The document discusses thrombosis (blood clots) and their formation. It states that thrombosis is primarily caused by endothelial injury, abnormal blood flow (stasis or turbulence), and hypercoagulability of the blood. Thrombi form in arteries at sites of endothelial injury or abnormal flow and contain platelets, while venous thrombi form in areas of stasis and contain more red blood cells. Over time, thrombi can propagate, embolize, dissolve, organize through recanalization, or degrade if infected.

1. THROMBOSIS
Dr G VENKATA RAMANA
MBBS DNB FAMILY MEDICINE

2. THROMBOSIS
• The primary abnormalities that
lead to intravascular thrombosis
are
(1) Endothelial injury
(2) Stasis or turbulent blood flow
(3) Hypercoagulability of the blood
(“Virchow triad”)

5. Endothelial Injury
• Predominant factor for thrombosis in the heart and arterial
circulation where the high rates of blood flow impede clot
formation
• cardiac and arterial clots are typically rich in platelets
• Platelet adherence and activation is a necessary
prerequisite for thrombus formation under high shear
stress, such as exists in arteries
• Causes of endothelial activation or dysfunction
• Physical injury
• Infectious agents
• Abnormal blood flow
• Inflammatory mediators
• Metabolic abnormalities, such as hypercholesterolemia or
homocystinemia
• Toxins absorbed from cigarette smoke
• Hypertension

6. • ENDOTHELIAL CELL ACTIVATION CAUSES
• Procoagulant changes
• Downregulate the expression of thrombomodulin
• This may result in sustained activation of thrombin,
which can in turn stimulate platelets and augment
inflammation through PARs expressed on platelets
and inflammatory cells
• Downregulates the expression of other
anticoagulants, such as protein C and tissue factor
protein inhibitor, changes that further promote a
procoagulant state
• Anti-fibrinolytic effects
• Activated endothelial cells secrete Plasminogen
activator inhibitors (PAI), which limit fibrinolysis and
downregulate the expression of t-PA, alterations
that also favor the development of thrombi

7. Abnormal blood flow
• Turbulence (chaotic blood flow)
• Contributes to arterial and cardiac thrombosis by causing
endothelial injury or dysfunction, as well as by forming
countercurrents and local pockets of stasis
• Stasis is a major factor in the development of venous thrombi.
• Under conditions of normal laminar blood flow, platelets (and other
blood cells) are found mainly in the center of the vessel lumen,
separated from the endothelium by a slower-moving layer of plasma
• Stasis and turbulence have the following deleterious effects:
• Both promote endothelial cell activation and enhanced
procoagulant activity, in part through flow-induced changes in
endothelial gene expression
• Stasis allows platelets and leukocytes to come into contact with the
endothelium when the flow is sluggish
• Stasis also slows the washout of activated clotting factors and
impedes the inflow of clotting factor inhibitors

9. • Ulcerated atherosclerotic plaques not only expose
subendothelial ECM but also cause turbulence
• Abnormal aortic and arterial dilations called aneurysms create
local stasis and consequently are fertile sites for thrombosis
• Acute myocardial infarction results in focally noncontractile
myocardium. Ventricular remodeling after more remote
infarction can lead to aneurysm formation. In both cases,
cardiac mural thrombi are more easily formed because of the
local blood stasis
• Mitral valve stenosis (e.g., after rheumatic heart disease)
results in left atrial dilation. In conjunction with atrial fibrillation,
a dilated atrium also produces stasis and is a prime location
for the development of thrombi
• Hyperviscosity syndromes (such as polycythemia vera)
increase resistance to flow and cause small vessel stasis
• The deformed red cells in sickle cell anemia cause vascular
occlusions, and the resultant stasis also predisposes to
thrombosis

11. Hypercoagulability
• Refers to an abnormally high tendency of the blood to clot
• Caused by alterations in coagulation factors
• It contributes infrequently to arterial or intracardiac thrombosis but is an
important underlying risk factor for venous thrombosis.
• Primary causes
• Factor V mutation ( Leiden mutation)
• The mutation alters an amino acid residue in factor V and renders it resistant
to proteolysis by protein C.
• Prothrombin mutation
• A single-nucleotide substitution (G to A) in the 3′-untranslated region of the
prothrombin gene is a fairly common allele
• This variant results in increased prothrombin transcription
• Elevated levels of homocysteine
• contribute to arterial and venous thrombosis, as well as to the development of
atherosclerosis
• The prothrombotic effects of homocysteine may be due to thioester linkages
formed between homocysteine metabolites and a variety of proteins,
including fibrinogen
• Marked elevations of homocysteine may be caused by an inherited deficiency
of cystathione β-synthetase
• Less common primary hypercoagulable states include inherited deficiencies
of anti-coagulants such as antithrombin III, protein C, or protein S

12. • Secondary (acquired) hypercoagulability
• In some situations (e.g., cardiac failure or trauma),
stasis or vascular injury may be the most important
factor
• The hypercoagulability associated with oral
contraceptive use and the hyperestrogenic state of
pregnancy may be related to increased hepatic
synthesis of coagulation factors and reduced synthesis
of anti-thrombin III
• In disseminated cancers, release of procoagulant
tumor products (e.g., mucin from adenocarcinoma)
predisposes to thrombosis
• The hypercoagulability seen with advancing age has
been attributed to increased platelet aggregation and
reduced release of PGI2 from endothelium
• Smoking and obesity promote hypercoagulability by
unknown mechanisms

13. • Heparin-induced thrombocytopenia (HIT) syndrome
• Development of autoantibodies that bind complexes of
heparin and platelet membrane protein (platelet factor-4)
• These antibodies may also bind similar complexes
present on platelet and endothelial surfaces, resulting in
platelet activation,aggregation, and consumption

14. • Anti-phospholipid antibody syndrome
• Recurrent thromboses, repeated miscarriages, cardiac valve
vegetations,and thrombocytopenia
• Fetal loss does seems to stem from antibody-mediated interference
with the growth and differentiation of trophoblasts, leading to a
failure of placentation.
 Clinical criteria  Lab criteria
 Vascular thrombosis
 arterial or venous
 Pregnancy morbidity
 a) ≥1death of normal fetus at≥
10 weeks
 b) ≥1premature birth at≤34 wks
due to preeclampsia
 c) ≥3 consecutive abortions at
<10wks
 d)placental insufficiency at<34
wks
 Anti-Cardiolipin IgG/IgM
 Anti-beta-2 glycoprotein1
 Lupus anticoagulant
 Medium to high titer
 At least 2 times
 12 weeks apart
 Definite APS:
 1 clinical +1 Lab criteria

16. Arterial thrombi
• Arterial or cardiac thrombi typically arise at sites of
endothelial injury or turbulence
• Focally attached to the underlying vascular surface
and tend to propagate toward the heart
• Grow in a retrograde direction from the point of
attachment
• The propagating portion of a thrombus tends to be
poorly attached and therefore prone to fragmentation
and migration through the blood as an embolus
• Frequently occlusive
• Rich in platelets
• Causes
• Ruptured atherosclerotic plaque
• Vasculitis
• Trauma

17. Thrombi can have grossly (and microscopically) apparent
laminations called lines of Zahn
These represent pale platelet and fibrin layers alternating with
darker red cell–rich layers
Such lines are significant in that they are only found in thrombi that
form in flowing blood; their presence can therefore usually
distinguish antemortem thrombosis from the bland nonlaminated
clots that form in the postmortem state

18. Venous thrombi (phlebothrombosis)
• Characteristically occur at sites of stasis.
• Extend in the direction of blood flow
• Almost invariably occlusive
• Frequently propagate some distance toward the heart,
forming a long cast within the vessel lumen that is
prone to give rise to emboli.
• Because these thrombi form in the sluggish venous
circulation, they tend to contain more enmeshed red
cells, leading to the moniker red, or stasis, thrombi
• The veins of the lower extremities are most commonly
affected (90% ofvenous thromboses)
• Venous thrombi also can occur in the upper
extremities, periprostatic plexus, or ovarian and
periuterine veins, and under special circumstances
they may be found in the dural sinuses, portal vein, or
hepatic vein.

19. • Superficial venous thrombi
• Usually arise in the saphenous system,
particularly in the setting of varicosities
• Rarely embolize
• Can be painful
• Can cause local congestion and swelling
from impaired venous outflow
• Predispose the overlying skin to the
development of infections and varicose
ulcers

20. • Deep venous thromboses
• Arise in the larger leg veins at or above the knee joint (e.g.,
popliteal, femoral, and iliac veins)
• More serious because they are prone to embolize
• May cause local pain and edema
• Collateral channels often circumvent the venous obstruction
• Predisposing factors
• Congestive heart failure
• Bed rest
• Immobilization
• Trauma,
• Surgery,
• Burns
• Tumor associated procoagulant release
• Age >50 years
• Pregnancy

21. Mural thrombi
• Thrombi occurring in heart
chambers or in the aortic
lumen are designated as
mural thrombi
• Abnormal myocardial
contraction(arrhythmias,
dilated cardiomyopathy, or
myocardial infarction) or
endomyocardial injury
(myocarditis, catheter
trauma) promote cardiac
mural thrombi,whereas
ulcerated atherosclerotic
plaques and aneurysmal
dilation promote aortic
thrombosis

23. Infective endocarditis
• Thrombi on heart valves are called vegetations
• Bacterial or fungal bloodborne infections can cause valve damage,
leading to the development of large thrombotic masses
(infective endocarditis)

24. Nonbacterial thrombotic endocarditis
Sterile vegetations also can develop on noninfected valves in
hypercoagulable states—the lesions of so-called “nonbacterial
thrombotic endocarditis”

25. Libman- Sacks endocarditis
• Less commonly, sterile, verrucous endocarditis (Libman- Sacks
endocarditis) can occur in the setting of systemic lupus
erythematosus

26. FATE OF A THROMBUS
• Propagation
• The thrombus enlarges through the accretion
of additional platelets and fibrin, increasing
the odds of vascular occlusion or
embolization
• Propagation of a thrombus is always towards
the heart
• Venous thrombi-Towards the blood flow
• Arterial thrombi-Retrograde to the blood flow
• Embolization
• Part or all of the thrombus is dislodged and
transported elsewhere in the vasculature.

27. • Dissolution
• If a thrombus is newly formed, activation of
fibrinolytic factors may lead to its rapid
shrinkage and complete dissolution
• With older thrombi, extensive fibrin
polymerization renders the thrombus
substantially more resistant to plasmin-
induced proteolysis, and lysis is ineffectual
• This acquisition of resistance to lysis has
clinical significance, as therapeutic
administration of fibrinolytic agents (e.g., t-PA
in the setting of acute coronary thrombosis)
generally is not effective unless administered
within a few hours of thrombus formation

28. • Organization and recanalization
• Older thrombi become organized by the ingrowth of
endothelial cells, smooth muscle cells, and fibroblasts
• In time, capillary channels are formed that—to a limited
extent—create conduits along the length of the thrombus,
thereby reestablishing the continuity of the original lumen
• Further recanalization can sometimes convert a thrombus into
avascularized mass of connective tissue that is eventually
incorporated into the wall of the remodeled vessel
• Occasionally, instead of organizing, the center of a thrombus
undergoes enzymatic digestion, presumably because of the
release of lysosomal enzymes from entrapped leukocytes
• If bacterial seeding occurs, the contents of degraded thrombi
serve as an ideal culture medium, and the resulting infection
may weaken the vessel wall, leading to the formation of a
mycotic aneurysm

29. FATE OF A THROMBUS