Haemodynamic disorders thrombosis and shock Flashcards
What are the 5 causes of oedema
- Increased hydrostatic pressure
- Reduced plasma oncotic pressure
- Lymphatic obstruction
- Salt retention
- Leaky endothelium
Give examples of scenarios that result in increased hydrostatic pressure
- Impaired venous return
- CHF
- Constrictive pericarditis
- Ascites (liver cirrhosis)
- Venous obstruction or compression (thrombosis or external pressure e.g mass)
- Lower extremity inactivity with prolonged dependency - Arteriolar dilation
- Heat
- Neurohumoral dysregulation
Give examples of scenarios that reduce plasma oncotic pressure
- malnutrition
- liver cirrhosis (ascites)
- Protein losing glomerulopathies (nephrotic syndrome)
- Protein losing gastroenteropathy
Give examples of clinical scenarios that result in lymphatic obstruction
inflammatory
neoplastic
postsurgical
post-irradiation
Give examples of clinical scenarios that cause salt retention
- Excessive salt intake with renal insufficiency
- Increased tubular reabsorption of Na > renal hypoperfusion, increased renin-angiotensin-aldosterone secretion
Increased endothelial permeability is the pathogenesis of oedema occurring in…
- local anaphylaxis
- adult respiratory distress syndrome
Development of generalised oedema in chronic liver failure involves
- increased renal Na retention
- increased renal renin secretion
- reduced plasma colloid osmotic pressure
Intact endothelium synthesizes and secrete or ‘presents’
- thrombomodulin
- adenosine diphosphatase (ADP-ase)
- prostacyclin (PGI2)
- plasminogen activator
- NO
- Heparin like molecules
What is an exudate
Protein rich fluid that accumulates due to increase in vascular permeability caused by inflammatory mediators.
Protein rich, cloudy due to presence of white cells.
What is a transudate
Non inflammatory and protein poor effusions (e.g heart failure etc)
Normally translucent, straw coloured with the exception of peritoneal effusions caused by lymphatic blockage (chylous effusion), can be milky due to presence of lipid.
Compare and contrast hyperemia and congestion
Both stem from increased blood volumes in tissues.
Hyperemia - active process, active arteriolar dilation (e.g sites of inflammation or muscle during exercise). Leads to increased blood flow and oxygen delivery. RED TISSUE
Congestion - passive process due to reduced venous outflow, can be systemic (CHF) or localised (DVT). CYANOTIC. Can lead to scarring.
Outline the general sequence of events leading to haemostasis at the site of vascular injury
- Arteriolar vasoconstriction
- Occurs immediately, due to neurogenic mechanisms and release of endothelin.
- Transient effect. - Primary haemostasis
- Formation of the platelet plug
- Disrupted endothelium exposes subendothelial vWF and collagen which promotes platelet adherence and activation.
- Activated platelets release secretory granules and change their shape (spiky increasing their surface area)
- Secretion promotes more platelets and aggregation = primary haemostatic plug. - Secondary haemostasis
- Tissue factor is exposed by vasular injury.
- A membrane bound glycoprotein (found in subendothelial cells).
- Tissue factor binds to factor 7, kicks off coagulation cascade. Thrombin cleaves fibrinogen to fibrin = mesh network + potent activator of platelets = more platelets = consolidation of plug. - Clot stabilisation and resorption.
- Fibrin and platelet contract = solid permanent plug.
- Counter-regulatory mechanisms e.g TPA limit clotting to site of injury and eventually lead to clot resorption and repair.
What cells are the central regulators of haemostasis
Endothelial cells, balance between the antithrombic/prothrombotic activites determine if thrombus formation, propogation or dissolution occur.
What shape are platelets are where are they found
- Anucleate disc shaped cell shed from megakaryocytes in bone barrow and float in circulation.
What critical role do platelets play in haemostasis
Formation of primary plug
Provide a surface that binds and concentrates activated coagulation factors.
What two granules do platelets release
- Alpha granules: Have the adhesion molecule P-selectin in their membrane. Contain proteins involved in coagulation (vWF, V, fibrinogen), as well as factors involved in healing like PDGF).
- Dense bodies/delta granules: Contain ADP, ATP, calcium, serotonin, adrenaline.
4 steps involved in formation of primary plug
- Platelet adhesion
- Platelet shape change
- Secretion of granules
- Aggregation
Outline how platelet adhesion works (first step in plug formation)
Mediated by interactions between Gp1b (platelet receptor) and vWF.
Gp1a/IIa also invovled
Outline how platelets change shape (second step in plug formation)
- Go from smooth discs to spiky sea urchins that increase SA.
- Results in a conformational change in cell surface glycoprotein (iib/iiia) which increases affinity for fibrinogen AND translocation of negatively charged phospholipids (bind calcium and acts as sites for assembly of coag complexes)
Outline the secretory step of platelet plug formation
Occurs alongside the change in shape (these two steps are often referred together as platelet activation).
Triggered by multiple factors including thrombin and ADP.
Thrombin activates platelets by GPCR (protease activated receptor).
ADP is a component of dense granules. It acts as mediator for further platelet activation (i.e recruitment).
Activated platelets produce TXA2 which induces platelet aggregation.
Outline the steps in platelet aggregation.
Platelet activation is followed by platelet aggregation.
Conformational change of GPIIa/IIIa allows fibrinogen to bind, which forms a bridge between adjacent platelets.
Initial wave of aggregation is reversible.
Thrombin is then activated, promotes more platelet aggregation + irreversible platelet contraction.
Thrombin also converts fibrinogen into the insoluble fibrin = secondary haemostatic plug.
Following injury to a small artery, the formation of a temporary platelet plug is… (4 things)
- unaffected by therapeutic doses of heparin
- unaffected by therapeutic doses of dicoumarol
- associated with local vasoconstriction
- is not followed by the conversion of insoluble plasma fibrinogen to insoluble fibrin
What does the PT asssess
extrinsic pathway
What does PTT assay scree for
Intrinsic pathway
Coagulation cascade ####
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Anti-thrombotic properties of intact endothelium that are directed at platletets
PGI2 (COX1)
NO (eNOS)
ADPase (inhibits ADP)
Anti-thrombotic properties of intact endothelium that are directed at coagulation
- Thrombomodulin activation of Protein C/S
(thrombomodulin protein C receptor bind thrombin and protein C, this activates protein C/ S complex that inhibits coagulation via Va and VIIIa). - Alpha macroglobulin
- Heparin like molecules activate Antithrombin III (inhibits thrombin and factors 9,10,11,12)
Anti-thrombotic properties of intact endothelium that are directed at fibrinolysis.
tPA
Prothrombotic properties of the injured endothelium that are directed at platelets
vWF
pAF
Prothrombotic properties of the injured endothelium that are directed at coagulation
Tissue facor
binding factors 9a, 10a
Factor V
Pro-thrombotic properties of the injured endothelium that are directed fibrinolysis
t-pA inhibitor
What is virkows triad
Abnormalities that lead to thrombosis
1. Endothelial injury
2. Stasis or turbulent blood flow
3. Hyper-coagulability of blood
How does abnormal blood flow contribute to thrombosis
Normally flow is laminar, and platelets travel in centre of the lumen. Disruption to laminar flow leads to
- Platelets touching endothelium inappropriately
- Promotion of endothelial activation (changes expression of pro-inflammatory factors)
- Prevents washout and dilution of activated clotting factors (i.e clots remain and clotting factor inhibitors cant get in)
How does endothelial injury contribute to thrombosis
Exposed vwf and TF
activated endothelial cells secrete PAI’s which limit fibronolysis and down regular t-PA
Activated endothelial cells also downregulate thrommbomodulin
How does a hypercoagulable state pre-dispose to thrombosis (give a genetic example)
Alterations in coagulation factors can be genetic or acquired.
V gene mutations
- 2-15% of white population
- 60% with recurrent DVT
carry a mutation call the Leiden mutation, renders factor V resistant to cleavage by activated protein C (counter regulatory pathway is lost)
What conditions pre-dispose to thrombosis
- Polyarteritis nodosa
- Giant cell arteritis
- Buerger’s disease
- T akayasu’ s disease
What 4 things might a PE cause
- pulmonary artery atherosclerosis
- chronic pulmonary hypertension 3. no clinical effect
- cardiogenic shock
What 4 things might a fat emboli cause
- result from severe soft tissue trauma
- results from abdominal trauma in the alcoholic 3. cause DIC
- cause the ARDS
Relationship between mitral stenosis, PE and infarction.
if a patient with mitral stenosis has a pulmonary embolus, infarction is esp. likely to occur BECAUSE
The bronchial arterial supply is reduced in mitral stenosis
What is the fate of a thrombus
Fate of a thrombus
1. Propogate: causing progressive complete vessel obstruction (by accumulation of additional platelets and fibrin)
2. Embolism > Dislodge and travel to other sites (PE)
3. Dissolution by fibrinolytic activity
- Only in recent thrombi, once established they become resistant to lysis (i.e this is why you cant give t-pa too late)
4. Organization & recanalization (small amount of lumen re-established, clot becomes part of the wall)
What is a fat embolisation characterised by
Pulmonary insufficiency
Neurologic symptoms
Anaemia
Thrombocytopenia
Death (in 5-15%)
- result from severe soft tissue trauma
- results from abdominal trauma in the alcoholic
- cause DIC
- cause the ARDS
4 things about PE
- fatal PE is usually due to impaction of a large embolus in the main pulmonary artery and its branches, or in the RV
- to do this > the embolus must be large, and has to come from the leg, normally
- thrombi can occur in both pelvic and leg veins
- but in fatal pulmonary embolus > the cause is rarely from the pelvis
