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Biology of Disease > Vascular Response to Injury > Flashcards

Vascular Response to Injury Flashcards

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1
Q

Describe the adhesion and activation of platelets during haemostasis:

A

Adhesion:
- Adheres strongly to ECM proteins (E.g. collagen)
- Glycoprotein IB binds collagen using Von Willebrand (vWF) factor

Activation:
- Shape change (disc to flat plate with processes): modified GpIIb/IIIa conformation with movement of -ve phospholipids to cell surface
- Chemical signals released such as ADP (activates more platelets); TxA2 (induces aggregation); 5HT; HA

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1
Q

What are platelets and what are the stages of their involvement in haemostasis?

A

A nuclear discs due to fragmentation of megakaryocytes in bone marrow (live for 7 days)

Stages of involvement:
- Adhesion
- Activation
- Aggregation

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2
Q

Describe the aggregation of platelets:

A

Primary haemostatic plug:
- Fibrinogen (via GpIIb/IIIa complex)
- Activation of coagulation cascade
- Platelet contraction (close apposition –> fusion)

Secondary haemostatic plug: fibrinogen –> fibrin
- Formed by fibrin (traps RBCs)
- Stimulated by thrombin
- Activates other coagulation cascade members

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3
Q

Detail the effects of loss of specific members of the coagulation cascade:

A
  • Loss of platelets: purpura from spontaneous haemorrhage in capillaries
  • Factor VIII loss: haemophilia A
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4
Q

What is the principle behind the coagulation cascade?

A

Provides amplification:

  1. Stimulus
  2. Enzyme + substrate + cofactor (on phospholipid surface)
  3. Thrombin activation
  4. Coagulation
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5
Q

What are the actions of thrombin?

A
  • Cleaves soluble fibrinogen into fibrin
  • Activates factor XIII: cross links the fibrin monomers
  • Activates other coagulation factors (XI, V, VIII) = positive feedback
  • Binds to various cell receptors (activating platelets, endothelial cells, leukocytes)
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6
Q

What are the two stimulus pathways for the coagulation system?

A
  • Extrinsic: tissue factor from damaged tissue (DAMP) released
  • Intrinsic: negatively charged surfaces (E.g. phosphatidyl serine (‘eat me’))

Both cause prothrombin to thrombin

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7
Q

What is the fibrinolytic system?

A

Antihaemostatic = disassembles haemolytic plug:
- Plasminogen precipitated with fibrin
- Plasminogen to plasmin caused by activators (streptokinase, uPA)
- Plasmin is a fibrinolytic protease

PAI-I inhibits this system (is pro-haemostatic)

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8
Q

How do endothelial cells normally prevent haemostasis?

A

Coagulation inhibition:
- Physical barrier
- Tissue factor pathway inhibitor (TFPI)
- Thrombomodulin expressed on cell surface
- Endothelial protein C receptor
- Heparin-like molecules

Platelet inhibition:
- Physical barrier against vWF
- Prostacyclin and NO produced (potent inhibitors)

Activation of fibrinolysis:
- Plasminogen activation tPA

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9
Q

How do endothelial coagulation inhibitors work?

A

Protein C receptors:
- Allows protein C to bind co-factor protein S
- Inhibits Va and VIIIa

Heparin-like molecules:
- Bind antithrombin III to inhibit thrombin

Thrombomodulin:
- Alters thrombin confirmation
- Activates protein C

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10
Q

How does injury affect endothelial control of haemostasis?

A

Haemostasis promoted since vWF, ECF, tissue factor exposed:
- Downregulation of anti-haemostatic factors (TFRI, protein C receptors…)
- Upregulation of pro-haemostatic factors (E.g. plasminogen activating inhibitors (PAIs))

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11
Q

What is the difference between a thrombus, embolus and blood clot?

A

Thrombus:
- From blood constituents
- Within circulation
- Composed of fibrin/platelets/RBCs.

Blood clot:
- Static blood with primary involvement of coagulation system
- Without interaction of platelets of the vessel wall (e.g. can be in vitro/post mortem)
- Is soft/jelly like

Embolus:
- Intravascular mass carrier by blood flow from origin to impact a distant site

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12
Q

What is Virchow’s triad law?

A

Predisposing factors for thrombosis are due to:
- A change in vessel wall (endothelial injury/activation)
- Changes in blood flow (Due to turbulence/aneurysm)
- Changes in blood constituents (e.g. increased tendency to coagulate due to genetic lack of protein C)

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13
Q

What are some differences between thrombi formed in arteries and veins?

A

Arteries:
- Compact, firm and granular masses.
- Contain laminations (lines of Zahn) with pale branching fibrin/platelets and darker RBC layers

Veins:
- Pale head with long tail.
- Little lamination but tail mainly red due to enmeshed RBCs

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14
Q

What are some outcomes of thrombus?

A

Recovery:
- Organisation inducing inflammatory reaction (restoring blood flow)

Progression:
- Lysis
- Propagation towards heart (bad)
- Stenosis (narrowing) or occlusion (blocking)
- Migration of smooth muscle cells and fibroblasts
- Infection may lead to pyaemia and abscess formation
- Embolism (thromboembolism)

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15
Q

Give 4 functions of the vascular endothelium:

A
  • Containment of blood
  • Selective transport of fluid
  • Haemostatic control
  • Regulation of blood pressure

Adventitia contains fibroblasts, leukocytes and nerves to achieve this

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16
Q

Describe the different forms of lipoproteins and how they are controlled by the body:

A

Lipid core with apolipoproteins:
- LDLs to deliver cholesterol to periphery
- HDLs to transport cholesterol from periphery to liver (excreted in bile)

Control:
- LDLs taken into cells by native LDL receptors pathway which breaks it down
- Scavenger receptor pathway allows macrophages to take up modified LDLs (E.g. oxidised) becoming foam cells

17
Q

What is dyslipoproteinemia? How can it be caused?

A

Abnormal concentration of lipoprotein in blood

Caused by:
- Under-activation of native LDL pathway (hypercholesterolaemia)
- Increased cholesterol intake
- Increased lipoprotein a – makes sticky LDL

18
Q

Detail the risk factors for atherosclerosis:

A

Constitutive (non-modifiable):
- Genetics (polygenic E.g
affecting blood pressure or single gene E.g. familial hypercholesterolaemia = mutations in LDL receptor)
- Age, sex

Acquired (modifiable)
- Hypertension
- Diabetes (can be due to dyslipidaemia; elevated PAI-1 factors)
- Dyslipidaemia
- Smoking
- Diet: high cholesterol,
- Lifestyle factors which decrease HDL levels: no alcohol (!), lack of exercise, obesity

Treatment: involves cholesterol lowering drugs (statins to reduce liver synthesis of cholesterol)

19
Q

How does injury of the endothelium lead to atherosclerosis?

A

Injury –> Chronic inflammatory process –> dysfunction

  • Increased permeability (allows entry of macrophages/T cells)
  • Adhesion molecule expression (P/E selectin; iCAMs)
  • Inflammatory mediators (IL1, TNF-α, eicosanoids)
  • Thrombosis
20
Q

What immune responses are activated following endothelial damage?

A

Immune cell recruitment:
- Monocytes amplify signal

Smooth muscle activation:
- Due to PDGF and FGF
- Phenotype of SM cells changes from contractile to synthetic
- Proliferation induced; ECM and remodelling enzymes released (collagenase)

21
Q

Describe the +ve feedback effect of lipoprotein modification for atherosclerosis:

A
  • LDL oxidised by ROS/collagenase
  • Acts as chemoattractant for monocytes
  • Are phagocytosed by macrophages (foam cells)
  • Induce dysfunction/apoptosis in smooth muscle/endothelium/macrophages
  • Simulate cytokine/GF release
  • Encourage haemostasis (inhibits plasminogen)
22
Q

What is the morphology of atherosclerotic development?

A
  1. Isolated monocytes in intima and fatty streaks
  2. fibro-fatty plaques
  3. Develop fibrous caps (collagen, T-cells) with lipid core (foam cells)
  4. Complicated plaques (calcification, rupture, thrombosis, aneurysm)
  5. Heart disease; vascular disease….death
23
Q

Why might atherosclerosis lead to an aneurysm?

A
  1. Atherosclerosis
  2. Increase in diffusion distance
  3. Medial thinning/ elastic laminae fragmentation
  4. Higher blood pressure due to vessel stiffness
  5. Aneurysm
24
Q

What are some common causes of ischemia (and infarction)?

A

Narrowing of vessels:
- External: due to compression (bed rest) or tumour pressure
- Internal: atherosclerosis; thrombosis or sickle cell/malaria

Spasm of vessel:
- E.g. due to frost-bite

Shock (circulatory failure):
- Low arterial blood pressure
- Cardiogenic (outflow obstruction; arrythmia)
- Hypovolaemic (haemorrhage)
- Septic
- Anaphylactic (type 1 hypersensitivity

25
Q

What are the consequences of infarction?

A

Direct effect of reduced blood on cells:
- Hypoxia (mt damage, ATP depletion and ROS build up)
- Dysfunction of cell membranes
- Damage to macromolecules (including DNA) (cytoskeletal damage due to Ca2+ influx)

Morphological damage (can be either reversible or irreversible):
- Cell/organelle swelling
- Plasma membrane blebs
- Chromatin clumping
- Necrotic (irreversible) damage due to denaturation

26
Q

Detail irreversible (necrotic damage) caused by an infarction:

A

Denaturing of cytoplasmic proteins and enzymatic degradation;
- Lysosomal/cell membrane breakdown (induces immune response)
- Deposits of electron dense material from mt leakage

Coagulative necrosis may result
- Histologically seen as increased eosinophilia; karyolysis and pyknosis

27
Q

Which factors alter the diversity of outcome from ischemia?

A

Susceptibility of cells (due to perfusion and metabolic usage):
- Neurons badly affected > myocardium > macrophages
- Organ perfusion (brain perfused well by Circle of Willis) and gut has collateral circulation which resists ischemia
- Kidneys at risk as single blood supply

Ischemia presentation:
- Size of block (large vs. small artery)
- Demand of tissue
- Speed of onset (adaptation time?)

28
Q

Describe the structure of haemoglobin and how it can vary:

A

Haemoglobin tetramers (large variation):
- Foetal type (HbF) = α2 γ2 (1% in adult)
- Major adult form (HbA) = α2 β2 (96%)
- Minor adult form (HbA2) = α2 δ2

HbA2 has higher resistance to thermal denaturation and inhibits polymerisation of deoxy sickle haemoglobin.

29
Q

What is anaemia? How does the body try and compensate for it?

A

Anaemia = reduction in total circulating red cell mass with reduced O2 carrying capacity due to an imbalance between rate of production and destruction/loss of RBCs.

Compensated for:
- Raised cardiac output
- Raised heart rate
- Raised breathing rate
- Hyperplasia of haematopoietic stem cells in bone marrow

30
Q

What are the different types of dyserythropoiesis?

A

Impaired generation of RBCs/their constituents:
- Aplastic anaemias (abnormal stem cells)
- Defective DNA synthesis
- Defective haemoglobin deficiency (iron deficiency)
- Defective globin synthesis (thalassemias)

31
Q

What are the different types of haemolytic anaemias?

A

Increased destruction of RBCs (either extravascular (macrophages/spleen) or intravascular (lysis in circulation))

Intrinsic (hereditary):
- Deformed RBCs which become trapped in sinusoids of spleen (ingested by macrophages)

Extrinsic abnormalities (acquired):
- Immune (haemolytic disease of newborn)
- Physical (valve replacement)
- Chemical (lead poisoning)
- Infection (malaria)

32
Q

Detail some intrinsic abnormalities which can result in haemolytic anaemias:

A

Deformed RBCs which are trapped in sinusoids of spleen and ingested by macrophages.
- Structural defects (spherocytosis = cytoskeletal
- Enzymatic defects (pyruvate kinase deficiency leading to reduced ATP from glycolysis)
- Haemoglobin abnormalities (thalassaemias)

33
Q

How might a megaloblastic anaemia be caused? What are the effects?

A

Impaired DNA synthesis due to B12 deficiency
- B12 needed for co-enzymes in thymidine synthesis

Results in reduced haematopoiesis/nuclear division:
- Haematopoietic tissue expansion
- RBC precursors (E.g. megaloblasts) enlarged and may appear in blood
- Anisocytosis (different RBC sizes)
- Poikilocytosis (different RBC shapes)
- Iron cannot be utilised and may be deposited in body
- Other cells affected: neutrophils with large/hypersegmented nuclei

34
Q

Why is vitamin B12 necessary? How is it absorbed?

A
  • Required for conversion of me-FH4 to FH4 – FH4 (folate) which enables thymidine synthesis
  • Obtained from terminal ileum absorption (requires intrinsic factor (IF) from gastric mucosa)
  • IF binds to B12 then complex binds cubilin (IF receptor) for absorption
  • Stored in liver (up to 5 years)
  • Deficiency can occur due to reduced intake or increased need
35
Q

What circumstances may lead to B12 or folate deficiency?

A

Reduced intake:
- Vegans, elderly
- Chronic alcoholic (for folate)
- Folate destroyed during cooking
- Ileal disease
- Pernicious anaemia (autoimmune destruction of gastric mucosa)
- Agonist (E.g. methotrexate against folate)

Increased need:
- Pregnancy

36
Q

How does the body regulate iron? Why might a deficiency occur?

A
  • Storage pool bound as ferritin (or haemosiderin if overload)
  • Regulated by iron absorption in duodenum – negative feedback via hepcidin
  • Iron absorption when liver levels high (converts iron to ferritin in mucosal cells which are shed)

Deficiency:
- Caused by impaired absorption (small bowel disease);
- Increased demand (pregnancy);
- Increased loss (e.g. peptic ulcer)
- Poor intake (poverty; old age)

37
Q

What is the cause of sickle cell disease?

A

Due to point mutation:
- Polar glu –> non-polar val on HbS α2 β2 6)
- Low pO2/pH (E.g. dehydration) causes aggregation/polymerisation due to distortion of RBC shape.
- Reversible initially.

Consequences:
- Occlusion of microvasculature during ‘crisis’
- Most where flow is slow
- Pain due to hypoxia/infarction

38
Q

What causes thalassamias?

A

Diminished production of globin chains:
- Absent/reduced synthesis of globin chains of HbA (α2 β2)

Consequences:
- Low globin levels and hypochromic/microcytic RBCs
- Relative excess of other chains (E.g. α4 β4) which precipitate in inclusions
- Damage to cell membrane/impaired DNA synthesis leading to destruction of erythroblasts

39
Q

What is the difference between α and β thalassaemias ?

A

α thalassaemia:
- Due to deletion of two duplicated genes on chromosome 16 (4 total)
- Code for alpha chains
- Severity depends on number of deleted genes

β thalassaemias;
- Coded by single gene on chromosome 11
- Compensatory increase in HbF and HbA2

Free β/γ chains more soluble than free α chains so haemolysis in α less severe

40
Q

What are the stages of wound healing?

A

Haemostasis:
- Coagulation
1. Collagen and vWF exposed at wound site
2. Platelets adhere to collagen via GP6 on surface
3. Thromboxane release then converts GpIIa to active form
4. Fibrin to fibrinogen and platelets degranulate (+ve feedback – recruit more platelets)

Inflammation:
- Immune cell recruitment (leukocytes; monocytes; T-cells; B-cells)

New tissue formation (re-epithelialisation):
- Angiogenesis (VEGF)
- Collagen
- ECM formation
- Removal of platelet plug (plasminogen)

Biology of Disease (7 decks)

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