fluid pathology Flashcards
Shock (general and hypovlaemic/haemorrhagic)
What is the definition of shock?
A reduction in cardiac output or the effective circulating blood volume, resulting in
hypotension, impaired tissue perfusion and cellular hypoxia
What are the major categories of shock? Please give examples
● Cardiogenic - AMI, cardiotoxins, arrhythmias
● Obstructive - tension pneumothorax, cardiac tamponade, massive PE
● Hypovolaemic - haemorrhagic, burns, GI losses
● Distributive - anaphylaxis, adrenal crisis
● Neurogenic - spinal injury , spinal anaesthetic
● Some people add in an additional category of Septic shock or systemic
inflammation but this can also be considered a form of distributive shock - sepsis,
pancreatitis, trauma (independent of haemorrhage)
Describe the stages of haemorrhagic shock
There are three main stages
● Non progressive - where reflex compensatory mechanisms are able to maintain
vital organ perfusion
● Progressive- which is characterised by tissue hypo-perfusion and the onset of
some early metabolic disturbances
● Irreversible - characterised by non reversible cellular injury, manifesting as
multi-organ failure
What happens at the cellular and tissue level during the irreversible phase?
● At a cellular level there is lysosomal rupture, cell membrane damage and
mitochondrial dysfunction
● At a tissue level, it is useful to think about the major organs critically affected in
the shock process:
○ Decreased myocardial contractility
○ Acute tubular necrosis leading to acute renal failure
○ Ischaemic gut leading to bacteraemic shock
Describe the initial clinical presentation of shock
● Tachycardia
● Tachypnoea
● Reduced urine output
● Cool peripheries, clammy skin and Increased capillary refill time
● Narrowed pulse pressure
● As shock progresses - hypotension, altered mental state and cyanosis
Septic Shock
What are the mechanisms of gram negative sepsis?
Combination of direct microbial injury and overwhelming activation of host inflammatory
responses by endotoxins.
These mechanisms include:
● Activation of the innate cells of the immune system - neutrophils, macrophages
and monocytes
● Humoral interaction to activate complement and coagulation pathways
● Direct endothelial injury and activation
This leads to
● Inflammatory mediator release - TNF, IL (1,6,8,10), PGS, NO, PAF, ROS.
● Metabolic abnormalities (insulin resistance, hyperglycaemia, glucocorticoid
disturbances)
● Immune suppression via activation of counter regulatory mechanisms with
anti-inflammatory mediators, lymphocyte apoptosis and hyperglycaemic inhibition
of neutrophils.
What is an endotoxin?
Endotoxin refers to bacterial cell wall lipopolysaccharides, usually associated with gram
negative bacilli. These are only produced when the bacteria lyses - or ‘ends’ hence
endotoxin).
In contrast exotoxins are proteins which are produced and actively excreted by bacteria
(excreted exotoxins, life ending endotoxins)
Consists of a generic fatty acid core and a complex polysaccharide coat unique for each
species.
What is the effect of endothelial cell activation and injury during septic shock?
Thrombosis, increased vascular permeability and vasodilation.
What chemical mediators are involved in septic shock?
● Vasoactive amines - histamine and serotonin
● Plasma proteases - complement, kinins
● Platelet activating factor
● Cytokines - IL-1 and TNF
● Lysosomal constituents - proteases, lysozymes
● Oxygen free radicals, neuropeptides and nitric oxide
What are the effects of the inflammatory mediators on the coagulation pathway?
Microvascular thrombosis, decreased fibrinolysis and DIC
What factors determine the severity and outcome of septic shock in an individual?
● Disease factors: Extent and virulence of the infection
● Host factors: Immune status, Presence of other comorbidity, Pattern and level of
mediator production
What are the potential outcomes of septic shock?
Good to try and break it down by organ here:
● At the heart we might see depression of myocardial activity, or cardiomyopathy
● Our large blood vessels dilate causing distributive hypotension
● In our lungs, leaky blood vessels permit fluid accumulation in small airways
causing ARDS
● Inappropriate activation of the clotting cascade results in DIC
● Finally theres a cascade of progressive multi organ dysfunction / failure leading
to confusion, coma and death
● Liver failure
● Renal failure
Haemostasis
Describe the sequence of events at the site of a vascular injury
● Immediate local blood vessel response: reflexive vasoconstriction mediated by
endothelin
● Primary haemostasis, activated by exposed ECM permits platelet plug formation
● Secondary haemostasis activated by intrinsic / extrinsic pathways permits
stabilisation of the platelet plug with fibrin meshwork
○ Tissue factors exposed, Factor III, thromboplastin, Fac tor VII,
consolidation of the platelet plug with the generation of thrombin and fibrin
● All the while, counter regulatory mechanisms (including tPA) prevent
inappropriate clot extension and local vessel occlusion
Describe the process of primary haemostasis
Primary haemostasis refers to formation of the platelet plug.
These steps include: (1) adherence (2) activation (3) aggregation
● Endothelial damage exposes extracellular matrix (collagen, vWF)
● Platelet adhesion via GP1b to the von Willebrand Factor (vWF) on exposed ECM
● Platelets activate, causing shape change from flat to round and secrete granules
- ADP, TXA2 and phospholipids
● Platelet aggregation via platelet GpIIb-IIIa receptor binding to fibrinogen
What are the haematological and clinical effects of von Willebrand disease?
● Von Willebrand Disease (VWD) refers to either a deficiency in von Willebrand
Factor. This can either be a functional or true deficiency.
● The main function of vWF is facilitation of the adhesion of platelets to
subendothelial collagen in haemostasis.
● It also leads to factor VIII dysfunction because in normal physiology vWF forms a
complex with Factor VIII preventing it from being degraded.
Haem effects: Increased bleeding time with normal platelets, (Types 1 & 3)
Clinical effects: Spontaneous bleeding from mucous membranes, increased bleeding
from wounds, menorrhagia, bleeding into joints is rare outside of type 3
What are the types of VWF?
Three main types:
● Type 1 most common (70%), autosomal dominant, decreased circulating vWF,
usually mild.
● Type 2 less common(15-20%), autosomal dominant, defective vWF, mild.
● Type 3 rare, autosomal recessive, decreased circulating vWF, severe.
Coagulation Cascade
Give an overview of the coagulation cascade.
● It is the component of haemostasis resulting in thrombosis.
● It involves a series of conversions of inactive pro-enzymes to activated enzymes,
culminating in the formation of thrombin and insoluble fibrin meshwork.
● It comprises extrinsic and intrinsic pathways.
● The extrinsic pathway is activated by tissue factor exposed at sites of tissue
injury
● The intrinsic pathway is activated by Factor XII
● These pathways converge at the activation of Factor X into the common pathway
● The common pathway involves factor X, prothrombin, thrombin, Factor V,
Calcium and ultimately leads to the conversion of the soluble plasma protein
fibrinogen to fibrin, which is an insoluble protein.
● Fibrin then ultimately becomes cross linked.
What does prothrombin time measure?
Extrinsic and common coagulation pathways (factors VII, V, X, prothrombin, and
fibrinogen)
What does the partial thromboplastin time measure?
Intrinsic and common pathways
The way I remember this is that the PT, which is a shorter acronym, tests the shorter
pathway (extrinsic)
In the normal coagulation cascade, what happens after factor X is activated?
Activation of factor 10 marks the start of the of the common coagulation cascade
● Conversion of prothrombin (II) to thrombin (IIa) requires calcium and activated
Factor V (Va) as cofactors. It occurs on the surface of damaged endothelium
● Activated factor 2 (also known as thrombin) catalyses fibrinogen (I) to fibrin (Ia) in
the presence of calcium
● Thrombin also catalyses factor XIII to XIIIa, which is known as stabilising factor,
permitting increased cross linking of fibrin and the formation of a stable fibrin clot
Regulation of Clot Formation
What mechanisms restrict the activity of the coagulation cascade to the site of a
vascular injury?
● Firstly Factor activation is restricted to the site of exposed phospholipids
● Secondly, there are Natural anticoagulants, of which there are three types
○ Antithrombins (e.g AT3) inhibit the activity of thrombin and other serine
proteases (IXa, Xa, XIa, XIIa). AT3 is activated by binding to heparin like
molecules on the endothelium - which is the mechanism we take
advantage of when we use heparin for anticoagulation
○ Protein C & S - these are vitamin K dependent proteins which directly
inactivate factors Va and VIIIa.
○ Tissue Factor Pathway Inhibitor (TFPI) impedes the early stages of the
coagulation cascade through affinity for factors VIIa and Xa
● Fibrinolytic Cascade Activation:
○ Plasmin - Plasminogen is converted to plasmin by factor XII or by the two
other plasminogen activators (u-PA or t-PA). It breaks down fibrin and
interferes with polymerisation. The resulting fibrin degradation products
also act as weak anticoagulants.
● Endothelial cells modulate the coagulation/anticoagulation balance by releasing
Plasminogen activator inhibitor (PAI) which blocks fibrinolysis by inhibiting the
binding of t-PA to fibrin
Describe the process of normal fibrinolysis
● Plasmin is produced from circulating plasminogen either by factor XIIa dependent
pathway or by plasminogen activators
● Plasmin breaks down fibrin to fibrin degradation products (detected by D-dimer
test) and disrupts polymerisation
● t-PA from endothelial cells is the most important PA and is most active when
attached to fibrin. Urokinase is similar to t-PA (u-PA) and is a circulating protein
that has the same effect
● Free plasmin is inactivated by alpha 2 plasmin inhibitor
Haemophilia
What is Haemophilia A?
A reduction in the amount or activity of factor VIII (also called anti-haemophilic factor)
Factor VIII is a cofactor for factor IX in the activation of Factor X
How is haemophilla A inherited?
X-linked recessive trait, so affects males and homozygous females
30% have no family history so it can occur as a result of random mutation
