Chapter 4 – Hemodynamic Disorders, Thromboembolic Disease, and Shock

Question 1

Approximately 60% of lean body weight is_____________

Answer 1

water

Question 2

Two thirds of the body’s water is __________
and the remainder is in extracellular compartments, mostly the interstitium (or third space) that
lies between cells

Answer 2

intracellular,

Question 3

How many percent of Total body water is blood plasma?

Answer 3

only about 5% of total body water is in blood plasma

Question 4

The movement of water
and low molecular weight solutes such as salts between the intravascular and interstitial spaces
is controlled primarily by the opposing effect of vascular ____________

Answer 4

hydrostatic pressure and plasma
colloid osmotic pressure.

Question 5

Normally the outflow of fluid from the arteriolar end of the
microcirculation into the interstitium is nearly balanced by inflow at the venular end; a small
residual amount of fluid may be left in the interstitium and is drained by the lymphatic vessels,
ultimately returning to the bloodstream via the thoracic duct. _Either increased capillary
pressure or diminished colloid osmotic pressure can result in increased interstitial fluid_

Question 6

Normally the outflow of fluid from the arteriolar end of the
microcirculation into the interstitium is nearly balanced by inflow at the venular end; a small
residual amount of fluid may be left in the interstitium and is drained by the lymphatic vessels, ultimately returning to the bloodstream via the thoracic duct. Either increased capillary
pressure or diminished colloid osmotic pressure can result in increased interstitial fluid

Question 7

What is edema?

Answer 7

If the movement of water into tissues (or body cavities) exceeds lymphatic drainage, fluid accumulates. An abnormal increase in interstitial fluid within tissues is called edema, while fluid
collections in the different body cavities are variously designated hydrothorax,
hydropericardium, and hydroperitoneum (the last is more commonly called ascites).

Question 8

What is Anasarca?

Answer 8

Anasarca is
a severe and generalized edema with widespread subcutaneous tissue swelling.

Question 9

Answer 9

FIGURE 4-1 Factors influencing fluid transit across capillary walls. Capillary hydrostatic and osmotic forces are normally balanced so that there is no net loss or gain of fluid across the
capillary bed. However, increased hydrostatic pressure or diminished plasma osmotic pressure will cause extravascular fluid to accumulate. Tissue lymphatics remove much of the
excess volume, eventually returning it to the circulation via the thoracic duct; however, if the capacity for lymphatic drainage is exceeded, tissue edema results.

Question 10

What is a transudate?

Answer 10

There are several pathophysiologic categories of edema ( Table 4-1 ). Edema caused by

• *increased hydrostatic pressure or reduced plasma protein** is typically a protein-poor fluid called
• *a transudate.**

Edema fluid of this type is seen in patients suffering from heart failure, renal
failure, hepatic failure, and certain forms of malnutrition,

Question 11

What is an exudate?

Answer 11

In contrast, inflammatory edema is a protein-rich exudate that is a result of increased vascular permeability. Edema in inflamed tissues is discussed in

Question 12

Pathophysiologic Categories of Edema

Answer 12

• INCREASED HYDROSTATIC PRESSUREREDUCED PLASMA
• OSMOTIC PRESSURE (HYPOPROTEINEMIA
• LYMPHATIC OBSTRUCTION
• SODIUM RETENTION
• INFLAMMATION

Question 13

Under the TABLE 4-1 – Pathophysiologic Categories of Edema
INCREASED HYDROSTATIC PRESSURE is brought about by diseases such as:

Answer 13

• Impaired venous return
  
  • Congestive heart failure
  • Constrictive pericarditis
  • Ascites (liver cirrhosis)
    
    • Venous obstruction or compression
    • Thrombosis
    • External pressure (e.g., mass)
    • Lower extremity inactivity with prolonged
      dependency
• Arteriolar dilation
  
  • Heat
  • Neurohumoral
  • dysregulation

Question 14

REDUCED PLASMA OSMOTIC PRESSURE (HYPOPROTEINEMIA

Answer 14

• Protein-losing glomerulopathies (nephrotic
  syndrome)
• Liver cirrhosis (ascites)
• Malnutrition
• Protein-losing gastroenteropathy

Question 15

LYMPHATIC OBSTRUCTION

Answer 15

• Inflammatory
• Neoplastic
• Postsurgical
• Postirradiation

Question 16

SODIUM RETENTION

Answer 16

• Excessive salt intake with renal insufficiency
• Increased tubular reabsorption of sodium
• Renal hypoperfusion
• Increased renin-angiotensin-aldosterone secretion

Question 17

INFLAMMATION

Answer 17

Acute inflammation
Chronic
inflammation
Angiogenesis

Question 18

Answer 18

FIGURE 4-2 Pathways leading to systemic edema from primary heart failure, primary renal
failure, or reduced plasma osmotic pressure (e.g., from malnutrition, diminished hepatic
synthesis, or protein loss from nephrotic syndrome).

Question 19

What happens in Increased Hydrostatic Pressure.

Answer 19

Regional increases in hydrostatic pressure can result from a focal impairment in venous return.
Thus, deep venous thrombosis in a lower extremity may cause localized edema in the affected
leg.

On the other hand, generalized increases in venous pressure, with resulting systemic edema, occur most commonly in congestive heart failure ( Chapter 12 ), where compromised
right ventricular function leads to pooling of blood on the venous side of the circulation.

Question 20

When does reduced plasma osmotic pressure occurs?

Answer 20

Reduced plasma osmotic pressure occurs when albumin, the major plasma protein, is not
synthesized in adequate amounts or is lost from the circulation.

Question 21

An important cause of albumin
loss is the__________ ( Chapter 20 ), in which glomerular capillaries become leaky; patients typically present with generalized edema.

Reduced albumin synthesis occurs in the
setting of severe liver diseases (e.g., cirrhosis, Chapter 18 ) or protein malnutrition ( Chapter 9
). In each case, reduced plasma osmotic pressure leads to a net movement of fluid into the
interstitial tissues with subsequent plasma volume contraction.

The reduced intravascular
volume leads to decreased renal perfusion. This triggers increased production of renin, angiotensin, and aldosterone, but the resulting salt and water retention cannot correct the
plasma volume deficit because the primary defect of low serum protein persists.

Answer 21

nephrotic syndrome

Question 22

When does reduce osmotic pressure occurs?

Answer 22

• Reduced plasma osmotic pressure occurs when albumin, the major plasma protein, is not synthesized in adequate amounts or is lost from the circulation.
• An important cause of albumin loss is the nephrotic syndrome ( Chapter 20 ), in which glomerular capillaries become leaky;
• patients typically present with generalized edema. Reduced albumin synthesis occurs in the
• setting of severe liver diseases (e.g., cirrhosis, Chapter 18 ) or protein malnutrition ( Chapter 9
• ). In each case, reduced plasma osmotic pressure leads to a net movement of fluid into the
• interstitial tissues with subsequent plasma volume contraction.
• The reduced intravascular volume leads to decreased renal perfusion. This triggers increased production of renin, angiotensin, and aldosterone, but the resulting salt and water retention cannot correct the plasma volume deficit because the primary defect of low serum protein persists.

Question 23

How can salt retention cause edema?

Answer 23

Salt and water retention can also be a primary cause of edema.

Increased salt retention—with
obligate associated water—causes both increased hydrostatic pressure (due to intravascular
fluid volume expansion)anddiminished vascular colloid osmotic pressure (due to dilution).

Salt retention occurs whenever renal function is compromised, such as in primary disorders of the kidney and disorders that decrease renal perfusion.

One of the most important causes of renal
hypoperfusion is congestive heart failure, which (like hypoproteinemia) results in the activation
of the renin-angiotensin-aldosterone axis.

In early heart failure, this response tends to be
beneficial, as the retention of sodium and water and other adaptations, including increased vascular tone and elevated levels of antidiuretic hormone (ADH), improve cardiac output and restore normal renal perfusion. [1,] [2]

However, as heart failure worsens and cardiac output
diminishes, the retained fluid merely increases the venous pressure, which (as already
mentioned) is a major cause of edema in this disorder.

Unless cardiac output is restored or
renal sodium and water retention is reduced (e.g., by salt restriction, diuretics, or aldosterone
antagonists), a downward spiral of fluid retention and worsening edema ensues.

Salt restriction,
diuretics, and aldosterone antagonists are also of value in managing generalized edema arising
from other causes.

Primary retention of water (and modest vasoconstriction) is produced by the release of ADH from the posterior pituitary, which normally occurs in the setting of reduced
plasma volumes or increased plasma osmolarity. [2]

Inappropriate increases in ADH are seen in
association with certain malignancies and lung and pituitary disorders and can lead to
hyponatremia and cerebral edema (but interestingly not to peripheral edema).

Question 24

Impaired lymphatic drainage results in lymphedema that is typically localized; causes include
chronic inflammation with fibrosis, invasive malignant tumors, physical disruption, radiation
damage, and certain infectious agents.

One dramatic example is seen in parasitic filariasis, in
which lymphatic obstruction due to extensive inguinal lymphatic and lymph node fibrosis can result in edema of the external genitalia and lower limbs that is so massive as to earn the appellation elephantiasis. Severe edema of the upper extremity may also complicate surgical
removal and/or irradiation of the breast and associated axillary lymph nodes in patients with
breast cancer.

Question 25

Edema is easily recognized grossly; microscopically, it is appreciated as:

Answer 25

wellinclearing and separation of the extracellular matrix and subtle cell sg.

Any organ or

tissue can be involved, but edema is most commonly seen in subcutaneous tissues, the
lungs, and the brain.

Question 26

What is subcutaneous edma?

Answer 26

Subcutaneous edema can be diffuse or more conspicuous in regions with high hydrostatic pressures.

Question 27

What is dependent edema?

Answer 27

In most cases the distribution is influenced by gravity and is
termed dependent edema (e.g., the legs when standing, the sacrum when recumbent).

Question 28

What is pitting edema?

Answer 28

Finger pressure over substantially edematous subcutaneous tissue displaces the interstitial
fluid and leaves a depression, a sign called pitting edema.

Question 29

Edema as a result of ________ can affect all parts of the body. It often initially
manifests in tissues with loose connective tissue matrix, such as the eyelids;

Answer 29

renal dysfunction

periorbital

edema is thus a characteristic finding in severe renal disease.

Question 30

What is the characteristic of pulmonary edema?

Answer 30

With pulmonary edema, the
lungs are often two to three times their normal weight, and sectioning yields frothy, bloodtinged
fluid—a mixture of air, edema, and extravasated red cells.

Question 31

What is the characterisitc of brain edema?

Answer 31

Brain edema can be
localized or generalized depending on the nature and extent of the pathologic process or
injury.

With generalized edema the brain is grossly swollen with narrowed sulci; distended
gyri show evidence of compression against the unyielding skull ( Chapter 28 ).

Question 32

Subcutaneous tissue
edema is important primarily because it signals potential underlying cardiac or renal disease; however, when significant, it can also impair wound healing or the clearance of infection.

Question 33

Pulmonary edema is a common clinical problem that is most frequently seen in the setting of left ventricular failure; it can also occur with renal failure, acute respiratory distress syndrome (
Chapter 15 ), and pulmonary inflammation or infection.

Not only does fluid collect in the alveolarsepta around capillaries and impede oxygen diffusion, but edema fluid in the alveolar spaces
also creates a favorable environment for bacterial infection.

Question 34

Brain edema is life-threatening; if
severe, brain substance can herniate (extrude) through the foramen magnum, or the brain stem
vascular supply can be compressed. Either condition can injure the medullary centers and
cause death

Question 35

Answer 35

FIGURE 4-3 Liver with chronic passive congestion and hemorrhagic necrosis. A, Central
areas are red and slightly depressed compared with the surrounding tan viable
parenchyma, forming a “nutmeg liver” pattern (so-called because it resembles the cut
surface of a nutmeg. B, Centrilobular necrosis with degenerating hepatocytes and
hemorrhage.

Question 36

What is hemorrhage?

Answer 36

Hemorrhage is defined as the extravasation of blood into the extravascular space.

Question 37

What are hemorrhagic diatheses.?

Answer 37

As describedabove, capillary bleeding can occur under conditions of chronic congestion; an increased
tendency to hemorrhage (usually with insignificant injury) also occurs in a variety of clinical
disorders that are collectivelycalled hemorrhagic diatheses. Rupture of a large artery or vein
results in severe hemorrhage and is almost always due to vascular injury, including trauma,
atherosclerosis, or inflammatory or neoplastic erosion of the vessel wall.

Question 38

Tissue hemorrhage can occur in distinct patterns, each with its own clinical implications:

Answer 38

1. hematoma
2. petechiae
3. purpura
4. ecchymoses.
5. Depending on the location, a large accumulation of blood in a body cavity is denoted as
   a hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis (in joints).

Question 39

What is a hematoma?

Answer 39

Hemorrhage may be external or contained within a tissue; any accumulation is called a
hematoma. Hematomas may be relatively insignificant or so massive that death ensues.

Question 40

What is a petechiae?

Answer 40

Minute **1- to 2-mm** hemorrhages into **skin, mucous membranes, or serosal surfaces** are
called petechiae ( Fig. 4-4A ).

These are most commonly associated with locally
increased intravascular pressure, low platelet counts (thrombocytopenia), or defective
platelet function (as in uremia).

Question 41

What is a purpura?

Answer 41

Slightly larger (≥3 mm) hemorrhages are called purpura.

These may be associated with
many of the same disorders that cause petechiae or can be secondary to trauma, vascular inflammation (vasculitis), or increased vascular fragility (e.g., in amyloidosis).

Question 42

What is an ecchymoses?

Answer 42

Larger (>1 to 2 cm) subcutaneous hematomas (i.e., bruises) are called ecchymoses.
The red cells in these lesions are degraded and phagocytized by macrophages; the hemoglobin (red-blue color) is then enzymatically converted into bilirubin (blue-green
color) and eventually into hemosiderin (gold-brown color), accounting for the characteristic color changes in a bruise.

Question 43

The clinical significance of hemorrhage depends on the ________________.

Answer 43

volume and rate of bleeding

Question 44

Rapid loss of up to 20% of the blood volume or slow losses of even larger amounts may have little
impact in healthy adults; greater losses, however, can cause hemorrhagic (hypovolemic) shock
(discussed later).

T or F

The site of hemorrhage is also important. For example, bleeding that is trivial
in the subcutaneous tissues can cause death if located in the brain ( Fig. 4-4B ); because the
skull is unyielding, intracranial hemorrhage can result in an increase in pressure that is sufficient to compromise the blood supply or to cause the herniation of the brainstem ( Chapter
28 ). Finally, chronic or recurrent external blood loss (e.g., peptic ulcer or menstrual bleeding)
causes a net loss in iron and can lead to an iron deficiency anemia. In contrast, when red cells
are retained (e.g., hemorrhage into body cavities or tissues), iron is recovered and recycled for
use in the synthesis of hemoglobin

Answer 44

True

Question 45

What is normal hemostasis?

Answer 45

Normal hemostasis is a consequence of tightly regulated processes that maintain blood in a
fluid state in normal vessels, yet also permit the rapid formation of a hemostatic clot at the site
of a vascular injury.

Question 46

What is thrombosis?

Answer 46

The pathologic counterpart of hemostasis is thrombosis; it involves blood
clot (thrombus) formation within intact vessels.

Question 47

Both hemostasis and thrombosis involve three
components:

Answer 47

1. the vascular wall (particularly the endothelium),
2. platelets,
3. and the coagulation cascade.

Question 48

The general sequence of events in hemostasis at a site of vascular injury is shown in Figure 4-
5 . [3,] [4]

Answer 48

1. brief period of arteriolar vasoconstriction
2. facilitating platelet adherence and activationthis process is referred to as primary hemostasis ( Fig. 4-5B ).
3. • Tissue factor is also exposed at the site of injury. Also known as factor III and thromboplastin, secondary hemostasis, consolidates the initial platelet plug ( Fig. 4-5C ).
4. Polymerized fibrin and platelet aggregates form a solid, permanent plug to prevent any further hemorrhage.

Question 49

After initial injury there is a brief period of arteriolar vasoconstriction which is mediated by____________

The effect is
transient, however, and bleeding would resume if not for activation of the platelet and
coagulation systems.

Answer 49

reflex neurogenic mechanisms and augmented by the local secretion of factors such as endothelin (a potent endothelium-derived vasoconstrictor; Fig. 4-5A ).

Question 50

What facilitates platelet adherence and activation.

Answer 50

Endothelial injury exposes highly thrombogenic subendothelial extracellular matrix
(ECM),

Question 51

What happens in primary hemostasis?

Answer 51

Activation of platelets results in a dramatic shape change (from small rounded discs to flat plates with markedly increased
surface area), as well as the release of secretory granules.

Within minutes the secreted
products recruit additional platelets (aggregation) to form a hemostatic plug; this
process is referred to as primary hemostasis

Question 52

Tissue factor is also exposed at the site of injury. Also known as ____________,

Answer 52

factor III and thromboplastin

Question 53

Where is tissue factor/ factor 3/ thromboplastin produced?

Answer 53

tissue factor is a membrane-bound procoagulant glycoprotein
synthesized by endothelial cells.

Question 54

What happens in secondary hemostasis?

Answer 54

Tissue factor is also exposed at the site of injury. Also known as factor III andthromboplastin, tissue factor is a membrane-bound procoagulant glycoprotein
synthesized by endothelial cells.

It acts in conjunction with factor VII (see below) as the
major in vivo initiator of the coagulation cascade, eventually culminating in thrombin
generation.

Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin
meshwork, and also induces additional platelet recruitment and activation. This
sequence, secondary hemostasis, consolidates the initial platelet plug

Question 55

major in vivo initiator of the coagulation cascade

Answer 55

Tissue factor is also exposed at the site of injury. Also known as factor III and
thromboplastin

Question 56

WHat does thrombin do?

Answer 56

Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork, and also induces additional platelet recruitment and activation

Question 57

Answer 57

FIGURE 4-5 Normal hemostasis. A, After vascular injury local neurohumoral factors induce a
transient vasoconstriction. B, Platelets bind via glycoprotein Ib (GpIb) receptors to von
Willebrand factor (vWF) on exposed extracellular matrix (ECM) and are activated,
undergoing a shape change and granule release. Released adenosine diphosphate (ADP)
and thromboxane A2 (TxA2) induce additional platelet aggregation through platelet GpIIb-IIIa
receptor binding to fibrinogen, and form the primary hemostatic plug. C, Local activation of
the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin
polymerization, “cementing” the platelets into a definitive secondary hemostatic plug. D,
Counter-regulatory mechanisms, mediated by tissue plasminogen activator (t-PA, a
fibrinolytic product) and thrombomodulin, confine the hemostatic process to the site of injury.

Question 58

Endothelial cells play a role in hemeostasis by?

Answer 58

Endothelial cells are key players in the regulation of homeostasis, as the balance between the
anti- and prothrombotic activities of endothelium determines whether thrombus formation,
propagation, or dissolution occurs. [5] [6] [7]

Question 59

Normally, endothelial cells exhibit antiplatelet,
anticoagulant, and fibrinolytic properties; however, after injury or activation they acquire
numerous procoagulant activities ( Fig. 4-6 ). Besides trauma, endothelium can be activated by
infectious agents, hemodynamic forces, plasma mediators, and cytokines.

Answer 59

antiplatelet,
anticoagulant, and fibrinolytic properties; however, after injury or activation they acquire
numerous procoagulant activities ( Fig. 4-6 ). Besides trauma, endothelium can be activated by
infectious agents, hemodynamic forces, plasma mediators, and cytokines.

Question 60

after injury or activation endothelial cells :

Answer 60

acquire
numerous procoagulant activities ( Fig. 4-6 ).

Question 61

Besides trauma, endothelium can be activated by

Answer 61

• infectious agents,
• hemodynamic forces,
• plasma mediators, a
• and cytokines.

Question 62

Answer 62

FIGURE 4-6 Anti- and procoagulant activities of endothelium. NO, nitric oxide; PGI2,
prostacyclin; t-PA, tissue plasminogen activator; vWF, von Willebrand factor. The thrombin
receptor is also called a protease-activated receptor (PAR).

Question 63

Antithrombotic Properties
Under normal circumstances endothelial cells actively prevent thrombosis by producing factors
that variously block platelet adhesion and aggregation, inhibit coagulation, and lyse clots.

Answer 63

• Antiplatelet effects
• Anticoagulant effects.
• Fibrinolytic effects

Question 64

How do endothelial cells produce antiplatelet effect?

Answer 64

Antiplatelet effects.

• Intact endothelium prevents platelets (and plasma coagulation factors) from engaging the highly thrombogenic subendothelial ECM.
• Nonactivated platelets do not adhere to endothelial cells, and even if platelets are activated, prostacyclin (PGI2) and nitric oxide produced by the endothelial cells impede platelet adhesion. Both of these mediators are potent vasodilators and inhibitors of platelet aggregation; their synthesis by the endothelium is stimulated by several factors produced during coagulation (e.g., thrombin and cytokines).
• Endothelial cells also elaborate adenosine diphosphatase, which degrades adenosine diphosphate (ADP) and further inhibits platelet aggregation

Question 65

Antiplatelet effects. Nonactivated
platelets do not adhere to endothelial cells, and even if platelets are activated,
__________produced by the endothelial cells impede platelet
adhesion.

Both of these mediators are potent vasodilators and inhibitors of platelet aggregation; their synthesis by the endothelium is stimulated by several factors
produced during coagulation (e.g., thrombin and cytokines).

Answer 65

prostacyclin (PGI2) and nitric oxide

Question 66

Endothelial cells also
elaborate adenosine diphosphatase iand how does this promote ant i platelet effect?

Answer 66

which degrades adenosine diphosphate (ADP)
and further inhibits platelet aggregation

Question 67

How do the endothelial cells produce Anticoagulant effects. [8]

Answer 67

These effects are mediated by endothelial tmembraneassociated heparin-like molecules, thrombomodulin, and tissue factor pathway inhibitor
(see Fig. 4-6 ).

The heparin-like molecules act indirectly; they are cofactors that greatly enhance the inactivation of thrombin and several other coagulation factors by the plasma protein antithrombin III (see later).

Thrombomodulin binds to thrombin and
converts it from a procoagulant into an anticoagulant via its ability to activate protein C, which inhibits clotting by inactivating factors Va and VIIIa. [9] Endothelium also produces

protein S, a co-factor for protein C, and tissue factor pathway inhibitor (TFPI) , a cell
surface protein that directly inhibits tissue factor–factor VIIa and factor Xa activities

Question 68

How do endothelial cells promote fibrinolytic action?

Answer 68

Fibrinolytic effects.

Endothelial cells synthesize tissue-type plasminogen activator (t-PA), a protease that cleaves plasminogen to form plasmin; plasmin, in turn, cleaves fibrin to
degrade thrombi

Question 69

What is tissue-type plasminogen activator (t-PA)?

Answer 69

, a protease that cleaves plasminogen to form plasmin; plasmin, in turn, cleaves fibrin to
degrade thrombi

Question 70

Prothrombotic Properties
While normal endothelial cells limit clotting, trauma and inflammation of endothelial cells induce
a prothrombotic state that alters the activities of platelets, coagulation proteins, and the
fibrinolytic system.

Answer 70

1. Platelet effects
2. Procoagulant effects
3. Antifibrinolytic effects

Question 71

With the Platelet effects how does the endothelia cell promote prothrombosis?

Answer 71

Endothelial injury allows platelets to contact the underlying extracellular matrix; subsequent adhesion occurs through interactions with von Willebrand factor
(vWF), which is a product of normal endothelial cells and an essential cofactor for
platelet binding to matrix elements

Question 72

What is a von Willebrand factor

(vWF)

Answer 72

It is a product of normal endothelial cells and an essential cofactor for platelet binding to matrix elements

Question 73

How do endothelial cells promote procoagulant effects?

Answer 73

Procoagulant effects.

In response to cytokines (e.g., tumor necrosis factor [TNF] or
interleukin-1 [IL-1]) or bacterial endotoxin, endothelial cells synthesize tissue factor , the
major activator of the extrinsic clotting cascade. [10,] [12]

In addition, activated
endothelial cells augment the catalytic function of activated coagulation factors IXa and
Xa.

Question 74

How do endothelial cells promote antifibrinolytic effect?

Answer 74

Antifibrinolytic effects.

Endothelial cells secrete inhibitors of plasminogen activator
(PAIs), which limit fibrinolysis and tend to favor thrombosis.

Question 75

Answer 75

FIGURE 4-7 Platelet adhesion and aggregation. Von Willebrand factor functions as an
adhesion bridge between subendothelial collagen and the glycoprotein Ib (GpIb) platelet
receptor. Aggregation is accomplished by fibrinogen bridging GpIIb-IIIa receptors on different
platelets. Congenital deficiencies in the various receptors or bridging molecules lead to the
diseases indicated in the colored boxes. ADP, adenosine diphosphate.

Question 76

In summary, intact, nonactivated endothelial cells inhibit platelet adhesion and blood clotting.
Endothelial injury or activation, however, results in a procoagulant phenotype that enhances
thrombus formation.

Question 77

Platelets are disc-shaped, anucleate cell fragments that are shed from megakaryocytes in the bone marrow into the blood stream.

They play a critical role in normal hemostasis, [13] by
forming the hemostatic plug that initially seals vascular defects, and by providing a surface that
recruits and concentrates activated coagulation factors.

Their function depends on several

Answer 77

• glycoprotein receptors,
• a contractile cytoskeleton,
• and two types of cytoplasmic granules. α- Granules have the adhesion molecule P-selectin on their membranes ( Chapter 2 ) and contain fibrinogen, fibronectin, factors V and VIII, platelet factor 4 (a heparin-binding chemokine),platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β).
• Dense (or δ) granules contain ADP and ATP, ionized calcium, histamine, serotonin, and epinephrine.

Question 78

α- Granules have the a:

Answer 78

• dhesion molecule P-selectin on their membranes ( Chapter 2 ) and
• contain fibrinogen,
• fibronectin,
• factors V and VIII,
• platelet factor 4 (a heparin-binding chemokine),
• platelet-derived growth factor (PDGF),
• and transforming growth factor-β (TGF-β).

Question 79

Dense (or δ)
granules contains :

Answer 79

• ADP and ATP,
• ionized calcium
• histamine,
• serotonin,
• and epinephrine.

Question 80

After vascular injury, platelets encounter ECM constituents such as collagen and the adhesive
glycoprotein vWF.

On contact with these proteins, platelets undergo:

Answer 80

(1) adhesion and shape
change,

(2) secretion (release reaction),

and (3) aggregation

Question 81

Platelet adhesion to ECM is mediated largely via interactions with__________, which acts as a
bridge between platelet surface receptors (e.g., glycoprotein Ib [GpIb]) and exposed
collagen ( Fig. 4-8 ).

Answer 81

vWF

Although platelets can also adhere to other components of the
ECM (e.g., fibronectin), vWF-GpIb associations are necessary to overcome the high
shear forces of flowing blood.

Reflecting the importance of these interactions, genetic
deficiencies of vWF (von Willebrand disease; Chapter 14 ) or its receptor (Bernard- Soulier syndrome) result in bleeding disorders.

Question 82

Although platelets can also adhere to other components of the
ECM (e.g., fibronectin), vWF-GpIb associations are necessary to ___________

Answer 82

overcome the high
shear forces of flowing blood.

Reflecting the importance of these interactions, genetic

deficiencies of vWF (von Willebrand disease; Chapter 14 ) or its receptor (Bernard- Soulier syndrome) result in bleeding disorders

Question 83

What is the disease associated when there is deficiency in the receptor of Vwilliebrand factor ?

Answer 83

Reflecting the importance of these interactions, genetic
deficiencies of vWF (von Willebrand disease; Chapter 14 ) or its receptor (Bernard- Soulier syndrome)

Question 84

Secretion (release reaction) of both granule types occurs soon after adhesion.

Various
agonists can bind platelet surface receptors and initiate an intracellular protein phosphorylation cascade ultimately leading to degranulation.

Answer 84

1. Release of the contents of dense-bodies is especially important, since calcium is required in the coagulation cascade,
2. and ADP is a potent activator of platelet aggregation. ADP also begets additional ADP release, amplifying the aggregation process.
3. Finally, platelet activation leads to the appearance of negatively charged phospholipids (particularly phosphatidylserine) on their surfaces. These phospholipids bind calcium and serve as critical nucleation sites for the assembly of complexes containing the various coagulation factors

Question 85

Platelet aggregation follows adhesion and granule release.

What does thromboxane A-2 does?

Answer 85

In addition to ADP, the
vasoconstrictor thromboxane A2 (TxA2; Chapter 2 ) is an important platelet-derived stimulus that amplifies platelet aggregation, which leads to the formation of the primary
hemostatic plug.

Question 86

Although this initial wave of aggregation is reversible, concurrent activation of the coagulation cascade generates thrombin, which stabilizes the platelet plug via two mechanisms.

Answer 86

1. First, thrombin binds to a protease-activated receptor (PAR, see below) on the platelet membrane and in concert with ADP and TxA2 causes further platelet aggregation. This is followed by platelet contraction, an event that is dependent on the platelet cytoskeleton that creates an irreversibly fused mass of platelets, which constitutes the definitive secondary hemostatic plug.
2. Second, thrombin converts fibrinogen to fibrin in the vicinity of the platelet plug, functionally cementing the platelets in place.

Question 87

Answer 87

FIGURE 4-8 The coagulation cascade. Factor IX can be activated either by factor XIa or factor VIIa; in lab tests, activation is predominantly dependent on factor XIa of the intrinsic
pathway. Factors in red boxes represent inactive molecules; activated factors are indicated
with a lower case “a” and a green box. Note also the multiple points where thrombin (factor
IIa; light blue boxes) contributes to coagulation through positive feedback loops. The red “X”s
denote points of action of tissue factor pathway inhibitor (TFPI), which inhibits the activation
of factors X and IX by factor VIIa. PL, phospholipid; HMWK, high-molecular-weight kininogen.

Question 88

Noncleaved fibrinogen is also an important component of platelet aggregation because :

.

Answer 88

Platelet activation by ADP triggers a conformational change in the platelet GpIIb-IIIa receptors.

Question 89

What does GpIIb-IIIa receptors do?

Answer 89

the platelet GpIIb-IIIa receptors that induces binding to fibrinogen, a large protein that forms bridging interactions between platelets that promote platelet aggregation (see Fig. 4-7 ).

Question 90

What is Glanzmann thrombasthenia [16]

Answer 90

Predictably, inherited deficiency of GpIIb-IIIa
results in a bleeding disorde

NOTE: The recognition of the central

role of the various receptors and mediators in platelet cross-linking has led to the development

activity, [17] by blocking ADP binding (clopidogrel), or by binding to the GpIIb-IIIa receptors (synthetic antagonists or monoclonal antibodies). [18]

Antibodies against GpIb are on the
horizon. of therapeutic agents that block platelet aggregation—for example, by interfering with thrombin

Question 91

Thrombin also drives thrombus-associated
inflammation by:

Answer 91

directly stimulating neutrophil and monocyte adhesion and by generating
chemotactic fibrin split products during fibrinogen cleavage.

Red cells and leukocytes are also found in hemostatic plugs. Leukocytes adhere to platelets via
P-selectin and to endothelium using several adhesion receptors ( Chapter 2 ); they contribute
to the inflammation that accompanies thrombosis.

Question 92

The interplay of platelets and endothelium has a profound impact on clot formation.

The endothelial cell-derived:

Answer 92

• prostaglandin PGI2 (prostacyclin) inhibits platelet aggregation and is a potent vasodilator; conversely,
• the platelet-derived prostaglandin TxA2 activates platelet aggregation and is a vasoconstrictor ( Chapter 2 ).
• Effects mediated by PGI2 and TxA2 are exquisitely balanced to effectively modulate platelet and vascular wall function: at baseline, platelet aggregation is prevented, whereas endothelial injury promotes hemostatic plug formation.
• The clinical utility of aspirin (an irreversible cyclooxygenase inhibitor) in persons at
• risk for coronary thrombosis resides in its ability to permanently block platelet TxA2 synthesis. Although endothelial PGI2 production is also inhibited by aspirin, endothelial cells can resynthesize active cyclooxygenase and thereby overcome the blockade. In a manner similar to PGI2, endothelial-derived nitric oxide also acts as a vasodilator and inhibitor of platelet aggregation (see Fig. 4-6 ).

Question 93

What is the coagulation cascade?

Answer 93

The coagulation cascade is essentially an amplifying series of enzymatic conversions; each step proteolytically cleaves an inactive proenzyme into an activated enzyme, culminating in
thrombin formation

Question 94

__________ is the most important coagulation factor, and indeed can act at numerous stages in the process (see blue boxes in Fig. 4-8 ). [20

Answer 94

​.Thrombin

At the conclusion of the
proteolytic cascade, thrombin converts the soluble plasma protein fibrinogen into fibrin
monomers that polymerize into an insoluble gel. The fibrin gel encases platelets and other
circulating cells in the definitive secondary hemostatic plug, and the fibrin polymers are
covalently cross-linked and stabilized by factor XIIIa (which itself is activated by thrombin).

Question 95

Each reaction in the coagulation pathway results from the assembly of a complex composed of an enzyme
(activated coagulation factor), a substrate (proenzyme form of coagulation factor), and a
cofactor (reaction accelerator).

These components are typically assembled on a____________

Answer 95

phospholipid
surface and held together by calcium ions (as an aside, the clotting of blood is prevented by the
presence of calcium chelators).

The requirement that coagulation factors be brought close
together ensures that clotting is normally localized to the surface of activated platelets or endothelium; [4] as shown in Figure 4-9 , it can be likened to a “dance” of complexes, in which coagulation factors are passed successfully from one partner to the next

.

Question 96

Parenthetically, the binding of coagulation factors II, XII, IX, and X to calcium depends on the addition of γ-carboxyl groups to certain glutamic acid residues on these proteins.

This reaction uses ____________ as a
cofactor and is antagonized by drugs such as coumadin, which is a widely used anticoagulant.

Answer 96

vitamin K

1972

Question 97

Answer 97

FIGURE 4-9 Schematic illustration of the conversion of factor X to factor Xa via the extrinsic
pathway, which in turn converts factor II (prothrombin) to factor IIa (thrombin). The initial
reaction complex consists of a proteolytic enzyme (factor VIIa), a substrate (factor X), and a
reaction accelerator (tissue factor), all assembled on a platelet phospholipid surface.
Calcium ions hold the assembled components together and are essential for the reaction.
Activated factor Xa becomes the protease for the second adjacent complex in the
coagulation cascade, converting prothrombin substrate (II) to thrombin (IIa) using factor Va
as the reaction accelerator.

Question 98

Blood coagulation is traditionally classified into extrinsic and intrinsic pathways that converge on
the activation of__________ (see Fig. 4-8 ).

Answer 98

factor X

Question 99

The extrinsic pathway was so designated because_____________

Answer 99

it
required the addition of an exogenous trigger (originally provided by tissue extracts);

Question 100

the intrinsic pathway only required____________

Answer 100

exposing factor XII (Hageman factor) to thrombogenic surfaces
(even glass would suffice)

. However, such a division is largely an artifact of in vitro testing; there are, in fact, several interconnections between the two pathways.

Question 101

Moreover, the _____________ is the most physiologically relevant pathway for coagulation occurring when vascular
damage has occurred;it is activated by tissue factor (also known as thromboplastin or factor
III),a membrane-bound lipoprotein expressed at sites of injury (see Fig. 4-8 ). [12]

Answer 101

extrinsic
pathway

Question 102

What activates the extrinsic pathway?

Answer 102

it is activated by tissue factor (also known as thromboplastin or factor
III), a membrane-bound lipoprotein expressed at sites of injury (see Fig. 4-8 ). [12]

Question 103

In addition to catalyzing the final steps in the coagulation cascade, thrombin exerts a wide
variety of proinflammatery effects ( Fig. 4-10 ).

Most of these effects of thrombin occur through
its activation of a family of ________that belong to the seventransmembrane
G protein–coupled receptor family [21,] [22] (see also Fig. 4-6 ).

Answer 103

protease activated receptors (PARs)

Question 104

PARs are
expressed on

Answer 104

endothelium, monocytes, dendritic cells, T lymphocytes, and other cell types.
Receptor activation is initiated by cleavage of the extracellular end of the PAR; this generates a
tethered peptide that binds to the “clipped” receptor, causing a conformational change that
triggers signaling.

Question 105

Clinical laboratories assess the function of the two arms of the coagulation pathway through two
standard assays: ___________ The PT assay
assesses the function of the proteins in the extrinsic pathway (factors VII, X, II, V, and
fibrinogen). This is accomplished by adding tissue factor and phospholipids to citrated plasma
(sodium citrate chelates calcium and prevents spontaneous clotting). Coagulation is initiated by
the addition of exogenous calcium and the time for a fibrin clot to form is recorded. The partial
thromboplastin time (PTT) screens for the function of the proteins in the intrinsic pathway
(factors XII, XI, IX, VIII, X, V, II, and fibrinogen). In this assay, clotting is initiated through the
addition of negative charged particles (e.g., ground glass), which you will recall activates factor
XII (Hageman factor), phospholipids, and calcium, and the time to fibrin clot formation is
recorded

Answer 105

• prothrombin time (PT)
• and partial thromboplastin time (PTT)

Question 106

The PT assay
assesses the function of the proteins in the ___________

Answer 106

extrinsic pathway (factors VII, X, II, V, and
fibrinogen).

PET

Question 107

How is the PT assay accomplished?

Answer 107

This is accomplished by adding tissue factor and phospholipids to citrated plasma
(sodium citrate chelates calcium and prevents spontaneous clotting)

. Coagulation is initiated by

the addition of exogenous calcium and the time for a fibrin clot to form is recorded

Question 108

. The partial
thromboplastin time (PTT) screens for the function of the proteins in the \_\_\_\_\_\_\_\_\_\_.

Answer 108

intrinsic pathway
(factors XII, XI, IX, VIII, X, V, II, and fibrinogen)

PITT

Question 109

In this PTT assay, clotting is initiated through the
addition of ___________

Answer 109

negative charged particles (e.g., ground glass), which you will recall activates factor
XII (Hageman factor), phospholipids, and calcium, and the time to fibrin clot formation is
recorded

Question 110

Answer 110

FIGURE 4-10 Role of thrombin in hemostasis and cellular activation. Thrombin plays a
critical role in generating cross-linked fibrin (by cleaving fibrinogen to fibrin, and by activating
factor XIII), as well as activating several other coagulation factors (see Fig. 4-8 ). Through
protease-activated receptors (PARs, see text), thrombin also modulates several cellular
activities. It directly induces platelet aggregation and TxA2 production, and activates ECs to
express adhesion molecules, and a variety of fibrinolytic (t-PA), vasoactive (NO, PGI2), and
cytokine mediators (e.g., PDGF). Thrombin also directly activates leukocytes. ECM,
extracellular matrix; NO, nitric oxide; PDGF, platelet-derived growth factor; PGI2, prostacyclin;
TxA2, thromboxane A2; t-PA, tissue plasminogen activator. See Figure 4-7 for additional
anticoagulant activities mediated by thrombin, including via thrombomodulin.

Question 111

Once activated, the coagulation cascade must be restricted to the site of vascular injury to
prevent runaway clotting of the entire vascular tree. Besides restricting factor activation to sites
of exposed phospholipids, three categories of endogenous anticoagulants also control clotting.

Answer 111

(1) Antithrombins
(2) Proteins C and S
(3) TFPI i

Question 112

What are your antithrombins?

Answer 112

(1) Antithrombins (e.g., antithrombin III) inhibit the activity of thrombin and other serine
* *proteases, including factors IXa, Xa, XIa, and XIIa.**

Question 113

How is antithrombin activated?

Answer 113

Antithrombin III is activated by binding to
heparin-like molecules on endothelial cells; hence the clinical usefulness of administering
heparin to minimize thrombosis (see Fig. 4-6 ).

Question 114

What are Proteins C and S

Answer 114

are vitamin K–dependent
proteins that act in a complex that proteolytically inactivates factors Va and VIIIa. Protein C
activation by thrombomodulin was described earlier.

Question 115

What is TFPI?

Answer 115

is a protein produced by endothelium (and other cell types) that inactivates tissue factor–factor VIIa complexes (see
Figs. 4-6 and 4-8 ). [10]

Question 116

Activation of the coagulation cascade also sets into motion a fibrinolytic cascade that moderates the size of the ultimate clot. Fibrinolysis is largely accomplished through the
enzymatic activity of _______________, which breaks down fibrin and interferes with its polymerization (
Fig. 4-11 ).

Answer 116

plasmin

PILAS!!!!! PILASMIN

Question 117

The resulting fibrin split products (FSPs or fibrin degradation products) can
also act as weak anticoagulants.

True or False

Answer 117

True

Question 118

How is plasmin generated?

Answer 118

Plasmin
is generated by enzymatic catabolism of the inactive circulating precursor plasminogen, either
by a factor XII–dependent pathway or by plasminogen activators (PAs; see Fig. 4-11 ).

Question 119

The most
important of the PAs is ___________; it is synthesized principally by endothelium and is most active when
bound to fibrin.

Answer 119

t-PA

Question 120

The affinity for fibrin makes t-PA a useful therapeutic agent, since _

Answer 120

it largely
confines fibrinolytic activity to sites of recent thrombosis

Question 121

What is Urokinase-like PA?

Answer 121

Urokinase-like PA (u-PA) is another PA
present in plasma and in various tissues; it can activate plasmin in the fluid phase.

Question 122

What does streptokinase do?

Answer 122

Finally,
plasminogen can be cleaved to plasmin by the bacterial enzyme streptokinase, an activity that may be clinically significant in certain bacterial infections.

Question 123

As with any potent regulator, plasmin
activity is tightly restricted

. To prevent excess plasmin from lysing thrombi indiscriminately
elsewhere in the body, free plasmin is rapidly inactivated by α2-plasmin inhibitor

Answer 123

α2-plasmin inhibitor

Question 124

Answer 124

FIGURE 4-11 The fibrinolytic system, illustrating various plasminogen activators and
inhibitors (see text).

Question 125

Endothelial cells also fine-tune the coagulation/anticoagulation balance by ______________

Answer 125

releasing plasminogen activator inhibitor (PAI);

it blocks fibrinolysis by inhibiting t-PA binding to fibrin and
confers an overall procoagulant effect (see Fig. 4-11 ).

PAI production is increased by thrombin
as well as certain cytokines, and probably plays a role in the intravascular thrombosis accompanying severe inflammation.

Question 126

What is the virchows triad?

Answer 126

primary abnormalities that lead to thrombus formation (called Virchow’s triad) :

(1) endothelial
injury,

(2) stasis or turbulent blood flow, and
(3) hypercoagulability of the blood

Question 127

Answer 127

FIGURE 4-12 Virchow’s triad in thrombosis. Endothelial integrity is the most important factor.
Injury to endothelial cells can alter local blood flow and affect coagulability. Abnormal blood
flow (stasis or turbulence), in turn, can cause endothelial injury. The factors promote
thrombosis independently or in combination.

Question 128

Endothelial injury is particularly important for thrombus formation in the heart or the arterial
circulation because?

Answer 128

, where the normally high flow rates might otherwise impede clotting by preventing platelet adhesion and washing out activated coagulation factors.

Thus, thrombus formation

within cardiac chambers (e.g., after endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely a consequence of endothelial cell injury.

Question 129

Explain endothelial injury in relation to thrombosis?

Answer 129

Clearly, physical loss of
endothelium can lead to exposure of the subendothelial ECM, adhesion of platelets, release of
tissue factor, andlocal depletion of PGI2 and plasminogen activators.

However, it should be emphasized that endothelium need not be denuded or physically disrupted to contribute to the
development of thrombosis; any perturbation in the dynamic balance of the prothombotic and antithrombotic activities of endothelium can influence local clotting events (see Fig. 4-6 ). Thus,dysfunctional endothelial cells can produce more procoagulant factors (e.g., platelet adhesion molecules, tissue factor, PAIs) or may synthesize less anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA).

Question 130

Endothelial dysfunction can be induced by a wide variety of
insults, including ________

Answer 130

• hypertension,
• turbulent blood flow,
• bacterial endotoxins,
• radiation injury,
• metabolic abnormalities such as homocystinemia or hypercholesterolemia,
• and toxins absorbedfrom cigarette smoke.

Question 131

Alterations in Normal Blood Flow.

How does turbulence contribute to arterial and cardiac thrombosis?

Answer 131

Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or
dysfunction, as well as by forming countercurrents and local pockets of stasis;

Question 132

What is the major
contributor in the development of venous thrombi. [25]

Answer 132

stasis

Question 133

What is the normal blood flow?

Answer 133

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.

Question 134

Stasis and turbulence therefore:

Answer 134

• Promote endothelial activation, enhancing procoagulant activity, leukocyte adhesion, etc., in part through flow-induced changes in endothelial cell gene expression. [21]
• • Disrupt laminar flow and bring platelets into contact with the endothelium[26]
• • Prevent washout and dilution of activated clotting factors by fresh flowing blood and the inflow of clotting factor inhibitors

Question 135

Turbulence and stasis contribute to thrombosis in several clinical settings.

Answer 135

• Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause turbulence.
• Aortic and arterial dilations called aneurysms result in local stasis and are therefore fertile sites for thrombosis ( Chapter 11 ).
• Acute myocardial infarctions result in areas of noncontractile myocardium and sometimes cardiac aneurysms; both are associated with stasis and flow abnormalities that promote the formation of cardiac mural thrombi ( Chapter 12 ).
• Rheumatic mitral valve stenosis results in left atrial dilation; in conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for developing thrombi ( Chapter 12 ).
• Hyperviscosity (such as is seen with polycythemia vera; Chapter 13 ) increases resistance to flow and causes small vessel stasis; the deformed red cells in sickle cell anemia ( Chapter 14 ) cause vascular occlusions, with the resulting stasis also predisposing to thrombosis.

Question 136

What is hypercoagulability or thrombophilia?

Answer 136

Hypercoagulability (also called thrombophilia) is a less frequent contributor to thrombotic states
but is nevertheless an important component in the equation, and in some situations can
predominate.

It is loosely defined as any alteration of the coagulation pathways that
predisposes to thrombosis;

Question 137

Hypercoagulability can be divided into :

Answer 137

1. primary (genetic)
2. and secondary (acquired) disorders ( Table 4-2 ). [27] [28] [29]

Question 138

Of the inherited causes of hypercoagulability,____________ are the most common.

Answer 138

point
mutations in the factor V gene and prothrombin gen

Question 139

What is Leiden mutation?

Answer 139

Approximately 2% to 15% of Caucasians carry a single-nucleotide mutation in factor V (called the Leiden mutation, after the city in the Netherlands where it was discovered).

Question 140

Among individuals with recurrent deep venous thrombosis the frequency of leiden mutation
is considerably higher, approaching 60%. How does this mutation occur?

Answer 140

The mutation results in a glutamine to

• *arginine substitution at position 506 that renders factor V resistant to cleavage by**
• *protein C**.

As a result, an important antithrombotic counter-regulatory pathway is lost (see Fig. 4-6 ).

Indeed, heterozygotes have a five-fold increased relative risk of venous thrombosis, and homozygotes have a 50-fold increase

Question 141

A _____________ is another fairly common mutation in individuals with hypercoagulability (1% to 2%
of the population); it is associated with elevated prothrombin levels and an almost
threefold increased risk of venous thromboses.

Answer 141

single nucleotide change (G20210A) in the 3′-untranslated region of the prothrombin gene

Question 142

How does homocystein contribute to arterial and venous thrombosis?

Answer 142

Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as the development of atherosclerosis ( Chapter 11 ).

The prothrombotic effects of homocysteine may be due to thioester linkages formed between homocysteine
metabolites and a variety of proteins, including fibrinogen. [32] Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione βsynthetase.
Much more common is a variant form of the enzyme 5,10-methylenetetrahydrofolate reductase that causes mild homocysteinemia in 5% to 15% of Caucasian and eastern
Asian populations; this possible etiology for hypercoagulability is therefore as common as factor V Leiden. [27]

However, while folic acid, pyridoxine, and/or vitamin B12 supplements can reduce plasma homocysteine concentrations (by stimulating its metabolism), they fail to lower the risk of thromboses, raising questions about the
significance of modest homocysteinemia.

Question 143

Rare inherited causes of primary hypercoagulability include :_____________

Answer 143

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. [27

] Various polymorphisms in coagulant factor genes
can result in increased synthesis and impart an elevated risk of venous thrombosis

Question 144

TABLE 4-2 – Hypercoagulable States

PRIMARY (GENETIC)

Answer 144

Common

• Factor V mutation (G1691A mutation; factor V Leiden)
• Prothrombin mutation (G20210A variant)
• 5,10-Methylenetetrahydrofolate reductase (homozygous C677T
• mutation)
• Increased levels of factors VIII, IX, XI, or fibrinogen

Rare

• Antithrombin III deficiency
• Protein C deficiency
• Protein S deficiency

Very Rare

• Fibrinolysis defects
• Homozygous homocystinuria (deficiency of cystathione β-
  synthetase)

Question 145

TABLE 4-2 – Hypercoagulable States

SECONDARY (ACQUIRED)

Answer 145

High Risk for Thrombosis

• Prolonged bedrest or immobilization
• Myocardial infarction
• Atrial fibrillation
• Tissue injury (surgery, fracture, burn)
• Cancer
• Prosthetic cardiac valves
• Disseminated intravascular
• coagulation
• Heparin-induced thrombocytopenia
• Antiphospholipid antibody syndrome

Lower Risk for Thrombosis

• Cardiomyopathy
• Nephrotic syndrome
• Hyperestrogenic states (pregnancy and
• postpartum)
• Oral contraceptive use
• Sickle cell anemia
• Smoking

Question 146

The most common thrombophilic genotypes found in various populations _______________ impart only a moderately increased risk of
thrombosis; most individuals with these genotypes, when otherwise healthy, are free of
thrombotic complications.

Answer 146

(heterozygosity for
factor V Leiden and heterozygosity for prothrombin)

Thus, factor V Leiden heterozygosity (which by itself has only
a modest effect) may trigger deep venous thrombosis when combined with enforced inactivity,
such as during prolonged plane travel. Consequently, inherited causes of hypercoagulability
must be considered in patients under the age of 50 who present with thrombosis—even when
acquired risk factors are present

Question 147

However, mutations in____________-are frequent enough
that homozygosity and compound heterozygosity are not rare, and such genotypes are
associated with greater risk.

[35]

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 bedrest).

Answer 147

factor V and prothrombin

Question 148

Unlike hereditary disorders, the pathogenesis of acquired thrombophilia is frequently multifactorial (see Table 4-2 )

. In some cases (e.g., cardiac failure or trauma), stasis or vascular injury may be most important.

Question 149

Hypercoagulability due to oral contraceptive use or the
hyperestrogenic state of pregnancy is probably caused by ________________38]

Answer 149

increased hepatic synthesis of
coagulation factors and reduced anticoagulant synthesis. [

Question 150

What predisposes cancer to thrombosis?

Answer 150

In disseminated cancers, release
of procoagulant tumor products predisposes to thrombosis. [39]

Question 151

The hypercoagulability seen
with advancing age may be due to ____________.

Answer 151

to reduced endothelial PGI2.

Question 152

Smoking and obesity promote
hypercoagulability by unknown mechanisms.

Question 153

Among the acquired thrombophilic states, two that are particularly important clinical problems
deserve special mention.

Answer 153

1. Heparin-induced thrombocytopenia (HIT) syndrome.
2. Antiphospholipid antibody syndrome

Question 154

What is Heparin-induced thrombocytopenia (HIT) syndrome.

Answer 154

HIT occurs following the administration of unfractionated heparin, which may induce the
appearance of antibodies that recognize complexes of heparin and platelet factor 4 on the
surface of platelets ( Chapter 14 ), as well as _complexes of heparin-like molecules and platelet
factor 4-like proteins on endothelial cells_. [40] [41] [42]

Question 155

Why does Heparin-induced thrombocytopenia (HIT) syndrome has thrombocytopenia?

Answer 155

Binding of these antibodies to platelets
results in their activation, aggregation, and consumption (hence the thrombocytopenia in the syndrome name).

This effect on platelets and endothelial damage combine to produce a
prothrombotic state, even in the face of heparin administration and low platelet counts.

Newer
low-molecular weight heparin preparations induce antibody formation less frequently, but still cause thrombosis if antibodies have already formed. [41]

Other anticoagulants such as

• *fondaparinux** (a pentasaccharide inhibitor of factor X) also cause a HIT-like syndrome on rare
• *occasions.**

Question 156

What is Antiphospholipid antibody syndrome

Answer 156

(previously called the lupus anticoagulant syndrome).

This syndrome has protean clinical
manifestations, including recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia.

Question 157

What is the clinical presentation of Antiphospholipid antibody syndrome

Answer 157

Depending on the vascular bed involved, the clinical presentations can include:

• pulmonary embolism (following lower extremity venous thrombosis),
• pulmonary hypertension (from recurrent subclinical pulmonary emboli),
• stroke,
• bowel infarction,
• or renovascular hypertension.
• Fetal loss is attributable to antibody-mediated inhibition of t-PA activity necessary for trophoblastic invasion of the uterus.

Antiphospholipid antibody syndrome​is also a cause of renal microangiopathy, resulting in renal failure associated with multiple capillary and arterial thromboses

Question 158

Why is antiphospholipid antibody syndrom a misnomer?

Answer 158

The name antiphospholipid antibody syndrome is a bit of a misnomer, as it is believed that the
most important pathologic effects are mediated through binding of the antibodies to epitopes on
plasma proteins(e.g., prothrombin) that are somehow inducedor “unveiled” by phospholipids.

In vivo, these autoantibodies induce a hypercoagulable state by causing endothelial injury, by
activating platelets and complement directly, and through interaction with the catalytic domains
of certain coagulation factors. [43]

However, in vitro (in the absence of platelets and endothelial
cells), the autoantibodies interfere with phospholipids and thus inhibit coagulation. The
antibodies also frequently give a false-positive serologic test for syphilis because the antigen in
the standard assay is embedded in cardiolipin.

Question 159

Antiphospholipid antibody syndrome has two forms:

Answer 159

Antiphospholipid antibody syndrome has primary and secondary forms

Question 160

What is a primary antiphospholipid syndrome?

Answer 160

In primary antiphospholipid syndrome , patients exhibit only the manifestations of a hypercoagulable state and lack evidence of other autoimmune disorders; occasionally this happens in association with certain drugs or infections.

Question 161

What is the secondary form of antiphospholipid syndrome?

Answer 161

Individuals with a welldefined
autoimmune disease, such as systemic lupus erythematosus ( Chapter 6 ), are
designated as having secondary antiphospholipid syndrome (hence the earlier term lupus
anticoagulant syndrome).

Question 162

A particularly
aggressive form _____________characterized by widespread smallvessel thrombi and multi-organ failure has a 50% mortality. [44]

Answer 162

(catastrophic antiphospholipid syndrome)

The antibodies also make
surgical procedures more difficult; for example, nearly 90% of patients with anti-phospholipid
antibodies undergoing cardiovascular surgery have complications related to the antibodies. [45]
Therapy involves anticoagulation and immunosuppression. Although antiphospholipid
antibodies are clearly associated with thrombotic diatheses, they have also been identified in 5% to 15% of apparently normal individuals, implying that they are necessary but not sufficient
to cause the full-blown syndrome.

Question 163

Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiac chambers, on valves, or in arteries, veins, or capillaries).

The size and shape of thrombi
depend on the site of origin and the cause.

Question 164

Arterial or cardiac thrombi usually begin at sites____________;

Answer 164

of
turbulence or endothelial injury

Question 165

venous thrombi characteristically occur at sites of________-

Answer 165

stasis.

Question 166

Thrombi are focally attached to the ________

Answer 166

underlying vascular surface

Question 167

What is the difference of the growth of thrombi of arterial vs venous?

Answer 167

• *arterial thromb**i tend to grow retrograde from the point of attachment, while venous thrombi extend in the direction of blood
• *flow (thus both propagate toward the heart)**.

aRterial : Retrogade

The propagating portion of a thrombus is often
poorly attached and therefore prone to fragmentation and embolization

Question 168

The propagating portion of a thrombus is often
poorly attached and therefore prone to fragmentation and embolization

T or F

Answer 168

T

Question 169

What is the line of Zhan?

Answer 169

Thrombi often have grossly and microscopically apparent laminations called lines of Zahn;
these represent 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 thrombosis from the bland nonlaminated clots that occur postmortem (see below).

Question 170

How to differentiate antemortem from postmortem thrombi?

Answer 170

Such laminations signify that a thrombus has formed in flowing blood; their presence can therefore distinguish antemortem

thrombosis from the bland nonlaminated clots that occur
postmortem (see below).

Question 171

What is a mural thrombi.

Answer 171

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 or catheter trauma) promotes cardiac mural

thrombi ( Fig. 4-13A ), while ulcerated atherosclerotic plaque and aneurysmal dilation are the precursors of aortic thrombus ( Fig. 4-13B ).

Question 172

What are arterial thrombi?

Answer 172

Arterial thrombi are frequently occlusive;

They typically cosist of a friable
meshwork of platelets, fibrin, red cells, and degenerating leukocytes. Although these are usually superimposed on a ruptured atherosclerotic plaque, other vascular injuries (vasculitis,
trauma) may be the underlying cause.

Question 173

the most common sites of arterial thrombi in decreasing order of
frequency are the

Answer 173

1. coronary,
2. cerebral,
3. and femoral arteries.

Question 174

What arer Venous thrombosis (phlebothrombosis) ?

Answer 174

Venous thrombosis (phlebothrombosis) is almost **invariably****occlusive**, with the thrombus
**forming a long cast of the lumen.**

Because 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.**

Question 175

What is the most commonly involved venous thrombi?

Answer 175

​ The **veins of the lower extremities** are most
commonly involved (90% of cases); however, upper extremities, periprostatic plexus, or the
ovarian and periuterine veins can also develop venous thrombi.

Under special circumstances,
they can also occur in the dural sinuses, portal vein, or hepatic vein.

Question 176

Describe postmortem clots

Answer 176

Postmortem clots can sometimes be mistaken for antemortem venous thrombi.

However, postmortem clots are gelatinous with a dark red dependent portion where red cells have
settled by gravity and a yellow “chicken fat” upper portion; they are usually not attached to the underlying wall.

Question 177

Describe red thrombi.

Answer 177

In comparison, red thrombi are firmer and are focally attached, and sectioning typically reveals gross and/or microscopic lines of Zahn.

Question 178

What are vegetations?

Answer 178

Thrombi on heart valves are called vegetations.

Blood-borne bacteria or fungi can adhere
to previously damaged valves (e.g., due to rheumatic heart disease) or can directly cause valve damage; in both cases, endothelial injury and disturbed blood flow can induce the
formation of large thrombotic masses (infective endocarditis; Chapter 12 ).

Question 179

What are nonbacterial thrombotic endocarditis ?

Answer 179

Sterile vegetations can also develop on noninfected valves in persons with hypercoagulable states,
so-called nonbacterial thrombotic endocarditis ( Chapter 12 ).

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

Question 180

Answer 180

FIGURE 4-13 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 picture) .

Question 181

Fate of the Thrombus.
If a patient survives the initial thrombosis, in the ensuing days to weeks thrombi undergo some
combination of the following four events:

Answer 181

• Propagation
• Embolization
• Dissolution.
• Organization and recanalization

Question 182

Describe embolizaiton in relation the fate of thrombi.

Answer 182

Embolization. Thrombi dislodge and travel to other sites in the vasculature. This process
is described below

Question 183

Discuss propagation as the fate of thrombi.

Answer 183

Propagation. Thrombi accumulate additional platelets and fibrin. This process was
discussed earlier.

Question 184

Describe the process of dissolution in relation to thrombi.

Answer 184

Dissolution. Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi.

In contrast, the extensive fibrin deposition
and crosslinking in older thrombi renders them more resistant to lysis.

This distinction
explains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in the setting of acute coronary thrombosis) is generally effective only when given in the first
few hours of a thrombotic episode.

Question 185

Why is fibrinolytic agents sucg as t-PA only effective on first few hours of thrombotic episode?

Answer 185

the extensive fibrin deposition
and crosslinking in older thrombi renders them more resistant to lysis.

This distinction
explains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in the setting of acute coronary thrombosis) is generally effective only when given in the first
few hours of a thrombotic episode.

Question 186

Describe Organization and recanalization in relation to the fate of thrombi.

Answer 186

Older thrombi become organized by the ingrowth of
endothelial cells, smooth muscle cells, and fibroblasts ( Fig. 4-14 ). Capillary channels eventually form that re-establish the continuity of the original lumen, albeit to a variable
degree.

Question 187

Answer 187

FIGURE 4-14 Low-power view of a thrombosed artery stained for elastic tissue. The original
lumen is delineated by the internal elastic lamina (arrows) and is totally filled with organized
thrombus, now punctuated by several recanalized endothelium-lined channels (white
spaces).

Question 188

Clinical Consequences

Thrombi are significant because they cause obstruction of arteries and veins , and are sources of emboli.

Which effect predominates depends on the site of the thrombosis.

Venous thrombi
can cause congestion and edema in vascular beds distal to an obstruction, but they are far more worrisome for their capacity to embolize to the lungs and cause death (see below).
Conversely, although arterial thrombi can embolize and cause downstream infarctions, a
thrombotic occlusion at a critical site (e.g., a coronary artery) can have more serious clinical
consequences.

Question 189

Venous Thrombosis (Phlebothrombosis).

Most venous thrombi occur in the________ [25]

Answer 189

superficial or deep veins of the leg.

Question 190

Superficial venous
thrombi typically occur in the _________ in the setting of varicosities.

Answer 190

saphenous veins

Although such
thrombi can cause local congestion, swelling, pain, and tenderness, they rarely embolize.
Nevertheless, the local edema and impaired venous drainage do predispose the overlying skin to infections from slight trauma and to the development of varicose ulcers.

Question 191

Why is Deep venous
thrombosis (DVT) in the larger leg veins—at or above the knee (e.g., popliteal, femoral, and
iliac veins)—is more serious

Answer 191

because such thrombi more often embolize to the lungs and give rise to pulmonary infarction (see below and Chapter 15 ). Although they can cause local pain and edema, venous obstructions from DVTs can be rapidly offset by collateral channels.
Consequently, DVTs are asymptomatic in approximately 50% of affected individuals and are recognized only in retrospect after embolization.

Question 192

Lower extremity DVTs are associated with _________, as described earlier (see
Table 4-2 ).

Answer 192

hypercoagulable states

Question 193

What are the Common predisposing factors of lower ext DVT?
Regardless of the specific clinical setting, advanced age also increases the risk of DVT.

Answer 193

• include bed rest and immobilization (because they reduce the milking action of the leg muscles, resulting in reduced venous return),
• and congestive heart failure (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 altered t-PA production.
• Many elements contribute to the thrombotic diathesis of pregnancy; besides the potential for amniotic fluid infusion into the circulation at the time of delivery, late pregnancy and the postpartum period are also associated with systemic hypercoagulability.
• Tumor-associated inflammation and coagulation factors (tissue factor, factor VIII) and procoagulants (e.g., mucin) released from tumor cells all contribute to the increased risk of thromboembolism in disseminated cancers, so-called migratory thrombophlebitis or Trousseau syndrome. [39,] [46]

Question 194

What is migratory thrombophlebitis or Trousseau syndrome

Answer 194

procoagulants (e.g., mucin) released from tumor cells all contribute to the increased risk of thromboembolism in
disseminated cancers, so-called migratory thrombophlebitis or Trousseau syndrome

Question 195

What is the major cause of arterial thromboses?

Answer 195

• *Atherosclerosis** is a major cause of arterial thromboses, because it is associated with loss of
• *endothelial integrity** and with abnormal vascular flow (see Fig. 4-13B ).

Myocardial infarction
can predispose to cardiac mural thrombi by causing dyskinetic myocardial contraction as well as
damage to the adjacent endocardium (see Fig. 4-13A ), and rheumatic heart disease may engender atrial mural thrombi as discussed above.

Besides local obstructive consequences,cardiac and aortic mural thrombi can also embolize peripherally.

Although any tissue can be
affected, the brain, kidneys, and spleen are particularly likely targets because of their rich blood supply.

Question 196

What is DIC?

Answer 196

Disorders ranging from obstetric complications to advanced malignancy can be complicated by DIC, the sudden or insidious onset of widespread fibrin thrombi in the microcirculation.

Although these thrombi are not grossly visible, they are readily apparent microscopically and can cause diffuse circulatory insufficiency, particularly in the brain, lungs, heart, and kidneys. To complicate matters, the widespread microvascular thrombosis results in platelet and coagulation protein consumption (hence the synonym consumption coagulopathy), and at the same time, fibrinolytic mechanisms are activated.
Thus, an initially thrombotic disorder can evolve into a bleeding catastrophe. It should be emphasized that DIC is not a primary disease but rather a potential complication of any condition associated with widespread activation of thrombin. [47]

It is discussed in greater detail along with other bleeding diatheses in Chapter 14 .

Question 197

What is an embolus?

Answer 197

An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the
blood to a site distant from its point of origin.

The term embolus was coined by Rudolf Virchow
in 1848 to describe objects that lodge in blood vessels and obstruct the flow of blood. Almost all
emboli represent some part of a dislodged thrombus, hence the term thromboembolism.

Question 198

Rare forms of emboli include:

However, unless otherwise
specified, emboli should be considered thrombotic in origin.

Answer 198

• fat droplets,
• nitrogen bubbles,
• atherosclerotic debris (cholesterol emboli),
• tumor fragments,
• bone marrow,
• or even foreign bodies.

Question 199

Inevitably, emboli lodge in vessels
too small to permit further passage, causing partial or complete vascular occlusion;

a major
consequence is__________of the downstream tissue. Depending on where they originate, emboli can lodge anywhere in the vascular tree; the clinical outcomes are best
understood based on whether emboli lodge in the pulmonary or systemic circulations.

Answer 199

ischemic necrosis (infarction)

Question 200

Embolism

Answer 200

• PULMONARY EMBOLISM
• SYSTEMIC THROMBOEMBOLISM
• FAT AND MARROW EMBOLISM
• AIR EMBOLISM
• AMNIOTIC FLUID EMBOLISM
  *

Question 201

In more than 95% of cases, PEs originate from ___________
although it is important to realize that DVTs occur roughly two to three times more frequently
than PEs.

Answer 201

leg deep vein thromboses (DVTs),

Question 202

Explain Pulmonary Embolism

Answer 202

Fragmented thrombi from DVTs are carried through progressively larger channels and the right side of the heart before slamming into the pulmonary arterial vasculature.

Depending on the size of the embolus, it can occlude the main pulmonary artery, straddle the pulmonary artery
bifurcation (saddle embolus), or pass out into the smaller, branching arteries ( Fig. 4-15 ).
Frequently there are multiple emboli, perhaps sequentially or as a shower of smaller emboli from a single large mass; in general, the patient who has had one PE is at high risk of having more.

Rarely, an embolus can pass through an interatrial or interventricular defect and gain
access to the systemic circulation (paradoxical embolism) .

A more complete discussion of PEs is
presented in Chapter 15 ; an overview is offered here

Question 203

What is a saddle embolus?

Answer 203

Fragmented thrombi from DVTs are carried through progressively larger channels and the right
side of the heart before slamming into the pulmonary arterial vasculature. Depending on the
size of the embolus, it can occlude the main pulmonary artery, straddle the pulmonary artery
bifurcation (saddle embolus), or pass out into the smaller, branching arteries

Question 204

What is (paradoxical embolism) ?

Answer 204

Rarely, an embolus can pass through an interatrial or interventricular defect and gain access to the systemic circulation (paradoxical embolism) .

A more complete discussion of PEs is
presented in Chapter 15 ; an overview is offered here.

Question 205

Most pulmonary emboli (60% to 80%) are_________-

Answer 205

clinically silent because they are small.

Question 206

What is a fibrous web?

Answer 206

With time they become organized and are incorporated into the vascular wall; in some cases
organization of the thromboembolus leaves behind a delicate, bridging fibrous web.

Question 207

Sudden death, right heart failure (cor pulmonale) , or cardiovascular collapse occurs
when emboli obstruct________- of the pulmonary circulation.

Answer 207

60% or more

Question 208

Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in__________.

Answer 208

pulmonary hemorrhage

Question 209

Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in pulmonary hemorrhage but usually does not cause pulmonary infarction.

Why?

Answer 209

This is because the lung has a dual blood supply, and the intact bronchial circulation continues
to perfuse the affected area.

*_**However, a similar embolus in the setting of left-sided
cardiac failure (and compromised bronchial artery flow) can result in infarction.**_*

Question 210

Embolic obstruction of small end-arteriolar pulmonary branches usually does result in
______________

Answer 210

hemorrhage or infarction

Question 211

Multiple emboli over time may cause___________

Answer 211

pulmonary hypertension and right ventricular
failure.

Question 212

Answer 212

FIGURE 4-15 Embolus from a lower extremity deep venous thrombosis, now impacted in a
pulmonary artery branch

Question 213

What is systemic thromboembolism?

Answer 213

Systemic thromboembolism refers to emboli in the arterial circulation

Question 214

Where does systemic thromboembolism mostly arise?

Answer 214

• Most (80%) arise from intracardiac mural thrombi,
• two thirds of which are associated with left ventricular wall infarcts
• and another quarter with left atrial dilation and fibrillation.
• The remainder originate from aortic aneurysms, thrombi on ulcerated atherosclerotic plaques, or fragmentation of a valvular vegetation, with a small fraction due to paradoxical emboli ;
• 10% to 15% of systemic emboli are of unknown origin.

Question 215

In contrast to venous emboli, which tend to lodge primarily in one vascular bed (the lung), arterial emboli can travel to a wide variety of sites; the point of arrest depends
on the source and the relative amount of blood flow that downstream tissues receive.

Question 216

Major
sites for arteriolar embolization are the:

Answer 216

• lower extremities (75%)
• and the brain (10%),
• with the
• intestines, kidneys, spleen, and upper extremities involved to a lesser extent.

Question 217

The consequences of embolization in a tissue depend on its :

Answer 217

• vulnerability to ischemia,
• the caliber of the occluded vessel,
• and whether there is a collateral blood supply;

in general, arterial emboli cause infarction of the affected tissues.

Question 218

What is FAT AND MARROW EMBOLISM

Answer 218

Microscopic fat globules—with or without associated hematopoietic marrow elements—can be
found in the circulation and impacted in the pulmonary vasculature after fractures of long bones
(which have fatty marrow)or,rarely, in the setting of soft tissue trauma and burns.

Question 219

How is Fat and marrow embolism happens?

Answer 219

Fat and associated cells released by marrow or adipose tissue injury may enter the circulation after the
rupture of the marrow vascular sinusoids or venules.

Question 220

Fat and marrow PEs are very common
incidental findings ___________.

Answer 220

after vigorous cardiopulmonary resuscitation and are probably of no clinical
consequence

Question 221

Indeed, fat embolism occurs in some 90% of individuals with __________( Fig. 4-16 )

Answer 221

severe skeletal
injuries

Question 222

Indeed, fat embolism occurs less than 10% of such patients have any clinical findings.

Question 223

Answer 223

FIGURE 4-16 Bone marrow embolus in the pulmonary circulation. The cellular elements on the left side of the embolus are hematopoietic precursors, while the cleared vacuoles
represent marrow fat. The relatively uniform red area on the right of the embolus is an early
organizing thrombus.

Question 224

What is Fat embolism syndrome?

Answer 224

Fat embolism syndrome is the term applied to the minority of patients who become symptomatic.
It is characterized by pulmonary insufficiency, neurologic symptoms, anemia, and
thrombocytopenia,and is fatal in about 5% to 15% of cases.

[52,] [53] Typically, 1 to 3 days
after injury there is a sudden onset of tachypnea, dyspnea, and tachycardia;

irritability and
restlessness can progress to delirium or coma.

Thrombocytopenia is attributed to platelet
adhesion to fat globules and subsequent aggregation or splenic sequestration; anemia can result from similar red cell aggregation and/or hemolysis.

A diffuse petechial rash (seen in 20%
to 50% of cases) is related to rapid onset of thrombocytopenia and can be a useful diagnostic
feature.

Question 225

WHat is the pathogenesis of fat emboli syndrome?

Answer 225

The pathogenesis of fat emboli syndrome probably involves both mechanical obstruction and
biochemical injury. [52]

Fat microemboli and associated red cell and platelet aggregates can occlude the pulmonary and cerebral microvasculature.

Release of free fatty acids from the fat
globules exacerbates the situation by causing local toxic injury to endothelium, and platelet activation and granulocyte recruitment (with free radical, protease, and eicosanoid release) complete the vascular assault.

Because lipids are dissolved out of tissue preparations by the
solvents routinely used in paraffin embedding, the microscopic demonstration of fat microglobules (in the absence of accompanying marrow) typically requires specialized
techniques, including frozen sections and stains for fat.

Question 226

How does Air embolism occurs?

Answer 226

Gas bubbles within the circulation can coalesce to form frothy masses that obstruct vascular flow (and cause distal ischemic injury)

. For example, a very small volume of air trapped in a
coronary artery during bypass surgery, or introduced into the cerebral circulation by neurosurgery in the “sitting position,” can occlude flow with dire consequences.

Question 227

In air embolism , generally, more
than ______________ of air are required to have a clinical effect in the pulmonary circulation; however,
this volume of air can be inadvertently introduced during obstetric or laparoscopic procedures,
or as a consequence of chest wall injury.

Answer 227

100 cc

Question 228

What is decompression sickness?

Answer 228

A particular form of gas embolism, called decompression sickness, occurs when individuals
experience sudden decreases in atmospheric pressure. [55] Scuba and deep sea divers,
underwater construction workers, and individuals in unpressurized aircraft in rapid ascent are all at risk.

When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) are dissolved in the blood and tissues.

If the diver then ascends (depressurizes) too rapidly, the nitrogen comes out of solution in the tissues and the
blood.

Question 229

What are bends?

Answer 229

The rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints is responsible for the painful condition called the bends

Question 230

What are chokes?

Answer 230

In the lungs, gas bubbles in the
vasculature cause edema,hemorrhage, and focal atelectasis or emphysema, leading to a form
of respiratory distress called the chokes.

Question 231

What is caisson’s disease?

Answer 231

A more chronic form of decompression sickness is
called caisson disease (named for the pressurized vessels used in the bridge construction; workers in these vessels suffered both acute and chronic forms of decompression sickness).

Question 232

In caisson disease, persistence of gas emboli in the skeletal system leads to multiple foci of
ischemic necrosis; the more common sites are the ____________

Answer 232

• femoral heads,
• tibia,
• humeri.

FTH

Question 233

How is acute decompression sickness treated?

Answer 233

Acute decompression sickness is treated by placing the individual in a high pressure chamber, which serves to force the gas bubbles back into solution.

Subsequent slow decompression
theoretically permits gradual resorption and exhalation of the gases so that obstructive bubbles
do not re-form.

Question 234

What is amniotic embolism?

Answer 234

Amniotic fluid embolism is an ominous complication of labor and the immediate postpartum
period.

Although the incidence is only approximately 1 in 40,000 deliveries, the mortality rate is up to 80%, making amniotic fluid embolism the fifth most common cause of maternal mortality worldwide; it accounts for roughly 10% of maternal deaths in the United States and results in permanent neurologic deficit in as many as 85% of survivors. [56]

Question 235

What is the characteristic amniotic embolism?

Answer 235

The onset is characterized by
sudden severe dyspnea, cyanosis, and shock, followed by neurologic impairment ranging from
headache to seizures and coma.

If the patient survives the initial crisis, pulmonary edema
typically develops, along with (in half the patients) DIC, as a result of release of thrombogenic
substances from the amniotic fluid

Question 236

What is the pathophysiology of amniotic embolsm?

Answer 236

The underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal circulation
via a tear in the placental membranes or rupture of uterine veins.

Classic findings include the
presence of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and
mucin derived from the fetal respiratory or gastrointestinal tract in the maternal pulmonary microvasculature( Fig. 4-17 ). Other findings include marked pulmonary edema, diffuse
alveolar damage( Chapter 15 ), and thepresence of fibrin thrombi in many vascular beds due
to DIC.

Question 237

Answer 237

FIGURE 4-17 Amniotic fluid embolism. Two small pulmonary arterioles are packed with laminated swirls of fetal squamous cells.

There is marked edema and congestion, and
elsewhere in the lung were small organizing thrombi consistent with disseminated
intravascular coagulation.

Question 238

What is an infarction?

Answer 238

An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage.

Tissue infarction is a common and extremely important cause of clinical illness. Roughly 40% of all deaths in the

United States are caused by cardiovascular disease,
and most of these are attributable to myocardial or cerebral infarction.

Pulmonary infarction is
also a common complication in many clinical settings, bowel infarction is frequently fatal, and
ischemic necrosis of the extremities (gangrene) is a serious problem in the diabetic population.

Question 239

Nearly all infarcts result from______________

Answer 239

thrombotic or embolic arterial occlusions.

Occasionally infarctions
are caused by other mechanisms, including local vasospasm, hemorrhage into an
atheromatous plaque, or extrinsic vessel compression (e.g., by tumor).

Rarer causes include torsion of a vessel (e.g., in testicular torsion or bowel volvulus), traumatic rupture, or vascular
compromise by edema (e.g., anterior compartment syndrome) or by entrapment in a hernia
sac.

Question 240

Although venous thrombosis can cause infarction, the more common outcome is just__________; in this setting, bypass channels rapidly open and permit vascular outflow, which
then improves arterial inflow.

Infarcts caused by venous thrombosis are thus more likely in
organs with a single efferent vein (e.g., testis and ovary).

Answer 240

congestion

Question 241

Morphology.

Infarcts are classified according to color and the presence or absence of
infection;

they are either

Answer 241

• red (hemorrhagic) or white (anemic)
• and may be septic or bland.

Question 242

Red infarcts ( Fig. 4-18A ) occur

Answer 242

• (1) with venous occlusions (e.g., ovary),
• (2) in loose tissues (e.g., lung) where blood can collect in the infarcted zone,
• (3) in tissues with\ dual circulations (e.g., lung and small intestine) that allow blood flow from an unobstructed parallel supply into a necrotic zone,
• (4) in tissues previously congested by sluggish venous outflow,
• and (5) when flow is re-established to a site of previous
• arterial occlusion and necrosis (e.g., following angioplasty of an arterial obstruction).

Question 243

White infarcts ( Fig. 4-18B ) occur with arterial occlusions in

Answer 243

• *solid organs with endarterial**
• *circulation** (e.g., heart, spleen, and kidney), and where tissue density limits the seepage of blood from adjoining capillary beds into the necrotic area.

Question 244

Infarcts tend to be___________

Answer 244

• wedge-shaped,
• with the occluded vessel at the apex and the periphery of the organ forming the base (see Fig. 4-18 );
• when the base is a serosal surface there can be an overlying fibrinous exudate.

Question 245

Acute infarcts are poorly defined and slightly hemorrhagic.

With time the margins tend to become better defined by a narrow rim of congestion
attributable to inflammation.

Question 246

Infarcts resulting from arterial occlusions in organs without a dual blood supply typically

Extravasated red
cells in hemorrhagic infarcts are phagocytosed by macrophages, which convert heme iron
into hemosiderin; small amounts do not grossly impart any appreciable color to the tissue, but
extensive hemorrhage can leave a firm, brown residuum.

Answer 246

become progressively paler and more sharply defined with time (see Fig. 4-18B ). By comparison, in the lung hemorrhagic infarcts are the rule (see Fig. 4-18A ).

Question 247

The dominant histologic characteristic of infarction is__________

Answer 247

ischemic coagulative necrosis ( Chapter 1 ).

Question 248

It is important to recall that if the vascular occlusion has occurred shortly (minutes to hours) before the death of the person, no demonstrable histologic changes may
be evident;

it takes _____________- for the tissue to show frank necrosis.

Answer 248

4 to 12 hours

Question 249

Acute inflammation is
present along the margins of infarcts within a few hours and is usually well defined within___________

Eventually the inflammatory response is followed by a reparative response beginning
in the preserved margins ( Chapter 2 ).

In stable or labile tissues, parenchymal regeneration
can occur at the periphery where underlying stromal architecture is preserved.

However, most
infarcts are ultimately replaced by scar ( Fig. 4-19 ). The brain is an exception to these
generalizations, as central nervous system infarction results in liquefactive necrosis (

Answer 249

1 to
2 days.

Question 250

What are septic infarctions?

Answer 250

Septic infarctions occur when infected cardiac valve vegetations embolize or when
microbes seed necrotic tissue.

In these cases the infarct is converted into an abscess, with a
correspondingly greater inflammatory response ( Chapter 2 ). The eventual sequence of
organization, however, follows the pattern already described.

Question 251

Answer 251

FIGURE 4-18 Red and white infarcts. A, Hemorrhagic, roughly wedge-shaped pulmonary
red infarct. B, Sharply demarcated white infarct in the spleen

Question 252

FIGURE 4-19 Remote kidney infarct, now replaced by a large fibrotic scar.

Answer 252

FIGURE 4-19 Remote kidney infarct, now replaced by a large fibrotic scar.

Question 253

Factors That Influence Development of an Infarct.

Answer 253

The effects of vascular occlusion can range from no or minimal effect to causing the death of a tissue or person.

The major determinants of the eventual outcome are:

• (1) the nature of the vascular supply,
• (2) the rate at which an occlusion develops,
• (3) vulnerability to hypoxia, and
• (4) the oxygen content of the blood .

Question 254

Factors That Influence Development of an Infarct.

Explain the Nature of the vascular supply when it comes to influencing the development of infarct.

Answer 254

The availability of an alternative blood supply is the most important determinant of whether vessel occlusion will cause damage.

As already
mentioned, the lungs have a dual pulmonary and bronchial artery blood supply that provides protection from thromboembolism-induced infarction.

Similarly, the liver, with its
dual hepatic artery and portal vein circulation,

and the hand and forearm, with their dual radial and ulnar arterial supply, are all relatively resistant to infarction.

In contrast, renal
and splenic circulations are end-arterial, and vascular obstruction generally causes
tissue death.

Question 255

What organns have dual blood supply that are resistant to infarction?

Answer 255

• the lungs have a dual pulmonary and bronchial artery blood supply that provides protection from thromboembolism-induced infarction.
• Similarly, the liver, with its dual hepatic artery and portal vein circulation,
• and the hand and forearm, with their dual radial and ulnar arterial supply, are all relatively resistant to infarction.

Question 256

In the factors the influenec development of infatct, discuss rate of occlusion development.

Answer 256

Rate of occlusion development.

• *Slowly developing occlusions are less likely to cause**
• *infarction**, because they provide time to develop alternate perfusion pathways.

For example, small interarteriolar anastomoses—normally with minimal functional flow —interconnect the three major coronary arteries in the heart. If one of the coronaries is
only slowly occluded (i.e., by an encroaching atherosclerotic plaque), flow within this collateral circulation may increase sufficiently to prevent infarction, even though the
larger coronary artery is eventually occluded.

Question 257

In line with the factors that influence the development of an infarct, discuss the vulnerability to hypoxia.

Answer 257

Vulnerability to hypoxia.

• Neurons undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes.
• Myocardial cells, though hardier than neurons, are also quite sensitive and die after only 20 to 30 minutes of ischemia.
• In contrast, fibroblasts within myocardium remain viable even after many hours of ischemia (
• Chapter 12 ).

Question 258

In line with the factors that influence the development of an infarct, discuss the Oxygen content of blood.

Answer 258

Oxygen content of blood .

A partial obstruction of a small vessel that would be without
effect in an otherwise normal individual might cause infarction in an anemic or cyanotic
patient.

Question 259

What is Shock?

Answer 259

Shock is the final common pathway for several potentially lethal clinical events, including severe hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism, and microbial sepsis.

Question 260

What is the characteristic of SHOCK?

Answer 260

Shock is characterized by:

• systemic hypotension due either to reduced cardiac output or to reduced effective circulating blood volume.

Question 261

The consequences of SHOCK are:

Answer 261

impaired tissue perfusion and cellular hypoxia .

At the outset the cellular injury is reversible;
however, prolonged shock eventually leads to irreversible tissue injury that often proves fatal.

Question 262

The causes of shock fall into three general categories

Answer 262

1. Cardiogenic
2. Hypovolemic
3. Septic

Question 263

Explain Cardiogenic Shock.

Answer 263

Cardiogenic shock results from low cardiac output due to myocardial pump failure.

Question 264

Cardiogenic shock can be due to:

Answer 264

This can be due to:

• intrinsic myocardial damage (infarction),
• ventricular arrhythmias,
• extrinsic compression (cardiac tamponade; Chapter 12 ),
• or outflow obstruction (e.g., pulmonary embolism).
• Myocardial infarction
• Ventricular rupture
• Arrhythmia
• Cardiac tamponade
• Pulmonary embolism

Question 265

What is the principal mechanism of Cardiogenic shock?

Answer 265

Failure of myocardial pump resulting from intrinsic myocardial
damage, extrinsic pressure, or obstruction to outflow

Question 266

Define Hypoveolemic Shock.

Answer 266

Hypovolemic shock results from low cardiac output due to the loss of blood or plasma
volume,such as can occur with massive hemorrhage or fluid loss from severe burns.

Question 267

Give an example of Hypovolemic Shock

Answer 267

Fluid loss (e.g.,
hemorrhage, vomiting,
diarrhea, burns, or
trauma)

Question 268

What is the principal mechanism of Hypovolemic shock?

Answer 268

Inadequate blood or plasma volume

Question 269

Define Septic Shock.

Answer 269

Septic shock results from vasodilation and peripheral pooling of blood as part of a
systemic immune reaction to bacterial or fungal infection.

Its complex pathogenesis is
discussed in further detail below.

Question 270

What are example of clinical setting of Septic Shock.

Answer 270

Overwhelming

• microbial infections (bacterial and fungal)
• Superantigens (e.g., toxic shock syndrome)

Question 271

What is the principal mechanism of Septic Shock?

Answer 271

• Peripheral vasodilation and pooling of blood;
• endothelial activation/injury; leukocyte-induced damage, disseminated intravascular coagulation;
• activation of cytokine cascades

Question 272

Define neurogenic shock and when does it mostly occur.

Answer 272

Less commonly, shock can occur in the setting of anesthetic accident or a spinal cord injury (neurogenic shock), as a result of loss of vascular tone and peripheral pooling of blood.

Question 273

What is anaphylactic shock?

Answer 273

Anaphylactic shock denotes systemic vasodilation and increased vascular permeability caused
by an IgE–mediated hypersensitivity reaction ( Chapter 6 ). In these situations, acute widespread vasodilation results in tissue hypoperfusion and hypoxia.

Question 274

What is the pathogenesis of Septic Shock?

Answer 274

Septic shock is associated with severe hemodynamic and hemostatic derangements, and
therefore merits more detailed consideration here.

With a mortality rate near 20%, septic shock
ranks first among the causes of death in intensive care units and accounts for over 200,000
lost lives each year in the United States. [57]

Its incidence is rising, ironically due to
improvements in life support for critically ill patients and the growing ranks of immunocompromised hosts (due to chemotherapy, immunosuppression, or HIV infection).

Question 275

What is the most currently triggering factor of septic shock?

Answer 275

Currently, septic shock is most frequently triggered by gram-positive bacterial infections, followed by gram-negative bacteria and fungi. [57]

Hence, the older synonym of “endotoxic
shock” is not appropriate.

Question 276

Discuss what happens in septic shock.

Answer 276

In septic shock, systemic vasodilation and pooling of blood in the periphery leads to tissue
hypoperfusion,even though cardiac output may be preserved or even increased early in the
course.

This is accompanied by widespread endothelial cell activation and injury, often leading to a hypercoagulable state that can manifest as DIC.

In addition, septic shock is associated with
changes in metabolism that directly suppress cellular function.

Question 277

What is the net effect of the pathogenesis of Septic shock?

Answer 277

The net effect of these
abnormalities is hypoperfusion and dysfunction of multiple organs—culminating in the extraordinary morbidity and mortality associated with sepsis.

Question 278

The ability of diverse microorganisms to cause septic shock (sometimes even when the infection is localized to one area of the body) [58] is consistent with the idea that several
microbial constituents can initiate the process.

As you will recall from Chapter 2 , macrophages,
neutrophils, and other cells of the innate immune system express a number of receptors that respond to a variety of substances derived from microorganisms.

Once activated, these cells release inflammatory mediators, as well as a variety of immunosuppressive factors that modify
the host response. In addition, microbial constituents also activate humoral elements of innate immunity, particularly the complement and coagulation pathways.

These mediators combine with
the direct effects of microbial constituents on endothelium in a complex, incompletely
understood fashion to produce septic shock ( Fig. 4-20 ). [59]

Question 279

The major factors
contributing to its pathophysiology include the following:

Answer 279

1. Inflammatory mediators
2. Endothelial cell activation and injury .
3. Metabolic abnormalities
4. Immune suppression
5. Organ dysfunction

Question 280

How do inflammatory mediators contribute to the pathophysiology of septic shock?

Answer 280

Various microbial cell wall constituents engage receptors on
neutrophils, mononuclear inflammatory cells, and endothelial cells, leading to cellularactivation.

Toll-like receptors (TLRs, Chapter 2 ) recognize microbial elements and trigger the responses that initiate sepsis. However, mice genetically deficient in TLRs still
succumb to sepsis, [59,] [60] and it is believed that other pathways are probably also involved in the initiation of sepsis in humans (e.g., G-protein coupled receptors that
detect bacterial peptides and nucleotide oligomerization domain proteins 1 and 2
[NOD1, NOD2]). [62]

Upon activation, inflammatory cells produce TNF, IL-1, IFN-γ, IL-12, and IL-18, as well as other inflammatory mediators such as high mobility group box 1 protein (HMGB1). [62

] Reactive oxygen species and lipid mediators such as
prostaglandins and platelet activating factor (PAF) are also elaborated.

These effector molecules activate endothelial cells (and other cell types) resulting in adhesion molecule expression, a procoagulant phenotype, and secondary waves of cytokine
production. [61]

The complement cascade is also activated by microbial components, both directly and through the proteolytic activity of plasmin ( Chapter 2 ), resulting in the
production of anaphylotoxins (C3a, C5a),chemotactic fragments (C5a), and opsonins (C3b) that contribute to the pro-inflammatory state. [63]

In addition, microbial
components such as endotoxincan activate coagulation directly through factor XII and indirectly through altered endothelial function (discussed below).

The systemic
procoagulant state induced by sepsis not only leads to thrombosis, but also augments
inflammation through effects mediated by protease-activated receptors (PARs) found on inflammatory cells.

Question 281

Explain how Endothelial cell activation and injury contribute to the pathophysio of Septic Shock.

Answer 281

Endothelial cell activation by microbial constituents
or inflammatory mediators produced by leukocytes has three major sequelae:

• (1)thrombosis;
• (2) increased vascular permeability;
• and (3) vasodilation.

The derangement in coagulation is sufficient to produce the fearsome complication of DIC in up to half of septic patients. [60]

Sepsis alters the expression of many factors so as to favor

coagulation.

Pro-inflammatory cytokines result in increased tissue factor production by endothelial cells (and monocytes as well), while at the same time reining in fibrinolysis by increasing PAI-1 expression (see Fig. 4-6B and Fig. 4-8 ).

The production of other endothelial anti-coagulant factors, such as tissue factor pathway inhibitor, thrombomodulin, and protein C (see Fig. 4-6 and Fig. 4-8 ), are diminished. [60,] [61,] [64]

The procoagulant tendency is further exacerbated by

decreased blood flow at the level of small vessels, producing stasis and diminishing the washout of activated coagulation factors.

Acting in concert, these effects promote the

deposition of fibrin-rich thrombi in small vessels, often throughout the body, which also contributes to the hypoperfusion of tissues. [60] In full-blown DIC, the consumption of coagulation factors and platelets is so great that deficiencies of these factors appear, leading to concomitant bleeding and hemorrhage ( Chapter 14 ).

The increase in vascular permeability leads to exudation of fluid into the interstitium, causing edema and an increase in interstitial fluid pressure that may further impede blood flow into tissues, particularly following resuscitation of the patient with intravenous fluids.

The endothelium also increases its expression of inducible nitric oxide synthetase and the production of

nitric oxide (NO).

These alterations, along with increases in vasoactive inflammatory mediators (e.g., C3a, C5a, and PAF), cause the systemic relaxation of vascular smooth muscle, leading to hypotension and diminished tissue perfusion.

Question 282

Explain how metabolic abnormalitiies contribute to Septic Shock.

Answer 282

Metabolic abnormalities.

Septic patients exhibit insulin resistance and hyperglycemia.
Cytokines such as TNF and IL-1, stress-induced hormones (such as glucagon, growth hormone, and glucocorticoids), and catecholamines all drive gluconeogenesis.

At the same time, the pro-inflammatory cytokines suppress insulin release while simultaneously promoting insulin resistance in the liver and other tissues, likely by impairing the surface expression of GLUT-4, [65] a glucose transporter.

Hyperglycemia decreases neutrophil function—thereby suppressing bactericidal activity—and causes increased adhesion molecule expression on endothelial cells. [65] Although sepsis is initially associated with an acute surge in glucocorticoid production, this phase is frequently followed by adrenal insufficiency and a functional deficit of glucocorticoids.

This may stem from depression of the synthetic capacity of intact adrenal glands or frank adrenal necrosis due to DIC
(Waterhouse-Friderichsen syndrome, Chapter 24 ).

Question 283

How does immune suppression contribute to Septic shock pathology?

Answer 283

Immune suppression.

The hyperinflammatory state initiated by sepsis can activate counter-regulatory immunosuppressive mechanisms, which may involve both innate and
adaptive immunity. [59] [60] [61]

Proposed mechanisms for the immune suppression
include a shift from pro-inflammatory (TH1) to anti-inflammatory (TH2) cytokines ( Chapter 6 ), production of anti-inflammatory mediators (e.g., soluble TNF receptor, IL-1
receptor antagonist, and IL-10), lymphocyte apoptosis, the immunosuppressive effects of apoptotic cells, and the induction of cellular anergy. [59] [60] [61]

It is still debated whether immunosuppressive mediators are deleterious or protective in sepsis

Question 284

How does organ dysfunciton contribute to the pathophysiology of Septic shock?

Answer 284

Systemic hypotension, interstitial edema, and small vessel
thrombosis all decrease the delivery of oxygen and nutrients to the tissues, which fail to properly utilize those nutrients that are delivered due to changes in cellular metabolism.

High levels of cytokines and secondary mediators may diminish myocardial contractility and cardiac output, and increased vascular permeability and endothelial injury can lead
to the adult respiratory distress syndrome ( Chapter 15 ). Ultimately, these factors may
conspire to cause the failure of multiple organs, particularly the kidneys, liver, lungs, and
heart, culminating in death.

Question 285

Answer 285

FIGURE 4-20 Major pathogenic pathways in septic shock. Microbial products activate
endothelial cells and cellular and humoral elements of the innate immune system, initiating a cascade of events that lead to end-stage multiorgan failure. Additional details are given in
the text. DIC, disseminated vascular coagulation; HMGB1, high mobility group box 1 protein; NO, nitric oxide; PAF, platelet activating factor; PAI-1, plasminogen activator inhibitor 1;
STNFR, soluble TNF receptor; TF, tissue factor; TFPI, tissue factor pathway inhibitor.

Question 286

The severity and outcome of septic shock are likely dependent upon the:

Answer 286

• extent and virulence of the infection;
• the immune status of the host;
• the presence of other co-morbid conditions;
• andthe pattern and level of mediator production.

The multiplicity of factors and the complexity of the
interactions that underlie sepsis explain why most attempts to intervene therapeutically with antagonists of specific mediators have been of very modest benefit at best, and may even have had deleterious effects in some cases. [59]

Question 287

What is the standard of care for septic shock?

Answer 287

The standard of care remains treatment with:

• appropriate antibiotics,
• intensive insulin therapy for hyperglycemia,
• fluid resuscitation to maintain systemic pressures, and “physiologic doses” of corticosteroids to correct relative adrenal insufficiency.
• [59] Administration of activated protein C (to prevent thrombin generation and thereby reduce coagulation and inflammation) may have some benefit in cases of severe sepsis, but this remains controversial.
• Suffice it to say, even in the best of clinical centers, septic shock remains an obstinate clinical challenge

Question 288

How do superantigens cause a syndrome similar to septic shock?

Answer 288

It is worth mentioning here that an additional group of secreted bacterial proteins called
superantigens also cause a syndrome similar to septic shock (e.g., toxic shock syndrome).
Superantigens are polyclonal T-lymphocyte activators that induce the release of high levels of cytokines that result in a variety of clinical manifestations, ranging from a diffuse rash to
vasodilation, hypotension, and death.

Question 289

STAGES OF SHOCK

Shock is a progressive disorder that, if uncorrected, leads to death.

The exact mechanism(s) of death from sepsis are still unclear; aside from increased lymphocyte and enterocyte apoptosis there is only minimal cell death, and patients rarely have refractory hypotension. [61]

For hypovolemic and cardiogenic shock, however, the pathways to death are reasonably well
understood. Unless the insult is massive and rapidly lethal (e.g., a massive hemorrhage from a ruptured aortic aneurysm), shock in those settings tends to evolve through three general (albeit somewhat artificial) phases:

Answer 289

• An initial nonprogressive phase
• A progressive stage
• •An irreversible stage

Question 290

Describe the initial progressive phase.

Answer 290

An initial nonprogressive phase during which reflex compensatory mechanisms are activated and perfusion of vital organs is maintained

Question 291

Discuss the progressive stage.

Answer 291

A progressive stage characterized by tissue hypoperfusion and onset of worsening
circulatory and metabolic imbalances,including acidosis

Question 292

Discuss the irreversible stage.

Answer 292

An irreversible stage that sets in after the body has incurred cellular and tissue injury so severe that even if the hemodynamic defects are corrected, survival is not possible

Question 293

In the early nonprogressive phase of shock, a variety of neurohumoral mechanisms help to
maintain cardiac output and blood pressure.

These include

Answer 293

• baroreceptor reflexes,
• catecholamine release,
• activation of the renin-angiotensin axis,
• ADH release,
• and generalized sympathetic stimulation.

Question 294

What is the net effect of the neurohormonal mechanism of the nonprogressive stage?

Answer 294

The net effect is:

• tachycardia,
• peripheral vasoconstriction,
• and renal conservation of fluid.
• Cutaneous vasoconstriction, for example, is responsible for the characteristic coolness and pallor of the skin in well-developed shock (although septic shock can initially cause cutaneous vasodilation and thus present with warm, flushed skin).
• Coronary and cerebral vessels are less sensitive to the sympathetic response and thus maintain relatively normal caliber, blood flow, and oxygen delivery.

Question 295

Explain the coolness and pallor of the skin in well developed shocked.

Answer 295

Cutaneous vasoconstriction, for example, is responsible for the characteristic coolness and pallor of the skin in well-developed shock.

Question 296

although septic shock can initially cause cutaneous vasodilation and thus present with warm, flushed skin

T or F

Answer 296

T

Question 297

If the underlying causes are not corrected, shock passes imperceptibly to the progressive phase, during which there is ____________.

Answer 297

widespread tissue hypoxia

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 and blunts the vasomotor response; arterioles dilate, and blood begins to pool in the microcirculation.
Peripheral pooling not only worsens the cardiac output, but also puts EC at risk for developing anoxic injury with subsequent DIC.

With widespread tissue hypoxia, vital organs are affected
and begin to fail.

Question 298

Without intervention, the process eventually enters an irreversible stage.

Widespread cell injury
is reflected in ________

Answer 298

lysosomal enzyme leakage, further aggravating the shock state.

Myocardial
contractile function worsens in part because of nitric oxidesynthesis.

If ischemic bowel allows intestinal flora to enter the circulation, bacteremic shock may be superimposed.

At this point the patient has complete renal shutdown as a result of acute tubular necrosis ( Chapter 20 ), and
despite heroic measures the downward clinical spiral almost inevitably culminates in death.

Question 299

The cellular and tissue changes induced by cardiogenic or hypovolemic shock are essentially those of __________ ( Chapter 1 );

Answer 299

hypoxic injury

changes can manifest in any tissue although they are particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract.

Question 300

The adrenal changes in shock are those seen in all forms of _____________

Answer 300

stress; essentially there is cortical cell lipid depletion.

This does not reflect adrenal exhaustion but
rather conversion of the relatively inactive vacuolated cells to metabolically active cells that utilize stored lipids for the synthesis of steroids.

The kidneys typically exhibit acute tubular
necrosis ( Chapter 20 ).

Question 301

What is a shock lung?

Answer 301

The lungs are seldom affected in pure hypovolemic shock,
because they are somewhat resistant to hypoxic injury. However, when shock is caused by
bacterial sepsis or trauma, changes of diffuse alveolar damage ( Chapter 15 ) may develop, the so-called shock lung.

Question 302

In septic shock, the development of DIC leads to
widespread deposition of fibrin-rich microthrombi, particularly in the ______________

The consumption of platelets and
coagulation factors also often leads to the appearance of petechial hemorrhages on serosal surface and the skin.

Answer 302

brain, heart, lungs, kidney, adrenal glands, and gastrointestinal tract.

Question 303

With the exception of _________ ischemic loss, virtually all of these tissues may revert to normal if the individual survives. Unfortunately, most patients with irreversible
changes due to severe shock die before the tissues can recover.

Answer 303

neuronal and myocyte

Question 304

The clinical manifestations of shock depend on the precipitating insult.

In hypovolemic and cardiogenic shock the patient presents

Answer 304

• with hypotension;
• a weak,rapid pulse;
• tachypnea;
• and cool, clammy,
• cyanotic skin.

Question 305

What is the clinical presentation in septic shock?

Answer 305

In septic shock the skin may initially be warm and flushed because of peripheral vasodilation.

The initial threat to life stems from the underlying catastrophe that precipitated the shock (e.g., myocardial infarct, severe hemorrhage, or sepsis).

Rapidly, however, the cardiac, cerebral, and pulmonary changes secondary to shock worsen the
problem.

Eventually, electrolyte disturbances and metabolic acidosis also exacerbate the
situation.

Individuals who survive the initial complications may enter a second phase dominated by renal insufficiency and marked by a progressive fall in urine output as well as severe fluid
and electrolyte imbalances.

Question 306

The prognosis varies with the origin of shock and its duration. Thus, greater than 90% of
young, otherwise healthy patients with hypovolemic shock survive with appropriate management; in comparison, septic shock, or cardiogenic shock associated with extensive
myocardial infarction, can have substantially worse mortality rates, even with optimal care.

Answer 306

RIP mama :(