A descriptive guide to thromboembolism.

1. Thrombosis
• formation of a blood clot (thrombus) within intact blood vessels or heart
chambers.
• Hemostasis: Prevents bleeding after vascular injury.
• Thrombosis: Blood clot forms without vessel rupture, leading to obstruction.

2. Virchow’s Triad (Key Concept)
Three primary influences on thrombus formation:
– Endothelial injury
– Abnormal blood flow
– Hypercoagulability of blood

3. Endothelial Injury
• Most important cause for arterial thrombosis.
• Exposes subendothelial matrix → platelet adhesion → tissue factor release
→ coagulation cascade activation.
• Examples:
– Atherosclerosis
– Vasculitis
– Trauma
– Infective endocarditis

4. Endothelial Dysfunction (Functional Injury)
A shift in endothelial function from antithrombotic to prothrombotic,
either due to structural damage or functional changes, promoting
thrombosis.
Causes of Endothelial Injury/Dysfunction
Direct Injury (structural):Atherosclerosis (plaque rupture)Trauma,
endocarditis
Functional Alteration: Hypertension, diabetes Smoking,
hyperlipidaemia Inflammation, toxins, radiation

5. Procoagulant Changes: When the endothelium becomes dysfunctional or
injured, it shifts from anticoagulant to procoagulant activity by
 High Tissue Factor (TF) expression: Tissue factor directly activates the
extrinsic coagulation pathway, leading to thrombin generation and fibrin
formation.
 Low Thrombomodulin expression: Normally thrombomodulin binds
thrombin and activates protein C, an anticoagulant.
 Dysfunctional endothelium reduces thrombomodulin less protein C
activation more coagulation.
Antifibrinolytic Effects:
 Dysfunctional endothelium blocks the natural breakdown of clots by:
 High PAI-1 (Plasminogen Activator Inhibitor-1) production:PAI-1 inhibits
tissue plasminogen activator, normally convert plasminogen to plasmin.
Plasmin is the enzyme that dissolves clots (fibrinolysis).Therefore, more PAI-1
→ less plasmin → reduced fibrinolysis → clot persists.

6. Lower level of
 Protein c
 Thrombomodulin
 Tissue factor inhibitor
 Plasminogen activator

7. Abnormal Blood Flow
Abnormal Blood Flow
It contributes to
• Promote endothelial activation
• Allows platelets and leukocytes to come in contact with endothelium
• Slow down the washout of clotting factors
Turbulence: Causes endothelial injury, promotes thrombus formation
(common in arteries).
Stasis: Slows blood flow, promotes clotting (common in veins).
Examples:
• Mitral valve stenosis
• Dvt

8. Abnormal Blood Flow
It contributes to
• Promote endothelial activation
• Allows platelets and leukocytes to come in contact with endothelium
• Slow down the washout of clotting factors
Turbulence: Causes endothelial injury, promotes thrombus formation
(common in arteries).
Stasis: Slows blood flow, promotes clotting (common in veins).
Examples:
• Mitral valve stenosis
• Dvt

9. Hypercoagulability (Thrombophilia)
Increased tendency of blood to clot.
Types:
– Primary (genetic): Factor V Leiden mutation, Prothrombin mutation,
Antithrombin III deficiency.
– Secondary (acquired): Prolonged bed rest, cancer, pregnancy, oral
contraceptives, antiphospholipid syndrome.

10. Primary (Genetic) Hypercoagulability
These are often due to mutations in coagulation regulatory genes.
Factor V Leiden
It results from a specific genetic point mutation in the Factor V gene, activated Protein c resistance
Prothrombin Gene Mutation
Increases prothrombin (Factor II) levels in plasma.
High prothrombin → more thrombin → more fibrin → increased clotting.
MTHFR Mutation(methylenetetrahydrofolate reductase)
less folate activation → impaired homocysteine metabolism Homocysteine accumulates in blood. Elevated
homocysteine levels are prothrombotic:
Deficiencies of Natural Anticoagulants
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Elevated Clotting Factors
High levels of Factors VIII, IX, XI, or fibrinogen can enhance the clotting cascade.

11. • Antithrombin III deficiency
• Protein C deficiency
• Protein S deficiency
• Fibrinolysis defects

12. High Risk for Thrombosis
Prolonged bed rest or immobilization
• Myocardial infarction
• Atrial fibrillation
• Tissue injury (surgery, fracture, burn) Cancer Prosthetic cardiac valves
Disseminated intravascular coagulation
• Heparin-induced thrombocytopenia
• Antiphospholipid antibody syndrome

13. Lower Risk for Thrombosis
• Cardiomyopathy
• Nephrotic syndrome
• Oestrogen excess: Pregnancy, postpartum, oral contraceptives.
• Smoking
• Sickle cell anaemia

14. Fate of the Thrombus
Propagation
The thrombus enlarges due to accumulation of more platelets and fibrin.
Increases the risk of complete vascular occlusion or embolization (breaking
off into circulation)
Cause obstruction
Embolization
A piece of the thrombus detaches and travels through the bloodstream. It
may lodge elsewhere, e.g., lungs (PE), brain (stroke), kidneys, etc.

15. Dissolution
Fibrinolytic pathways (e.g., plasmin) degrade the thrombus.
Early thrombi (fresh) → susceptible to fibrinolysis.
Older thrombi → more cross-linked fibrin, become resistant to lysis.
The body’s primary system for thrombus dissolution is the fibrinolytic
system, which is activated after a clot has served its purpose. It involves the
conversion of plasminogen (a precursor) to plasmin, which degrades fibrin
and dissolves the thrombus.

16. Recanalization& organization
Definition:
Over time, older thrombi undergo organization, and new blood vessels
(capillaries) may form within the thrombus. This process is known as
recanalization.
Endothelial cells, smooth muscle cells, and fibroblasts invade the thrombus,
forming a granulation tissue. By closing the gap between endothelial cell and heal
wound.
New capillaries formation
 Bacterial residence
 Central enzymatic digestion occurs,
 Necrosis

17. Arterial Thrombi (White Thrombus):
Color: Pale or whitish, due to a predominance of platelets and fibrin (which are
lighter in color).
Composition: Rich in platelets, fibrin, and few red blood cells. Arterial thrombi
form rapidly and are usually associated with high shear stress.
Venous Thrombi (Red Thrombus):
Color: Red or dark red, due to a high concentration of red blood cells trapped
within the thrombus.
Composition: Rich in red blood cells and fibrin, with a lower platelet content
compared to arterial thrombi. Venous thrombi are generally associated with low
shear stress, which allows for the accumulation of red blood cells.

18. Microscopic Features of Thrombi
Platelets
Fibrin
Red blood cells
White blood cells
Endothelial cells

19. Changes in Thrombus Over Time
Acute thrombus: A freshly formed thrombus is loosely packed, and often
consists of platelets and fibrin.
Organizing thrombus: Over time, fibroblasts and endothelial cells invade the
thrombus, and new blood vessels (recanalization) may form within it. This
process helps restore some degree of blood flow through the vessel.
Recanalization: This is the formation of new vascular channels within the
thrombus, allowing partial restoration of the lumen.
Old thrombus: As thrombi age, they become firm and fibrous, often becoming
incorporated into the vessel wall. The thrombus may also undergo fibrosis or
calcification, making it more resistant to fibrinolysis.

20. Embolism
Embolism is the process by which an
Embolus
A mass of material travels through the bloodstream and becomes lodged in a
blood vessel, blocking normal circulation.
This blockage can cause ischemia (reduced blood flow) and damage to tissues
or organs.
Embolism is a significant pathological event and can have severe clinical
consequences depending on the location of the embolus.

21. Pulmonary Embolism (PE):
Source: Most often originates from thrombi in the deep veins of the legs (deep
vein thrombosis, or DVT), though it can also come from other parts of the body,
like the pelvic veins.
Pathophysiology: A thrombus breaks off and travels through the right side of
the heart, lodging in the pulmonary arteries, obstructing blood flow to the
lungs.
Clinical Consequences: Can lead to shortness of breath, chest pain, hypoxia,
and sudden death if the embolus is large enough.

22. Systemic Embolism
Source: Most commonly originates from the left side of the heart, especially
in conditions like atrial fibrillation, left ventricular mural thrombus, or
infective endocarditis.
Pathophysiology: The embolus travels through the aorta and into the arterial
circulation, potentially lodging in distant organs such as the brain (causing
stroke), kidneys, or legs (leading to limb ischemia).
Clinical Consequences: Depends on the site of occlusion; can cause stroke,
kidney infarcts, or limb ischemia.

23. Fat Embolism
Source: Occurs when fat globules are released into the bloodstream, most
commonly after bone fractures (especially of long bones) or trauma
involving adipose tissue.
Pathophysiology: Fat particles enter the bloodstream and can block small
vessels in the lungs, brain, or kidneys.
Clinical Consequences: Causes respiratory distress, neurologic symptoms,
and in some cases, petechial hemorrhages (small spots of bleeding on the
skin).

24. Air Embolism:
Source: Occurs when air or gas enters the vascular system, typically during
surgical procedures, trauma, or invasive medical procedures like central
venous catheter insertion.
Pathophysiology: Air bubbles enter the bloodstream, particularly affecting
venous circulation, and can impair blood flow.
Clinical Consequences: Causes hypotension, dyspnoea, chest pain, cyanosis,
and potentially cardiac arrest.

25. Amniotic Fluid Embolism:
Source: Amniotic fluid, which contains fetal cells, hair, and vernix (skin
covering), enters the maternal bloodstream during labour or delivery.
Pathophysiology: This leads to an inflammatory response and occlusion of
small pulmonary vessels.
Clinical Consequences: Results in respiratory distress, hypotension,
cardiogenic shock, coagulopathy, and disseminated intravascular
coagulation (DIC).

26. Disseminated Intravascular Coagulation (DIC)
DIC is a secondary condition where there is widespread thrombosis in the
microcirculation, leading to consumption of platelets and clotting factors, and
activation of fibrinolysis, which can cause both thrombosis and bleeding.
Causes:
• Obstetric complications (e.g., placental abruption, amniotic fluid embolism)
• Sepsis, especially from gram-negative bacteria
• Advanced malignancy
• Major trauma or burns

27. • Clinical Features:
• Microvascular thrombosis → organ dysfunction (e.g., brain, kidneys,
lungs, heart).
• Consumption coagulopathy: Platelet and coagulation factor depletion
leads to bleeding (e.g., petechiae, ecchymoses).
• Fibrinolytic activation → fibrinogen degradation, resulting in excessive
bleeding.

28. Shock
Shock is a clinical syndrome characterized by systemic hypoperfusion due to
either reduced cardiac output or reduced effective circulating blood volume,
resulting in cellular hypoxia and organ dysfunction.

29. Pathophysiological Mechanisms
Impaired Tissue Perfusion:
Shock leads to decreased cardiac output or widespread vasodilation, resulting
in insufficient blood flow to the tissues.
Anaerobic metabolism begins in tissues, leading to lactic acidosis worsening
cellular dysfunction.
Cellular Hypoxia:
Cells switch from aerobic to anaerobic metabolism due to oxygen deficiency.
Lactate and H⁺ ions accumulate, lowering tissue pH and impairing enzyme
function.
Inadequate oxygen delivery leads to mitochondrial dysfunction, compromising
ATP production.

30. Increased Capillary Permeability:
 Inflammatory mediators (e.g., cytokines, histamine, bradykinin) increase
capillary permeability, allowing fluid to leak into the interstitial space.
 Edema worsens tissue hypoxia and can impair organ function.
Vasodilation vs. Vasoconstriction:
 Distributive shock (especially septic shock) causes excessive vasodilation,
lowering systemic vascular resistance (SVR), and decreasing blood pressure.
 In hypovolemic and cardiogenic shock, there is compensatory
vasoconstriction to maintain blood pressure, which can shunt blood away
from non-essential organs (e.g., kidneys, skin)

31. Compensatory Mechanisms in Shock:
Neurohormonal Response:
Baroreceptor reflex detects low BP and activates the sympathetic nervous
system to increase heart rate (tachycardia) and contractility.
• The renin-angiotensin-aldosterone system (RAAS) activates to conserve
sodium and water, increasing blood volume.
• Antidiuretic hormone (ADH) is released to retain water and maintain vascular
tone.
Catecholamine Release:
• Increased epinephrine and norepinephrine further stimulate vasoconstriction
and heart rate/contractility .
• Nitric oxide (NO) production is inhibited in some shock types (especially
hypovolemic shock) to maintain vasoconstriction.

32. TYPES OF SHOCK
Shock is classified as follows:
1. Hypovolemic shock
2. Cardiogenic shock
3. Obstructive shock
4. Distributive shock
Anaphylactic shock
Septic shock
Neurogenic shock

33. ETIOLOGY
 Severe allergic reaction
 Significant blood loss
 Heart failure
 Blood infections
 Dehydration
 Poisoning
 Burns

34. Stages of Shock
Initial (Compensated) Stage – Reversible
There is low tissue perfusion due to low cardiac output or low circulating volume. However,
vital organs still receive adequate perfusion due to compensatory mechanisms.
Compensatory Responses:
Baroreceptor reflex → activates sympathetic nervous system
↑ Heart rate, ↑ cardiac contractility, vasoconstriction
⮕
RAAS activation (renin-angiotensin-aldosterone system)
Vasoconstriction and sodium/water retention
⮕
ADH release from posterior pituitary
Water reabsorption in kidneys
⮕
Catecholamine release (epinephrine, norepinephrine)
Maintains BP and perfusion
⮕

35. Clinical Signs & Symptoms
Tachycardia, narrowed pulse pressure
Cool, pale, clammy skin (due to peripheral vasoconstriction)
Mild hypotension or normal BP
Tachypnoea
Anxiety, restlessness
Slightly decreased urine output (early oliguria)
Capillary refill >2 seconds

36. Progressive Stage – Tissue
Hypoperfusion
Mechanism:
 Prolonged hypoperfusion → switch to anaerobic metabolism
 ↑ Lactic acid → metabolic acidosis
 Acidosis impairs vasoconstriction → vasodilation → pooling of
blood
 Endothelial injury → capillary leakage → tissue edema
 Decreased myocardial contractility due to acidosis and hypoxia
 Mitochondrial dysfunction → ↓ ATP → cell swelling, apoptosis
 Microvascular thrombosis due to endothelial damage and DIC risk

37. Clinical Signs & Symptoms
1. Marked hypotension and tachycardia
2. Rapid, shallow breathing (respiratory compensation for acidosis)
3. Cold, mottled skin
4. Oliguria ,rising serum creatinine
5. Confusion, altered mental status (early CNS hypoxia)
6. Possible signs of pulmonary congestion (especially cardiogenic shock)

38. Irreversible Stage (Refractory Shock)
Mechanism:
• Profound cellular and organ damage
• Mitochondrial failure → energy failure → irreversible cell injury
• Lysosomal enzyme leakage → autodigestion
• Loss of vasomotor tone → unresponsive vasodilation
• systemic inflammation/sepsis
• Disseminated intravascular coagulation (DIC) → bleeding and
thrombosis
• Multiple Organ Dysfunction Syndrome (MODS) develops

39. Clinical Signs & Symptoms
 Severe hypotension, bradycardia, weak or absent pulses
 Cold, cyanotic skin
 Coma, GCS ↓
 Anuria
 Respiratory failure → need for mechanical ventilation
 Liver failure → ↑ bilirubin, ↑ AST/ALT
 Bleeding (DIC) – petechiae, oozing from lines
 Metabolic acidosis (very low pH, high lactate)

40. End Organ Dysfunction
Kidneys: Renal hypoperfusion leads to oliguria, and acute kidney injury (AKI)
may develop.
Heart: Myocardial ischemia may worsen, leading to cardiac failure.
Liver: Impaired blood flow and hypoxia lead to liver dysfunction (e.g.,
elevated liver enzymes, jaundice).
Brain: Cerebral hypoxia leads to altered mental status, ranging from
confusion to coma.

41. Microvascular and Metabolic Changes
In severe shock, there is microvascular thrombosis (formation of clots in small
vessels), leading to increased capillary permeability and fluid leakage into
tissues.
The inflammatory response causes release of cytokines (e.g., TNF-α, IL-1),
leading to further endothelial damage, vascular leakage, and organ damage.

42. Systemic Effects of Shock
Hypoxia leads to acid-base disturbances, such as metabolic acidosis.
Lactic acidosis accumulates due to anaerobic metabolism, further worsening
cellular injury.
Acute inflammatory response leads to the release of pro-inflammatory
cytokines, which contribute to vascular damage, organ dysfunction, and end-
organ failure.

43. Hypovolemic Shock
A type of shock caused by a significant loss of intravascular volume, leading to
inadequate preload and reduced cardiac output
Cause: Severe fluid or blood loss (e.g., haemorrhage, dehydration, burns).
Pathophysiology:
Decreased circulating blood volume → ↓ preload → ↓ stroke volume (SV)
→ ↓ cardiac output (CO).
Compensatory vasoconstriction via sympathetic stimulation → increased
SVR → maintained BP in early stages.
Progressive vasodilation and endothelial dysfunction occur in severe stages,
worsening hypoperfusion.

44. Signs and Symptoms
 Tachycardia
 Hypotension
 Cold, clammy skin
 Oliguria
 Mental confusion
 Weak peripheral pulse

45. Cardiogenic Shock
It Occurs due to failure of the heart to pump effectively, resulting in
decreased cardiac output, despite adequate blood volume.
Cause: Inability of the heart to pump effectively (e.g., acute myocardial
infarction, heart failure).
Pathophysiology:
Impaired cardiac output → poor tissue perfusion → hypoxia and acidosis.
Pulmonary congestion occurs due to left-sided heart failure, leading to
pulmonary edema.
Reflex vasoconstriction and increased afterload increase the workload on
the heart, worsening the cycle.

46. Signs and Symptoms
 Hypotension
 Tachycardia
 Pulmonary edema (dyspnoea, crackles)
 Cool, clammy skin
 Distended neck veins (JVD)
 Chest pain
 Weak pulses

47. Distributive Shock (Septic, Anaphylactic,
Neurogenic)
Cause: Excessive vasodilation caused by infection (septic), allergic reactions
(anaphylactic), or loss of sympathetic tone (neurogenic).
Pathophysiology:
Septic Shock: Endotoxins and cytokine release cause widespread vasodilation and
increased capillary permeability, leading to fluid leakage and hypotension. Caused
by overwhelming infection and systemic inflammation.
Signs:
• Warm skin (early), cool skin (late)
• Fever or hypothermia
• Tachycardia
• Bounding pulses
• Confusion
• Hypotension

48. Anaphylactic Shock
Severe allergic reaction (e.g., drugs, insect stings).IgE-mediated mast cell
degranulation releases histamine and other mediators → vasodilation,
bronchospasm, and increased vascular permeability.
Signs:
• Hypotension
• Urticaria (hives)
• Wheezing, stridor
• Angioedema
• Flushed skin

49. NEUROGENIC SHOCK
• It is caused by spinal cord injury usually as a result of a traumatic injury or
accident
• There is failure of sympathetic outflow and adequate vascular tone.
• Damage to CNS impairs cardiac function by reducing heart rate and Losing of
sympathetic tone causes vasodilation, hypotension, and bradycardia.
Signs:
o Hypotension
o Bradycardia (unique among shock types)
o Warm, dry skin
o Decreased vascular tone

50. Obstructive Shock
Cause: Mechanical obstruction of blood flow (e.g., pulmonary embolism, cardiac
tamponade).
Pathophysiology:
Obstruction to blood flow → reduced venous return and inadequate perfusion to
organs.
Increased afterload (due to right-sided heart strain in PE or tamponade) impairs
cardiac output.
Signs and Symptoms:
 Hypotension
 Distended neck veins
 Pulsus paradoxus
 Dyspnea, cyanosis (if PE)
 Muffled heart sounds (if tamponade)