Hemostasis, Hemorrhagic

Disorders, and Thrombosis

HEMOSTASIS
DEFINITION
 Precisely orchestrated process involving
platelets, clotting factors, and endothelium
that occurs at the site of vascular injury
and culminates in the formation of a
blood clot, which serves to prevent or
limit the bleeding
General sequence of events
leading to hemostasis at a site
of vascular injury:
 Arteriolar vasoconstriction: occurs
immediately and it reduces blood flow to
the injured area.
 It is mediated by reflex neurogenic
mechanisms and augmented by the local
secretion of factors such as endothelin, a
potent endotheliumderived
vasoconstrictor.
 This effect is transient, and bleeding
would resume if activation of platelets and
coagulation factors does not occur.
 Primary hemostasis: the formation of
the platelet plug;
o Disruption of the endothelium exposes
subendothelial von Willebrand factor
(vWF) and collagen, which promote
platelet adherence and activation.
 Activation of platelets results in a shape
change (from small rounded discs to flat
plates with spiky protrusions that
markedly increased surface area), and
release of secretory granules.
 Secreted products recruit additional
platelets, which undergo aggregation to
form a primary hemostatic plug.
 Secondary hemostasis: deposition of
fibrin; Tissue factor is exposed at the site
of injury.
 Tissue factor is a membranebound
procoagulant glycoprotein that is normally
expressed by smooth muscle cells and
fibroblasts of vessel wall.
 Tissue factor binds and activates factor
VII, setting in cascade of reactions that
culiminates in thrombin generation.
 Thrombin cleaves circulating fibrinogen
into insoluble fibrin, creating a fibrin
meshwork, and also is a potent activator
of platelets, leading to additional platelet
aggregation at the site of injury.
 Secondary hemostasis, consolidates the
initial platelet plug.
 Clot stabilization and resorption;
Polymerized fibrin and platelet aggregates
undergo contraction to form a solid,
permanent plug that prevents further
hemorrhage.
 At this stage, counter-regulatory
mechanisms (e.g., tissue plasminogen
activator, t-PA) are set into motion that
limit clotting to the site of injury and
eventually lead to clot resorption and
tissue repair.
PLATELETS
 Platelets are discshaped anucleate cell
fragments that are shed from
megakaryocytes in the bone marrow into
the bloodstream
 Role of platelets in hemostasis:
1. Platelets form the primary plug that
initially seals vascular defects
2. by providing a surface that binds and
concentrates activated coagulation
factors
Their function depends on:
1. several glycoprotein receptors
2. contractile cytoskeleton
3. two types of cytoplasmic granules.
i- α-Granules
ii- Dense (or δ) granules
 α-Granules have
1. Adhesion molecule: Pselectin
2. Coagulation factors: fibrinogen, factor V
and vWF
3.Proteins involved in wound healing:
fibronectin, platelet factor 4 (a heparin-
binding chemokine), PDGF, and TGFβ
 Dense (or δ) granules: contain ADP,
ATP, ionized calcium, serotonin, and
epinephrine
 After a traumatic vascular injury, platelets
encounter constituents of the
subendothelial connective tissue, such as
vWF and collagen.
 On contact with these proteins, platelets
undergo a sequence of reactions that
culminate in the formation of a platelet
plug.
 Platelet adhesion is mediated largely via
interactions with vWF, which acts as a
bridge between the platelet surface
receptor glycoprotein Ib (GpIb) and
exposed collagen.
 Notably, genetic deficiencies of vWF (von
Willebrand disease) or GpIb result in
bleeding disorder called Bernard Soulier
syndrome.
 Platelets rapidly change shape following
adhesion, being converted from smooth
discs to spiky “sea urchins” with greatly
increased surface area.
 This change is accompanied by alterations
in glycoprotein IIb/IIIa that increase its
affinity for fibrinogen and by the
translocation of negatively charged
phospholipids (particularly
phosphatidylserine) to the platelet surface
 These phospholipids bind calcium and
serve as nucleation sites for the assembly
of coagulation factor complexes
 Secretion (release reaction) of
granule contents occurs along with
changes in shape; these two events are
often referred to together as platelet
activation
 Platelet activation is triggered by a
number of factors, including the
coagulation factor thrombin and ADP
 Thrombin activates platelets through a
special type of Gprotein– coupled
receptor referred to as a protease-
activated receptor (PAR), which is
switched on by a proteolytic cleavage
carried out by thrombin.
 ADP is a component of dense body
granules; thus, platelet activation and ADP
release result in additional rounds of
platelet activation, a phenomenon
referred to as recruitment
 Activated platelets also produce the
prostaglandin thromboxane A2 (TxA2), a
potent inducer of platelet aggregation
 Aspirin inhibits platelet aggregation and
produces a mild bleeding defect by
inhibiting cyclooxygenase, a platelet
enzyme that is required for TxA2
synthesis
 Platelet aggregation follows their
activation;
 The conformational change in
glycoprotein IIb/IIIa that occurs with
platelet activation allows binding of
fibrinogen, a large bivalent plasma
polypeptide that forms bridges between
adjacent platelets, leading to their
aggregation.
 Predictably, inherited deficiency of GpIIb-
IIIa results in a bleeding disorder called
Glanzmann thrombasthenia.
 The initial wave of aggregation is
reversible, but concurrent activation of
thrombin stabilizes the platelet plug by
causing further platelet activation and
aggregation, and by promoting irreversible
platelet contraction.
 Platelet contraction is dependent on the
cytoskeleton and consolidates the
aggregated platelets
 In parallel, thrombin also converts
fibrinogen into insoluble fibrin, cementing
the platelets in place and creating the
definitive secondary hemostatic plug
 Entrapped red cells and leukocytes are
also found in hemostatic plugs, in part due
to adherence of leukocytes to Pselectin
expressed on activated platelets.
COAGULATION CASCADE
 The coagulation cascade is series of
amplifying enzymatic reactions that leads
to the deposition of an insoluble fibrin
clot.
 The dependency of clot formation on
various factors differs in the laboratory
test tube (vitro) and in blood vessels in
(vivo).
 Clotting in vitro and in vivo both follow
the same general principles.
General Principles
 Each reaction step involves an enzyme (an
activated coagulation factor), a substrate
(an inactive proenzyme form of a
coagulation factor), and a cofactor (a
reaction accelerator).
 These components are assembled on a
negatively charged phospholipid surface,
which is provided by activated platelets.
 The enzymatic reactions that produce γ-
carboxylated glutamic acid use vitamin K
as a cofactor and are antagonized by
drugs such as coumadin, a widely used
anticoagulant.
 Assembly of reaction complexes also
depends on calcium, which binds to
γ(Gamma)carboxylated glutamic acid
residues that are present in factors II,VII,
IX, and X.
 Based on assays carried out in clinical
laboratories, the coagulation cascade has
traditionally been divided into the
extrinsic and intrinsic pathways.
 The prothrombin time (PT) assay
assesses the function of the proteins in
the extrinsic pathway (factors VII, X,V, II,
and fibrinogen).
In vitro
 In brief, tissue factor, phospholipids, and
calcium are added to plasma and the time
for a fibrin clot to form is recorded.
 • The partial thromboplastin time
(PTT) assay: screens the function of the
proteins in the intrinsic pathway (factors
XII, XI, IX,VIII, X,V, II, and fibrinogen).
 In this assay, clotting of plasma is initiated by
addition of negative charged particles (e.g.,
ground glass) that activate factor XII
(Hageman factor) together with
phospholipids and calcium, and the time to
fibrin clot formation is recorded.
 PT and PTT assays are of great utility in
evaluating coagulation factor function in
patients, they fail to sum up the events that
lead to coagulation in vivo (blood vessels).
 Deficiencies of factors V,VII,VIII, IX, and X
are associated with moderate to severe
bleeding disorders, and prothrombin
deficiency is likely incompatible with life.
 In contrast, factor XI deficiency is
associated with mild bleeding, and
individuals with factor XII deficiency do
not bleed and in fact may be susceptible
to thrombosis.
Most important activities of
thrombin
 1. Conversion of soluble fibrinogen into
crosslinked insoluble fibrin
 2. Amplifies the coagulation process, by
activating factor XI, co-factors V and VIII.
 3. Stabilizes the secondary hemostatic
plug by activating factor XIII, which
covalently crosslinks fibrin.
 4. Platelet activation; Thrombin is a potent
inducer of platelet activation and
aggregation through its ability to activate
(protease activated receptors) PARs,
thereby linking platelet function to
coagulation.
 5. Pro-inflammatory effects; PARs are also
expressed on inflammatory cells,
endothelium, and other cell types, and
activation of these receptors by thrombin
is believed to mediate proinflammatory
effects that contribute to tissue repair
and angiogenesis.
 • Anticoagulant effects; Upon
encountering normal endothelium
thrombin changes from a procoagulant to
an anticoagulant.
 This reversal in function prevents clotting
from extending beyond the site of the
vascular injury.
Factors That Limit Coagulation
 Once initiated, coagulation must be
restricted to the site of vascular injury to
prevent deleterious consequences.
 One limiting factor is dilution; blood flowing
past the site of injury washes out
activated coagulation factors, which are
rapidly removed by the liver.
 A second is the requirement for negatively
charged phospholipids, which, are
provided by platelets that have been
activated by contact with subendothelial
matrix at sites of vascular injury.
 Counterregulatory mechanisms involve
factors that are expressed by intact
endothelium adjacent to the site of injury.
 Activation of the coagulation cascade also
sets into motion a fibrinolytic cascade that
limits the size of the clot and contributes
to its later dissolution.
 Fibrinolysis is accomplished through the
enzymatic activity of plasmin, which
breaks down fibrin and interferes with its
polymerization.
 An elevated level of breakdown products
of fibrinogen (often called fibrin split
products), most notably fibrinderived D-
dimers, are a useful clinical markers of
several thrombotic states.
 Plasmin is generated by enzymatic
catabolism of the inactive circulating
precursor plasminogen, either by a factor
XII–dependent pathway or by
plasminogen activators.
 The most important plasminogen
activator is tPA; it is synthesized
principally by endothelium and is most
active when bound to fibrin.
 This characteristic makes tPA a useful
therapeutic agent, since its fibrinolytic
activity is largely confined to sites of
recent thrombosis.
 Once activated, plasmin is in turn tightly
controlled by counterregulatory factors
such as α2plasmin inhibitor, a plasma
protein that binds and rapidly inhibits free
plasmin.
ENDOTHELIUM
 The balance between the anticoagulant
and procoagulant activities of
endothelium determines whether clot
formation, propagation, or dissolution
occurs.
 Normal endothelial cells express factors
that inhibit the procoagulant activities of
platelets and coagulation factors and that
augment fibrinolysis.
 These factors act to prevent thrombosis
and to limit clotting to sites of vascular
damage.
 However, if injured or exposed to
proinflammatory factors, endothelial cells
lose many of their antithrombotic
properties.
 Antithrombotic activities of normal
endothelium;
 The antithrombotic properties of
endothelium can be divided into activities
directed at platelets, coagulation factors,
and fibrinolysis.
 • Platelet inhibitory effects.
 An obvious effect of intact endothelium is
to serve as a barrier that shields platelets
from subendothelial vWF and collagen.
 However, normal endothelium also
releases a number of factors that inhibit
platelet activation and aggregation.
 Among the most important are
prostacyclin (PGI2), nitric oxide (NO),
and adenosine diphosphatase.
 Endothelial cells bind and alter the activity
of thrombin, which is one of the most
potent activators of platelets.
 Anticoagulant effects.
 Normal endothelium shields coagulation
factors from tissue factor in vessel walls
and expresses multiple factors that
actively oppose coagulation, most notably
thrombomodulin, endothelial protein C
receptor, heparin-like molecules, and
tissue factor pathway inhibitor.
 Thrombomodulin and endothelial protein C
receptor bind thrombin and protein C,
respectively, in a complex on the
endothelial cell surface.
 When bound in this complex, thrombin
loses its ability to activate coagulation
factors and platelets, and instead cleaves
and activates protein C, a vitamin K–
dependent protease that requires a
cofactor, protein S.
 Activated protein C/protein S complex is
a potent inhibitor of coagulation factors
Va and VIIIa.
 Heparin-like molecules on the surface of
endothelium bind and activate anti-
thrombin III, which then inhibits thrombin
and factors IXa, Xa, XIa, and XIIa.
 The clinical utility of heparin and related
drugs is based on their ability to stimulate
antithrombin III activity.
 Tissue factor pathway inhibitor(TFPI), like
protein C, requires protein S as a cofactor
and, as the name implies, binds and
inhibits tissue factor/factor VIIa
complexes.
 • Fibrinolytic effects. Normal endothelial
cells synthesize t-PA, is a key component
of the fibrinolytic pathway.
HEMORRHAGIC
DISORDERS
Disorders of primary hemostasis
 Usually due to abnormalities in platelets;
divided into qualitative or quantitative
disorders
 Clinical features include mucosal and skin
bleeding
Mucosal bleeding Skin bleeding
Epistaxis Petechiae (1-2mm)
Hemoptysis Purpura(>3mm)
GI bleeding Ecchymoses(>1cm)
Hematuria Easy bruising
menorrhagia
 Laboratory studies
1. Platelet count…….normal or decreased
2. Bleeding time……..usually prolonged
3. blood smear……..to assess number and
size of platelets
4. Bone marrow biopsy…..to assess
megakaryocytes
 Diseases involving primary hemostasis
1. ITP
2. TTP
3. HUS
4. Bernard soulier syndrome
5. Glanzmann thrombasthenia
Disorders of secondary hemostasis
 Usually due to clotting factors
abnormality or the factors needed for
their activation
o Exp to an activating substance
o Phospholipid surface of platelets
o Calcium
• Clinical features include deep tissue
bleeding into muscles and joints and
rebleeding after surgical procedures
 Laboratory studies include
1. PT….measures extrinsic and common
pathways of coagulation cascade
2. PTT…. Measures intrinsic and common
pathways of coagulation
 Diseases include;
Hemophilia A Factor VIII
Hemophilia B Factor IX
Coagulation factor inhibitor Antibodies(mixing studies)
vW Disease vWF
Vitamin K deficiency Newborns, antibiotic therapy,
malabsorption
Liver failure
Thrombosis:
 The primary abnormalities that lead to
thrombosis are (1) endothelial injury, (2)
stasis or turbulent blood flow, and (3)
hypercoagulability of the blood (the so-
called Virchow triad).
1. Endothelial Injury
 Endothelial injury leading to platelet
activation leads to thrombus formation in
the heart and the arterial circulation,
where the high rates of blood flow
impede clot formation.
 Obviously, severe endothelial injury may
trigger thrombosis by exposing vWF and
tissue factor.
 However, inflammation and other noxious
stimuli also promote thrombosis by shifting
the pattern of gene expression in
endothelium to one that is “prothrombotic.”
 This change is sometimes referred to as
endothelial activation or dysfunction and can
be produced by diverse exposures, including
infectious agents, abnormal blood flow,
inflammatory mediators, metabolic
abnormalities, such as hypercholesterolemia
or homocystinemia, and toxins absorbed
from cigarette smoke.
Major prothrombotic alterations:
 Procoagulant changes. Endothelial cells activated
by cytokines down regulate 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
 In addition, inflamed endothelium also down
regulates the expression of other anticoagulants,
such as protein C and tissue factor protein
inhibitor, these changes further promote a
procoagulant state
 • Antifibrinolytic effects.Activated
endothelial cells secrete plasminogen
activator inhibitors (PAIs), which limit
fibrinolysis, alterations that also favor the
development of thrombi.
2. Alternations in Normal Blood
Flow
 Turbulence contributes to arterial and
cardiac thrombosis by causing endothelial
injury or dysfunction, and by forming local
pockets of stasis.
 Stasis is a major contributor in the
development of venous thrombi.
 Normal blood flow is laminar such that the
platelets (and other blood cellular elements)
flow centrally in the vessel lumen, separated
from endothelium by a slower moving layer
of plasma.
 Stasis and turbulence therefore:
 Promote endothelial activation, enhancing
procoagulant activity and leukocyte adhesion,
in part through flowinduced changes in the
expression of adhesion molecules and pro-
inflammatory factors
 Disrupt laminar flow and bring platelets into
contact with the endothelium
 Prevent washout and dilution of activated
clotting factors by fresh flowing blood and
the inflow of clotting factor inhibitors
 Stasis and turbulence occurs in several clinical
settings. i.e. Ulcerated atherosclerotic
plaques, aortic, arterial aneurysms, acute MI
result in areas of noncontractile myocardium
and sometimes in cardiac aneurysms,
rheumatic mitral valve stenosis results in left
atrial dilation; in conjunction with atrial
fibrillation, hyperviscosity (such as is seen
with polycythemia vera) increases resistance
to flow and causes small vessel stasis, and
the deformed red cells in sickle cell anemia
impede blood flow through small vessels.
3. Hypercoagulability
 Hypercoagulability (also called
thrombophilia) has a particularly important
role in venous thrombosis and can be
divided into primary (genetic) and
secondary (acquired) disorders .
 Genetic causes of hypercoagulability; point
mutations in the factor V gene and prothrombin
gene .
 Single nucleotide mutation in factor V that is
called the factor V Leiden.
 Among individuals with recurrent DVT, the
frequency of this mutation is higher, approaching
60%.
 The mutation results in a glutamine to arginine
substitution at amino acid residue 506 that
renders factor V to cleavage and inactivation by
protein C.
 As a result, an important antithrombotic counter-
regulatory pathway is lost.
 A single nucleotide change (G20210A) in the
3′untranslated region of the prothrombin gene is
another common mutation (1% to 2% of the
population) associated with hypercoagulability.
 It leads to elevated prothrombin levels and
an almost threefold increased risk of venous
thrombosis.
 Elevated levels of homocysteine contribute
to arterial and venous thrombosis, as well as
the development of atherosclerosis.
 The prothrombotic effects of homocysteine
may be due to linkages formed between
homocysteine metabolites and fibrinogen.
 Marked elevations of homocysteine may be
caused by an inherited deficiency of
cystathione βsynthetase.
 • Rare inherited causes of primary
hypercoagulability include; deficiencies of
anticoagulants such as antithrombin III,
protein C, or protein S; affected individuals
typically present with venous thrombosis
and recurrent thromboembolism beginning
in adolescence or early adulthood.
 The most common thrombophilic genotypes
(heterozygosity for factor V Leiden and
heterozygosity for the prothrombin
G20210A variant) cause moderately
increased risk of thrombosis; most
individuals with these genotypes, when
otherwise healthy, are free of thrombotic
complications.
 Moreover, individuals with such mutations
have a significantly increased frequency of
venous thrombosis in the setting of other
acquired risk factors (e.g., pregnancy or
prolonged bed rest/prolong plane travel).
 Causes of acquired
thrombophilia/hypercoagualibility: In
some cases (e.g., cardiac failure or
trauma), stasis or vascular injury may be
most important.
 Hypercoagulability due to oral contraceptive
use or the hyperestrogenic state of
pregnancy is probably caused by increased
hepatic synthesis of coagulation factors and
reduced anticoagulant synthesis.
 In disseminated cancers, release of various
procoagulants from tumors predisposes to
thrombosis.
 The hypercoagulability seen with advancing
age may be due to reduced endothelial PGI2
production.
 Smoking and obesity promote
hypercoagulability by unknown mechanisms
(Reaserch).
 Among the acquired thrombophilic states,
the heparin induced thrombocytopenia
and the antiphospholipid antibody
syndromes are particularly important
clinical problems.
i. Heparin-Induced
Thrombocytopenia (HIT) Syndrome
 HIT occurs following the administration of
unfractionated heparin, which induce the
antibodies that recognize complexes of
heparin and platelet factor 4 on the surface
of platelets, and complexes of heparinlike
molecules and platelet factor 4like proteins
on endothelial cells.
 Binding of these antibodies to platelets
results in their activation, aggregation, and
consumption (hence the thrombocytopenia
in the syndrome name).
 Lowmolecularweight heparin preparations
induce HIT less frequently, and other
classes of anticoagulants such as direct
inhibitors of factor X and thrombin may
also obviate the risk.
ii. Antiphospholipid Antibody
Syndrome
 This syndrome (previously called the lupus
anticoagulant syndrome) has changeable
clinical manifestations, including recurrent
thromboses, repeated miscarriages, cardiac
valve vegetations, and thrombocytopenia.
 Depending on the vascular bed involved, the
clinical presentations can include pulmonary
embolism (PE) (following lower extremity
venous thrombosis), pulmonary
hypertension (from recurrent subclinical
pulmonary emboli), stroke, bowel infarction,
or renovascular hypertension.
 Fetal loss does not appear to be explained by
thrombosis, but rather seems to stem from
antibodymediated interference with the growth
and differentiation of trophoblasts, leading to a
failure of placentation.
 Antiphospholipid antibody syndrome is also a
cause of renal microangiopathy, resulting in renal
failure associated with multiple capillary and
arterial thromboses.
 Suspected antibody targets include; β2 glycoprotein
I, a plasma protein that associates with the
surfaces of endothelial cells and trophoblasts, and
thrombin, thereby inducing a hypercoagulable
state through uncertain mechanisms (Reaserch).
 These antibodies give a falsepositive serologic
test for syphilis because the antigen in the
standard assay is embedded in cardiolipin.
 Antiphospholipid antibody syndrome has primary
and secondary forms. Individuals with a well-
defined autoimmune disease, such as SLE, having
secondary antiphospholipid syndrome (hence the
earlier term lupus anticoagulant syndrome).
 In primary antiphospholipid syndrome, patients
exhibit only the manifestations of a
hypercoagulable state and lack evidence of other
autoimmune disorders; occasionally, it appears
following exposure to certain drugs or infections.
 Therapy involves anticoagulation and
immunosuppression.
 Although antiphospholipid antibodies are
clearly associated with thrombotic
diatheses.
Morphology of Thrombus
 Thrombi are focally attached to the
underlying vascular surface, particularly at
the point of initiation.
 From here, arterial thrombi tend to grow
retrograde, while venous thrombi extend
in the direction of blood flow; thus both
propagate toward the heart.
 The propagating portion of a thrombus is
often poorly attached and therefore
prone to fragmentation and embolization.
 Thrombi have grossly and microscopically
apparent laminations called lines of Zahn,
which are pale platelet and fibrin deposits
alternating with darker red cell–rich layers.
 Such laminations signify that a thrombus has
formed in flowing blood; their presence can
therefore distinguish antemortem clots from
the bland nonlaminated clots that occur
postmortem.
 Thrombi occurring in heart chambers or in
the aortic lumen are designated mural
thrombi.
 Arterial thrombi are frequently occlusive; the
most common sites in decreasing order of
frequency are the coronary, cerebral, and femoral
arteries.
 They typically consist of a friable meshwork of
platelets, fibrin, red cells, and degenerating
leukocytes.
 Venous thrombosis (phlebothrombosis) is
almost invariably occlusive.
 These thrombi form in the sluggish venous
circulation, they tend to contain more enmeshed
red cells (and relatively few platelets) and are
therefore known as red, or stasis thrombi.
 Venous thrombi are firm, are focally attached
to the vessel wall, and contain lines of Zahn.
 Postmortem clots form after death, are
gelatinous and have a dark red dependent
portion where red cells have settled by
gravity and a yellow upper portion, and are
usually not attached to the underlying vessel
wall.
 Thrombi on heart valves are called
vegetations.
Fate of the Thrombus
 If a patient survives the thrombosis, in the
ensuing days to weeks undergo following
four events:
 • Propagation.Thrombi accumulate additional
platelets and fibrin.
 • Embolization.Thrombi dislodge and travel
to other sites in the vasculature.
 • Dissolution. Dissolution is the result of
fibrinolysis, which can lead to the rapid
shrinkage and total disappearance of recent
thrombi.
 • Organization and recanalization. Older thrombi
become organized by the ingrowth of endothelial
cells, smooth muscle cells, and fibroblasts.
 Capillary channels eventually form that reestablish
the continuity of the original lumen, albeit to a
variable degree.
 Continued recanalization may convert a thrombus
into a smaller mass of connective tissue that
becomes incorporated into the vessel wall.
 Eventually, with remodeling and contraction of the
mesenchymal elements, only a fibrous lump may
remain to mark the original thrombus.
Organized thrombus
 Occasionally the centers of thrombi undergo
enzymatic digestion, presumably as a result
of the release of lysosomal enzymes from
trapped leukocytes and platelets.
 In the setting of bacteremia, such thrombi
may become infected, producing an
inflammatory mass that erodes and weakens
the vessel wall.
 If unchecked, this may result in a mycotic
aneurysm.
Clinical Features
 Thrombi come to clinical attention when they
obstruct arteries or veins, or give rise to emboli.
 The clinical presentation depends on the involved
site.
 Venous Thrombosis (Phlebothrombosis);
Most venous thrombi occur in the superficial or
deep veins of the leg.
 Superficial venous thrombi typically occur in the
saphenous veins in the setting of varicosities.
 Such thrombi can cause local congestion, swelling,
pain, and tenderness, but rarely embolize.
 The associated edema and impaired venous
drainage predispose the overlying skin to the
development of infections and ulcers
(varicose ulcers).
 DVT involving one of the large leg veins—at
or above the knee (e.g., the popliteal,
femoral, and iliac veins)—is more serious
because such thrombi more often embolize
to the lungs and give rise to pulmonary
infarction.
 Although DVTs may cause local pain and
edema due to venous obstruction, these
symptoms are often absent due the opening
of venous collateral channels.
 Consequently, DVTs are asymptomatic in
approximately 50% of affected individuals
and are recognized only in retrospect
after embolization.
 Common predisposing factors include;
bed rest and immobilization (because they
reduce the milking action of the leg
muscles, resulting in stasis), and CHF (also
a cause of impaired venous return).
 Trauma, surgery, and burns not only
immobilize a person but are also associated
with vascular insults, procoagulant release
from injured tissues, increased hepatic
synthesis of coagulation factors, and
decreased tPA production.
 Many elements contribute to the thrombotic
diathesis of pregnancy, including decreased
venous return from leg veins and systemic
hypercoagulability associated with the
hormonal changes of late pregnancy and the
postpartum period.
 Tumor associated inflammation and
coagulation factors (tissue factor, factor
VIII), as well as procoagulants (e.g., mucin)
released from tumor cells, all contribute
to the increased risk of
thromboembolism in disseminated
cancers, socalled migratory
thrombophlebitis or Trousseau
syndrome.
 Advanced age increases the risk of DVT.
 Arterial and Cardiac Thrombosis;Atherosclerosis
is a major cause of arterial thromboses because it
is associated with loss of endothelial integrity and
with abnormal blood flow.
 MI can predispose to cardiac mural thrombi by
causing dyskinetic myocardial contraction and
endocardial injury, and rheumatic heart disease
may engender atrial mural thrombi by causing
atrial dilation and fibrillation. Both cardiac and
aortic mural thrombi are prone to embolization.
 Although any tissue can be affected, the brain,
kidneys, and spleen are particularly likely targets
because of their rich blood supply.
Disseminated Intravascular
Coagulation;
 DIC is not a specific disease but rather a
complication of a large number of conditions
associated with systemic activation of
thrombin. Disorders ranging from obstetric
complications to advanced malignancy can
be complicated by DIC, which leads to
widespread formation of thrombi in the
microcirculation.
 These microvascular thrombi can cause
diffuse circulatory insufficiency and organ
dysfunction, particularly of the brain, lungs,
heart, and kidneys.
 DIC uses platelets and coagulation factors
(consumptive coagulopathy) and often
activates fibrinolytic mechanisms.
 Thus, symptoms initially related to
thrombosis can evolve into a bleeding
catastrophe, such as hemorrhagic stroke
or hypovolemic shock.