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Tamsin - Pathology > Haemodynamic disorders, Thombosis and Shock (Ch 4) > Flashcards

Haemodynamic disorders, Thombosis and Shock (Ch 4) Flashcards

1
Q

Name 5 different causes of oedema

A

1) Increased hydrostatic pressure eg CCF
2) Reduced plasma osmotic pressure eg nephrotic syndrome, liver cirrhosis
3) Lymphatic obstruction usually due to inflammatory/neoplastic process
4) Primary sodium retention resulting in water retention
5) Inflammation - increased vascular permeability

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2
Q

What is the microscopic appearance of oedema?

A

Subtle cell swelling and separation of the extracellular matrix

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3
Q

Pathological appearance of pulmonary oedema

A

Lungs 2-3 times their normal weight . Sectioning reveals frothy, blood tinged mixture of air oedema and erythrocytes

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4
Q

Pathological appearance of brain oedema

A

Grossly swollen brain with narrowed sulci and distended gyri flattened against the skull

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5
Q

What is hyperaemia?

A

Active process due to augmented blood inflow from arteriolar dilation. Tissues are red owing to engorgement with oxygenated blood eg skeletal muscle during exercise

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6
Q

What is congestion?

A

Passive process caused by impaired outflow from a tissue - can be systemic or local. Tissues are blue-red (cyanosis) due to an accumulation of deoxyhaemaglobin

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7
Q

What are haemosiderin laden macrophages?

A

Heart failure cells

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8
Q

What are the features of acute congestion?

A

Vessels are distended, organs grossly hyperaemic. Interstitial oedema

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9
Q

What are the features of chronic congestion?

A

Capillary rupture may cause focal haemorrhage. Erythrocyte breakdown results in haemosiderin-laden macrophages and fibrotic septa

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10
Q

What are the features of congestion in the liver?

A

Acute: Central vein and sinusoidal distension, central hepatocyte degeneration
Chronic congestion: Central regions of the hepatic lobules are grossly red-brown and slightly depressed relative to the surrounding uncongested tan liver (nutmeg liver)

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11
Q

What is the difference between haemorrhage and haematoma?

A
  • Haemorrhage is a release of blood into the extravascular space
  • Haematoma is haemorrhage enclosed within a tissue
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12
Q

What are petechiae?

A

1-2mm haemorrhages in skin, muscous membranes or serosal surfaces

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13
Q

What are purpura?

A

>3mm haemorrhages which occur due to thrombocytopaenia, defective platelet function, trauma, local vascular inflammation or increased vascular fragility

Non thrombocytopenic purpura causes include: meningococcaemia, HSP, hereditary telangiectasia

Thrombocytopenia is caused by a decreased production of platelets (HIV, anaemia), decreased platelet survival (SLE, HIV), sequestration of platelets (hypersplenism) and dilutional eg massive transfusion

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14
Q

What are eccymoses?

A

>1-2cm subcutaneous haematoma. Typically associated with trauma but also exacerbated by other bleeding disorders

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15
Q

What is haemostasis?

A

A normal, physiologic process maintaining blood in a fluid, clot-free state within normal vessels while inducing a rapid, localised haemostatic plug at sites of vascular injury.

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16
Q

What is thrombosis?

A

A pathological state - the inappropriate activation of haemostatic mechanisms in uninjured vessels or thrombotic occlusion after relatively minor injury

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17
Q

What are three components of haemostasis and thrombosis?

A
  1. Endothelium
  2. Platelets
  3. The coagulation cascade
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18
Q

Describe the steps in normal haemostasis

A
  1. Transient reflex arteriolar vasoconstriction augmented by endothelin (potent endothelial-derived vasoconstrictor)
  2. Platelet adhesion and activation by binding to exposed subendothelial extracellular matrix. Secreted products recruit other platelets to form a temproary haemostatic plug (primary haemostasis)
  3. Activation of the coagulation cascade by release of TF (factor 3 or thromboplastin) - a membrane bound lipoprotein synthesised by endothelium. Culminates in thrombin generation and conversion of fibrinogen to insoluble fibrin -formation of solid permanent plug (secondary haemostasis)
  4. Activation of conter-regulatory mechanisms restricts haemostatic plug to site of injury.
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19
Q

What properties are exhibited by normal endothelium?

A
  1. Antplatelet
  2. Anticoagulant
  3. Fibrinolytic
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20
Q

List the antithrombotic properties of endothelium

A

Antiplatelet

  • Prostacyclin (PGI2) and nitric oxide (NO) inhibit platelet binding/adhesion/aggregation
  • ADPase degrades ADP (a platelet aggregation inducer) which inhibits platelet aggregation

Anticoagulant

  • Thrombomodulin converts thrombin to an anticoagulant protein which activates protein C and S
  • Tissue factor pathway inhibitor (t-PA inhibitor) blocks factors VIIa and Xa
  • Heparin-like surface molecules facilitate plasma antithrombin-3 inactivation of thrombin

​Fibrinolytic

  • t-PA cleaves plasminogen to form plasmin which in turn degrades fibrin
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21
Q

List the prothrombotic properties of endothelium

A
  • EC (endothelial cells) produce vWF - allows interaction of platelets to the ECM
  • Tissue Factor (TF) is the major activator of the extrinsic clotting cascade
  • Plasminogen activator inhibitors (PAIs) limit fibrinolysis and favour thrombosis
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22
Q

Describe the process of platelet adhesion in the formation of the primary heamostatic plug

A

Platelet-ECM adhesion is mediated by vWF which acts as a cross-bridge between exposed collagen and glycoprotein 1b receptors on platelets.

Defeciency of glycoprotein 1b is called Bernard-Soulier syndrome

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23
Q

Describe the process of platelet secretion

A
  • Platelets secrete the contents of granules soon after adhesion
  • Alpha granules: Express adhesion molecule P selectin, contain coagulation and growth factors
  • Delta granules (dense bodies): Contain ADP, calcium and vasoactive amines eg histamine
    • ADP is a potent mediator of platelet aggregation
    • Calcium is important in the coagulation cascade
  • The release reaction also causes surface expression of phosphlipid complex - a binding site for Ca2+ and coagulation factors in the intrinsic clotting cascade
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24
Q

Describe the process of platelet aggregation

A
  • Platelet aggregation is promoted by ADP and TXA2
  • ADP activation changes platelet GP2b-3a receptor confirmation to allow fibrinogen binding.
  • Fibrinogen bridges multiple platelets forming large aggregates

Gp2b3a deficiencies result in Glanzmann thrombasthenia

  • PGI2 (endothelium derived) inhibits platelet aggregation and is a potent vasodilator
  • TXA2 (platelet derived) activates platelet aggregation and is a potent vasoconstrictor
25
Q

What is the coagulation cascade?

A
  • A sequence of inactive pro-enzymes converted into activated enzymes culminating in the conversion of soluble fibronogen to insoluble fibrin
  • Traditionally divided into extrinsic and intrinsic pathways that converge at the stage of factor X activation
  • Each step results from a complex composed of an enzyme (activated factor), a substrate (proenzyme for of a factor) and a cofactor all held together by Ca on a phosphlipid complex
26
Q

What are the steps in the intrinsic pathway?

A
  • Initiated by activation of factor XII (Hagemans factor) by high molecular weight kininogen (HMW-k) and kallikrein (Ka)
  • XIIa activates XI
  • XIa activates IX
  • IXa binds with VIIIa to activate X
  • VIII is activated when split from vWF
  • Xa enters the common pathway

Partial thromboplastin time (PTT) screens for the function of the proteins in the intrinsic pathway

27
Q

What are the steps in the extrinsic pathway?

A
  • Activated by tissue factor (TF or thromboplastin or factor III)
  • TF activates factor VII
  • VIIa and TF activates factor X
  • Xa enters the common pathway
  • VIIa also activates IX to IXa

Prothrombin time (PT) screens for the function of proteins in the extrinsic pathway (VII, X, II, V and fibrinogen)

28
Q

Describe the common pathway of the coagulation cascade

A
  • Xa activates factor II (promthrombin)
  • IIa (thrombin) coverts I (fibrinogen) to Ia (fibrin) and XIII to XIIIa
  • Factor XIIIa cross links fibrin and stabilises the secondary haemostatic plug
29
Q

What mechanisms prevent clotting of the entire vascular tree?

A
  1. Factor activation only occurs at sites of exposed phosphlipids
  2. Antithrombins complexed with heparin like cofactors on endothelium inhibit thrombin and other serine proteases (factors IXa, Xa, XIa, XIIa)
  3. Thrombomodulin modifies thrombin so that it can cleave Protein C and Protein S which inactivates factors Va and VIIIa
  4. TFPi inactivates TF-VIIa complexes and Xa
  5. Thrombin induces endothelial t-PA release
    • ​​​t-PA generates active plasmin from circulating plasminogen
    • Plasmin cleaves fibrin and interferes with polymerisation
    • Functional plasmin activity is restricted to sites of thrombosis

Note: Endothelium modulates anticoagulation by releasing plasminogen activator inhibitors which inhibit t-Pa binding to fibrin. Thrombin and certain cytokines increases PAI production

30
Q

What are the 3 primary influences on thrombus formation?

A

Virchow’s triad:

  1. Endothelial injury eg due to plaque, stress, vasculitis, toxins
  2. Alterations in normal blood flow - stasis and turbulence/increased viscosity
    • Disruption of laminar flow
    • Reduced dilution of clotting factors
    • Reduced flow of clotting factor inhibitors
    • Promote endothelial cell activation
  3. Hypercoagulability
    • Primary causes: Factor V mutations, deficiencies of AT3, protein C or protein S, homocysteinaemia
    • Secondary causes: immobilisation, MI, tissue damage, cancer, DIC, HIT, antiphospholipid syndromen
31
Q

What is the role of protein C and protein S

A
  • Inactivate Va and VIIIa
  • Activated by thrombin in the presence of endothelial thrombomodulin
32
Q

What is the pathophysiology of Factor V leiden?

A
  • Arg to Glu substitution in amino acid residue 506 leading to resistance to activated protein C
  • Factor Va is normally degraded by activated protein C
  • Therefore resistance to cleavage by protein C makes factor V remain active and increases the rate of thrombin generation (prothrombotic state)
33
Q

Describe the morphology of aortic, arterial, venous and valve thrombi

A

Aortic/cardiac

  • Typically non-occlusive (mural)
  • Occur in sites of endothelial injury or turbulence
  • Extend retrograde
  • Lines of Zahn - pale layers of platelets and fibrin alternating with darker erythrocyte rich layers, signify thrombus has fored in flowing blood

Arterial

  • Usually occlusive, firmly adherent to the injured arterial wall
  • Most common sites: coronary, cerebral, femoral

Venous

  • Invariably occlusive
  • Occur in sites of stasis
  • Extend in the direction of blood flow

Heart Valves

  • Only occur in special circumstances
    • Infective endocarditis
    • Sterile vegetations can develop in patients with hypercoagulable states

Post mortem clots

  • Gelatinous due to lack of fibrin with a dark red portion where red cells have settled with gravity and a yellow “chicken fat” upper portion
34
Q

What are the 4 potential outcomes of thrombosis

A
  1. Propagation - accumulation of more platelets and fibrin
  2. Embolisation - dislodgement and travel
  3. Dissolution - removal by fibrinolytic activity
  4. Organisation and recanalisation- induction of inflammation and fibrosis, re-establishing vascular flow by ingrowth of endothelial cells, smooth muscle and fibroblasts
35
Q

What is the pathophysiology of DIC?

A
  • Widespread fibrin microthrombi in the microcirculation and the secondary activation of generalised fibrinolytic mechanisms
  • Fibrin deposition > microthrombi > ischaemia
  • Triggered by release of TF into the circulation
  • Consumption coagulopathy - rapid concurrent consumption of platelets, fibrin and coagulation factors which can lead to uncontrollable bleeding
  • Not a primary disease but a complication of any diffuse thrombin activation
  • Obstetric complications are responsible for about 50% of cases
  • Malignant neoplasms are responsible for about 33% of cases
  • Also occurs in sepsis, severe trauma
36
Q

What is paradoxical embolism?

A

When venous embolus passes through an ASD or VSD into the systemic circulation

37
Q

The main origin of PE

A

95% originate from deep leg vein thrombi (DVT)

38
Q

Percentage of PE which are clinically silent

A

60-80%

39
Q

What is systemic thromboembolism?

A

Emboli in the arterial circulation

40
Q

What is the main origin of systemic thromboembolism?

A

80% arise from intracardiac mural thrombi

2/3 are secondary to myocardial infarcts and 25% arise in the setting of dilated left atria and fibrillation

41
Q

What are the major sites for arteriolar embolisation?

A

The lower extremities (75%)

Brain (10%)

42
Q

What % of severe skeletal injuries does fat embolism occur?

A

90%

<10% have any clinical findings

43
Q

What are the clinial features of fat embolism syndrome?

A
  • Sudden pulmonary insufficiency
  • Diffuse petechial rash (20-50%)
  • Irritability, restlessness, delirium, coma
  • Thrombocytopenia, anaemia
44
Q

What is the pathogenesis of fat embolism syndrome?

A
  • Mechanical obstruction by neutral fat microemboli followed by local platelet and erythrocyte aggregation.
  • Subsequent fatty acid release causes toxic injury to endothelium; platelet activation and granulocyte recruitment contribute free radicals, proteases and eicosanoids.
45
Q

What volume of air is required to be a clically significant air embolus?

A

100ml

46
Q

What is the pathogenesis of decompression sickness?

A

Air breathed at high pressure causes increasing amount of gas (mainly nitrogen) to be dissolved in blood and tissues. Subsequent rapid ascent allows the dissolved gases to expand and bubble out of solution to form gas emboli.

  • Formation of gas bubbles in skeletal muscles and joints causes painful “bends”
  • In lungs - oedema, haemorrhage, focal emphysema lead to respiratory distress
  • Gas emboli may cause focal ischaemia in a number of tissues eg brain or heart
  • Ciasson disease - persistent gas emobli in poorly vascularised portions of the skeleton lead to ischaemic necrosis eg head of femurs, tibia, humeri
47
Q

What are the clinical features of amniotic fluid embolism?

A
  • Uncommon (1 in 40,000 deliveries) but serious (mortality rate 80%)
  • Occur more often in multigravids
  • Sudden severe dyspnoea, cyanosis and hypotensive shock followed by seizures and coma
  • Underlying cause is infusion of amniotic fluid into the maternal circulation via a tear in the placental membranes or rupture of uterine veins
  • Diffuse alveloar damage and DIC ensue from release of toxic (fatty acid) and thrombogencic substances in amniotic fluid
48
Q

What is the definition of infarction?

A

Area of ischaemic necrosis caused by occlusion of either the arterial supply (97% of cases) or venous drainage in a particular tissue

49
Q

What are the causes of infarction?

A
  • Thrombotic or embolic events
  • Vasospasm, extrinsic compression eg tumour, trauma, hernial sac
  • Twisting of vessels eg torsion
50
Q

What are red and white infarcts?

A

Red infarcts (haemorrhagic):

  • Implies haemorrhage into the tissue
  • Occurs in venous occlusions, loose tissues, tissues with dual circulations eg lung and small intestine, tissues previously congested due to sluggish venous outflow, sites of previous occlusion and necrosis when flow is re-established

White infarcts (anaemic):

  • Occurs in arterial occlusion in solid organs with end arterial circulation eg heart, spleen, kidneys
51
Q

What is the dominant histological feature of necrosis?

A

ischaemic coagulative necrosis

52
Q

What is the main histological appearance of CNS infarction?

A

Liquefactive necrosis

53
Q

What factors influeunce the development of an infarct?

A
  1. Anatomic pattern of vascular supply
  2. Rate of development of occlusion
  3. Vulnerability to hypoxia
  4. Oxygen content of blood supply
54
Q

How many minutes of ischaemia does it take neurons to undergo irreversible damage?

A

3-4 minutes

55
Q

How many minutes of ischaemia before myocytes die?

A

20-30 minutes

56
Q

What is the definition of shock?

A

Systemic hypoperfusion caused by reduction in either cardiac output or effective ciruclating blood volume

Hypotension > Hypoperfusion > Cellular hypoxia

57
Q

Most common causes of septic shock

A
  1. Gram positive bacteria
  2. Gram negative bacteria
  3. Fungi
58
Q

Describe the pathological features of septic shock

A
  • Inflammatory response
    • Host immune cells possess pattern recognition receptors (PRR) which bind to microbial associated molecular patterns (MAMPs)
    • TLR (a type of PRR) activation via multiple secondary signalling pathways leads to translocation of nuclear factor kappa B (NF-kb) to thenucleus.
    • Activated NF-kb binds to trasncription sites and induces activation of pro-inflammatory cytokines (TNFa, IL1), chemokines (ICAM-1), vascular cell adhesion molecule and nitric oxide
    • TNFa and IL-1 trigger the cardinal pathophysiological mechanisms of sepsis - leukocyte activation and transmigration, endothelial damage and dysfunction and increased capillary permeability resulting in hypovolaemia and exposure of TF to circulating coagulation factors
  • Coagulation and complement cascades are directly activated
  • Endothelial cell (EC) activation and injury leads to increased thrombotic tendencies (DIC) and systemic leukocyte adhesion with pulmonary alveolar damage (ARDS)
  • Metabolic abnormalities
    • Insulin resistance, hyperglycaemia
    • Diminished oxidative phosporylation and increased lactate and acidosis
  • Immune supression - hyperinflammatory state activates potent conter-regulatory immunosupressive mechanisms
  • Organ dysfunction
59
Q

What are the 3 stages of septic shock?

A
  1. Initial (non-progressive) phase
    • Activation of reflex compensatory mechanisms (baroreceptors, catecholamine, RAAS, ADH release), perfusion of vital organs maintained
    • Clinically: Pale, clammy skin, warm flushed skin due to vasodilation
  2. Progressive phase
    • Tissue hypoperfusion, worsening circulatory and metabolic abnormalities
    • Lactic acidosis due to anaerobic glycolysis
    • Blunted vasomotor response due to acidosis leads to arteriolar vasodilation and pooling of blood in microcirculation
    • Clinically: confused patient, declining urine output
  3. Irreversible stage
    • Damage so severe that even if perfusion restored, survival not possible

Tamsin - Pathology (2 decks)

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