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BPS > Hemodynamic Disorders, Thromboembolic Disease, And Shock > Flashcards

Hemodynamic Disorders, Thromboembolic Disease, And Shock Flashcards

1
Q

What are the five pathophysiologic categories of oedema, and an example of each?

A
  • Increased Hydrostatic Pressure, Impaired venous return e.g. CHF, Arteriolar Dilation e.g. heat
  • Reduced Plasma Osmotic Pressure (Hypoproteinemia) e.g. protien losing glomerulopathies (nephrotic syndrome)
  • Lymphatic Obstruction e.g. post surgical
  • Sodium Retention e.g. increased tubular reabsorption of sodium as in renal hypoperfusion
  • Increased Vascular Permeability e.g. inflammation
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2
Q

What are the stepwise consequences of reduced plasma osmotic pressure?

A

Oedema -> reduced intravascular volume -> renal hypoperfusion -> secondary hyperaldosteronism -> renal salt and water retention-> exacerbated oedema

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3
Q

Give an example of an exception to the typical protein-poor, translucent, straw coloured nature of transudative effusions.

A

Peritoneal effusions caused by lymphatic blockage (chylous effusion). May be milky due to lipids absorbed from the gut.

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4
Q

What is the difference between hyperaemia and congestion?

A
  • Hyperaemia is an active process. Arteriolar dilation (e.g. at sites of inflammation or skeletal muscle in exercise), leads to increased blood flow. Erythema of affected tissues.
  • Congestion is a passive process. Reduced venous outflow of blood from a tissue. Systemic or local. Cyanosis of affected tissues.
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5
Q

What are some consequences of congestion?

A
  • resulting increased hydrostatic pressure means commonly oedema

If chronic:
- chronic hypoxia may result in ischemic tissue injury and scaring
- capillary rupture and subsequent catabolism of extravasated red cells can leave clusters of hemosiderin-laden macrophages

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6
Q

What are the four steps leading to hemostasis after vascular injury?

A
  1. Arteriolar vasoconstriction
  2. Primary hemostasis: the formation of the platelet plug
  3. Secondary hemostasis: deposition of fibrin
  4. Clot stabilisation and resorption
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7
Q

What is contained in the a-Granules and the d-(or dense)Granules of platelets respectively?

A
  • P-selectin, proteins involved in coagulation e.g. fibrinogen, coagulation factor V, vWF, proteins involved in wound healing e.g. fibronectin, PF4, PDGF, TGF-B
  • ADP, ATP, ionised calcium, serotonin and adrenaline
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8
Q

What two interactions is platelet adhesion mediated by?

A
  • platelet surface receptor glycoprotein Ib (GpIb) with vWF in the subendothelial matrix
  • platelet collagen receptor Gp1a/IIa with exposed collagen
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9
Q

What events are referred to as platelet activation, triggered by a number of factors including thrombin and ADP binding specific G-protein coupled receptors (e.g. PAR-1 for thrombin)?

A
  • shape change to greatly increase SA
  • conformational changes in cell surface glycoprotein IIb/IIIa that increase affinity for fibrinogen
  • translocation of negatively charged phospholipids (particularly phosphatidylserine) to platelet surface (serve as nucleation sites for assembly of coagulation factor complexes)
  • secretion of granule contents
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10
Q

How do activated platelets recruit more platelets?

A
  • Releasing ADP in dense granules which bind P2Y1 and P2Y12 G-protein coupled receptor of other platelets, activating them
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11
Q

What platelet aggregation promoting prostaglandin is produced by activated platelets?

A

Thromboxane A2

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12
Q

How does aspirin inhibit platelet aggregation?

A

Inhibits cyclooxygenase (required to produce TxA2)

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13
Q

How does thrombin help with the clot stabilisation stage of hemostasis?

A

Promotes irreversible platelet contraction, consolidating the aggregated platelets

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14
Q

Which factors of the coagulation cascade have y-carboxylated glutamic acid residues that bind calcium in the assembly of reaction complexes and require vitamin K to be produced?

A

II (prothrombin), VII, IX, X

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15
Q

In vitro, which coagulation cascade factors are part of the extrinsic pathway (assessed by PT), and which the intrinsic pathway (assessed by PTT) respectively?
(In doing so revise the pathways)

A
  • VII, X, V, II, fibrinogen
  • XII, XI, IX, VIII, X, V, II, fibrinogen
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16
Q

Deficiency of which coagulation cascade factors will:
1. Likely be incompatible with life
2. Lead to moderate to severe bleeding disorders
3. Lead to mild increase in bleeding
4. May lead to susceptibility to thrombosis

A
  1. II (prothrombin)
  2. V, VII, VIII, IX, X
  3. XI
  4. XII
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17
Q

In vivo what is believed to be the most important coagulation complexes that activate factor IX and X respectively?

A
  • factor VIIa/tissue factor complex
  • factor IXa/factor VIIIa complex
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18
Q

What factors of the coagulation cascade does thrombin (IIa) act on?

A

fibrinogen, XI, V, VIII, XIII (covalently cross links fibrin)

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19
Q

Outside of its effects on the coagulation cascade, what are three other important functions of thrombin?

A
  • Platelet activation (PAR-1 receptor)
  • Pro-inflammatory effects (through PAR receptors on other cell types)
  • Anticoagulant effects (when encounters normal endothelium)
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20
Q

What are some factors that limit the spread of coagulation from the site of injury?

A
  • Fibrinolysis, largely by plasmin (activated by a factor XII dependent pathway or plasminogen activators, note t-PA from endothelium most active bound to fibrin. Inhibited by e.g. a2 plasmin inhibitor)
  • Dilution from flowing blood
  • Requirement for negatively charged phospholipids
  • Factors expressed by endothelium adjacent to the site of injury (e.g. thrombomodulin)
  • Circulating inhibitors of coagulation factors (e.g. anti-thrombin III)
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21
Q

What are D-dimers?

A

A breakdown product of fibrin

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22
Q

What are three of the most important factors produced by normal endothelium that inhibit platelet activation and aggregation?

A

Prostacyclin (PGI2), NO, adenosine diphosphatase

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23
Q

What are four factors expressed by normal endothelium that actively oppose coagulation, and what do they do?

A
  • thrombomodulin
  • endothelial protein C receptor
    The above bind their ligands in a complex on the cell surface, thrombin cleaves protein C (and can no longer act on coagulation factors or platelets). Activated protein C with protein S inhibits Va and VIIIa
  • heparin-like molecules - activate anti-thrombin III (inhibits thrombin and IXa, Xa, XIa and XIIa
  • tissue factor pathway inhibitor - binds and inhibits tissue factor/factor VIIa complexes
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24
Q

Divide the anti thrombotic properties of endothelium into three categories

A
  • Platelet inhibitory effects
  • Anticoagulant effects
  • Fibrinolytic effects (synthesise t-PA)
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25
Q

What form are the small bleeds that defects of primary hemostasis can present with and why is this believed to be the case?

A
  • Petechiae (1-2mm) or purpura (>3mm) in skin or mucosal membranes
  • Capillaries of skin and mucosa prone to rupture following minor trauma which are normally sealed by platelets virtually immediately
26
Q

Describe three forms of bleeding that generalised defects involving small vessels (e.g. vasculitis, amyloidosis) can present with

A
  • palpable purpura
  • ecchymoses (1-2cm)
  • hematoma (when the volume of extravasated blood is large enough to create a palpable mass of blood)
27
Q

What do defects of secondary hemostasis often present with?

A

Bleeds into soft tissues or joints

28
Q

What are the primary abnormalities that lead to thrombosis (The Virchow Triad)?

A

Endothelial injury, Abnormal blood flow (stasis or turbulence), hypercoagulability

29
Q

What are six exposures that can lead to endothelial activation/dysfunction(gene expression pattern shift to prothrombotic)?

A
  • physical injury
  • infectious agents
  • inflammatory mediators
  • abnormal blood flow
  • metabolic abnormalities e.g. hypercholesterolemia
  • toxins from cigarette smoke
30
Q

What are two groups of prothrombotic alterations activated endothelium undergo?

A
  • Procoagulant changes (down regulation of anticoagulation factors)
  • Antifibrinolytic effects (secrete plasminogen activator inhibitors (PAIs) and downregulate t-PA expression)
31
Q

What are three ways in which turbulence and stasis can contribute to thrombosis?

A
  • Promote endothelial activation (flow induced changes and direct injury)
  • Disrupt laminar flow (bringing platelets into contact with endothelium)
  • Prevent washout and dilution of activated clotting factors (and inflow of inhibitors)
32
Q

What are the two most common inherited causes of hypercoagulability?

A
  • Factor V Leiden (single nucleotide mutation in factor V rendering it resistant to cleavage from protein C, 2-15% of caucasians)
  • Prothrombin G20210A variant (single nucleotide change leading to elevated prothrombin levels, 1-2% of the population)
33
Q

Heparin-Induced Thrombocytopenia (HIT) syndrome (an acquired hypercoagulabile state) can occur following administration of unfractionated heparin. What is this the result of?

A

Heparin-PF4 complexes lead to a conformational change in PF4 creating a neoantigen. IgG antibodies are formed against this. PF4-IgG attaches to and cross links the Fc receptors on platelet surfaces -> activation and aggregation (including release of more PF4 from a-granules) + removal of platelets by macrophages = thrombocytopenia + 50% get thrombosis which is the most serious complication.
In parallel maybe prothrombotic augmentation by activated endothelium from binding of HIT antibodies to PF4-like protein on their surface.

34
Q

What is the autoimmune disorder, that leads to a hypercoagulable state, antiphospholipid antibody syndrome (APS) characterised by?

A
  • presence of one or more antiphospholipid antibodies (directed against anionic phospholipids or associated proteins, particularly anti-B2-glycoprotein)
  • venous or arterial thromboses, or pregnancy complications like recurrent miscarriages, unexplained fetal death and premature birth
35
Q

What are two tests that APS can lead to unexpected results?

A
  • PTT - will prolong this due to interference with phospholipids
  • Syphilis serology - can result in a false positive as the antigen is embedded in cardiolipin (a phospholipid associated protein)
36
Q

In which direction do thrombi tend to propagate?

A

Towards the heart (retrograde arterially and with blood flow venously)

37
Q

How can antemortem thrombi be distinguished from postmortem clots?

A
  • the lines of Zahn (gross and microscopic laminations of pale platelet and fibrin deposits alternating with darker red cell risk layers) signify the thrombus formed in flowing blood.
  • postmortem clots are gelatinous with a gravity dependent dark red portion of settled red cells and a yellow upper portion. Usually not attached to the underlying vessel wall.
38
Q

A combination of what four events can occur to thrombi after formation?

A
  • Propagation (accumulate additional platelets and fibrin)
  • Embolisation
  • Dissolution (older thrombi more resistant to this as more extensive fibrin and cross linking)
  • Organisation and recanalisation (with ingrowth of endothelium, smooth muscle and fibroblasts)
39
Q

Disseminated intravascular coagulation (DIC) can be a complication of a large number of conditions associated with systemic activation of thrombin. How does it cause harm?

A
  • Microvascular thrombi can cause diffuse circulatory insufficiency and organ dysfunction- particularly brain, lungs, heart and kidneys
  • Platelets and coagulation factors are consumed leading to risk of a bleeding catastrophe like hemorrhagic stroke or hypovolemic shock
40
Q

What are five possible consequences of a PE?

A
  • Clinically silent (60-80%) and become organised and incorporated into the vascular wall
  • If 60%< of pulmonary circulation obstructed, sudden death, acute right heart failure or cardiovascular collapse
  • Pulmonary haemorrhage (from rupture following obstruction of medium sized arteries)
  • Haemorrhage or infarction when small end-arteriolar branches are obstructed
  • Pulmonary HTN following multiple emboli over time
41
Q

What are the possible sources of systemic emboli?

A
  • 80% intracardiac mural thrombi (2/3 left ventricular wall infarcts and 1/4 left atrial dilation and fibrillation)
  • aortic aneurysms
  • atherosclerotic plaques
  • valvular vegetations
  • venous thrombi (paradoxical emboli)
  • 10-15% unknown
42
Q

What is fat embolism syndrome characterised by?

A

Pulmonary insufficiency, neurologic symptoms, anemia and thrombocytopenia.

43
Q

How does the pathogenesis of fat embolism syndrome involve both mechanical obstruction and biochemical injury?

A

Mechanical obstruction- fat microemboli with associated red cell and platelet aggregates can occlude pulmonary and cerebral microvasculature

Biochemical injury - release of free fatty acids causes toxic injury to endothelium, platelet activation and granulocyte recruitment.

44
Q

1.What volume of air in vascular circulation is necessary to produce a clinical effect in the pulmonary circulation, and 2. what may be fatal?

A
  1. > 100ml
  2. 300-500ml at 100ml/sec
45
Q

How do air emboli cause harm?

A

By blocking downstream perfusion and by inducing an intense inflammatory response in pulmonary capillaries, leading to release of cytokines that may damage the aveoli

46
Q

In decompression sickness what causes 1. The bends, and 2. The chokes?

A
  1. Rapid formation of gas bubbles (as nitrogen comes out of solution) within skeletal muscles
  2. Gas bubbles in the lungs causing oedema, haemorrhage, and focal atelectasis or emphysema.
47
Q

What is caisson disease?

A

A chronic form of decompression sickness were persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis

48
Q

In amniotic fluid embolism, what is the cause of most of the morbidity and mortality?

A

Biochemical activation of coagulation factors, components of the innate immune system and release of vasoactive substances leading to acute pulmonary HTN and right heart failure, in turn resulting in hypoxia, left heart failure, pulmonary oedema and diffuse alveolar damage.

49
Q

What leads to a red infarct as opposed to a white infarct?

A

White infarcts occur with arterial occlusion in solid organs with end-arterial circulation, and where tissue density limits seepage of blood from adjoining capillary beds into the necrotic area. Whereas red infarcts can occur under any situation where blood collects in the necrotic tissue, either from outflow obstruction, seepage, or reestablished supply

50
Q

List five types of shock

A
  • Cardiogenic
  • Hypovolemic
  • Shock associated with systemic inflammation
  • Neurogenic
  • Anaphylactic
51
Q

What are five factors believed to play major roles in the pathogenesis of shock?

A
  • Inflammatory and counter-inflammatory responses
  • Endothelial activation and injury
  • Induction of a pro-coagulant state
  • Metabolic abnormalities
  • Organ dysfunction
52
Q

What are three metabolic abnormalities that occur in septic shock?

A
  • Insulin resistance and hyperglycaemia
  • Adrenal insufficiency and a functional deficit of glucocorticoids following an initial surge in production
  • Lactic acidosis due to hypoxia diminishing oxidative phosphorylation
53
Q

What causes insulin resistance and hyperglycaemia in septic shock, and what effect does this have?

A
  • Gluconeogenesis driven by cytokines (TNF, IL-1), stress-induced hormones (glucagon, growth hormone, glucocorticoids) and catecholamines
  • Pro-inflammatory cytokines suppress insulin release and promote insulin resistance
  • Hyperglycaemia decreases neutrophil function and increases endothelial adhesion molecule expression
54
Q

What is the name and function of the transcription factor that is activated and translocated to the nucleus in response to ligation of inflammatory receptors?

A

Nuclear factor-kB (NF-kB), increased expression of genes encoding inflammatory mediators

55
Q

What are the three general stages of the progression of shock?

A
  1. Nonprogressive stage - reflex compensatory mechanisms maintain vital organ perfusion
  2. Progressive stage - tissue hypoperfusion and onset of worsening circulatory and metabolic derangement, including acidosis
  3. Irreversible stage - even if hemodynamic defects are corrected, survival is not possible due to severity of cellular and tissue injury
56
Q

Where are fibrin thrombi most readily visualised?

A

Kidney glomeruli

57
Q

What can adrenal cortical cell lipid depletion reflect?

A

Increased use of stored lipids for steroid synthesis in stress.

58
Q

Septic shock is caused by a dysregulated host response to bacterial or fungal infection, what is it characterised by?

A

Endothelial cell activation, vasodilation, oedema, DIC and metabolic derangements

59
Q

What are some values and limitations of testing for activated protein C resistance (the coagulation times for a control and with added protein C are compared)

A
  • High sensitivity and specificity
    • unless on anticoagulant therapy
  • An abnormal APCR does not necessarily indicate predisposition to further thrombosis (about 5% of the population will have this)
60
Q

If a low level of protien C and/or protein S is detected repeat testing is recommended, why is this?

A

Numerous factors can reduce protien C and S, not just thrombophilia. (? Also levels naturally fluctuant ?)
E.g. anticoagulants, pregnancy

BPS (13 decks)

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