Hemodynamics

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) thatlies 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 waterand low molecular weight solutes such as salts between the intravascular and interstitial spacesis controlled primarily by the opposing effect of vascular ____________

Answer 4

hydrostatic pressure and plasmacolloid osmotic pressure.

Question 5

Normally the outflow of fluid from the arteriolar end of themicrocirculation into the interstitium is nearly balanced by inflow at the venular end; a smallresidual 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 capillarypressure or diminished colloid osmotic pressure can result in increased interstitial fluid

Question 6

Normally the outflow of fluid from the arteriolar end of themicrocirculation into the interstitium is nearly balanced by inflow at the venular end; a smallresidual 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 capillarypressure 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, fluidaccumulates. An abnormal increase in interstitial fluid within tissues is called edema, while fluidcollections 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 isa severe and generalized edema with widespread subcutaneous tissue swelling.

Question 9

What is a transudate?

Answer 9

There are several pathophysiologic categories of edema ( Table 4-1 ). Edema caused byincreased hydrostatic pressure or reduced plasma protein is typically a protein-poor fluid calleda transudate.Edema fluid of this type is seen in patients suffering from heart failure, renalfailure, hepatic failure, and certain forms of malnutrition,

Question 10

What is an exudate?

Answer 10

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

Question 11

Pathophysiologic Categories of Edema

Answer 11

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

Question 12

Under theTABLE 4-1 – Pathophysiologic Categories of EdemaINCREASED HYDROSTATIC PRESSURE is brought about by diseases such as:

Answer 12

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 13

REDUCED PLASMA OSMOTIC PRESSURE (HYPOPROTEINEMIA

Answer 13

Protein-losing glomerulopathies (nephrotic syndrome)

• Liver cirrhosis (ascites)
• Malnutrition
• Protein-losing gastroenteropathy

Question 14

LYMPHATIC OBSTRUCTION

Answer 14

Inflammatory Neoplastic Postsurgical Postirradiation

Question 15

SODIUM RETENTION

Answer 15

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

Question 16

INFLAMMATION

Answer 16

Acute inflammationChronicinflammationAngiogenesis

Question 17

What happens inIncreased Hydrostatic Pressure.

Answer 17

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

Question 18

When does reduced plasma osmotic pressure occurs?

Answer 18

Reduced plasma osmotic pressure occurs when albumin, the major plasma protein, is notsynthesized in adequate amounts or is lost from the circulation.

Question 19

An important cause of albuminloss is the__________ ( Chapter 20 ), in which glomerular capillaries become leaky;patients typically present with generalized edema.Reduced albumin synthesis occurs in thesetting 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 theinterstitial tissues with subsequent plasma volume contraction. The reduced intravascularvolume leads to decreased renal perfusion. This triggers increased production of renin,angiotensin, and aldosterone, but the resulting salt and water retention cannot correct theplasma volume deficit because the primary defect of low serum protein persists.

Answer 19

nephrotic syndrome

Question 20

When does reduce osmotic pressure occurs?

Answer 20

• Reduced plasma osmotic pressure occurs when albumin,the major plasma protein, is notsynthesized in adequate amounts or is lost from the circulation.
• An important cause of albuminloss 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 volumecontraction.
• The reduced intravascularvolume leads to decreased renal perfusion. This triggers increased production of renin,angiotensin, and aldosterone, but the resulting salt and water retention cannot correct theplasma volume deficit because the primary defect of low serum protein persists.

Question 21

How can salt retention cause edema?

Answer 21

Salt and water retention can also be a primary cause of edema.Increased salt retention—withobligate associated water—causes both increased hydrostatic pressure (due to intravascularfluid volume expansion) and diminished vascular colloid osmotic pressure (due to dilution). Saltretention occurs whenever renal function is compromised, such as in primary disorders of thekidney and disorders that decrease renal perfusion.One of the most important causes of renalhypoperfusion is congestive heart failure, which (like hypoproteinemia) results in the activationof the renin-angiotensin-aldosterone axis.In early heart failure, this response tends to bebeneficial, as the retention of sodium and water and other adaptations, including increasedvascular 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 outputdiminishes, the retained fluid merely increases the venous pressure, which (as alreadymentioned) is a major cause of edema in this disorder.Unless cardiac output is restored orrenal sodium and water retention is reduced (e.g., by salt restriction, diuretics, or aldosteroneantagonists), a downward spiral of fluid retention and worsening edema ensues.Salt restriction,diuretics, and aldosterone antagonists are also of value in managing generalized edema arisingfrom other causes.Primary retention of water (and modest vasoconstriction) is produced by therelease of ADH from the posterior pituitary, which normally occurs in the setting of reducedplasma volumes or increased plasma osmolarity. [2]Inappropriate increases in ADH are seen inassociation with certain malignancies and lung and pituitary disorders and can lead tohyponatremia and cerebral edema (but interestingly not to peripheral edema).

Question 22

Impaired lymphatic drainage results in lymphedema that is typically localized; causes includechronic inflammation with fibrosis, invasive malignant tumors, physical disruption, radiationdamage, and certain infectious agents.One dramatic example is seen in parasitic filariasis, inwhich lymphatic obstruction due to extensive inguinal lymphatic and lymph node fibrosis canresult in edema of the external genitalia and lower limbs that is so massive as to earn theappellation elephantiasis. Severe edema of the upper extremity may also complicate surgicalremoval and/or irradiation of the breast and associated axillary lymph nodes in patients withbreast cancer.

Question 23

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

Answer 23

wellinclearing and separation of the extracellular matrix and subtle cell sg.Any organ ortissue can be involved, but edema is most commonly seen in subcutaneous tissues, thelungs, and the brain.

Question 24

What is subcutaneous edma?

Answer 24

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

Question 25

What is dependent edema?

Answer 25

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

Question 26

What is pitting edema?

Answer 26

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

Question 27

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

Answer 27

renal dysfunctionperiorbitaledema is thus a characteristic finding in severe renal disease.

Question 28

What is the characteristic of pulmonary edema?

Answer 28

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

Question 29

What is the characterisitc of brain edema?

Answer 29

Brain edema can belocalized or generalized depending on the nature and extent of the pathologic process orinjury.With generalized edema the brain is grossly swollen with narrowed sulci; distendedgyri show evidence of compression against the unyielding skull ( Chapter 28 ).

Question 30

Subcutaneous tissueedema 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 31

Pulmonary edema is a common clinical problem that is most frequently seen in the setting of leftventricular 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 spacesalso creates a favorable environment for bacterial infection.

Question 32

Brain edema is life-threatening; ifsevere, brain substance can herniate (extrude) through the foramen magnum, or the brain stemvascular supply can be compressed. Either condition can injure the medullary centers andcause death

Question 33

What is hemorrhage?

Answer 33

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

Question 34

What are hemorrhagic diatheses.?

Answer 34

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

Question 35

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

Answer 35

• hematoma
• petechiae
• purpura
• ecchymoses. 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 36

What is a hematoma?

Answer 36

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

Question 37

What is a petechiae?

Answer 37

Minute 1- to 2-mm hemorrhages into skin, mucous membranes, or serosal surfaces arecalled petechiae ( Fig. 4-4A ).These are most commonly associated with locallyincreased intravascular pressure, low platelet counts (thrombocytopenia), or defectiveplatelet function (as in uremia).

Question 38

What is a purpura?

Answer 38

Slightly larger (≥3 mm) hemorrhages are called purpura.These may be associated withmany 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 39

What is an ecchymoses?

Answer 39

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; thehemoglobin (red-blue color) is then enzymatically converted into bilirubin (blue-greencolor) and eventually into hemosiderin (gold-brown color), accounting for thecharacteristic color changes in a bruise.

Question 40

The clinical significance of hemorrhage depends on the ________________.

Answer 40

volume and rate of bleeding

Question 41

Rapidloss of up to 20% of the blood volume or slow losses of even larger amounts may have littleimpact in healthy adults; greater losses, however, can cause hemorrhagic (hypovolemic) shock(discussed later).T or FThe site of hemorrhage is also important. For example, bleeding that is trivialin the subcutaneous tissues can cause death if located in the brain ( Fig. 4-4B ); because theskull is unyielding, intracranial hemorrhage can result in an increase in pressure that issufficient to compromise the blood supply or to cause the herniation of the brainstem ( Chapter28 ). 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 cellsare retained (e.g., hemorrhage into body cavities or tissues), iron is recovered and recycled foruse in the synthesis of hemoglobin

Answer 41

True

Question 42

What is normal hemostasis?

Answer 42

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

Question 43

What is thrombosis?

Answer 43

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

Question 44

Both hemostasis and thrombosis involve threecomponents:

Answer 44

the vascular wall (particularly the endothelium), platelets, and the coagulationcascade.

Question 45

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

Answer 45

brief period of arteriolarvasoconstriction facilitating platelet adherence and activationthisprocess is referred to as primaryhemostasis ( Fig. 4-5B ). • Tissue factor is also exposed at the site of injury. Also known as factor III andthromboplastin,secondary hemostasis, consolidates the initial platelet plug ( Fig. 4-5C ).
* Polymerized fibrin and platelet aggregates form a solid, permanent plug to prevent anyfurther hemorrhage.

Question 46

After initial injury there is a brief period of arteriolar vasoconstriction which is mediated by____________The effect istransient, however, and bleeding would resume if not for activation of the platelet andcoagulation systems.

Answer 46

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

Question 47

What facilitatesplatelet adherence and activation.

Answer 47

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

Question 48

What happens in primary hemostasis?

Answer 48

Activation of platelets results in adramatic shape change (from small rounded discs to flat plates with markedly increasedsurface area), as well as the release of secretory granules.Within minutes the secretedproducts recruit additional platelets (aggregation) to form a hemostatic plug; thisprocess is referred to as primary hemostasis

Question 49

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

Answer 49

factor III andthromboplastin

Question 50

Where is tissue factor/ factor 3/ thromboplastinproduced?

Answer 50

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

Question 51

What happens in secondary hemostasis?

Answer 51

Tissue factor is also exposed at the site of injury. Also known as factor III andthromboplastin, tissue factor is a membrane-bound procoagulant glycoproteinsynthesized by endothelial cells.It acts in conjunction with factor VII (see below) as themajor in vivo initiator of the coagulation cascade, eventually culminating in thrombingeneration.Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrinmeshwork, and also induces additional platelet recruitment and activation. Thissequence, secondary hemostasis, consolidates the initial platelet plug

Question 52

major in vivo initiator of the coagulation cascade

Answer 52

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

Question 53

WHat does thrombin do?

Answer 53

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

Question 54

Endothelial cells play a role in hemeostasis by?

Answer 54

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

Question 55

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

Answer 55

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

Question 56

after injury or activation endothelial cells :

Answer 56

acquirenumerous procoagulant activities ( Fig. 4-6 ).

Question 57

Besides trauma, endothelium can be activated by

Answer 57

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

Question 58

Antithrombotic PropertiesUnder normal circumstances endothelial cells actively prevent thrombosis by producing factorsthat variously block platelet adhesion and aggregation, inhibit coagulation, and lyse clots.

Answer 58

• Antiplatelet effects
• Anticoagulant effects.
• Fibrinolytic effects

Question 59

How do endothelial cells produce antiplatelet effect?

Answer 59

Antiplatelet effects.
Intact endothelium prevents platelets (and plasma coagulationfactors) 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 plateletadhesion. Both of these mediators are potent vasodilators and inhibitors of plateletaggregation; their synthesis by the endothelium is stimulated by several factorsproduced during coagulation (e.g., thrombin and cytokines).
Endothelial cells alsoelaborate adenosine diphosphatase, which degrades adenosine diphosphate (ADP)and further inhibits platelet aggregation

Question 60

Antiplatelet effects.Nonactivatedplatelets do not adhere to endothelial cells, and even if platelets are activated,__________produced by the endothelial cells impede plateletadhesion.Both of these mediators are potent vasodilators and inhibitors of plateletaggregation; their synthesis by the endothelium is stimulated by several factorsproduced during coagulation (e.g., thrombin and cytokines).

Answer 60

prostacyclin (PGI2) and nitric oxide

Question 61

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

Answer 61

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

Question 62

How dothe endothelial cellsproduce Anticoagulant effects. [8]

Answer 62

These effects are mediated by endothelial tmembraneassociatedheparin-like molecules, thrombomodulin, and tissue factor pathway inhibitor(see Fig. 4-6 ). The heparin-like molecules act indirectly; they are cofactors that greatlyenhance the inactivation of thrombin and several other coagulation factors by theplasma protein antithrombin III (see later). Thrombomodulin binds to thrombin andconverts 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 producesprotein S, a co-factor for protein C, and tissue factor pathway inhibitor (TFPI) , a cellsurface protein that directly inhibits tissue factor–factor VIIa and factor Xa activities

Question 63

How do endothelial cells promote fibrinolytic action?

Answer 63

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

Question 64

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

Answer 64

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

Question 65

Prothrombotic PropertiesWhile normal endothelial cells limit clotting, trauma and inflammation of endothelial cells inducea prothrombotic state that alters the activities of platelets, coagulation proteins, and thefibrinolytic system.

Answer 65

• Platelet effects
• Procoagulant effects
• Antifibrinolytic effects

Question 66

With the Platelet effects how does the endotheliacell promote prothrombosis?

Answer 66

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

Question 67

What is avon Willebrand factor(vWF)

Answer 67

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

Question 68

How do endothelial cells promoteprocoagulant effects?

Answer 68

Procoagulant effects.In response to cytokines (e.g., tumor necrosis factor [TNF] orinterleukin-1 [IL-1]) or bacterial endotoxin, endothelial cells synthesize tissue factor , themajor activator of the extrinsic clotting cascade. [10,] [12]In addition, activatedendothelial cells augment the catalytic function of activated coagulation factors IXa andXa.

Question 69

How do endothelial cells promote antifibrinolytic effect?

Answer 69

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

Question 70

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

Question 71

Platelets are disc-shaped, anucleate cell fragments that are shed from megakaryocytes in thebone marrow into the blood stream.They play a critical role in normal hemostasis, [13] byforming the hemostatic plug that initially seals vascular defects, and by providing a surface thatrecruits and concentrates activated coagulation factors.Their function depends on several

Answer 71

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 containfibrinogen, 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 72

α-Granuleshave the a:

Answer 72

dhesion molecule P-selectin on their membranes ( Chapter 2 ) and containfibrinogen, 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 73

Dense (or δ)granules contains :

Answer 73

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

Question 74

After vascular injury, platelets encounter ECM constituents such as collagen and the adhesiveglycoprotein vWF.On contact with these proteins, platelets undergo:

Answer 74

(1) adhesion and shapechange,(2) secretion (release reaction), and (3) aggregation

Question 75

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

Answer 75

vWFAlthough platelets can also adhere to other components of theECM (e.g., fibronectin), vWF-GpIb associations are necessary to overcome the highshear forces of flowing blood. Reflecting the importance of these interactions, geneticdeficiencies of vWF (von Willebrand disease; Chapter 14 ) or its receptor (Bernard-Soulier syndrome) result in bleeding disorders.

Question 76

Although platelets can also adhere to other components of theECM (e.g., fibronectin),vWF-GpIb associationsare necessary to ___________

Answer 76

overcome the highshear forces of flowing blood.Reflecting the importance of these interactions, geneticdeficiencies of vWF (von Willebrand disease; Chapter 14 ) or its receptor (Bernard-Soulier syndrome) result in bleeding disorders

Question 77

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

Answer 77

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

Question 78

Secretion (release reaction) of both granule types occurs soon after adhesion.Variousagonists can bind platelet surface receptors and initiate an intracellular proteinphosphorylation cascade ultimately leading to degranulation.

Answer 78

Release of the contents ofdense-bodies is especially important, since calcium is required in the coagulationcascade,
and ADP is a potent activator of platelet aggregation. ADP also begetsadditional ADP release, amplifying the aggregation process.
Finally, platelet activationleads to the appearance of negatively charged phospholipids (particularlyphosphatidylserine) on their surfaces. These phospholipids bind calcium and serve ascritical nucleation sites for the assembly of complexes containing the variouscoagulation factors

Question 79

Platelet aggregation follows adhesion and granule release.What does thromboxane A-2 does?

Answer 79

In addition to ADP, thevasoconstrictor thromboxane A2 (TxA2; Chapter 2 ) is an important platelet-derivedstimulus that amplifies platelet aggregation, which leads to the formation of the primaryhemostatic plug.

Question 80

Although this initial wave of aggregation is reversible, concurrentactivation of the coagulation cascade generates thrombin, which stabilizes the plateletplug via two mechanisms.

Answer 80

First, thrombin binds to a protease-activated receptor (PAR,see below) on the platelet membrane and in concert with ADP and TxA2 causes furtherplatelet aggregation. This is followed by platelet contraction, an event that is dependenton the platelet cytoskeleton that creates an irreversibly fused mass of platelets, whichconstitutes the definitive secondary hemostatic plug. Second, thrombin convertsfibrinogen to fibrin in thevicinity of the platelet plug, functionally cementing theplateletsin place.

Question 81

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

Answer 81

Plateletactivation by ADP triggers a conformational change in the plateletGpIIb-IIIa receptors.

Question 82

What doesGpIIb-IIIa receptors do?

Answer 82

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

Question 83

What isGlanzmann thrombasthenia[16]

Answer 83

Predictably, inherited deficiency of GpIIb-IIIaresults in a bleeding disordeNOTE: The recognition of the centralrole of the various receptors and mediators in platelet cross-linking has led to the developmentactivity, [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 thehorizon.of therapeutic agents that block platelet aggregation—for example, by interfering with thrombin

Question 84

Thrombin also drives thrombus-associatedinflammation by:

Answer 84

directly stimulating neutrophil and monocyte adhesion and by generatingchemotactic fibrin split products during fibrinogen cleavage.Red cells and leukocytes are also found in hemostatic plugs. Leukocytes adhere to platelets viaP-selectin and to endotheliumusing several adhesion receptors ( Chapter 2 ); they contributeto the inflammation that accompanies thrombosis.

Question 85

The interplay of platelets and endothelium has a profound impact on clot formation.Theendothelial cell-derived:

Answer 85

prostaglandin PGI2 (prostacyclin) inhibits platelet aggregation and is apotent vasodilator; conversely,
the platelet-derived prostaglandin TxA2 activates plateletaggregation and is a vasoconstrictor ( Chapter 2 ). Effects mediated by PGI2 and TxA2 areexquisitely balanced to effectively modulate platelet and vascular wall function: at baseline,platelet aggregation is prevented, whereas endothelial injury promotes hemostatic plugformation. 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 canresynthesize active cyclooxygenase and thereby overcome the blockade. In a manner similar toPGI2, endothelial-derived nitric oxide also acts as a vasodilator and inhibitor of plateletaggregation (see Fig. 4-6 ).

Question 86

What is the coagulation cascade?

Answer 86

The coagulation cascade is essentially an amplifying series of enzymatic conversions; eachstep proteolytically cleaves an inactive proenzyme into an activated enzyme, culminating inthrombin formation

Question 87

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

Answer 87

​.ThrombinAt the conclusion of theproteolytic cascade, thrombin converts the soluble plasma protein fibrinogen into fibrinmonomers that polymerize into an insoluble gel. The fibrin gel encases platelets and othercirculating cells in the definitive secondary hemostatic plug, and the fibrin polymers arecovalently cross-linked and stabilized by factor XIIIa (which itself is activated by thrombin).

Question 88

Each reaction in the coagulationpathway results from the assembly of a complex composed of an enzyme(activated coagulation factor), a substrate (proenzyme form of coagulation factor), and acofactor (reaction accelerator).These components are typically assembled on a____________

Answer 88

phospholipidsurface and held together by calcium ions (as an aside, the clotting of blood is prevented by thepresence of calcium chelators).The requirement that coagulation factors be brought closetogether ensures that clotting is normally localized to the surface of activated platelets orendothelium; [4] as shown in Figure 4-9 , it can be likened to a “dance” of complexes, in whichcoagulation factors are passed successfully from one partner to the next.

Question 89

Parenthetically, thebinding of coagulation factors II, XII, IX, and X to calcium depends on the addition of γ-carboxylgroups to certain glutamic acid residues on these proteins.This reaction uses ____________ as acofactor and is antagonized by drugs such as coumadin, which is a widely used anticoagulant.

Answer 89

vitamin K1972

Question 90

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

Answer 90

factor X

Question 91

The extrinsic pathway was so designated because_____________

Answer 91

itrequired theaddition of an exogenous trigger(originally provided by tissue extracts);

Question 92

theintrinsic pathway only required____________

Answer 92

exposing factor XII (Hageman factor) to thrombogenic surfaces(even glass would suffice). However, such a division is largely an artifact of in vitro testing; thereare, in fact, several interconnections between the two pathways.

Question 93

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

Answer 93

extrinsicpathway

Question 94

What activates the extrinsic pathway?

Answer 94

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

Question 95

In addition to catalyzing the final steps in the coagulation cascade, thrombin exerts a widevariety of proinflammatery effects ( Fig. 4-10 ).Most of these effects of thrombin occur throughits activation of a family of ________that belong to the seventransmembraneG protein–coupled receptor family [21,] [22] (see also Fig. 4-6 ).

Answer 95

protease activated receptors (PARs)

Question 96

PARs areexpressed on

Answer 96

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 atethered peptide that binds to the “clipped” receptor, causing a conformational change thattriggers signaling.

Question 97

Clinical laboratories assess the function of the two arms of the coagulation pathway through twostandard assays: ___________The PT assayassesses the function of the proteins in the extrinsic pathway (factors VII, X, II, V, andfibrinogen). This is accomplished by adding tissue factor and phospholipids to citrated plasma(sodium citrate chelates calcium and prevents spontaneous clotting). Coagulation is initiated bythe addition of exogenous calcium and the time for a fibrin clot to form is recorded. The partialthromboplastin 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 theaddition of negative charged particles (e.g., ground glass), which you will recall activates factorXII (Hageman factor), phospholipids, and calcium, and the time to fibrin clot formation isrecorded

Answer 97

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

Question 98

The PT assayassesses the function of the proteins in the ___________

Answer 98

extrinsic pathway (factors VII, X, II, V, andfibrinogen).PET

Question 99

How is the PT assay accomplished?

Answer 99

This is accomplished by adding tissue factor and phospholipids to citrated plasma(sodium citrate chelates calcium and prevents spontaneous clotting). Coagulation is initiated bythe addition of exogenous calcium and the time for a fibrin clot to form is recorded

Question 100

. The partialthromboplastin time (PTT) screens for the function of the proteins in the __________.

Answer 100

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

Question 101

In this PTT assay, clotting is initiated through theaddition of ___________

Answer 101

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

Question 102

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

Answer 102

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

Question 103

What are your antithrombins?

Answer 103

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

Question 104

How is antithrombin activated?

Answer 104

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

Question 105

What are Proteins C and S

Answer 105

are vitamin K–dependentproteins that act in a complex that proteolytically inactivates factors Va and VIIIa. Protein Cactivation by thrombomodulin was described earlier.

Question 106

What is TFPI?

Answer 106

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

Question 107

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

Answer 107

plasminPILAS!!!!! PILASMIN

Question 108

The resulting fibrin split products (FSPs or fibrin degradation products) canalso act as weak anticoagulants.True or False

Answer 108

True

Question 109

How is plasmin generated?

Answer 109

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

Question 110

The mostimportant of the PAs is ___________; it is synthesized principally by endothelium and is most active whenbound to fibrin.

Answer 110

t-PA

Question 111

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

Answer 111

it largelyconfinesfibrinolytic activity to sites of recent thrombosis

Question 112

What is Urokinase-like PA?

Answer 112

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

Question 113

What does streptokinase do?

Answer 113

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

Question 114

As with any potent regulator, plasminactivity is tightly restricted. To prevent excess plasmin from lysing thrombi indiscriminatelyelsewhere in the body, free plasmin is rapidly inactivated by α2-plasmin inhibitor

Answer 114

α2-plasmin inhibitor

Question 115

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

Answer 115

releasingplasminogen activator inhibitor (PAI);it blocks fibrinolysis by inhibiting t-PA binding to fibrin andconfers an overall procoagulant effect (see Fig. 4-11 ).PAI production is increased by thrombinas well as certain cytokines, and probably plays a role in the intravascular thrombosisaccompanying severe inflammation.

Question 116

Whatis the virchows triad?

Answer 116

primary abnormalities that lead to thrombus formation (called Virchow’s triad) :(1) endothelialinjury,(2) stasis or turbulent blood flow, and(3) hypercoagulability of the blood

Question 117

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

Answer 117

,where the normally high flow rates might otherwise impede clotting by preventingplatelet adhesion and washing out activated coagulation factors.Thus, thrombus formationwithin cardiac chambers (e.g., after endocardial injury due to myocardial infarction), overulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascularinjury (vasculitis) is largely a consequence of endothelial cell injury.

Question 118

Explain endothelial injury in relation to thrombosis?

Answer 118

Clearly, physical loss ofendothelium can lead to exposure of the subendothelial ECM, adhesion of platelets, release oftissue factor, and local depletion of PGI2 and plasminogen activators.However, it should beemphasized that endothelium need not be denuded or physically disrupted to contribute to thedevelopment of thrombosis; any perturbation in the dynamic balance of the prothombotic andantithrombotic activities of endothelium can influence local clotting events (see Fig. 4-6 ). Thus,dysfunctional endothelial cells can produce more procoagulant factors (e.g., platelet adhesionmolecules, tissue factor, PAIs) or may synthesize less anticoagulant effectors (e.g.,thrombomodulin, PGI2, t-PA).

Question 119

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

Answer 119

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

Question 120

Alterations in Normal Blood Flow.How does turbulence contribute to arterial and cardiac thrombosis?

Answer 120

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

Question 121

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

Answer 121

stasis

Question 122

What is the normal blood flow?

Answer 122

Normal blood flow is laminar such thatthe platelets (and other blood cellular elements) flow centrally in the vessel lumen, separatedfrom endothelium by a slower moving layer of plasma.

Question 123

Stasis and turbulence therefore:

Answer 123

• 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 theinflow of clotting factor inhibitors

Question 124

Turbulence and stasis contribute to thrombosis in several clinical settings.

Answer 124

Ulceratedatherosclerotic plaques not only expose subendothelial ECM but also cause turbulence. Aorticand arterial dilations called aneurysms result in local stasis and are therefore fertile sites forthrombosis ( Chapter 11 ). Acute myocardial infarctions result in areas ofnoncontractilemyocardium and sometimes cardiac aneurysms; both are associated with stasis and flowabnormalities that promote the formation of cardiac mural thrombi ( Chapter 12 ). Rheumaticmitral valve stenosis results in left atrial dilation; in conjunction with atrial fibrillation, a dilatedatrium 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 toflow 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 125

What is hypercoagulability or thrombophilia?

Answer 125

Hypercoagulability (also called thrombophilia) is a less frequent contributor to thrombotic statesbut is nevertheless an important component in the equation, and in some situations canpredominate.It is loosely defined as any alteration of the coagulation pathways thatpredisposes to thrombosis;

Question 126

Hypercoagulability can be divided into :

Answer 126

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

Question 127

Of the inherited causes of hypercoagulability,____________are the most common.

Answer 127

pointmutations in the factor V gene and prothrombin gen

Question 128

What is Leiden mutation?

Answer 128

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 129

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

Answer 129

The mutation results in a glutamine toarginine substitution at position 506 that renders factor V resistant to cleavage byprotein 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 venousthrombosis, and homozygotes have a 50-fold increase

Question 130

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 almostthreefold increased risk of venous thromboses.

Answer 130

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

Question 131

How does homocystein contribute to arterial and venous thrombosis?

Answer 131

Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well asthe development of atherosclerosis ( Chapter 11 ).The prothrombotic effects ofhomocysteine may be due to thioester linkages formed between homocysteinemetabolites and a variety of proteins, including fibrinogen. [32] Marked elevations ofhomocysteine may be caused by an inherited deficiency of cystathione βsynthetase.Much more common is a variant form of the enzyme 5,10-methylenetetrahydrofolatereductase that causes mild homocysteinemia in 5% to 15% of Caucasian and easternAsian populations; this possible etiology for hypercoagulability is therefore as commonas factor V Leiden. [27] However, while folic acid, pyridoxine, and/or vitamin B12supplements can reduce plasma homocysteine concentrations (by stimulating itsmetabolism), they fail to lower the risk of thromboses, raising questions about thesignificance of modest homocysteinemia.

Question 132

Rare inherited causes of primary hypercoagulability include :_____________

Answer 132

deficiencies ofanticoagulants such as antithrombin III, protein C, or protein S; affected individualstypically present with venous thrombosis and recurrent thromboembolism beginning inadolescence or early adulthood. [27] Various polymorphisms in coagulant factor genescan result in increased synthesis and impart an elevated risk of venous thrombosis

Question 133

TABLE 4-2 – Hypercoagulable StatesPRIMARY (GENETIC)

Answer 133

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 IIIdeficiency
* Protein C deficiency
* Protein S deficiency
Very Rare
* Fibrinolysis defects Homozygous homocystinuria (deficiency of cystathione β- synthetase)

Question 134

TABLE 4-2 – Hypercoagulable StatesSECONDARY (ACQUIRED)

Answer 134

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 135

The most common thrombophilic genotypes found in various populations _______________impart only a moderately increased risk ofthrombosis; most individuals with these genotypes, when otherwise healthy, are free ofthrombotic complications.

Answer 135

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

Question 136

However, mutations in____________-are frequent enoughthat homozygosity and compound heterozygosity are not rare, and such genotypes areassociated with greater risk.[35]Moreover, individuals with such mutations have a significantlyincreased frequency of venous thrombosis in the setting of other acquired risk factors (e.g.,pregnancy or prolonged bedrest).

Answer 136

factor V and prothrombin

Question 137

Unlike hereditary disorders, the pathogenesis of acquired thrombophilia is frequentlymultifactorial (see Table 4-2 ). In some cases (e.g., cardiac failure or trauma), stasis or vascularinjury may be most important.

Question 138

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

Answer 138

increased hepatic synthesis ofcoagulation factors and reduced anticoagulant synthesis. [

Question 139

What predisposes cancer to thrombosis?

Answer 139

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

Question 140

The hypercoagulability seenwith advancing age may be due to ____________.

Answer 140

to reduced endothelial PGI2.

Question 141

Smoking and obesity promotehypercoagulability by unknown mechanisms.

Question 142

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

Answer 142

• Heparin-induced thrombocytopenia (HIT) syndrome.

* Antiphospholipid antibody syndrome

Question 143

What isHeparin-induced thrombocytopenia (HIT) syndrome.

Answer 143

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

Question 144

Why doesHeparin-induced thrombocytopenia (HIT) syndrome has thrombocytopenia?

Answer 144

Binding of these antibodies to plateletsresults in their activation, aggregation, and consumption (hence the thrombocytopenia in thesyndrome name).This effect on platelets and endothelial damage combine to produce aprothrombotic state, even in the face of heparin administration and low platelet counts. Newerlow-molecular weight heparin preparations induce antibody formation less frequently, but stillcause thrombosis if antibodies have already formed. [41]Other anticoagulants such asfondaparinux (a pentasaccharide inhibitor of factor X) also cause a HIT-like syndrome on rareoccasions.

Question 145

What isAntiphospholipid antibody syndrome

Answer 145

(previously called the lupus anticoagulant syndrome).This syndrome has protean clinicalmanifestations, including recurrent thromboses, repeated miscarriages, cardiac valvevegetations, andthrombocytopenia.

Question 146

What is the clinical presentation ofAntiphospholipid antibody syndrome

Answer 146

Depending on the vascular bed involved, the clinicalpresentations 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-PAactivity necessary for trophoblastic invasion of the uterus.
Antiphospholipid antibody syndrome​is also a cause of renal microangiopathy, resulting in renal failure associated with multiplecapillary and arterial thromboses

Question 147

Why is antiphospholipid antibody syndrom a misnomer?

Answer 147

The name antiphospholipid antibody syndrome is a bit of a misnomer, as it is believed that themost important pathologic effects are mediated through binding of the antibodies to epitopes onplasma proteins (e.g., prothrombin) that are somehow induced or “unveiled” by phospholipids.In vivo, these autoantibodies induce a hypercoagulable state by causing endothelial injury, byactivating platelets and complement directly, and through interaction with the catalytic domainsof certain coagulation factors. [43]However, in vitro (in the absence of platelets and endothelialcells), the autoantibodies interfere with phospholipids and thus inhibit coagulation. Theantibodies also frequently give a false-positive serologic test for syphilis because the antigen inthe standard assay is embedded in cardiolipin.

Question 148

Antiphospholipid antibody syndrome has two forms:

Answer 148

Antiphospholipid antibody syndrome has primary and secondary forms

Question 149

What is a primary antiphospholipid syndrome?

Answer 149

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

Question 150

What is the secondary form of antiphospholipid syndrome?

Answer 150

Individuals with a welldefinedautoimmune disease, such as systemic lupus erythematosus ( Chapter 6 ), aredesignated as having secondary antiphospholipid syndrome (hence the earlier term lupusanticoagulant syndrome).

Question 151

A particularlyaggressive form _____________characterized by widespread smallvesselthrombi and multi-organ failure has a 50% mortality. [44]

Answer 151

(catastrophic antiphospholipid syndrome)The antibodies also makesurgical procedures more difficult; for example, nearly 90% of patients with anti-phospholipidantibodies undergoing cardiovascular surgery have complications related to the antibodies. [45]Therapy involves anticoagulation and immunosuppression. Although antiphospholipidantibodies are clearly associated with thrombotic diatheses, they have also been identified in5% to 15% of apparently normal individuals, implying that they are necessary but not sufficientto cause the full-blown syndrome.

Question 152

Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiacchambers, on valves, or in arteries, veins, or capillaries).The size and shape of thrombidepend on the site of origin and the cause.

Question 153

Arterial or cardiac thrombi usually begin at sites____________;

Answer 153

ofturbulence or endothelial injury

Question 154

venous thrombi characteristically occur at sites of________-

Answer 154

stasis.

Question 155

Thrombi are focally attached to the ________

Answer 155

underlying vascular surface

Question 156

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

Answer 156

arterial thrombi tend to growretrograde from the point of attachment, while venous thrombi extend in the direction of bloodflow (thus both propagate toward the heart). aRterial : RetrogadeThe propagating portion of a thrombus is oftenpoorly attached and therefore prone to fragmentation and embolization

Question 157

The propagating portion of a thrombus is oftenpoorly attached and therefore prone to fragmentation and embolizationT or F

Answer 157

T

Question 158

What is the line of Zhan?

Answer 158

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 cantherefore distinguish antemortem thrombosis from the bland nonlaminated clots that occurpostmortem (see below).

Question 159

How to differentiate antemortem from postmortem thrombi?

Answer 159

Such laminations signify that a thrombus has formed in flowing blood; their presence cantherefore distinguish antemortem thrombosis from the bland nonlaminated clots that occurpostmortem (see below).

Question 160

What is amural thrombi.

Answer 160

Thrombi occurring in heart chambers or in the aortic lumen are designated as mural thrombi.Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardialinfarction) or endomyocardial injury (myocarditis or catheter trauma) promotes cardiac muralthrombi ( Fig. 4-13A ), while ulcerated atherosclerotic plaque and aneurysmal dilation are theprecursors of aortic thrombus ( Fig. 4-13B ).

Question 161

What are arterial thrombi?

Answer 161

Arterial thrombi are frequently occlusive; They typically cosist of a friablemeshwork of platelets, fibrin, red cells, and degenerating leukocytes. Although these areusually superimposed on a ruptured atherosclerotic plaque, other vascular injuries (vasculitis,trauma) may be the underlying cause.

Question 162

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

Answer 162

coronary, cerebral, and femoral arteries.

Question 163

What arer Venous thrombosis (phlebothrombosis) ?

Answer 163

Venous thrombosis (phlebothrombosis) is almost invariablyocclusive, with the thrombusforming a long cast of the lumen.Because these thrombi form in the sluggish venouscirculation, they tend to contain more enmeshed red cells (and relatively few platelets) andare therefore known as red, or stasis, thrombi.

Question 164

What is the most commonly involved venous thrombi?

Answer 164

​The veins of the lower extremities are mostcommonly involved (90% of cases); however, upper extremities, periprostatic plexus, or theovarian 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 165

Describe postmortem clots

Answer 165

Postmortem clots can sometimes be mistaken for antemortem venous thrombi. However,postmortem clots are gelatinous with a dark red dependent portion where red cells havesettled by gravity and a yellow “chicken fat” upper portion; they are usually not attached tothe underlying wall.

Question 166

Describe red thrombi.

Answer 166

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

Question 167

What are vegetations?

Answer 167

Thrombi on heart valves are called vegetations.Blood-borne bacteria or fungi can adhereto previously damaged valves (e.g., due to rheumatic heart disease) or can directly causevalve damage; in both cases, endothelial injury and disturbed blood flow can induce theformation of large thrombotic masses (infective endocarditis; Chapter 12 ).

Question 168

What arenonbacterial thrombotic endocarditis ?

Answer 168

Sterilevegetations 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 systemiclupus erythematosus

Question 169

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

Answer 169

• Propagation
• Embolization
• Dissolution.
• Organization and recanalization

Question 170

Describe embolizaiton in relation the fate of thrombi.

Answer 170

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

Question 171

Discuss propagation as the fate of thrombi.

Answer 171

Propagation. Thrombi accumulate additional platelets and fibrin. This process wasdiscussed earlier.

Question 172

Describe the process of dissolution in relation to thrombi.

Answer 172

Dissolution. Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkageand total disappearance of recent thrombi.In contrast, the extensive fibrin depositionand crosslinking in older thrombi renders them more resistant to lysis.This distinctionexplains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in thesetting of acute coronary thrombosis) is generally effective only when given in the firstfew hours of a thrombotic episode.

Question 173

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

Answer 173

the extensive fibrin depositionand crosslinking in older thrombi renders them more resistant to lysis.This distinctionexplains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in thesetting of acute coronary thrombosis) isgenerally effective only when given in the firstfew hours of a thrombotic episode.

Question 174

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

Answer 174

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

Question 175

Clinical ConsequencesThrombi are significant because they cause obstruction of arteries and veins , and are sourcesof emboli.Which effect predominates depends on the site of the thrombosis.Venous thrombican cause congestion and edema in vascular beds distal to an obstruction, but they are farmore worrisome for their capacity to embolize to the lungs and cause death (see below).Conversely, although arterial thrombi can embolize and cause downstream infarctions, athrombotic occlusion at a critical site (e.g., a coronary artery) can have more serious clinicalconsequences.

Question 176

Venous Thrombosis (Phlebothrombosis).Most venous thrombi occur in the________ [25]

Answer 176

superficial or deep veins of the leg.

Question 177

Superficial venousthrombi typically occur in the _________ in the setting of varicosities.

Answer 177

saphenous veinsAlthough suchthrombi can cause local congestion, swelling, pain, and tenderness, they rarely embolize.Nevertheless, the local edema and impaired venous drainage do predispose the overlying skinto infections from slight trauma and to the development of varicose ulcers.

Question 178

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

Answer 178

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

Question 179

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

Answer 179

hypercoagulable states

Question 180

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 180

include bed rest and immobilization (because theyreduce the milking action of the leg muscles, resulting in reduced venous return), andcongestive heart failure (also a cause of impaired venous return). Trauma, surgery, and burnsnot 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-PAproduction. Many elements contribute to the thrombotic diathesis of pregnancy; besides thepotential for amniotic fluid infusion into the circulation at the time of delivery, late pregnancy andthe postpartum period are also associated with systemic hypercoagulability. Tumor-associatedinflammation and coagulation factors (tissue factor, factor VIII) and procoagulants (e.g., mucin)released from tumor cells all contribute to the increased risk of thromboembolism indisseminated cancers, so-called migratory thrombophlebitis or Trousseau syndrome. [39,] [46]

Question 181

What ismigratory thrombophlebitis or Trousseau syndrome

Answer 181

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

Question 182

What is the major cause of arterial thromboses?

Answer 182

Atherosclerosis is a major cause of arterial thromboses, because it is associated with loss ofendothelial integrity and with abnormal vascular flow (see Fig. 4-13B ). Myocardial infarctioncan predispose to cardiac mural thrombi by causing dyskinetic myocardial contraction as well asdamage to the adjacent endocardium (see Fig. 4-13A ), and rheumatic heart disease mayengender atrial mural thrombi as discussed above. Besides local obstructive consequences,cardiac and aortic mural thrombi can also embolize peripherally.Although any tissue can beaffected, the brain, kidneys, and spleen are particularly likely targets because of their rich bloodsupply.

Question 183

What is DIC?

Answer 183

Disorders ranging from obstetric complications to advanced malignancy can be complicated byDIC, the sudden or insidious onset of widespread fibrin thrombi in the microcirculation.Althoughthese thrombi are not grossly visible, they are readily apparent microscopically and can causediffuse circulatory insufficiency, particularly in the brain, lungs, heart, and kidneys. Tocomplicate matters, the widespread microvascular thrombosis results in platelet and coagulationprotein consumption (hence the synonym consumption coagulopathy), and at the same time,fibrinolytic mechanisms are activated.Thus, an initially thrombotic disorder can evolve into ableeding catastrophe. It should be emphasized that DIC is not a primary disease but rather apotential 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 184

What is an embolus?

Answer 184

An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by theblood to a site distant from its point of origin.The termembolus was coined by Rudolf Virchowin 1848 to describe objects that lodge in blood vessels and obstruct the flow of blood. Almost allemboli represent some part of a dislodged thrombus, hence the term thromboembolism.

Question 185

Rareforms of emboli include:However, unless otherwisespecified, emboli should be considered thrombotic in origin.

Answer 185

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

Question 186

Inevitably, emboli lodge in vesselstoo small to permit further passage, causing partial or complete vascular occlusion;a majorconsequence is__________of thedownstream tissue. Depending on wherethey originate, emboli can lodge anywhere in the vascular tree; the clinical outcomes are bestunderstood based on whether emboli lodge in the pulmonary or systemic circulations.

Answer 186

ischemic necrosis (infarction)

Question 187

Embolism

Answer 187

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

Question 188

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

Answer 188

leg deep vein thromboses (DVTs),

Question 189

Explain Pulmonary Embolism

Answer 189

Fragmented thrombi from DVTs are carried through progressively larger channels and the rightside of the heart before slamming into the pulmonary arterial vasculature.Depending on thesize of the embolus, it can occlude the main pulmonary artery, straddle the pulmonary arterybifurcation (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 embolifrom a single large mass; in general, the patient who has had one PE is at high risk of havingmore.Rarely, an embolus can pass through an interatrial or interventricular defect and gainaccess to the systemic circulation (paradoxical embolism) .A more complete discussion of PEs ispresented in Chapter 15 ; an overview is offered here

Question 190

What is a saddle embolus?

Answer 190

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

Question 191

What is(paradoxical embolism) ?

Answer 191

Rarely, an embolus can pass through an interatrial or interventricular defect and gainaccess to the systemic circulation (paradoxical embolism) .A more complete discussion of PEs ispresented in Chapter 15 ; an overview is offered here.

Question 192

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

Answer 192

clinically silent because they are small.

Question 193

What is a fibrous web?

Answer 193

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

Question 194

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

Answer 194

60% or more

Question 195

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

Answer 195

pulmonary hemorrhage

Question 196

Embolic obstruction of medium-sized arteries with subsequent vascular rupture canresult inpulmonary hemorrhagebut usually does not cause pulmonary infarction.Why?

Answer 196

This isbecause the lung has a dual blood supply, and the intact bronchial circulation continuesto perfuse the affected area.However, a similar embolus in the setting of left-sidedcardiac failure (and compromised bronchial artery flow) can result in infarction.

Question 197

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

Answer 197

hemorrhage or infarction

Question 198

Multiple emboli over time may cause___________

Answer 198

pulmonaryhypertension and right ventricularfailure.

Question 199

What is systemic thromboembolism?

Answer 199

Systemic thromboembolism refers to emboli in the arterial circulation

Question 200

Where does systemic thromboembolism mostly arise?

Answer 200

Most (80%) arise fromintracardiac 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 aorticaneurysms, thrombi on ulcerated atherosclerotic plaques, or fragmentation of a valvularvegetation, with a small fraction due to paradoxical emboli ;
10% to 15% of systemic emboli areof unknown origin.

Question 201

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

Question 202

Majorsites for arteriolar embolization are the:

Answer 202

lower extremities (75%) and the brain (10%), with the

intestines, kidneys, spleen, and upperextremitiesinvolved to a lesser extent.

Question 203

Theconsequences of embolization in a tissue depend on its :

Answer 203

vulnerability to ischemia,
the caliber ofthe occluded vessel,
and whether there is a collateral blood supply;
*
in general, arterialembolicause infarction of the affected tissues.

Question 204

What is FAT AND MARROW EMBOLISM

Answer 204

Microscopic fat globules—with or without associated hematopoietic marrow elements—can befound 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 205

How is Fat and marrow embolism happens?

Answer 205

Fat andassociated cells released by marrow or adipose tissue injury may enter the circulation after therupture of the marrow vascular sinusoids or venules.

Question 206

Fat and marrow PEs are very commonincidental findings ___________.

Answer 206

after vigorous cardiopulmonary resuscitation and are probably of no clinicalconsequence

Question 207

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

Answer 207

severe skeletalinjuries

Question 208

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

Question 209

What is Fat embolism syndrome?

Answer 209

Fat embolism syndrome is the term applied to the minority of patients who become symptomatic.It is characterized by pulmonary insufficiency, neurologic symptoms, anemia, andthrombocytopenia, and is fatal in about 5% to 15% of cases. [52,] [53] Typically, 1 to 3 daysafter injury there is a sudden onset of tachypnea, dyspnea, and tachycardia;irritability andrestlessness can progress to delirium or coma. Thrombocytopenia is attributed to plateletadhesion to fat globules and subsequent aggregation or splenic sequestration; anemia canresult 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 diagnosticfeature.

Question 210

WHat is the pathogenesis of fat emboli syndrome?

Answer 210

The pathogenesis of fat emboli syndrome probably involves both mechanical obstruction andbiochemical injury. [52]Fat microemboli and associated red cell and platelet aggregates canocclude the pulmonary and cerebral microvasculature.Release of free fatty acids from the fatglobules exacerbates the situation by causing local toxic injury to endothelium, and plateletactivation and granulocyte recruitment (with free radical, protease, and eicosanoid release)complete the vascular assault.Because lipids are dissolved out of tissue preparations by thesolvents routinely used in paraffin embedding, the microscopic demonstration of fatmicroglobules (in the absence of accompanying marrow) typically requires specializedtechniques, including frozen sections and stains for fat.

Question 211

How does Air embolism occurs?

Answer 211

Gas bubbles within the circulation can coalesce to form frothy masses that obstruct vascularflow (and cause distal ischemic injury). For example, a very small volume of air trapped in acoronary artery during bypass surgery, or introduced into the cerebral circulation byneurosurgery in the “sitting position,” can occlude flow with dire consequences.

Question 212

In air embolism , generally, morethan ______________ 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 212

100 cc

Question 213

What is decompression sickness?

Answer 213

A particular form of gas embolism, called decompression sickness, occurs when individualsexperience sudden decreases in atmospheric pressure. [55] Scuba and deep sea divers,underwater construction workers, and individuals in unpressurized aircraft in rapid ascent areall at risk. When air is breathed at high pressure (e.g., during a deep sea dive), increasedamounts of gas (particularly nitrogen) are dissolved in the blood and tissues. If the diver thenascends (depressurizes) too rapidly, the nitrogen comes out of solution in the tissues and theblood.

Question 214

What are bends?

Answer 214

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

Question 215

What are chokes?

Answer 215

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

Question 216

What is caisson’s disease?

Answer 216

A more chronic form of decompression sickness iscalled 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 217

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

Answer 217

femoral heads, tibia, humeri.

FTH

Question 218

How is acute decompression sickness treated?

Answer 218

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 decompressiontheoretically permits gradual resorption and exhalation of the gases so that obstructive bubblesdo not re-form.

Question 219

What is amniotic embolism?

Answer 219

Amniotic fluid embolism is an ominous complication of labor and the immediate postpartumperiod.Although the incidence is only approximately 1 in 40,000 deliveries, the mortality rate isup to 80%, making amniotic fluid embolism the fifth most common cause of maternal mortalityworldwide; it accounts for roughly 10% of maternal deaths in the United States and results inpermanent neurologic deficit in as many as 85% of survivors. [56]

Question 220

What is the characteristic amniotic embolism?

Answer 220

The onset is characterized bysudden severe dyspnea, cyanosis, and shock, followed by neurologic impairment ranging fromheadache to seizures and coma.If the patient survives the initial crisis, pulmonary edematypically develops, along with (in half the patients) DIC, as a result of release of thrombogenicsubstances from the amniotic fluid

Question 221

What is the pathophysiology of amniotic embolsm?

Answer 221

The underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal circulationvia a tear in the placental membranes or rupture of uterine veins.Classic findings include thepresence of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, andmucin derived from the fetal respiratory or gastrointestinal tract in the maternal pulmonarymicrovasculature ( Fig. 4-17 ). Other findings include marked pulmonary edema, diffusealveolar damage ( Chapter 15 ), and the presence of fibrin thrombi in many vascular beds dueto DIC.

Question 222

What is an infarction?

Answer 222

An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply orthe venous drainage.Tissue infarction is a common and extremely important cause of clinicalillness. Roughly 40% of all deaths in theUnited States are caused by cardiovascular disease,and most of these are attributable to myocardial or cerebral infarction.Pulmonary infarction isalso a common complication in many clinical settings, bowel infarction is frequently fatal, andischemic necrosis of the extremities (gangrene) is a serious problem in the diabetic population.

Question 223

Nearly all infarcts result from______________

Answer 223

thrombotic or embolic arterial occlusions.Occasionally infarctionsare caused by other mechanisms, including local vasospasm, hemorrhage into anatheromatous plaque, or extrinsic vessel compression (e.g., by tumor).Rarer causes includetorsion of a vessel (e.g., in testicular torsion or bowel volvulus), traumatic rupture, or vascularcompromise by edema (e.g., anterior compartment syndrome) or by entrapment in a herniasac.

Question 224

Although venous thrombosis can cause infarction, the more common outcome is just__________; in this setting, bypass channels rapidly open and permit vascular outflow, whichthen improves arterial inflow.Infarcts caused by venous thrombosis are thus more likely inorgans with a single efferent vein (e.g., testis and ovary).

Answer 224

congestion

Question 225

Morphology.Infarcts are classified according to color and the presence or absence ofinfection;they are either

Answer 225

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

Question 226

Red infarcts ( Fig. 4-18A ) occur

Answer 226

(1) with venous occlusions (e.g., ovary), (2) in loosetissues (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 anunobstructed parallel supply into a necrotic zone, (4) in tissues previously congestedby 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 227

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

Answer 227

solid organs with endarterialcirculation (e.g., heart, spleen, and kidney), and where tissue density limits theseepage of blood from adjoining capillary beds into the necrotic area.

Question 228

Infarcts tend to be___________

Answer 228

wedge-shaped,

with the occluded vessel at the apex and the periphery ofthe organ forming the base (see Fig. 4-18 );
when the base is a serosal surface there can bean overlying fibrinous exudate.

Question 229

Acute infarcts are poorly defined and slightly hemorrhagic.With time the margins tend to become better defined by a narrow rim of congestionattributable to inflammation.

Question 230

Infarcts resulting from arterial occlusions in organs without a dual blood supply typicallyExtravasated redcells in hemorrhagic infarcts are phagocytosed by macrophages, which convert heme ironinto hemosiderin; small amounts do not grossly impart any appreciable color to the tissue, butextensive hemorrhage can leave a firm, brown residuum.

Answer 230

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

Question 231

The dominant histologic characteristic of infarction is__________

Answer 231

ischemic coagulative necrosis (Chapter 1 ).

Question 232

It is important to recall that if the vascular occlusion hasoccurred shortly(minutes to hours) before the death of the person, no demonstrable histologic changes maybe evident;it takes _____________- for the tissue to show frank necrosis.

Answer 232

4 to 12 hours

Question 233

Acute inflammation ispresent 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 beginningin the preserved margins ( Chapter 2 ).In stable or labile tissues, parenchymal regenerationcan occur at the periphery where underlying stromal architecture is preserved.However, mostinfarcts are ultimately replaced by scar ( Fig. 4-19 ). The brain is an exception to thesegeneralizations, as central nervous system infarction results in liquefactive necrosis (

Answer 233

1 to2 days.

Question 234

What are septic infarctions?

Answer 234

Septic infarctions occur when infected cardiac valve vegetations embolize or whenmicrobes seed necrotic tissue.In these cases the infarct is converted into an abscess, with acorrespondingly greater inflammatory response ( Chapter 2 ). The eventual sequence oforganization, however, follows the pattern already described.

Question 235

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

Answer 235

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

Question 236

Factors That Influence Development of an Infarct.

Answer 236

The effects of vascular occlusion can range from no or minimal effect to causing the death of atissue or person.The major determinants of the eventual outcome are:

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

Question 237

Factors That Influence Development of an Infarct.Explain the Nature of the vascular supply when it comes to influencing the development of infarct.

Answer 237

The availability of an alternative blood supply is the mostimportant determinant of whether vessel occlusion will cause damage.As alreadymentioned, the lungs have a dual pulmonary and bronchial artery blood supply thatprovides protection from thromboembolism-induced infarction.Similarly, the liver, with itsdual hepatic artery and portal vein circulation,and the hand and forearm, with their dualradial and ulnar arterial supply, are all relatively resistant to infarction.In contrast, renaland splenic circulations are end-arterial, and vascular obstruction generally causestissue death.

Question 238

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

Answer 238

the lungs have a dual pulmonary and bronchial artery blood supplythatprovides protection from thromboembolism-induced infarction. Similarly, theliver, with itsdual hepatic artery and portal vein circulation,
and thehand and forearm,withtheir dualradial and ulnar arterial supply,are all relatively resistant to infarction.

Question 239

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

Answer 239

Rate of occlusion development. Slowly developing occlusions are less likely to causeinfarction, because they provide time to develop alternate perfusion pathways. Forexample, small interarteriolar anastomoses—normally with minimal functional flow—interconnect the three major coronary arteries in the heart. If one of the coronaries isonly slowly occluded (i.e., by an encroaching atherosclerotic plaque), flow within thiscollateral circulation may increase sufficiently to prevent infarction, even though thelarger coronary artery is eventually occluded.

Question 240

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

Answer 240

Vulnerability to hypoxia. Neurons undergo irreversible damage when deprived of theirblood supply for only 3 to 4 minutes. Myocardial cells, though hardier than neurons, arealso 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 241

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

Answer 241

Oxygen content of blood .A partial obstruction of a small vessel that would be withouteffect in an otherwise normal individual might cause infarction in an anemic or cyanoticpatient.

Question 242

What is Shock?

Answer 242

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

Question 243

What is the characteristic of SHOCK?

Answer 243

Shock is characterized by: systemic hypotension due either toreduced cardiac output or to reduced effective circulating blood volume.

Question 244

The consequences of SHOCKare:

Answer 244

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 245

The causes of shock fall into three general categories

Answer 245

• Cardiogenic
• Hypovolemic
• Septic

Question 246

Explain Cardiogenic Shock.

Answer 246

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

Question 247

Cardiogenic shock can be due to:

Answer 247

Thiscan be due to:

• intrinsic myocardial damage (infarction),
• ventricular arrhythmias,
• extrinsic compression (cardiac tamponade; Chapter 12 ),
• or outflow obstruction (e.g., pulmonaryembolism).
• Myocardialinfarction
• Ventricular rupture
• Arrhythmia
• Cardiactamponade
• Pulmonaryembolism

Question 248

What is the principal mechanism of Cardiogenic shock?

Answer 248

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

Question 249

Define Hypoveolemic Shock.

Answer 249

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

Question 250

Give an example of Hypovolemic Shock

Answer 250

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

Question 251

What is the principal mechanism of Hypovolemic shock?

Answer 251

Inadequate blood or plasma volume

Question 252

Define Septic Shock.

Answer 252

Septic shock results from vasodilation and peripheral pooling of blood as part of asystemic immune reaction to bacterial or fungal infection.Its complex pathogenesis isdiscussed in further detail below.

Question 253

What are example of clinical setting of Septic Shock.

Answer 253

Overwhelming microbial infections(bacterial andfungal) Superantigens(e.g., toxic shocksyndrome)

Question 254

What is the principal mechanism of Septic Shock?

Answer 254

Peripheral vasodilation and pooling of blood;

• endothelialactivation/injury; leukocyte-induced damage, disseminatedintravascular coagulation;
• activation of cytokine cascades

Question 255

Define neurogenic shock and when does it mostly occur.

Answer 255

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 256

What is anaphylactic shock?

Answer 256

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

Question 257

What is the pathogenesis of Septic Shock?

Answer 257

Septic shock is associated with severe hemodynamic and hemostatic derangements, andtherefore merits more detailed consideration here.With a mortality rate near 20%, septic shockranks first among the causes of death in intensive care units and accounts for over 200,000lost lives each year in the United States. [57]Its incidence is rising, ironically due toimprovements in life support for critically ill patients and the growing ranks ofimmunocompromised hosts (due to chemotherapy, immunosuppression, or HIV infection).

Question 258

What is the most currently triggering factor of septic shock?

Answer 258

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 “endotoxicshock” is not appropriate.

Question 259

Discuss what happens in septic shock.

Answer 259

In septic shock, systemic vasodilation and pooling of blood in the periphery leads to tissuehypoperfusion, even though cardiac output may be preserved or even increased early in thecourse. This is accompanied by widespread endothelial cell activation and injury, often leadingto a hypercoagulable state that can manifest as DIC.In addition, septic shock is associated withchanges in metabolism that directly suppress cellular function.

Question 260

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

Answer 260

The net effect of theseabnormalities is hypoperfusion and dysfunction of multiple organs—culminating in theextraordinary morbidity and mortality associated with sepsis.

Question 261

The ability of diverse microorganisms to cause septic shock (sometimes even when theinfection is localized to one area of the body) [58] is consistent with the idea that severalmicrobial 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 thatrespond to a variety of substances derived from microorganisms.Once activated, these cellsrelease inflammatory mediators, as well as a variety of immunosuppressive factors that modifythe host response. In addition, microbial constituents also activate humoral elements of innateimmunity, particularly the complement and coagulation pathways.These mediators combine withthe direct effects of microbial constituents on endothelium in a complex, incompletelyunderstood fashion to produce septic shock ( Fig. 4-20 ). [59]

Question 262

The major factorscontributing to its pathophysiology include the following:

Answer 262

• Inflammatory mediators
• Endothelial cell activation and injury .
• Metabolic abnormalities
• Immune suppression
• Organ dysfunction

Question 263

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

Answer 263

Various microbial cell wall constituents engage receptors onneutrophils, mononuclear inflammatory cells, and endothelial cells, leading to cellularactivation. Toll-like receptors (TLRs, Chapter 2 ) recognize microbial elements andtrigger the responses that initiate sepsis. However, mice genetically deficient in TLRs stillsuccumb to sepsis, [59,] [60] and it is believed that other pathways are probably alsoinvolved in the initiation of sepsis in humans (e.g., G-protein coupled receptors thatdetect 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 1protein (HMGB1). [62] Reactive oxygen species and lipid mediators such asprostaglandins and platelet activating factor (PAF) are also elaborated.These effectormolecules activate endothelial cells (and other cell types) resulting in adhesion moleculeexpression, a procoagulant phenotype, and secondary waves of cytokineproduction. [61]The complement cascade is also activated by microbial components,both directly and through the proteolytic activity of plasmin ( Chapter 2 ), resulting in theproduction of anaphylotoxins (C3a, C5a), chemotactic fragments (C5a), and opsonins(C3b) that contribute to the pro-inflammatory state. [63]In addition, microbialcomponents such as endotoxin can activate coagulation directly through factor XII andindirectly through altered endothelial function (discussed below).The systemicprocoagulant state induced by sepsis not only leads to thrombosis, but also augmentsinflammation through effects mediated by protease-activated receptors (PARs) found oninflammatory cells.

Question 264

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

Answer 264

Endothelial cell activation by microbial constituentsor inflammatory mediators produced by leukocytes has three major sequelae: (1)thrombosis; (2) increased vascular permeability; and (3) vasodilation.
The derangementin coagulation is sufficient to produce the fearsome complication of DIC in up to half ofseptic patients. [60] Sepsis alters the expression of many factors so as to favorcoagulation.Pro-inflammatory cytokines result in increased tissue factor production byendothelial cells (and monocytes as well), while at the same time reining in fibrinolysis byincreasing PAI-1 expression (see Fig. 4-6B and Fig. 4-8 ). The production of otherendothelial anti-coagulant factors, such as tissue factor pathway inhibitor,thrombomodulin, and protein C (see Fig. 4-6 and Fig. 4-8 ), arediminished. [60,] [61,] [64]The procoagulant tendency is further exacerbated bydecreased blood flow at the level of small vessels, producing stasis and diminishing thewashout of activated coagulation factors.Acting in concert, these effects promote thedeposition of fibrin-rich thrombi in small vessels, often throughout the body, which alsocontributes to the hypoperfusion of tissues. [60] In full-blown DIC, the consumption ofcoagulation factors and platelets is so great that deficiencies of these factors appear,leading to concomitant bleeding and hemorrhage ( Chapter 14 ).The increase invascular permeability leads to exudation of fluid into the interstitium, causing edema andan increase in interstitial fluid pressure that may further impede blood flow into tissues,particularly following resuscitation of the patient with intravenous fluids. The endotheliumalso increases its expression of inducible nitric oxide synthetase and the production ofnitric oxide (NO). These alterations, along with increases in vasoactive inflammatorymediators (e.g., C3a, C5a, and PAF), cause the systemic relaxation of vascular smoothmuscle, leading to hypotension and diminished tissue perfusion.

Question 265

Explain how metabolic abnormalitiies contribute to Septic Shock.

Answer 265

Metabolic abnormalities. Septic patients exhibit insulin resistance and hyperglycemia.Cytokines such as TNF and IL-1, stress-induced hormones (such as glucagon, growthhormone, and glucocorticoids), and catecholamines all drive gluconeogenesis.At thesame time, the pro-inflammatory cytokines suppress insulin release while simultaneouslypromoting insulin resistance in the liver and other tissues, likely by impairing the surfaceexpression of GLUT-4, [65] a glucose transporter. Hyperglycemia decreases neutrophil function—thereby suppressing bactericidal activity—and causes increased adhesionmolecule expression on endothelial cells. [65] Although sepsis is initially associated withan acute surge in glucocorticoid production, this phase is frequently followed by adrenalinsufficiency and a functional deficit of glucocorticoids. This may stem from depressionof the synthetic capacity of intact adrenal glands or frank adrenal necrosis due to DIC(Waterhouse-Friderichsen syndrome, Chapter 24 ).

Question 266

How does immune suppression contribute to Septic shock pathology?

Answer 266

Immune suppression.The hyperinflammatory state initiated by sepsis can activatecounter-regulatory immunosuppressive mechanisms, which may involve both innate andadaptive immunity. [59] [60] [61] Proposed mechanisms for the immune suppressioninclude a shift from pro-inflammatory (TH1) to anti-inflammatory (TH2) cytokines (Chapter 6 ), production of anti-inflammatory mediators (e.g., soluble TNF receptor, IL-1receptor antagonist, and IL-10), lymphocyte apoptosis, the immunosuppressive effectsof apoptotic cells, and the induction of cellular anergy. [59] [60] [61] It is still debatedwhether immunosuppressive mediators are deleterious or protective in sepsis

Question 267

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

Answer 267

Systemic hypotension, interstitial edema, and small vesselthrombosis all decrease the delivery of oxygen and nutrients to the tissues, which fail toproperly utilize those nutrients that are delivered due to changes in cellular metabolism.High levels of cytokines and secondary mediators may diminish myocardial contractilityand cardiac output, and increased vascular permeability and endothelial injury can leadto the adult respiratory distress syndrome ( Chapter 15 ). Ultimately, these factors mayconspire to cause the failure of multiple organs, particularly the kidneys, liver, lungs, andheart, culminating in death.

Question 268

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

Answer 268

• extent and virulence ofthe 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 theinteractions that underlie sepsis explain why most attempts to intervene therapeutically withantagonists of specific mediators have been of very modest benefit at best, and may even havehad deleterious effects in some cases. [59]

Question 269

What is the standard of care for septic shock?

Answer 269

The standard of care remains treatment with: appropriate antibiotics, intensive insulin therapy for hyperglycemia, fluid resuscitation tomaintain systemic pressures, and “physiologic doses” of corticosteroids to correct relativeadrenal insufficiency. [59] Administration of activated protein C (to prevent thrombin generationand thereby reduce coagulation and inflammation) may have some benefit in cases of severesepsis, but this remains controversial. Suffice it to say, even in the best of clinical centers,septic shock remains an obstinate clinical challenge

Question 270

How dosuperantigens cause a syndrome similar to septic shock?

Answer 270

It is worth mentioning here that an additional group of secreted bacterial proteins calledsuperantigens 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 ofcytokines that result in a variety of clinical manifestations, ranging from a diffuse rash tovasodilation, hypotension, and death.

Question 271

STAGES OF SHOCKShock is a progressive disorder that, if uncorrected, leads to death.The exact mechanism(s) ofdeath from sepsis are still unclear; aside from increased lymphocyte and enterocyteapoptosisthere is only minimal cell death, and patients rarely have refractory hypotension. [61]Forhypovolemic and cardiogenic shock, however, the pathways to death are reasonably wellunderstood. Unless the insult is massive and rapidly lethal (e.g., a massive hemorrhage from aruptured aortic aneurysm), shock in those settings tends to evolve through three general (albeitsomewhat artificial) phases:

Answer 271

An initial nonprogressive phase A progressive stage

•An irreversible stage

Question 272

Describe the initial progressive phase.

Answer 272

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

Question 273

Discuss the progressive stage.

Answer 273

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

Question 274

Discuss the irreversible stage.

Answer 274

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

Question 275

In the early nonprogressive phase of shock, a variety of neurohumoral mechanisms help tomaintain cardiac output and blood pressure.These include

Answer 275

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

Question 276

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

Answer 276

The net effect is:

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

Question 277

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

Answer 277

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

Question 278

although septic shockcan initially cause cutaneous vasodilation and thus present with warm, flushed skinT or F

Answer 278

T

Question 279

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

Answer 279

widespread tissue hypoxiaIn the setting of persistent oxygendeficit, intracellular aerobic respiration is replaced by anaerobic glycolysis with excessiveproduction of lactic acid.The resultant metabolic lactic acidosis lowers the tissue pH and bluntsthe 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 developinganoxic injury with subsequent DIC. With widespread tissue hypoxia, vital organs are affectedand begin to fail.

Question 280

Without intervention, the process eventually enters an irreversible stage.Widespread cell injuryis reflected in ________

Answer 280

lysosomal enzyme leakage, further aggravating the shock state.Myocardialcontractile function worsens in part because of nitricoxidesynthesis. If ischemic bowel allowsintestinal flora to enter the circulation, bacteremic shock may be superimposed. At this point thepatient has complete renal shutdown as a result of acute tubular necrosis ( Chapter 20 ), anddespite heroic measures the downward clinical spiral almost inevitably culminates in death.

Question 281

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

Answer 281

hypoxic injurychanges can manifest in any tissuealthough they are particularly evident in brain, heart, lungs, kidneys, adrenals, andgastrointestinal tract.

Question 282

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

Answer 282

stress;essentially there is cortical cell lipid depletion.This does not reflect adrenal exhaustion butrather conversion of the relatively inactive vacuolated cells to metabolically active cells thatutilize stored lipids for the synthesis of steroids. The kidneys typically exhibit acute tubularnecrosis ( Chapter 20 ).

Question 283

What is a shock lung?

Answer 283

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

Question 284

In septic shock, the development of DIC leads towidespread deposition of fibrin-rich microthrombi, particularly in the ______________ The consumption of platelets andcoagulation factors also often leads to the appearance of petechial hemorrhages on serosalsurface and the skin.

Answer 284

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

Question 285

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

Answer 285

neuronal and myocyte

Question 286

The clinical manifestations of shock depend on the precipitating insult.In hypovolemic andcardiogenic shock the patient presents

Answer 286

with hypotension;
a weak,rapid pulse;
tachypnea; andcool, clammy, cyanotic skin.

Question 287

What is the clinical presentation in septic shock?

Answer 287

In septic shock the skin may initially be warm and flushed becauseof peripheral vasodilation.The initial threat to life stems from the underlying catastrophe thatprecipitated the shock (e.g., myocardial infarct, severe hemorrhage, or sepsis).Rapidly,however, the cardiac, cerebral, and pulmonary changes secondary to shock worsen theproblem.Eventually, electrolyte disturbances and metabolic acidosisalso exacerbate thesituation.Individuals who survive the initial complications may enter a second phase dominatedby renal insufficiency and marked by a progressive fall in urine output as well as severe fluidand electrolyte imbalances.

Question 288

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

Answer 288

RIP mama :(