HEMODYNAMIC DISORDERS,

THROMBOEMBOLISM, AND Mrs. Bayan Subb Laban

SHOCK
 COAGULATION CASCADE
ØThe coagulation cascade is a series of amplifying enzymaic reactions that lead to the
deposition of an insoluble fibrin clot.
ØThe cascade of reactions in the pathway can be linked to a “dance”, in which coagulation
factors are passed from one partner to the next.
ØEach reaction step involves:
1) An enzyme ( an activated coagulation factor)
2) A substrate ( an inactive proenzyme from of a coagulation factor)
3) A cofactor ( a reaction accelerator)

ØThese components are assempled on a negatively charged phospholipid surface on

activated platelets.
ØAssembly af reaction complexes also depends on calcium, which binds to gamma-
carboxylated glutamic acid residues in factors II, VII,IX and X.
ØThe anzymatic reactions that produce gamma- carboxylated glutamic acid use vitamin K as
a cofactor. It can antagonized by drugs such as coumadin.
2
Sequential conversion of factor X to factor Xa by way of the extrinsic
pathway, followed by conversion of factor II (prothrombin) to factor IIa
(thrombin). The initial reaction complex consists of a protease (factor
VIIa), a substrate (factor X), and a reaction accelerator (tissue factor)
assembled on a platelet phospholipid surface. Calcium ions hold the
assembled components together and are essential for the reaction.
Activated factor Xa then becomes the protease component of the next
complex in the cascade, converting prothrombin to thrombin (factor IIa) in
the presence of a different reaction accelerator, factor Va. 3
COAGULATION CASCADE
ØAt each step in coagulation cascade process, a proenzyme is proteolyzed
to become an active enzyme, which in turn proteolyzes the next
proenzyme in the series, eventually leading to the activation of thrombin
and the formation of fibrin.

ØThrombin ( factor IIa) has a key role, as it acts at numerous points in the
cascade. Thrombin proteolyzes fibrinogen into fibrin monomers that
polymerize into an insoluble gel; this gel encases platelets and other
circulating cells in the definitive secondary hemostatic plug. Fibrin
polymers are stabilized by the cross-linking activity of factor XIIIa, which also
is activated by thrombin.

4
COAGULATION CASCADE
ØBlood coagulation traditionally is divided into extrinsic and intrinsic
pathways, converging at the activation of factor X.
ØThe extrinsic pathway was so designated because it required the
addition of an exogenous trigger (originally provided by tissue
extracts).
ØThe intrinsic pathway only required exposing factor XII (Hageman
factor) to a negatively charged surface.
ØThe extrinsic pathway is the most physiologically relevant
pathway for coagulation occurring after vascular damage; it is
activated by tissue factor, a membrane-bound glycoprotein
expressed at sites of injury.
5
The coagulation cascade.
Factor IX can be activated by
either factor XIa or factor VIIa:
In laboratory tests, activation is
predominantly dependent on
factor XIa, whereas in vivo,
factor VIIa appears to be the
predominant activator of factor
IX. Factors in red boxes
represent inactive molecules;
activated factors, indicated with
a lowercase a, are in green
boxes. Note that thrombin
(factor IIa) (in light blue boxes)
contributes to coagulation
through multiple positive
feedback loops. The red X’s
denote points at which tissue
factor pathway inhibitor (TFPI)
inhibits activation of factor X and
factor IX by factor VIIa. HMWK,
high-molecular-weight
kininogen; PL, phospholipid.

6
CLINICAL LABS ASSESS THE FUNCTION OF THE
TWO ARMS OF THE PATHWAY USING TWO
STANDARD ASSAYS:

1. Prothrombin time (PT)

Screens the activity of the proteins in the extrinsic
pathway (factors VII, X, II, V, and fibrinogen).
Because factor VII is the vitamin K–dependent
coagulation factor with the shortest half-life (roughly 7
hours), the PT is used to guide treatment of patients with
vitamin K antagonists (e.g., coumadin ’ warfarin’).

7
CLINICAL LABS ASSESS THE FUNCTION OF THE
TWO ARMS OF THE PATHWAY USING TWO
STANDARD ASSAYS:

2. Partial thromboplastin time (PTT)

Screens for the activity of the proteins in the intrinsic
pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen).
The PTT is sensitive to the anticoagulant effects of heparin
and is therefore used to monitor its efficacy.

8
THROMBIN
• Among the coagulation factors, thrombin is the most important, because its
various enzymatic activities control diverse aspects of hemostasis and link
clotting to inflamation and repair.
• Thrombin’s most important activities:
1) Conversion of fibrinogen into crosslinked fibrin.
2) Platelet activation.
3) Proinflammatory effects.
4) Anti-coagulant effects.

9
Role of thrombin in hemostasis and cellular activation. Thrombin generates fibrin
by cleaving fibrinogen, activates factor XIII (which is responsible for cross-linking fibrin
into an insoluble clot), and also activates several other coagulation factors, thereby
amplifying the coagulation cascade. Through protease-activated receptors (PARs),
thrombin activates (1) platelet aggregation and TxA2 secretion; (2) endothelium, which
responds by generating leukocyte adhesion molecules and a variety of fibrinolytic (t-
PA), vasoactive (NO, PGI2), or cytokine (PDGF) mediators; and (3) leukocytes,
increasing their adhesion to activated endothelium. ECM, extracellular matrix; NO,
nitric oxide; PDGF, platelet-derived growth factor; PGI2, prostaglandin I2 (prostacyclin);
TxA2, thromboxane A2; t-PA, tissue type plasminogen activator. 10
FACTRORS THAT LIMIT COAGULATION
Ø Once coagulation cascade initiated, it must be tightly restricted to
the site of injury to prevent inappropriate and potentially dangerous
clotting elsewhere in the vascular tree.
o One limiting factor is simple dilution, blood flowing past the site of
injury washes out activated coagulation factors.
oA second is the requirement for negatively charged
phospholipids, which are mainly provided by activated platelets at
site of vascular injury.
oThe most important mechanisms involve factors that are expressed
by intact endothelium adjacent to the site of injury.
oClotting also is controlled by three general categories of natural
anticoagulants
NATURAL ANTICOAGULANT
1) Antithrombins (e.g., antithrombin III) inhibit the activity of
thrombin and other serine proteases, namely factors IXa, Xa, XIa,
and XIIa. Antithrombin III is activated by binding to heparin-like
molecules on endothelial cells— hence the clinical utility of
heparin administration to limit thrombosis.
2) Protein C and protein S are two vitamin K–dependent proteins
that act in a complex to proteolytically inactivate cofactors Va
and VIIIa. protein S is a cofactor for protein C activity.
3) Tissue factor pathway inhibitor (TFPI) is a protein secreted by
endothelium (and other cell types) that inactivates factor Xa and
tissue factor–factor VIIa complexes.
FIBRINOLYTIC PATHWAY
ØFibrinolysis is largely accomplished through the enzymatic activity of
plasmin, which breaks down fibrin and interferes with its polymerization.
ØPlasmin is generated by proteolysis of plasminogen, an inactive plasma
precursor, either by factor XII or by plasminogen activators.
ØThe most important of the plasminogen activators is tissue-type
plasminogen activator (t-PA); t-PA is synthesized principally by
endothelial cells and is most active when attached to fibrin.
ØUrokinase-like plasminogen activator (u-PA) is another plasminogen
activator present in plasma and in various tissues; it can activate plasmin
in the fluid phase.

13
FIBRINPLYTIC PATHWAY
ØIn addition, plasminogen can be cleaved to its active form by the bacterial
product streptokinase.
ØAs with any potent regulatory component, the activity of plasmin is tightly
restricted. To prevent excess plasmin from lysing thrombi indiscriminately
throughout the body, free plasmin rapidly complexes with circulating α2-
antiplasmin and is inactivated.
ØEndothelial cells further modulate the coagulation– anticoagulation
balance by releasing plasminogen activator inhibitors (PAIs); these
block fibrinolysis and confer an overall procoagulation effect.
ØPAI production is ↑ by inflammatory cytokines (in particular interferon-γ)
and probably contributes to the intravascular thrombosis that accompanies
severe inflammation.

14
The fibrinolytic system, illustrating various plasminogen activators and inhibitors
15
SUMMARY COAGULATION FACTORS
• Coagulation occurs via the sequential enzymatic conversion of a cascade of circulating
and locally synthesized proteins.
• Tissue factor elaborated at sites of injury is the most important initiator of the coagulation
cascade in vivo.
• At the final stage of coagulation, thrombin converts fibrinogen into insoluble fibrin that
contributes to formation of the definitive hemostatic plug.
• Coagulation normally is restricted to sites of vascular injury by:
i. Limiting enzymatic activation to phospholipid surfaces provided by activated platelets
or endothelium.
ii. Natural anticoagulants elaborated at sites of endothelial injury or during activation of
the coagulation cascade.
iii. Expression of thrombomodulin on normal endothelial cells, which binds thrombin and
converts it into an Anticoagulant.
iv. Activation of fibrinolytic pathways (e.g., by association of tissue plasminogen activator
with fibrin).
16
THROMBOSIS
Having reviewed the process of normal hemostasis,
we now turn to the three primary abnormalities
that lead to thrombus formation (called Virchow’s
triad):

1) Endothelial injury
2) Stasis or turbulent blood flow
3) Hypercoagulability of the blood.
17
18
ENDOTHELIAL INJURY
ØEndothelial injury is an important cause of thrombosis, particularly in
the heart and the arteries, where high flow rates might otherwise
impede clotting by preventing platelet adhesion or diluting
coagulation factors.
ØExamples of thrombosis related to endothelial damage are the
formation of thrombi in the cardiac chambers after myocardial infarction,
over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic
or inflammatory vascular injury (vasculitis).
ØEndothelium need not be denuded or physically disrupted to
contribute to the development of thrombosis; any perturbation in the
dynamic balance of the prothrombotic and antithrombotic effects of
endothelium can influence clotting locally.
19
ENDOTHELIAL INJURY
ØDysfunctional endothelium elaborates greater amounts of
procoagulant factors (e.g., platelet adhesion molecules, tissue
factor, PAI) and synthesizes lesser amounts of anticoagulant
molecules (e.g., thrombomodulin, PGI2, t-PA).
ØEndothelial dysfunction can be induced by a variety of insults,
including hypertension, turbulent blood flow, bacterial products,
radiation injury, metabolic abnormalities such as homocystinuria
and hypercholesterolemia, and toxins absorbed from cigarette
smoke.
ABNORMAL BLOOD FLOW
ØTurbulence contributes to arterial and cardiac
thrombosis by causing endothelial injury or
dysfunction, as well as by forming
countercurrents and local pockets of stasis.
Ø Stasis is a major factor in the development of
venous thrombi.

21
ABNORMAL BLOOD FLOW
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. By contrast,
stasis and turbulent (chaotic) blood flow have the following deleterious
effects:
1. Both promote endothelial cell activation and enhanced
procoagulant activity, in part through flow-induced changes in
endothelial gene expression.
2. Stasis allows platelets and leukocytes to come into contact with the
endothelium when the flow is sluggish.
3. Stasis also slows the washout of activated clotting factors and
impedes the inflow of clotting factor inhibitors.
 HYPERCOAGULABILITY
ØHypercoagulability refers to an abnormally high tendency of the blood to clot, and
is typically caused by alterations in coagulation factors.
ØIt contributes infrequently to arterial or intracardiac thrombosis but is an
important underlying risk factor for venous thrombosis.
ØAny alteration of the coagulation pathways predisposes affected persons to
thrombosis, and can be divided into primary (genetic) and secondary (acquired)
disorders.
ØPrimary (inherited) hypercoagulability most often is caused by mutations in the
factor V and prothrombin genes.
ØSecondary (acquired) hypercoagulability is seen in many settings. In some
situations (e.g., cardiac failure or trauma), stasis or vascular injury may be the
most important factor. 23
HYPERCOAGULABILITY
Among the acquired thrombophilic states, two are particularly important
clinical problems and deserve special mention:
1- Heparin induced thrombocytopenic (HIT) syndrome. This syndrome
occurs in up to 5% of patients treated with unfractionated heparin (for
therapeutic anticoagulation). It is marked by the development of
autoantibodies that bind complexes of heparin and platelet membrane
protein (platelet factor-4).
2- Anti-phospholipid antibody syndrome. Includes recurrent thrombosis,
repeated miscarriages, cardiac valve vegetations, and thrombocytopenia; it
is associated with autoantibodies directed against anionic phospholipids
(e.g., cardiolipin) or—more accurately—plasma protein antigens that are
unveiled by binding to such phospholipids (e.g., prothrombin).
Hypercoagulable states

25
Mural thrombi.
A, Thrombus in the left and
right ventricular apices,
overlying white fibrous scar.
B, Laminated thrombus in a
dilated abdominal aortic
aneurysm. Numerous friable
mural thrombi are also
superimposed on advanced
atherosclerotic lesions of the
more proximal aorta (left side
of photograph). 26
FATE OF THE THROMBUS
If a patient survives an initial thrombotic event, during the ensuing days to weeks the thrombus
evolves through some combination of the following four processes:

1-Propagation: The thrombus enlarges through the accretion of additional platelets and fibrin,
increasing the odds of vascular occlusion or embolization.

2-Embolization: Part or all of the thrombus is dislodged and transported elsewhere in the
vasculature.

3-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 given within a few hours of thrombus formation.
27
FATE OF THE THROMBUS
4-Organization and recanalization: Older thrombi become organized by the
ingrowth of endothelial cells, smooth muscle cells, and fibroblasts into the
fibrin-rich thrombus. 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 a vascularized
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 formation of a mycotic aneurysm.
29
VENOUS THROMBOSIS (PHLEPOTHROMBOSIS)

ØMost venous thrombi occur in the superficial or the deep veins of the leg.
ØSuperficial venous thrombi usually arise in the sephenous system, these
rarely embolize but they can be painful and can cause local congestion
and swelling from impaired venous outflow, predisposing the overlying skin
to the development of infections and varicose ulcers.
ØDeep venous thrombosis (DVTs) in the larger leg veins at or above the
knee joint are most serious because they are prone to embolize.
ØConsequently, DVTs are entirely asymptomatic in approximately 50% of
patients and are recognized only after they have embolized to the lung.
ØLower-extrimity DVTs are assotiated with stasis and hypercoagulable
states.
ARTERIAL AND CARDIAC THROMBOSIS

ØAtherosclerosis is a major cause of arterial thrombosis because it is

associated with the loss of endothelial integrity and with abnormal blood
flow.
ØMyocardial infarction 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.
ØBoth cardiac and aortic mural thrombi are prone to embolization.
ØAlthough any tissue can be affected, the brain, kidneys, and spleens are
particularly likely targets because of their rich blood supply.
SUMMARY (THROMBOSIS)
• Thrombus development usually is related to one or more components of Virchow’s
triad:
a) endothelial injury (e.g., by toxins, hypertension, inflammation, or metabolic
products).
b) abnormal blood flow, stasis or turbulence (e.g., due to aneurysms,
atherosclerotic plaque).
c) hypercoagulability: either primary (e.g., factor V Leiden, ↑d prothrombin
synthesis, antithrombin III deficiency) or secondary (e.g., bed rest, tissue damage,
malignancy).
• Thrombi may propagate, resolve, become organized, or embolize.
• Thrombosis causes tissue injury by local vascular occlusion or by distal embolization.
32
LECTURE OUTLINE
I. Hyperemia and Congestion.
II. Edema.
III. Hemorrhage.
IV. Hemostasis and Thrombosis.
V. Embolism.
VI. Infarction.
VII. Shock.

33
EMBOLISM
• An embolus is a detached intravascular solid, liquid, or gaseous mass
that is carried by the blood from its point of origin to a distant site, where
it often causes tissue dysfunction or infarction.
• The vast majority of emboli derive from a dislodged thrombus—hence
the term thromboembolism.
• Less commonly, emboli are composed of fat droplets, bubbles of air or
nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments,
bits of bone marrow, and amniotic fluid.
• The primary consequence of systemic embolization is ischemic
necrosis (infarction) of downstream tissues, whereas embolization in the
pulmonary circulation leads to hypoxia, hypotension, and right-sided
heart failure.

34
PULMONARY THROMBOEMBOLISM
ØPulmonary emboli originate from deep venous thrombosis and
are responsible for the most common form of thromboembolic
disease.
ØThe incidence of pulmonary embolism (PE) is 2 to 4 per 1000
hospitalized patients. Although the rate of fatal pulmonary
embolus has declined considerably since the early 1990s, PE
still causes about 200,000 deaths per year in the United
States.
ØIn greater than 95% of cases, venous emboli originate from
thrombi within deep leg veins proximal to the popliteal
fossa; embolization from lower leg thrombi is uncommon.
35
PULMONARY THROMBOEMBOLISM
Major clinical clinical and pathological features are the following:
a) Most PE (60%-80%) are small and clinically scilent. With time, they
undergo orgenization and become incorporated into vascular wall.
b) A large embolus that blocks a major pulmonary artery can cause
sudden death.
c) Embolic obstruction of medium-sized artries and subsequent rupture of
downstream capillaries can cause pulmonary hemorrhage.
d) Embolism to small end-arteriolar pulmonary branches usually causes
infarction.
e) Multiple emboli occuring through time can cause pulmonary
hypertension and right ventricular failure.
Embolus derived from a lower-extremity deep venous thrombus lodged in a
pulmonary artery branch.
37
SYSTEMIC THROMBOEMBOLISM
ØSystemic thromboembolism refers to emboli travelling within the arterial
circulation.
ØMost systemic emboli (80%) arise from intracardiac mural thrombi; two
thirds are associated with left ventricular infarcts and another 25% with
dilated left atria (e.g., secondary to mitral valve disease). The remainder
originate from aortic aneurysms, thrombi overlying ulcerated
atherosclerotic plaques, fragmented valvular vegetations , or the venous
system (paradoxical emboli); 10% to 15% of systemic emboli are of
unknown origin.
ØBy contrast with venous emboli, which lodge primarily in the lung, arterial
emboli can travel virtually anywhere; their final resting place understandably
depends on their point of origin and the relative flow rates of blood to the
downstream tissues.
38
SYSTEMIC THROMBOEMBOLISM
ØCommon arteriolar embolization sites include the lower
extremities (75%) and central nervous system (10%); intestines,
kidneys, and spleen are less common targets.

ØThe consequences of embolization depend on the caliber of the

occluded vessel, the collateral supply, and the affected tissue’s
vulnerability to anoxia; arterial emboli often lodge in end arteries
and cause infarction.
FAT EMBOLISM
ØSoft tissue crush injury or rupture of marrow vascular sinusoids (long
bone fracture) releases microscopic fat globules into the circulation.
ØFat and marrow emboli are common incidental findings after vigorous
cardiopulmonary resuscitation but probably are of little clinical
consequence.
ØAlthough fat and marrow embolism occurs in some 90% of individuals with
severe skeletal injuries, less than 10% show any clinical findings.
ØHowever, a minority of patients develop a symptomatic fat embolism
syndrome characterized by pulmonary insufficiency, neurologic
symptoms, anemia, thrombocytopenia, and a diffuse petechial rash,
which is fatal in 10% of cases.
40
 A, Bone marrow embolus. The embolus is composed of
hematopoietic marrow and marrow fat cells (clear spaces)
attached to a thrombus. 41
AMNIOTIC FLUID EMBOLISM
ØAmniotic fluid embolism is an uncommon, grave complication of labor and
the immediate postpartum period occuring in 1 in 40000 deliveries.
ØThe mortality approaches 80%, making it most common cause of maternal
death in the developed world.
ØMost of survivors suffer some form of permanent neurologic defects.
Onset is characterized by sudden severe dyspnea, cyanosis, and
hypotensive shock, followed by seizures and coma.
ØIf the patients survive the initial crisis, pulmonary edema typicslly develops
along with disseminated intravascular coagulation.
ØThe underlying cause is the entry of amniotic fluid (and itd contents) into the
maternal circulation via tears in the placental membranes or uterine vein
rupture.
AIR EMBOLISM
ØGas bubbles within the circulation can coalesce and obstruct
vascular flow and cause distal ischemic injury.

ØThus, a small volume of air trapped in a coronary artery during

bypass surgery or introduced into the cerebral arterial circulation
by neurosurgery performed in an upright “sitting position” can
occlude flow, with dire consequences.
ØIt can occur upon rapid decompression, most commonly in
divers; it results from sudden bubbling of nitrogen dissolved in
blood at higher pressure.

43
SUMMARY (EMBOLISM)
ØAn embolus is a solid, liquid, or gaseous mass carried by the blood to a site distant
from its origin; most are dislodged thrombi.

ØPulmonary emboli derive primarily from lower-extremity deep vein thrombi; their
effects depend mainly on the size of the embolus and the location in which it
lodges. Consequences may include right-sided heart failure, pulmonary
hemorrhage, pulmonary infarction, or sudden death.

ØSystemic emboli derive primarily from cardiac mural or valvular thrombi, aortic
aneurysms, or atherosclerotic plaques; whether an embolus causes tissue infarction
depends on the site of embolization and the presence or absence of collateral
circulation. 44
SUMMARY (EMBOLISM)
• Fat embolism can occur after crushing injuries to the bones; symptoms
include pulmonary insufficiency and neurological damage.

• Amniotic fluid embolism may follow childbirth and can give rise to fatal
pulmonary and cerebral manifestations.

• Air embolism can occur upon repid decompression.

LECTURE OUTLINE
I. Hyperemia and Congestion.
II. Edema.
III. Hemorrhage.
IV. Hemostasis and Thrombosis.
V. Embolism.
VI. Infarction.
VII. Shock.

46
INFARCTION
ØAn infarct is an area of ischemic necrosis caused by occlusion of
the vascular supply to the affected tissue
ØInfarction primarily affecting the heart and the brain is a common
and extremely important cause of clinical illness.
ØPulmonary infarction is a common clinical complication.
ØBowel infarction often is fatal
ØIschemic necrosis of distal extremities (gangrene) causes
substantial morbidity in the diabetic population.

47
INFARCTION
ØArterial thrombosis or arterial embolism underlies the vast
majority of infarctions.

ØLess common causes of arterial obstruction include vasospasm,

expansion of an atheroma secondary to intraplaque hemorrhage,
and extrinsic compression of a vessel, such as by tumor, a
dissecting aortic aneurysm, or edema within a confined space
(e.g., in anterior tibial compartment syndrome).

48
 Red and white infarcts. A, Hemorrhagic, roughly wedge-shaped
pulmonary infarct (red infarct). B, Sharply demarcated pale infarct
in the spleen (white infarct).
49
FACTORS THAT INFLUENCE INFARCT
DEVELOPMENT.
ØThe effects of vascular occlusion range from
inconsequential to tissue necrosis leading to organ
dysfunction and sometimes death.

ØThe range of outcomes is influenced by:

1) the anatomy of the vascular supply
2) Rate of occlusion
3) the intrinsic vulnerability of the affected tissue to hypoxia
4) the blood oxygen content.
50
ANATOMY OF THE VASCULAR SUPPLY
ØThe presence or absence of an alternative blood supply is the most
important factor in determining whether occlusion of an individual vessel
causes damage.
ØThe dual supply of the lung by the pulmonary and bronchial arteries
means that obstruction of the pulmonary arterioles does not cause lung
infarction unless the bronchial circulation also is compromised.
ØSimilarly, the liver, which receives blood from the hepatic artery and
the portal vein, and the hand and forearm, which its parallel radial and
ulnar arterial supply, are resistant to infarction.
ØBy contrast, the kidney and the spleen both have end-arterial
circulations, and arterial obstruction generally leads to infarction in these
tissues. 51
Remote kidney infarct, now replaced by a large fibrotic scar.

52
RATE OF OCCLUSION
ØSlowly developing occlusions are less likely to cause infarction
because they allow time for the development of collateral blood
supplies.
ØFor example, small interarteriolar anastomoses, which normally
carry minimal blood flow, interconnect the three major coronary
arteries.
ØIf one coronary artery is slowly occluded (e.g., by encroaching
atherosclerotic plaque), flow in this collateral circulation may ↑
sufficiently to prevent infarction—even if the original artery
becomes completely occluded.

53
TISSUE VULNERABILITY TO ISCHEMIA.

ØNeurons undergo irreversible damage when deprived of

their blood supply for only 3 to 4 minutes.

ØMyocardial cells, although hardier than neurons, still die

after only 20 to 30 minutes of ischemia. By contrast,
fibroblasts within myocardium remain viable after many
hours of ischemia.

54
THE BLOOD OXYGEN CONTENT
Ø Understandably, abnormally low blood O2 content
(regardless of cause) ↑ both the likelihood and
extent of infarction.

55
SUMMARY
INFARCTION
ØInfarcts are areas of ischemic necrosis most commonly caused by arterial
occlusion (typically due to thrombosis or embolization); venous outflow
obstruction is a less frequent cause.
ØInfarcts caused by venous occlusion or occurring in spongy tissues typically
are hemorrhagic (red); those caused by arterial occlusion in compact tissues
typically are pale (white).
ØWhether or not vascular occlusion causes tissue infarction is influenced by
collateral blood supplies, the rate at which an obstruction develops, intrinsic
tissue susceptibility to ischemic injury, and blood oxygenation.

56
LECTURE OUTLINE
I. Hyperemia and Congestion.
II. Edema.
III. Hemorrhage.
IV. Hemostasis and Thrombosis.
V. Embolism.
VI. Infarction.
VII. Shock.

57
SHOCK
ØShock is the final common pathway for several potentially lethal events,
including severe hemorrhage, extensive trauma or burns, myocardial
infarction, pulmonary embolism, and sepsis.
ØShock is characterized by systemic hypoperfusion of tissues; it can be
caused by diminished cardiac output or by ↓ effective circulating blood
volume.
ØThe consequences are impaired tissue perfusion and cellular hypoxia
leading to multiple organ failure. Although shock initially is reversible,
prolonged shock eventually leads to irreversible tissue injury that often
proves fatal.

58
SHOCK
The most common forms of shock can be grouped into three
pathogenic categories:
vCardiogenic shock: results from low cardiac output due to
myocardial pump failure. It may be caused by myocardial damage
(infarction), ventricular arrhythmias, extrinsic compression
(cardiac tamponade), or outflow obstruction (e.g., pulmonary
embolism).
vHypovolemic shock: results from low cardiac output due to loss
of blood or plasma volume (e.g., due to hemorrhage or fluid loss
from severe burns).
SHOCK
vSeptic shock: results from arterial vasodilation and venous blood
pooling that stems from the systemic immune response to
microbial infection (high WBCs). It is associated with severe
systemic inflammatory response syndrome (SIRS)
Less commonly forms of shock:
vNeurogenic shock: shock can result from loss of vascular tone
associated with anesthesia or secondary to a spinal cord injury.
vAnaphylactic shock: results from systemic vasodilation and ↑
vascular permeability that is triggered by an immunoglobulin E–
mediated hypersensitivity reaction.
THREE MAJOR TYPES OF SHOCK
STAGES OF SHOCK
ØShock is a progressive disorder that leads to death if the
underlying problems are not corrected.
ØFor hypovolemic and cardiogenic shock, however, the
pathways leading to a patient’s demise are reasonably well
understood.
ØUnless the insult is massive and rapidly lethal (e.g.,
exsanguination from a ruptured aortic aneurysm),
shock tends to evolve through three general (albeit
somewhat artificial) stages.
62
STAGES OF SHOCK
These stages have been documented most clearly in hypovolemic
shock but are common to other forms as well:
1. An initial nonprogressive stage, during which reflex
compensatory mechanisms are activated and vital organ
perfusion is maintained.
2. A progressive stage, characterized by tissue hypoperfusion and
onset of worsening circulatory and metabolic derangement,
including acidosis.
3. An irreversible stage, in which cellular and tissue injury is so
severe that even if the hemodynamic defects are corrected,
survival is not possible.
STAGES OF SHOCK
ØIn the early non progressive phase of shock, various
neurohumoral mechanisms help maintain cardiac output and
blood pressure.
ØThese mechanisms include baroreceptors reflexes, release of
catecholamines and anti-diuretic hormone, activation of the renin-
angiotensin-aldosterone axis and generalized sympathetic
stimulation.
ØThe net effect is tachycardia, peripheral vasoconstriction, and
renal fluid conservation; cutaneous vasoconstriction causes the
characteristic “shocky” skin coolness and pallor (notably, septic
shock can initially cause cutaneous vasodilation, so the patient
may present with warm, flushed skin).
STAGES OF SHOCK
ØCoronary and cerebral vessels are less sensitive to sympathetic signals and
maintain relatively normal caliber, blood flow, and oxygen delivery. Thus, blood is
shunted away from the skin to the vital organs such as the heart and the brain.
ØIf the underlying causes are not corrected, shock passes imperceptibly to the
progressive phase, which as noted is characterized by widespread tissue
hypoxia.
Ø In the setting of persistent oxygen deficit, intracellular aerobic respiration is
replaced by anaerobic glycolysis with excessive production of lactic acid. The
resultant metabolic lactic acidosis lowers the tissue pH, which blunts the
vasomotor response; arterioles dilate, and blood begins to pool in the
microcirculation.
ØPeripheral pooling not only worsens the cardiac output but also puts endothelial
cells at risk for the development of anoxic injury with subsequent DIC. With
widespread tissue hypoxia, vital organs are affected and begin to fail.
ATAGES OF SHOCK
ØIn the absence of appropriate intervention, the process eventually
enters an irreversible stage.
ØWidespread cell injury is reflected in lysosomal enzyme leakage,
further aggravating the shock state.
ØMyocardial contractile function worsens, in part because of ↑
nitric oxide synthesis. The ischemic bowel may allow intestinal
flora to enter the circulation, and thus bacteremic shock may be
superimposed. Commonly, further progression to renal failure
occurs as a consequence of ischemic injury of the kidney, and
despite the best therapeutic interventions, the downward spiral
frequently culminates in death.
CLINICAL FEATURES
• The clinical manifestations of shock depend on the precipitating
insult.
• In hypovolemic and cardiogenic shock, patients exhibit
hypotension, a weak rapid pulse, tachypnea, and cool, clammy,
cyanotic skin.
• In septic shock, the skin may be warm and flushed owing to
peripheral vasodilation.
• Prognosis varies with the origin of shock and its duration. Thus,
more than 90% of young, otherwise healthy patients with
hypovolemic shock survive with appropriate management; by
comparison, septic or cardiogenic shock is associated with
substantially worse outcomes, even with state-of-the-art care. 67
SUMMARY (SHOCK)
ØShock is defined as a state of systemic tissue hypoperfusion resulting
from reduced cardiac output and/or reduced effective circulating blood
volume.
ØThe major ypes of shock are cardiogenic (e,g., myocardial infarction),
hypovolumic (e.g, blood loss), and septic (e.g., infections)
ØShock of any form can lead to hypoxic tissue injury if not corrected.
ØSeptic shock is caused by the host response to bacterial or fungal
infections; it is characterized by endothelial cell activation, vasidilation,
edema, disseminated intravascular coagulation, and metabolic
dearrangment.