Thrombosis complete

1. THROMBOSIS
DR. D. VAMSHIKRISHNA.
MD (HOMOEO)

2. THROMBOSIS
Definition:
• Thrombosis is the process of formation of
solid mass in circulation from the constituents
of flowing blood; the mass itself is called a
thrombus.
THROMBUS.

3. • Haemostatic plugs are the blood clots formed in healthy
individuals at the site of bleeding e.g. in injury to the
blood vessel.
• Haemostatic plugs are useful as they stop escape of
blood and plasma, whereas thrombi developing in the
unruptured cardiovascular system may be life-
threatening by causing one of the following harmful
effects:
1. Ischaemic injury: Thrombi may decrease or stop the
blood supply to part of an organ or tissue and cause
ischaemia which may subsequently result in infarction.
2. Thromboembolism: Thrombus or its part may get
dislodged and be carried along in the bloodstream as
embolus to lodge in a distant vessel.

4. Ischaemic injury:

5. Thromboembolism:

6. Pathophysiology/Thrombogenesis
• Human beings possess inbuilt system by which
the blood remains in fluid state normally and
guards against the hazards of thrombosis and
hemorrhage.
• However, injury to the blood vessel initiates
thrombogenesis.

7. • Virchow described three primary events which
predispose to thrombus formation (Virchow’s
triad):
ENDOTHELIAL
INJURY
ALTERED
BLOOD FLOW
VIRCHOW’S
TRIAD
HYPERCOAGULABILITY

8. • Virchow's Triad
• Activation of Platelets
• Activation of Clotting System
THROMBOSIS.

9. Events in THROMBOGENESIS
1. ENDOTHELIAL INJURY
2. ROLE OF PLATELETS
3. ROLE OF COAGULATION SYSTEM
4. ALTERATION OF BLOOD FLOW
5. HYPERCOAGULABLE STATES
(THROMBOPHILIA)

10. 1. ENDOTHELIAL INJURY
INTACT ENDOTHELIUM
1. Protects the flowing blood from
Thrombogenic influence of
Subendothelium.
2. Releases Anti-thrombotic factors
(thrombosis Inhibitory factors)
• Heparin-like substance which accelerates
the action of antithrombin III and
inactivates some other clotting factors.
• Thrombomodulin which converts
thrombin into activator of protein C, an
anticoagulant.
• Inhibitors of platelet aggregation:
ADPase, PGI2, NO.
• Tissue plasminogen activator which
accelerates fibrinolytic activity.

11. N.O
PLATELETS
PGI2
PREVENTS
PLATELETS
ADHESION
HEPARIN
SULPHATE
ANTITHROMBIN III INACTIVATES
THROMBIN
XA
IXa
THROMBIN
THROMBOMODULIN
PROTEIN-C
DIGESTS VA, VIIIA
ADPase
TISSUE PLASMINOGEN ACTIVATOR
INACTIVE PLASMINOGEN
ACTIVE PLASMIN ENZYME
BREAKDOWN OF
FIBRIN STRANDS
TO
FIBRIN SPLIT PRODUCTS (FSP).

12. INTACT ENDOTHELIUM
3. Releases a few prothrombotic factors which have procoagulant
properties (thrombosis favoring factors) as under:
a) Thromboplastin or tissue factor released from endothelial cells.
b) Von Willebrand Factor that causes adherence of platelets to the
subendothelium.
c) Platelet activating factor which is activator and aggregator of
platelets.
d) Inhibitor of plasminogen activator that suppresses fibrinolysis.

13. • Vascular injury exposes the subendothelial
extracellular matrix or ECM which is
thrombogenic and thus plays an important
role in initiating thrombosis.
• Endothelial injury is of major significance in
the formation of arterial thrombi and thrombi
of the heart, especially of the left ventricle.

14. • A number of factors and conditions may cause
vascular injury and predispose to the formation
of thrombi.
These are as under:
Ulcerated plaques in advanced atherosclerosis.
Haemodynamic stress in hypertension.
Arterial diseases.
Diabetes mellitus.
Endogenous chemical agents such as
hypercholesterolaemia, endotoxins.
Exogenous chemical agents such as cigarette
smoke.

15. ULCERATED PLAQUES IN
ADVANCED ATHEROSCLEROSIS.

16. HAEMODYNAMIC STRESS IN HYPERTENSION.

17. HYPERCHOLESTEROLAEMIA

18. 2. ROLE OF PLATELETS
• Following endothelial cell injury, platelets
come to play a central role in normal
haemostasis as well as in thrombosis.
• The sequence of events is as under
i) Platelet adhesion
ii) Platelet release reaction
iii) Platelet aggregation

19. I) PLATELET ADHESION
• Glycoprotein Ib (GpIb) receptor on the
platelets recognises the site of endothelial
injury and the circulating platelets adhere to
exposed subendothelial ECM (primary
aggregation).
• von Willebrand’s factor (vWF), synthesised by
the endothelial cells binds to GpIb and forms a
firm adhesion of platelets with ECM.

20. Thus,
• Deficiency of vWF leads to von Willebrand’s
disease
• Absence of GpIb lead to Bernard-Soulier disease
would result in defective
platelet adhesion and cause
abnormal bleeding.

21. SUBENDOTHELIUM
SUBENDOTHELIUM
SMOOTH MUSCLE
SMOOTH MUSCLE

22. VON WILLIBRAND FACTORINJURY

23. platelet
Platelet adhesion
(PRIMARY AGGREGATION)
Thromboxane A-2 (A vasoconstrictor)
Gp1b receptors

24. II) PLATELET RELEASE REACTION
• Activated platelets then undergo release reaction by
which the platelet granules are released to the exterior.
• Two main types of platelet granules are released:
A) DENSE BODIES: release
- ADP (adenosine diphosphate),
- ionic calcium,
- 5-HT (serotonin), histamine and epinephrine.
• Release of contents of dense bodies are more
important since ADP is further an activator of platelets,
and calcium is required in the coagulation cascade.

25. B) ALPHA GRANULES: Their release produces
- Fibrinogen,
- Fibronectin,
- Platelet-derived growth factor (PDGF),
- Platelet factor 4 (an antiheparin) and
- Thrombospondin.

26. Platelets granules

27. iii) Platelet aggregation :
• Following release of ADP, a potent platelet
aggregating agent, aggregation of additional
platelets takes place (secondary aggregation).
• This results in formation of temporary
haemostatic plug.

28. Platelet aggregation
(Secondary Aggregation)
by ADP

29. 3. ROLE OF COAGULATION SYSTEM
• Coagulation mechanism is the conversion of
the plasma fibrinogen into solid mass of fibrin.
SOLUBLE FIBRINOGEN  INSOLUBLE FIBRIN.

30. COAGULATION PATHWAYS
• INTRINSIC PATHWAY
• EXTRINSIC PATHWAY

31. INTRINSIC PATHWAY
• The intrinsic pathway is activated by trauma
inside the vascular system, and is activated by
platelets, exposed endothelium or collagen.
• This pathway is slower than the extrinsic
pathway.
• It involves factors XII, XI, IX, VIII

32. • In the intrinsic pathway, contact with
abnormal surface (e.g. ECM in the
subendothelium) leads to activation of factor
XII and the sequential interactions of factors
XI, IX, VIII.

33. XII
XIIa
`
XI
XIa
IX
IXa
Ca++
X
Xa
VIII,
PF3,Ca++
Ca++, V, PF3
PROTHROMBIN
THROMBIN (II a)
FIBRINOGEN
FIBRINS

34. EXTRINSIC PATHWAY
• The extrinsic pathway is activated by external
trauma that causes blood to escape from the
vascular system.
• Tissue damage results in release of tissue
factor or thromboplastin.
• Tissue factor on interaction with factor VII
activates factor X.

35. TISSUE FACTOR
X
Xa
TISSUE FACTOR
VII, Ca++
Ca++, V, PF3
PROTHROMBIN
THROMBIN (II a)
FIBRINOGEN
FIBRINS

36. Regulation of coagulation system
Normally, the blood is kept in fluid state and the
coagulation system is kept in check by controlling
mechanisms.
These are as under:
i) Protease inhibitors: These act on coagulation factors so
as to oppose the formation of thrombin e.g.
antithrombin III, protein C.
ii) Fibrinolytic system: Plasmin, a potent fibrinolytic
enzyme, is formed by the action of plasminogen activator
on plasminogen present in the normal plasma.
- Plasmin so formed acts on fibrin to destroy the clot and
produces fibrin split products (FSP).

37. 4. ALTERATION OF BLOOD FLOW
• Normally, there is axial flow of blood in which
the most rapidly-moving central stream
consists of leucocytes and red cells.
• The platelets are present in the slow-moving
laminar stream adjacent to the central stream
while the peripheral stream consists of most
slow-moving cell-free plasma close to
endothelial layer

38. NORMAL AXIAL FLOW OF BLOOD
Formed elements (LEUCOCYTES+RBC+ PLATELETS

39. MARGINATION AND PAVEMENTING OF BLOOD ELEMENTS

41. • Turbulence and stasis causes THROMBOSIS
(Turbulence means unequal flow while stasis
means slowing.)
• When blood slows down, the blood cells
including platelets marginate to the periphery
and form a kind of pavement close to
endothelium (margination and pavementing)

42. • Formation of arterial and cardiac thrombi is
facilitated by turbulence in the blood flow,
while stasis initiates the venous thrombi even
without evidence of endothelial injury.

43. 5. HYPERCOAGULABLE STATES (THROMBOPHILIA)
• Thrombophilia or hypercoagulable states are a
group of conditions having increased risk or
predisposition to develop venous thrombosis.
• These conditions may be
- Hereditary (or primary)
- Acquired (or secondary)

46. Fate of Thrombus
• 1. RESOLUTION
• 2. ORGANISATION
• 3. PROPAGATION
• 4. THROMBOEMBOLISM

48. 1. RESOLUTION
• Thrombus activates the fibrinolytic system with
consequent release of plasmin which may dissolve
the thrombus completely resulting in resolution.
• Usually, lysis is complete in small venous thrombi
while large thrombi may not be dissolved.
• Fibrinolytic activity can be accentuated by
Administration of thrombolytic substances (e.g.
urokinase, streptokinase), especially in the early
stage when fibrin is in monomeric form e.g.
thromobytic therapy in early stage acute myocardial
infarction.

51. 2. ORGANISATION AND RECANALISATION
• Thrombi may be invaded by fibroblast and
endothelial cells.
• Thus, fibrovascular granulation tissue is formed
which subsequently becomes dense and less vascular
and is covered over by endothelial cells.
• The thrombus in this way is excluded from the
vascular lumen and becomes part of vessel
wall.(ORGANISATION)

52. ORGANISATION

53. • The thrombus is now converted to fibrous
connective tissue.
• This scar tissue may shrink with time allowing
for re-establishment of blood flow through the
recanalized vessel.(RECANALISATION)

54. RECANALISATION

55. 3. PROPAGATION
• The thrombus may enlarge in size due to more
and more deposition from the constituents of
flowing blood.
• In this way, it may ultimately cause
obstruction of some important vessel.

57. 4. THROMBOEMBOLISM
• The thrombi in early stage and infected
thrombi are quite friable and may get
detached from the vessel wall.
• These are released in part or completely in
blood-stream as emboli which produce ill-
effects at the site of their lodgment

59. Different types of Thrombosis
• Thrombosis is normally categorized by where
it occurs in the body.
• Within these categories, it may be classified
further.
1. Venous Thrombosis
2. Arterial Thrombosis

60. Feature Arterial Thrombi Venous Thrombi
Blood flow Rapidly flowing
Coronary Artery, Aorta
Slow moving blood
Deep Veins of Leg
Thrombogenesis Endothelial Cell Injury Venous Stasis
Development Usually Mural Usually Occlusivemay
and may propagate in both
Directions.
Macroscopic Appearance Grey-White Lines of Zahn Red Blue Lines of Zahn
Microscopic Appearance Distinct lines of Zahn
composed of platelets, fibrin
with entangled
red and white blood Cells
Lines of Zahn with
more abundant red
cells
Effects Ischemia leading to Infarcts Thrombo-embolism, Oedema,
Skin Ulcers, Poor wound
healing
DISTINGUISHING FEATURES OF ARTERIAL AND VENOUS THROMBI.

61. • Mural thrombi (non-occlusive) are thrombi
that adhere to the wall of a blood vessel.
• Occlusive thrombi are thrombi that
completely occlude the blood vessel.

64. DISTINGUISHING FEATURES OF ANTEMORTEM THROMBUS AND
POSTMORTEM CLOT