distally

33
Q

Describe Venous Thromboembolism

A

Thrombosis usually on lower limb veins
Leg swelling, pain, tenderness
Embolism can move to lungs –> chest pain, dyspnea, right heart strain and possibly death

34
Q

What are the possible outcomes of thrombosis?

A

Propagation: Accumulates more fibrin and platelets. Propagation occurs proximally in venous thrombosis
Embolisation: Dislodges and travels to other sites
- Venous thrombi embolise through the heart and lodge in the lung
- Arterial thrombi lodge distally
Dissolution: Fibrinolytic activity dissolves the clot (best outcome)
Organisation: With inflammation and fibrosis, followed by recanalisation or incorporation into the vessel wall.

35
Q

What are some Risk Factors for Venous Thrombosis?

A 
Acquired:
 - Age
 - Previous Thrombosis
 - Immobilisation
 - Major surgery
 - Malignancy
 - Oral contraception
Inherited:
 - Antithrombin III deficiency
 - Protein C deficiency
 - Protein S deficiency

Pathology (18 decks)

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