Etiopathogenesis;
1. Damage associated: burn, trauma,
Systemic intestinal ischemia hematologic
malignancy
inflammatory 2. Pathogen associated: bacterial,
viral, fungal, toxic shock
response syndrome
- Defense response of body to a
stressor eg: infection, trauma - Sepsis starts w SIRS and
- Involves release of acute phase progresses to multiple organ
reactants dysfunction syndrome (MODS). 5
- Dysregulated cytokine reaction can stages from SIRS -> MODS
cause a massive inflammatory
cascade that can lead to
irreversible or reversible organ 1. Normal inflammatory response:
dysfunction or death Local reaction at site of injury that
- SIRS occurs when there is an aims at containing injury and limit
unbalance between spread.
proinflammatory and - Immune effector cells at
antiinflammatory phases tilting the site release cytokines that
balance to proinflammatory phase stimulate
monocyte/macrophage
SIRS phases: system promoting wound
1. Proinflammatory: starts w repair thru local
activation of cellular process inflammation
designed to restore tissue function - Local vasodilation
2. Anti-inflammatory; avoids - Leakage of cells and
excessive proinflammatory activity protein rich fluid in
and restores patient homeostasis extravascular space causes
swelling and increased heat
SIRS needs at least 2 of these; - Inflammatory mediators
- temp : >38 / <36 affect sensory nerves
- HR; >90bpm causing pain and loss of
- Resp; >20 or PaCO2: <32 function (so body can repair
- WBC: >1200 / <4000 and avoid use)
2. Early antiinflammatory response
Sepsis: SIRS w a suspected source of (CARS): attempt to maintain
infection. immunological balance
Severe sepsis: one or more end organ 3. Scale tips towards proinflammatory
failures SIRS resulting in endothelial
Septic shock: sepsis w a hemodynamic dysfunction, coagulopathy and
instability regardless of intravascular activation of coagulation pathway.
volume - Results in end end organ
microthrombosis and increase in
- Almost all septic patients have capillary permeability w plasma
SIRS but not all SIRS are septic filtering interstitial space
4. State of relative
immunosuppression. Patient
, becomes susceptible to 2ry snd adrenaline release. results in
infections, perpetuating the sepsis tachycardia, higher cardiac output
cascade 2. stimulation of pituitary hormones.
5. Manifests in MODS w persistent
dysregulation of SIRS and CARS
response Hormones involved in SIRS;
- Neutrophils, macrophages, - ACH: released amount is
mast cells, platelets and proportional to injury, promotes
endothelial cells activated cortisol production
- 3 pathways - Catecholamine; activates
1. Activation of IL-1 adrenergic system thru release of
and tumour necrosis epinephrine and norepinephrine
factor alpha - induces hypermetabolic state
(TNF-a), which are - reduce insulin and increase
early mediators glucagon -> hyperglycemia
within the 1st hour
2. Activation of - Insulin; anabolic effect
prostaglandin and - Aldosterone; maintains
leukotriene pathway intravascular volume, keeps Na+
3. Activation of and removes K+ and H+
C3a-C5a - Deficiency leads to hypotension
complement and hyperkalemia
pathway
The release of IL1 nad TNF-a result in
dissociation of nuclear factor kB (NF-kB) HEMOSTASIS AND
from its inhibitor which releases other
proinflammatory cytokines (IL6/8) COAGULATION
- IL1 & TNF-a also responsible for
● Stops bleeding after vascular injury
alteration of coagulation causing ● Keeps blood fluid in intact vessels
microcirculatoy abnormalities ● Involves a balance between:
- Fibronolysis becomes impaired ○ Clot formation
○ Clot removal (fibrinolysis)
and there is direct endothelial
injury which activates coagulation OVERVIEW OF STEPS
cascade
- as a result there is widespread Hemostasis occurs in three major stages:
microvascular thrombosis,
1. Vascular constriction
increase in permeability, fragility all 2. Primary hemostasis (platelet plug formation)
leading to organ dysfunction 3. Secondary hemostasis (coagulation cascade
→ fibrin clot)
the compensatory anti inflammatory
response is mediated by IL4 & IL10 which
inhibit TNF-a,IL1/6/8 1️⃣ VASCULAR
CONSTRICTION
How nervous system regulates
inflammation ● Immediate response to injury
● Short-lived (minutes to hours)
1. activation of sympathetic nervous
● Reduces blood flow
system that leads to noradrenaline
, ○ GpIIb/IIIa receptors
Mechanism ○ Fibrinogen bridges
● Injury → smooth muscle contraction in vessel 👉 Forms a temporary platelet plug
📌 Important Points
wall
● Mediated by:
○ Reflex neurogenic mechanisms
○ Local factors
● Called Primary Hemostasis
Important Mediators ●
●
Rapid (seconds–minutes)
Reversible
● Not affected by heparin
● Thromboxane A₂ (TXA₂) → vasoconstriction + ● Defects → cause:
platelet aggregation ○ Petechiae
● Serotonin → vasoconstriction ○ Mucosal bleeding
● Endothelin → potent vasoconstrictor from
endothelium
3️⃣ SECONDARY
2️⃣ PRIMARY HEMOSTASIS HEMOSTASIS
(PLATELET PLUG) Platelets
(COAGULATION)
(Thrombocytes)
● Normal count: 150,000–400,000/mm³ Purpose
● Lifespan: ~7–10 days
● Produced in bone marrow (megakaryocytes) ● Stabilizes platelet plug with fibrin mesh
● Forms a strong, permanent clot
Steps in Platelet Plug
COAGULATION CASCADE
Formation
A series of inactive clotting factors → activated
1. Adhesion sequentially
● Platelets adhere to exposed collagen PATHWAYS
● Requires:
○ von Willebrand factor (vWF)
Extrinsic Pathway (FAST)
○ Platelet receptor: GpIb
● Trigger: tissue injury
👉 Occurs only at damaged endothelium ●
●
Key factor: Factor VII
Involves:
○ Tissue factor (Factor III)
2. Activation ○ Calcium
●
●
Platelets change shape (spiky → sticky)
Release granules:
👉 Clinically measured by: PT (Prothrombin Time)
Intrinsic Pathway (SLOW)
Dense granules:
● Trigger: blood contact with collagen
● ADP → recruits more platelets
● Factors involved:
● Calcium → required for coagulation
○ XII → XI → IX → VIII
● Serotonin → vasoconstriction
Alpha granules:
👉 Measured by: aPTT
● Fibrinogen Common Pathway
● Factor V
● Platelet factor 4 (PF4) Both pathways converge at:
3. Aggregation ● Factor X → Xa
● Leads to:
● Platelets stick to each other ○ Prothrombin (II) → Thrombin
● Mediated by:
1. Damage associated: burn, trauma,
Systemic intestinal ischemia hematologic
malignancy
inflammatory 2. Pathogen associated: bacterial,
viral, fungal, toxic shock
response syndrome
- Defense response of body to a
stressor eg: infection, trauma - Sepsis starts w SIRS and
- Involves release of acute phase progresses to multiple organ
reactants dysfunction syndrome (MODS). 5
- Dysregulated cytokine reaction can stages from SIRS -> MODS
cause a massive inflammatory
cascade that can lead to
irreversible or reversible organ 1. Normal inflammatory response:
dysfunction or death Local reaction at site of injury that
- SIRS occurs when there is an aims at containing injury and limit
unbalance between spread.
proinflammatory and - Immune effector cells at
antiinflammatory phases tilting the site release cytokines that
balance to proinflammatory phase stimulate
monocyte/macrophage
SIRS phases: system promoting wound
1. Proinflammatory: starts w repair thru local
activation of cellular process inflammation
designed to restore tissue function - Local vasodilation
2. Anti-inflammatory; avoids - Leakage of cells and
excessive proinflammatory activity protein rich fluid in
and restores patient homeostasis extravascular space causes
swelling and increased heat
SIRS needs at least 2 of these; - Inflammatory mediators
- temp : >38 / <36 affect sensory nerves
- HR; >90bpm causing pain and loss of
- Resp; >20 or PaCO2: <32 function (so body can repair
- WBC: >1200 / <4000 and avoid use)
2. Early antiinflammatory response
Sepsis: SIRS w a suspected source of (CARS): attempt to maintain
infection. immunological balance
Severe sepsis: one or more end organ 3. Scale tips towards proinflammatory
failures SIRS resulting in endothelial
Septic shock: sepsis w a hemodynamic dysfunction, coagulopathy and
instability regardless of intravascular activation of coagulation pathway.
volume - Results in end end organ
microthrombosis and increase in
- Almost all septic patients have capillary permeability w plasma
SIRS but not all SIRS are septic filtering interstitial space
4. State of relative
immunosuppression. Patient
, becomes susceptible to 2ry snd adrenaline release. results in
infections, perpetuating the sepsis tachycardia, higher cardiac output
cascade 2. stimulation of pituitary hormones.
5. Manifests in MODS w persistent
dysregulation of SIRS and CARS
response Hormones involved in SIRS;
- Neutrophils, macrophages, - ACH: released amount is
mast cells, platelets and proportional to injury, promotes
endothelial cells activated cortisol production
- 3 pathways - Catecholamine; activates
1. Activation of IL-1 adrenergic system thru release of
and tumour necrosis epinephrine and norepinephrine
factor alpha - induces hypermetabolic state
(TNF-a), which are - reduce insulin and increase
early mediators glucagon -> hyperglycemia
within the 1st hour
2. Activation of - Insulin; anabolic effect
prostaglandin and - Aldosterone; maintains
leukotriene pathway intravascular volume, keeps Na+
3. Activation of and removes K+ and H+
C3a-C5a - Deficiency leads to hypotension
complement and hyperkalemia
pathway
The release of IL1 nad TNF-a result in
dissociation of nuclear factor kB (NF-kB) HEMOSTASIS AND
from its inhibitor which releases other
proinflammatory cytokines (IL6/8) COAGULATION
- IL1 & TNF-a also responsible for
● Stops bleeding after vascular injury
alteration of coagulation causing ● Keeps blood fluid in intact vessels
microcirculatoy abnormalities ● Involves a balance between:
- Fibronolysis becomes impaired ○ Clot formation
○ Clot removal (fibrinolysis)
and there is direct endothelial
injury which activates coagulation OVERVIEW OF STEPS
cascade
- as a result there is widespread Hemostasis occurs in three major stages:
microvascular thrombosis,
1. Vascular constriction
increase in permeability, fragility all 2. Primary hemostasis (platelet plug formation)
leading to organ dysfunction 3. Secondary hemostasis (coagulation cascade
→ fibrin clot)
the compensatory anti inflammatory
response is mediated by IL4 & IL10 which
inhibit TNF-a,IL1/6/8 1️⃣ VASCULAR
CONSTRICTION
How nervous system regulates
inflammation ● Immediate response to injury
● Short-lived (minutes to hours)
1. activation of sympathetic nervous
● Reduces blood flow
system that leads to noradrenaline
, ○ GpIIb/IIIa receptors
Mechanism ○ Fibrinogen bridges
● Injury → smooth muscle contraction in vessel 👉 Forms a temporary platelet plug
📌 Important Points
wall
● Mediated by:
○ Reflex neurogenic mechanisms
○ Local factors
● Called Primary Hemostasis
Important Mediators ●
●
Rapid (seconds–minutes)
Reversible
● Not affected by heparin
● Thromboxane A₂ (TXA₂) → vasoconstriction + ● Defects → cause:
platelet aggregation ○ Petechiae
● Serotonin → vasoconstriction ○ Mucosal bleeding
● Endothelin → potent vasoconstrictor from
endothelium
3️⃣ SECONDARY
2️⃣ PRIMARY HEMOSTASIS HEMOSTASIS
(PLATELET PLUG) Platelets
(COAGULATION)
(Thrombocytes)
● Normal count: 150,000–400,000/mm³ Purpose
● Lifespan: ~7–10 days
● Produced in bone marrow (megakaryocytes) ● Stabilizes platelet plug with fibrin mesh
● Forms a strong, permanent clot
Steps in Platelet Plug
COAGULATION CASCADE
Formation
A series of inactive clotting factors → activated
1. Adhesion sequentially
● Platelets adhere to exposed collagen PATHWAYS
● Requires:
○ von Willebrand factor (vWF)
Extrinsic Pathway (FAST)
○ Platelet receptor: GpIb
● Trigger: tissue injury
👉 Occurs only at damaged endothelium ●
●
Key factor: Factor VII
Involves:
○ Tissue factor (Factor III)
2. Activation ○ Calcium
●
●
Platelets change shape (spiky → sticky)
Release granules:
👉 Clinically measured by: PT (Prothrombin Time)
Intrinsic Pathway (SLOW)
Dense granules:
● Trigger: blood contact with collagen
● ADP → recruits more platelets
● Factors involved:
● Calcium → required for coagulation
○ XII → XI → IX → VIII
● Serotonin → vasoconstriction
Alpha granules:
👉 Measured by: aPTT
● Fibrinogen Common Pathway
● Factor V
● Platelet factor 4 (PF4) Both pathways converge at:
3. Aggregation ● Factor X → Xa
● Leads to:
● Platelets stick to each other ○ Prothrombin (II) → Thrombin
● Mediated by:
