Hemodynamics Flashcards
1
Q
Approximately 60% of lean body weight is_____________
A
water
2
Q
Two thirds of the body’s water is __________and the remainder is in extracellular compartments, mostly the interstitium (or third space) thatlies between cells
A
intracellular,
3
Q
How many percent of Total body water is blood plasma?
A
only about 5% of total body water is in blood plasma
4
Q
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 ____________
A
hydrostatic pressure and plasmacolloid osmotic pressure.
5
Q
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
A
6
Q
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
A
7
Q
What is edema?
A
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).
8
Q
What is Anasarca?
A
Anasarca isa severe and generalized edema with widespread subcutaneous tissue swelling.
9
Q
What is a transudate?
A
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,
10
Q
What is an exudate?
A
In contrast, inflammatory edema is a protein-rich exudate that is a result ofincreased vascular permeability. Edema in inflamed tissues is discussed in
11
Q
Pathophysiologic Categories of Edema
A
- INCREASED HYDROSTATIC PRESSUREREDUCED PLASMA
- OSMOTIC PRESSURE (HYPOPROTEINEMIA
- LYMPHATIC OBSTRUCTION
- SODIUM RETENTION
- INFLAMMATION
12
Q
Under theTABLE 4-1 – Pathophysiologic Categories of EdemaINCREASED HYDROSTATIC PRESSURE is brought about by diseases such as:
A
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
13
Q
REDUCED PLASMA OSMOTIC PRESSURE (HYPOPROTEINEMIA
A
Protein-losing glomerulopathies (nephrotic syndrome)
- Liver cirrhosis (ascites)
- Malnutrition
- Protein-losing gastroenteropathy
14
Q
LYMPHATIC OBSTRUCTION
A
Inflammatory Neoplastic Postsurgical Postirradiation
15
Q
SODIUM RETENTION
A
Excessive salt intake with renal insufficiency Increased tubular reabsorption of sodium Renal hypoperfusion Increased renin-angiotensin-aldosteronesecretion
16
Q
INFLAMMATION
A
Acute inflammationChronicinflammationAngiogenesis
17
Q
What happens inIncreased Hydrostatic Pressure.
A
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.
18
Q
When does reduced plasma osmotic pressure occurs?
A
Reduced plasma osmotic pressure occurs when albumin, the major plasma protein, is notsynthesized in adequate amounts or is lost from the circulation.
19
Q
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.
A
nephrotic syndrome
20
Q
When does reduce osmotic pressure occurs?
A
- 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.
21
Q
How can salt retention cause edema?
A
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).
22
Q
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.
A
23
Q
Edema is easily recognized grossly; microscopically, it is appreciated as:
A
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.
24
Q
What is subcutaneous edma?
A
Subcutaneous edema can be diffuse or more conspicuous in regionswith high hydrostatic pressures.
25
What is dependent edema?
In most cases the distribution is influenced by gravity and istermed dependent edema (e.g., the legs when standing, the sacrum when recumbent).
26
What is pitting edema?
Finger pressure over substantially edematous subcutaneous tissue displaces the interstitialfluid and leaves a depression, a sign called pitting edema.
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;
renal dysfunction periorbitaledema is thus a characteristic finding in severe renal disease.
28
What is the characteristic of pulmonary edema?
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.
29
What is the characterisitc of brain edema?
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 ).
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.
31
Pulmonary edema is a common clinical problem that is most frequently seen in the setting of left ventricular failure; it can also occur with renal failure, acute respiratory distress syndrome (Chapter 15 ), and pulmonary inflammation or infection.Not only does fluid collect in the alveolarsepta around capillaries and impede oxygen diffusion, but edema fluid in the alveolar spacesalso creates a favorable environment for bacterial infection.
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
33
What is hemorrhage?
Hemorrhage is defined as the extravasation of blood into the extravascular space.
34
What are hemorrhagic diatheses.?
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.
35
Tissue hemorrhage can occur in distinct patterns, each with its own clinical implications:
* 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).
36
What is a hematoma?
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.
37
What is a petechiae?
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).
38
What is a purpura?
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).
39
What is an ecchymoses?
Larger (>1 to 2 cm) subcutaneous hematomas (i.e., bruises) are called ecchymoses.The red cells in these lesions are degraded and phagocytized by macrophages; the hemoglobin (red-blue color) is then enzymatically converted into bilirubin (blue-greencolor) and eventually into hemosiderin (gold-brown color), accounting for the characteristic color changes in a bruise.
40
The clinical significance of hemorrhage depends on the ________________.
volume and rate of bleeding
41
Rapid loss 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 is sufficient 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
True
42
What is normal hemostasis?
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.
43
What is thrombosis?
The pathologic counterpart of hemostasis is thrombosis; it involves bloodclot (thrombus) formation within intact vessels.
44
Both hemostasis and thrombosis involve threecomponents:
the vascular wall (particularly the endothelium), platelets, and the coagulation cascade.
45
The general sequence of events in hemostasis at a site of vascular injury is shown in Figure 4-5 . [3,] [4]
brief period of arteriolar vasoconstriction facilitating platelet adherence and activationthis process is referred to as primary hemostasis ( Fig. 4-5B ). • Tissue factor is also exposed at the site of injury. Also known as factor III and thromboplastin, secondary hemostasis, consolidates the initial platelet plug ( Fig. 4-5C ).
* Polymerized fibrin and platelet aggregates form a solid, permanent plug to prevent any further hemorrhage.
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.
reflex neurogenic mechanisms and augmented by the local secretion of factors such as endothelin (a potent endothelium-derived vasoconstrictor; Fig. 4-5A ).
47
What facilitates platelet adherence and activation.
Endothelial injury exposes highly thrombogenic subendothelial extracellular matrix(ECM),
48
What happens in primary hemostasis?
Activation of platelets results in a dramatic 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
49
Tissue factor is also exposed at the site of injury. Also known as ____________,
factor III and thromboplastin
50
Where is tissue factor/ factor 3/ thromboplastin produced?
tissue factor is a membrane-bound procoagulant glycoproteinsynthesized by endothelial cells.
51
What happens in secondary hemostasis?
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
52
major in vivo initiator of the coagulation cascade
Tissue factor is also exposed at the site of injury. Also known as factor III andthromboplastin
53
WHat does thrombin do?
Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork, and also induces additional platelet recruitment and activation
54
Endothelial cells play a role in hemeostasis by?
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]
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.
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.
56
after injury or activation endothelial cells :
acquirenumerous procoagulant activities ( Fig. 4-6 ).
57
Besides trauma, endothelium can be activated by
infectious agents, hemodynamic forces, plasma mediators, a and cytokines.
58
Antithrombotic PropertiesUnder normal circumstances endothelial cells actively prevent thrombosis by producing factorsthat variously block platelet adhesion and aggregation, inhibit coagulation, and lyse clots.
* Antiplatelet effects
* Anticoagulant effects.
* Fibrinolytic effects
59
How do endothelial cells produce antiplatelet effect?
Antiplatelet effects.
Intact endothelium prevents platelets (and plasma coagulation factors) from engaging the highly thrombogenic subendothelial ECM. Nonactivated platelets do not adhere to endothelial cells, and even if platelets are activated, prostacyclin (PGI2) and nitric oxide produced by the endothelial cells impede platelet adhesion. Both of these mediators are potent vasodilators and inhibitors of platelet aggregation; their synthesis by the endothelium is stimulated by several factors produced during coagulation (e.g., thrombin and cytokines).
Endothelial cells also elaborate adenosine diphosphatase, which degrades adenosine diphosphate (ADP) and further inhibits platelet aggregation
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 platelet aggregation; their synthesis by the endothelium is stimulated by several factorsproduced during coagulation (e.g., thrombin and cytokines).
prostacyclin (PGI2) and nitric oxide
61
Endothelial cells alsoelaborate adenosine diphosphatase iand how does this promote ant i platelet effect?
which degrades adenosine diphosphate (ADP)and further inhibits platelet aggregation
62
How do the endothelial cells produce Anticoagulant effects. [8]
These effects are mediated by endothelial tmembraneassociated heparin-like molecules, thrombomodulin, and tissue factor pathway inhibitor(see Fig. 4-6 ). The heparin-like molecules act indirectly; they are cofactors that greatly enhance the inactivation of thrombin and several other coagulation factors by the plasma protein antithrombin III (see later). Thrombomodulin binds to thrombin 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
63
How do endothelial cells promote fibrinolytic action?
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
64
What is tissue-type plasminogen activator (t-PA)?
, a protease that cleaves plasminogen to form plasmin; plasmin, in turn, cleaves fibrin todegrade thrombi
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.
* Platelet effects
* Procoagulant effects
* Antifibrinolytic effects
66
With the Platelet effects how does the endothelia cell promote prothrombosis?
Endothelial injury allows platelets to contact the underlying extracellular matrix; subsequent adhesion occurs through interactions with von Willebrand factor(vWF), which is a product of normal endothelial cells and an essential cofactor forplatelet binding to matrix elements
67
What is a von Willebrand factor(vWF)
It is a product of normal endothelial cells and an essential cofactor for platelet binding to matrix elements
68
How do endothelial cells promote procoagulant effects?
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.
69
How do endothelial cells promote antifibrinolytic effect?
Antifibrinolytic effects.Endothelial cells secrete inhibitors of plasminogen activator(PAIs), which limit fibrinolysis and tend to favor thrombosis.
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.
71
Platelets are disc-shaped, anucleate cell fragments that are shed from megakaryocytes in the bone marrow into the blood stream.They play a critical role in normal hemostasis, [13] 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
glycoprotein receptors, a contractile cytoskeleton, and two types of cytoplasmic granules. α- Granules have the adhesion molecule P-selectin on their membranes ( Chapter 2 ) and contain fibrinogen, fibronectin, factors V and VIII, platelet factor 4 (a heparin-binding chemokine),platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β). Dense (or δ) granules contain ADP and ATP, ionized calcium, histamine, serotonin, and epinephrine.
72
α- Granules have the a:
dhesion molecule P-selectin on their membranes ( Chapter 2 ) and contain fibrinogen, fibronectin, factors V and VIII, platelet factor 4 (a heparin-binding chemokine), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β).
73
Dense (or δ)granules contains :
ADP and ATP, ionized calcium histamine, serotonin, and epinephrine.
74
After vascular injury, platelets encounter ECM constituents such as collagen and the adhesiveglycoprotein vWF.On contact with these proteins, platelets undergo:
(1) adhesion and shapechange,(2) secretion (release reaction), and (3) aggregation
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 ).
vWF Although 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.
76
Although 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
77
What is the disease associated when there is deficiency in the receptor of Vwilliebrand factor ?
Reflecting the importance of these interactions, geneticdeficiencies of vWF (von Willebrand disease; Chapter 14 ) or its receptor (Bernard- Soulier syndrome)
78
Secretion (release reaction) of both granule types occurs soon after adhesion.Variousagonists can bind platelet surface receptors and initiate an intracellular protein phosphorylation cascade ultimately leading to degranulation.
Release of the contents of dense-bodies is especially important, since calcium is required in the coagulation cascade,
and ADP is a potent activator of platelet aggregation. ADP also begets additional ADP release, amplifying the aggregation process.
Finally, platelet activation leads to the appearance of negatively charged phospholipids (particularly phosphatidylserine) on their surfaces. These phospholipids bind calcium and serve as critical nucleation sites for the assembly of complexes containing the various coagulation factors
79
Platelet aggregation follows adhesion and granule release. What does thromboxane A-2 does?
In addition to ADP, thevasoconstrictor thromboxane A2 (TxA2; Chapter 2 ) is an important platelet-derived stimulus that amplifies platelet aggregation, which leads to the formation of the primaryhemostatic plug.
80
Although this initial wave of aggregation is reversible, concurrent activation of the coagulation cascade generates thrombin, which stabilizes the platelet plug via two mechanisms.
First, thrombin binds to a protease-activated receptor (PAR, see below) on the platelet membrane and in concert with ADP and TxA2 causes further platelet aggregation. This is followed by platelet contraction, an event that is dependent on the platelet cytoskeleton that creates an irreversibly fused mass of platelets, which constitutes the definitive secondary hemostatic plug. Second, thrombin converts fibrinogen to fibrin in the vicinity of the platelet plug, functionally cementing the platelets in place.
81
Noncleaved fibrinogen is also an important component of platelet aggregation because :.
Platelet activation by ADP triggers a conformational change in the platelet GpIIb-IIIa receptors.
82
What does GpIIb-IIIa receptors do?
the platelet GpIIb-IIIa receptors that induces binding to fibrinogen, a large protein that forms bridging interactions between platelets that promote platelet aggregation (see Fig. 4-7 ).
83
What is Glanzmann thrombasthenia [16]
Predictably, inherited deficiency of GpIIb-IIIaresults in a bleeding disorde NOTE: The recognition of the centralrole of the various receptors and mediators in platelet cross-linking has led to the development activity, [17] by blocking ADP binding (clopidogrel), or by binding to the GpIIb-IIIa receptors (synthetic antagonists or monoclonal antibodies). [18]Antibodies against GpIb are on thehorizon. of therapeutic agents that block platelet aggregation—for example, by interfering with thrombin
84
Thrombin also drives thrombus-associatedinflammation by:
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 endothelium using several adhesion receptors ( Chapter 2 ); they contributeto the inflammation that accompanies thrombosis.
85
The interplay of platelets and endothelium has a profound impact on clot formation. The endothelial cell-derived:
prostaglandin PGI2 (prostacyclin) inhibits platelet aggregation and is a potent vasodilator; conversely,
the platelet-derived prostaglandin TxA2 activates platelet aggregation and is a vasoconstrictor ( Chapter 2 ). Effects mediated by PGI2 and TxA2 are exquisitely balanced to effectively modulate platelet and vascular wall function: at baseline, platelet aggregation is prevented, whereas endothelial injury promotes hemostatic plug formation. The clinical utility of aspirin (an irreversible cyclooxygenase inhibitor) in persons at risk for coronary thrombosis resides in its ability to permanently block platelet TxA2 synthesis. Although endothelial PGI2 production is also inhibited by aspirin, endothelial cells can resynthesize active cyclooxygenase and thereby overcome the blockade. In a manner similar to PGI2, endothelial-derived nitric oxide also acts as a vasodilator and inhibitor of platelet aggregation (see Fig. 4-6 ).
86
What is the coagulation cascade?
The coagulation cascade is essentially an amplifying series of enzymatic conversions; each step proteolytically cleaves an inactive proenzyme into an activated enzyme, culminating inthrombin formation
87
__________ is the most important coagulation factor, and indeed can act at numerous stages in the process (see blue boxes in Fig. 4-8 ). [20
.Thrombin At 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).
88
Each reaction in the coagulation pathway results from the assembly of a complex composed of an enzyme(activated coagulation factor), a substrate (proenzyme form of coagulation factor), and acofactor (reaction accelerator).These components are typically assembled on a____________
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 or endothelium; [4] as shown in Figure 4-9 , it can be likened to a “dance” of complexes, in which coagulation factors are passed successfully from one partner to the next.
89
Parenthetically, the binding of coagulation factors II, XII, IX, and X to calcium depends on the addition of γ-carboxyl groups to certain glutamic acid residues on these proteins. This reaction uses ____________ as acofactor and is antagonized by drugs such as coumadin, which is a widely used anticoagulant.
vitamin K 1972
90
Blood coagulation is traditionally classified into extrinsic and intrinsic pathways that converge onthe activation of__________ (see Fig. 4-8 ).
factor X
91
The extrinsic pathway was so designated because_____________
itrequired the addition of an exogenous trigger (originally provided by tissue extracts);
92
the intrinsic pathway only required____________
exposing factor XII (Hageman factor) to thrombogenic surfaces(even glass would suffice) . However, such a division is largely an artifact of in vitro testing; there are, in fact, several interconnections between the two pathways.
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]
extrinsicpathway
94
What activates the extrinsic pathway?
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]
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 ).
protease activated receptors (PARs)
96
PARs areexpressed on
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.
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
prothrombin time (PT) and partial thromboplastin time (PTT)
98
The PT assayassesses the function of the proteins in the ___________
extrinsic pathway (factors VII, X, II, V, andfibrinogen). PET
99
How is the PT assay accomplished?
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
100
. 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) PITT
101
In this PTT 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
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.
(1) Antithrombins (2) Proteins C and S (3) TFPI i
103
What are your antithrombins?
(1) Antithrombins (e.g., antithrombin III) inhibit the activity of thrombin and other serineproteases, including factors IXa, Xa, XIa, and XIIa.
104
How is antithrombin activated?
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 ).
105
What are Proteins C and S
are vitamin K–dependentproteins that act in a complex that proteolytically inactivates factors Va and VIIIa. Protein Cactivation by thrombomodulin was described earlier.
106
What is TFPI?
is a protein produced by endothelium (and other cell types) that inactivates tissue factor–factor VIIa complexes (seeFigs. 4-6 and 4-8 ). [10]
107
Activation of the coagulation cascade also sets into motion a fibrinolytic cascade that moderates the size of the ultimate clot. Fibrinolysis is largely accomplished through theenzymatic activity of _______________, which breaks down fibrin and interferes with its polymerization (Fig. 4-11 ).
plasmin PILAS!!!!! PILASMIN
108
The resulting fibrin split products (FSPs or fibrin degradation products) canalso act as weak anticoagulants. True or False
True
109
How is plasmin generated?
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 ).
110
The mostimportant of the PAs is ___________; it is synthesized principally by endothelium and is most active whenbound to fibrin.
t-PA
111
The affinity for fibrin makes t-PA a useful therapeutic agent, since _
it largelyconfines fibrinolytic activity to sites of recent thrombosis
112
What is Urokinase-like PA?
Urokinase-like PA (u-PA) is another PApresent in plasma and in various tissues; it can activate plasmin in the fluid phase.
113
What does streptokinase do?
Finally,plasminogen can be cleaved to plasmin by the bacterial enzyme streptokinase, an activity that may be clinically significant in certain bacterial infections.
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
α2-plasmin inhibitor
115
Endothelial cells also fine-tune the coagulation/anticoagulation balance by ______________
releasing plasminogen 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 thrombosis accompanying severe inflammation.
116
What is the virchows triad?
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
117
Endothelial injury is particularly important for thrombus formation in the heart or the arterialcirculation because?
, where the normally high flow rates might otherwise impede clotting by preventing platelet adhesion and washing out activated coagulation factors. Thus, thrombus formationwithin cardiac chambers (e.g., after endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely a consequence of endothelial cell injury.
118
Explain endothelial injury in relation to thrombosis?
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 be emphasized that endothelium need not be denuded or physically disrupted to contribute to thedevelopment of thrombosis; any perturbation in the dynamic balance of the prothombotic and antithrombotic activities of endothelium can influence local clotting events (see Fig. 4-6 ). Thus, dysfunctional endothelial cells can produce more procoagulant factors (e.g., platelet adhesion molecules, tissue factor, PAIs) or may synthesize less anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA).
119
Endothelial dysfunction can be induced by a wide variety ofinsults, including ________
hypertension, turbulent blood flow, bacterial endotoxins, radiation injury, metabolic abnormalities such as homocystinemia or hypercholesterolemia, and toxins absorbedfrom cigarette smoke.
120
Alterations in Normal Blood Flow. How does turbulence contribute to arterial and cardiac thrombosis?
Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury ordysfunction, as well as by forming countercurrents and local pockets of stasis;
121
What is the majorcontributor in the development of venous thrombi. [25]
stasis
122
What is the normal blood flow?
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.
123
Stasis and turbulence therefore:
* Promote endothelial activation, enhancing procoagulant activity, leukocyte adhesion, etc., in part through flow-induced changes in endothelial cell gene expression. [21]
* • Disrupt laminar flow and bring platelets into contact with the endothelium[26]
* • Prevent washout and dilution of activated clotting factors by fresh flowing blood and the inflow of clotting factor inhibitors
124
Turbulence and stasis contribute to thrombosis in several clinical settings.
Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause turbulence. Aortic and arterial dilations called aneurysms result in local stasis and are therefore fertile sites for thrombosis ( Chapter 11 ). Acute myocardial infarctions result in areas of noncontractile myocardium and sometimes cardiac aneurysms; both are associated with stasis and flow abnormalities that promote the formation of cardiac mural thrombi ( Chapter 12 ). Rheumatic mitral valve stenosis results in left atrial dilation; in conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for developing thrombi ( Chapter 12 ). Hyperviscosity (such as is seen with polycythemia vera; Chapter 13 ) increases resistance to flow and causes small vessel stasis; the deformed red cells in sickle cell anemia ( Chapter 14 ) cause vascular occlusions, with the resulting stasis also predisposing to thrombosis.
125
What is hypercoagulability or thrombophilia?
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;
126
Hypercoagulability can be divided into :
primary (genetic) and secondary (acquired) disorders ( Table 4-2 ). [27] [28] [29]
127
Of the inherited causes of hypercoagulability,____________ are the most common.
pointmutations in the factor V gene and prothrombin gen
128
What is Leiden mutation?
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).
129
Among individuals with recurrent deep venous thrombosis the frequency of leiden mutationis considerably higher, approaching 60%. How does this mutation occur?
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 venous thrombosis, and homozygotes have a 50-fold increase
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.
single nucleotide change (G20210A) in the 3′-untranslated region of the prothrombin gene
131
How does homocystein contribute to arterial and venous thrombosis?
Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as the development of atherosclerosis ( Chapter 11 ).The prothrombotic effects of homocysteine may be due to thioester linkages formed between homocysteinemetabolites and a variety of proteins, including fibrinogen. [32] Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione βsynthetase.Much more common is a variant form of the enzyme 5,10-methylenetetrahydrofolate reductase that causes mild homocysteinemia in 5% to 15% of Caucasian and easternAsian populations; this possible etiology for hypercoagulability is therefore as common as factor V Leiden. [27] However, while folic acid, pyridoxine, and/or vitamin B12 supplements can reduce plasma homocysteine concentrations (by stimulating its metabolism), they fail to lower the risk of thromboses, raising questions about thesignificance of modest homocysteinemia.
132
Rare inherited causes of primary hypercoagulability include :_____________
deficiencies of anticoagulants such as antithrombin III, protein C, or protein S; affected individuals typically present with venous thrombosis and recurrent thromboembolism beginning inadolescence or early adulthood. [27] Various polymorphisms in coagulant factor genescan result in increased synthesis and impart an elevated risk of venous thrombosis
133
TABLE 4-2 -- Hypercoagulable States PRIMARY (GENETIC)
Common
* Factor V mutation (G1691A mutation; factor V Leiden)
* Prothrombin mutation (G20210A variant)
* 5,10-Methylenetetrahydrofolate reductase (homozygous C677T
* mutation)
* Increased levels of factors VIII, IX, XI, or fibrinogen
Rare
* Antithrombin III deficiency
* Protein C deficiency
* Protein S deficiency
Very Rare
* Fibrinolysis defects Homozygous homocystinuria (deficiency of cystathione β- synthetase)
134
TABLE 4-2 -- Hypercoagulable States SECONDARY (ACQUIRED)
```
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
```
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.
(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
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).
factor V and prothrombin
137
Unlike hereditary disorders, the pathogenesis of acquired thrombophilia is frequently multifactorial (see Table 4-2 ). In some cases (e.g., cardiac failure or trauma), stasis or vascular injury may be most important.
138
Hypercoagulability due to oral contraceptive use or thehyperestrogenic state of pregnancy is probably caused by ________________38]
increased hepatic synthesis ofcoagulation factors and reduced anticoagulant synthesis. [
139
What predisposes cancer to thrombosis?
In disseminated cancers, releaseof procoagulant tumor products predisposes to thrombosis. [39]
140
The hypercoagulability seenwith advancing age may be due to ____________.
to reduced endothelial PGI2.
141
Smoking and obesity promotehypercoagulability by unknown mechanisms.
142
Among the acquired thrombophilic states, two that are particularly important clinical problemsdeserve special mention.
* Heparin-induced thrombocytopenia (HIT) syndrome.
| * Antiphospholipid antibody syndrome
143
What is Heparin-induced thrombocytopenia (HIT) syndrome.
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]
144
Why does Heparin-induced thrombocytopenia (HIT) syndrome has thrombocytopenia?
Binding of these antibodies to plateletsresults in their activation, aggregation, and consumption (hence the thrombocytopenia in the syndrome 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 still cause 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.
145
What is Antiphospholipid antibody syndrome
(previously called the lupus anticoagulant syndrome).This syndrome has protean clinicalmanifestations, including recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia.
146
What is the clinical presentation of Antiphospholipid antibody syndrome
Depending on the vascular bed involved, the clinical presentations can include: pulmonary embolism (following lower extremity venous thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary emboli), stroke, bowel infarction, or renovascular hypertension. Fetal loss is attributable to antibody-mediated inhibition of t-PA activity necessary for trophoblastic invasion of the uterus.
Antiphospholipid antibody syndromeis also a cause of renal microangiopathy, resulting in renal failure associated with multiple capillary and arterial thromboses
147
Why is antiphospholipid antibody syndrom a misnomer?
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.
148
Antiphospholipid antibody syndrome has two forms:
Antiphospholipid antibody syndrome has primary and secondary forms
149
What is a primary antiphospholipid syndrome?
In primary antiphospholipid syndrome , patients exhibit only the manifestations of a hypercoagulable state and lack evidence of other autoimmune disorders; occasionally this happens in association with certain drugs or infections.
150
What is the secondary form of antiphospholipid syndrome?
Individuals with a welldefinedautoimmune disease, such as systemic lupus erythematosus ( Chapter 6 ), aredesignated as having secondary antiphospholipid syndrome (hence the earlier term lupusanticoagulant syndrome).
151
A particularlyaggressive form _____________characterized by widespread smallvessel thrombi and multi-organ failure has a 50% mortality. [44]
(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 in 5% to 15% of apparently normal individuals, implying that they are necessary but not sufficientto cause the full-blown syndrome.
152
Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiac chambers, on valves, or in arteries, veins, or capillaries).The size and shape of thrombidepend on the site of origin and the cause.
153
Arterial or cardiac thrombi usually begin at sites____________;
ofturbulence or endothelial injury
154
venous thrombi characteristically occur at sites of________-
stasis.
155
Thrombi are focally attached to the ________
underlying vascular surface
156
What is the difference of the growth of thrombi of arterial vs venous?
arterial thrombi tend to grow retrograde from the point of attachment, while venous thrombi extend in the direction of bloodflow (thus both propagate toward the heart). aRterial : Retrogade The propagating portion of a thrombus is oftenpoorly attached and therefore prone to fragmentation and embolization
157
The propagating portion of a thrombus is oftenpoorly attached and therefore prone to fragmentation and embolization T or F
T
158
What is the line of Zhan?
Thrombi often have grossly and microscopically apparent laminations called lines of Zahn;these represent pale platelet and fibrin deposits alternating with darker red cell–rich layers.Such laminations signify that a thrombus has formed in flowing blood; their presence can therefore distinguish antemortem thrombosis from the bland nonlaminated clots that occur postmortem (see below).
159
How to differentiate antemortem from postmortem thrombi?
Such laminations signify that a thrombus has formed in flowing blood; their presence can therefore distinguish antemortem thrombosis from the bland nonlaminated clots that occurpostmortem (see below).
160
What is a mural thrombi.
Thrombi occurring in heart chambers or in the aortic lumen are designated as mural thrombi. Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) or endomyocardial injury (myocarditis or catheter trauma) promotes cardiac muralthrombi ( Fig. 4-13A ), while ulcerated atherosclerotic plaque and aneurysmal dilation are the precursors of aortic thrombus ( Fig. 4-13B ).
161
What are arterial thrombi?
Arterial thrombi are frequently occlusive; They typically cosist of a friablemeshwork of platelets, fibrin, red cells, and degenerating leukocytes. Although these are usually superimposed on a ruptured atherosclerotic plaque, other vascular injuries (vasculitis,trauma) may be the underlying cause.
162
the most common sites of arterial thrombi in decreasing order offrequency are the
coronary, cerebral, and femoral arteries.
163
What arer Venous thrombosis (phlebothrombosis) ?
Venous thrombosis (phlebothrombosis) is almost invariably occlusive, 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.
164
What is the most commonly involved venous thrombi?
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.
165
Describe postmortem clots
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 to the underlying wall.
166
Describe red thrombi.
In comparison, red thrombi are firmer and are focally attached, and sectioning typically reveals gross and/or microscopic lines of Zahn.
167
What are vegetations?
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 cause valve damage; in both cases, endothelial injury and disturbed blood flow can induce theformation of large thrombotic masses (infective endocarditis; Chapter 12 ).
168
What are nonbacterial thrombotic endocarditis ?
Sterile vegetations can also develop on noninfected valves in persons with hypercoagulable states,so-called nonbacterial thrombotic endocarditis ( Chapter 12 ). Less commonly, sterile,verrucous endocarditis (Libman-Sacks endocarditis) can occur in the setting of systemic lupus erythematosus
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:
* Propagation
* Embolization
* Dissolution.
* Organization and recanalization
170
Describe embolizaiton in relation the fate of thrombi.
Embolization. Thrombi dislodge and travel to other sites in the vasculature. This processis described below
171
Discuss propagation as the fate of thrombi.
Propagation. Thrombi accumulate additional platelets and fibrin. This process wasdiscussed earlier.
172
Describe the process of dissolution in relation to thrombi.
Dissolution. Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi.In contrast, the extensive fibrin 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 the setting of acute coronary thrombosis) is generally effective only when given in the firstfew hours of a thrombotic episode.
173
Why is fibrinolytic agents sucg as t-PA only effective on first few hours of thrombotic episode?
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 the setting of acute coronary thrombosis) is generally effective only when given in the firstfew hours of a thrombotic episode.
174
Describe Organization and recanalization in relation to the fate of thrombi.
Older thrombi become organized by the ingrowth ofendothelial cells, smooth muscle cells, and fibroblasts ( Fig. 4-14 ). Capillary channels eventually form that re-establish the continuity of the original lumen, albeit to a variabledegree.
175
Clinical ConsequencesThrombi are significant because they cause obstruction of arteries and veins , and are sources of emboli.Which effect predominates depends on the site of the thrombosis.Venous thrombican cause congestion and edema in vascular beds distal to an obstruction, but they are far more worrisome for their capacity to embolize to the lungs and cause death (see below).Conversely, although arterial thrombi can embolize and cause downstream infarctions, athrombotic occlusion at a critical site (e.g., a coronary artery) can have more serious clinicalconsequences.
176
Venous Thrombosis (Phlebothrombosis).Most venous thrombi occur in the________ [25]
superficial or deep veins of the leg.
177
Superficial venousthrombi typically occur in the _________ in the setting of varicosities.
saphenous veins Although suchthrombi can cause local congestion, swelling, pain, and tenderness, they rarely embolize.Nevertheless, the local edema and impaired venous drainage do predispose the overlying skin to infections from slight trauma and to the development of varicose ulcers.
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
because such thrombi more often embolize to the lungs and give rise to pulmonary infarction (see below and Chapter 15 ). Although they can cause local pain and edema, venous obstructions from DVTs can be rapidly offset by collateral channels.Consequently, DVTs are asymptomatic in approximately 50% of affected individuals and are recognized only in retrospect after embolization.
179
Lower extremity DVTs are associated with _________, as described earlier (seeTable 4-2 ).
hypercoagulable states
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.
include bed rest and immobilization (because they reduce the milking action of the leg muscles, resulting in reduced venous return), and congestive heart failure (also a cause of impaired venous return). Trauma, surgery, and burns not only immobilize a person but are also associated with vascular insults, procoagulant release from injured tissues, increased hepatic synthesis of coagulation factors, and altered t-PA production. Many elements contribute to the thrombotic diathesis of pregnancy; besides the potential for amniotic fluid infusion into the circulation at the time of delivery, late pregnancy and the postpartum period are also associated with systemic hypercoagulability. Tumor-associated inflammation and coagulation factors (tissue factor, factor VIII) and procoagulants (e.g., mucin) released from tumor cells all contribute to the increased risk of thromboembolism in disseminated cancers, so-called migratory thrombophlebitis or Trousseau syndrome. [39,] [46]
181
What is migratory thrombophlebitis or Trousseau syndrome
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
182
What is the major cause of arterial thromboses?
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 may engender atrial mural thrombi as discussed above. Besides local obstructive consequences,cardiac and aortic mural thrombi can also embolize peripherally.Although any tissue can beaffected, the brain, kidneys, and spleen are particularly likely targets because of their rich blood supply.
183
What is DIC?
Disorders ranging from obstetric complications to advanced malignancy can be complicated by DIC, the sudden or insidious onset of widespread fibrin thrombi in the microcirculation.Although these thrombi are not grossly visible, they are readily apparent microscopically and can cause diffuse circulatory insufficiency, particularly in the brain, lungs, heart, and kidneys. To complicate matters, the widespread microvascular thrombosis results in platelet and coagulation protein consumption (hence the synonym consumption coagulopathy), and at the same time, fibrinolytic mechanisms are activated.Thus, an initially thrombotic disorder can evolve into a bleeding catastrophe. It should be emphasized that DIC is not a primary disease but rather a potential complication of any condition associated with widespread activation of thrombin. [47]It is discussed in greater detail along with other bleeding diatheses in Chapter 14 .
184
What is an embolus?
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 term embolus 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.
185
Rare forms of emboli include: However, unless otherwisespecified, emboli should be considered thrombotic in origin.
fat droplets, nitrogen bubbles, atherosclerotic debris (cholesterol emboli), tumor fragments, bone marrow, or even foreign bodies.
186
Inevitably, emboli lodge in vesselstoo small to permit further passage, causing partial or complete vascular occlusion;a majorconsequence is__________of the downstream tissue. Depending on where they 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.
ischemic necrosis (infarction)
187
Embolism
* PULMONARY EMBOLISM
* SYSTEMIC THROMBOEMBOLISM
* FAT AND MARROW EMBOLISM
* AIR EMBOLISM
* AMNIOTIC FLUID EMBOLISM
*
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.
leg deep vein thromboses (DVTs),
189
Explain Pulmonary Embolism
Fragmented thrombi from DVTs are carried through progressively larger channels and the right side of the heart before slamming into the pulmonary arterial vasculature. Depending on the size of the embolus, it can occlude the main pulmonary artery, straddle the pulmonary 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 emboli from a single large mass; in general, the patient who has had one PE is at high risk of having more. Rarely, an embolus can pass through an interatrial or interventricular defect and gainaccess to the systemic circulation (paradoxical embolism) . A more complete discussion of PEs ispresented in Chapter 15 ; an overview is offered here
190
What is a saddle embolus?
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
191
What is (paradoxical embolism) ?
Rarely, an embolus can pass through an interatrial or interventricular defect and gain access to the systemic circulation (paradoxical embolism) .A more complete discussion of PEs ispresented in Chapter 15 ; an overview is offered here.
192
Most pulmonary emboli (60% to 80%) are_________-
clinically silent because they are small.
193
What is a fibrous web?
With time they become organized and are incorporated into the vascular wall; in some casesorganization of the thromboembolus leaves behind a delicate, bridging fibrous web.
194
Sudden death, right heart failure (cor pulmonale) , or cardiovascular collapse occurswhen emboli obstruct________- of the pulmonary circulation.
60% or more
195
Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in__________.
pulmonary hemorrhage
196
Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in pulmonary hemorrhage but usually does not cause pulmonary infarction. Why?
This is because 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.
197
Embolic obstruction of small end-arteriolar pulmonary branches usually does result in______________
hemorrhage or infarction
198
Multiple emboli over time may cause___________
pulmonary hypertension and right ventricularfailure.
199
What is systemic thromboembolism?
Systemic thromboembolism refers to emboli in the arterial circulation
200
Where does systemic thromboembolism mostly arise?
Most (80%) arise from intracardiac mural thrombi,
two thirds of which are associated with left ventricular wall infarcts
and another quarter with left atrial dilation and fibrillation. The remainder originate from aortic aneurysms, thrombi on ulcerated atherosclerotic plaques, or fragmentation of a valvular vegetation, with a small fraction due to paradoxical emboli ;
10% to 15% of systemic emboli are of unknown origin.
201
In contrast to venous emboli, which tend to lodge primarily in one vascular bed (the lung), arterial emboli can travel to a wide variety of sites; the point of arrest dependson the source and the relative amount of blood flow that downstream tissues receive.
202
Majorsites for arteriolar embolization are the:
lower extremities (75%) and the brain (10%), with the
| intestines, kidneys, spleen, and upper extremities involved to a lesser extent.
203
The consequences of embolization in a tissue depend on its :
vulnerability to ischemia,
the caliber of the occluded vessel,
and whether there is a collateral blood supply;
*
in general, arterial emboli cause infarction of the affected tissues.
204
What is FAT AND MARROW EMBOLISM
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.
205
How is Fat and marrow embolism happens?
Fat and associated cells released by marrow or adipose tissue injury may enter the circulation after therupture of the marrow vascular sinusoids or venules.
206
Fat and marrow PEs are very commonincidental findings ___________.
after vigorous cardiopulmonary resuscitation and are probably of no clinicalconsequence
207
Indeed, fat embolism occurs in some 90% of individuals with __________( Fig. 4-16 )
severe skeletalinjuries
208
Indeed, fat embolism occurs less than 10% of such patients have any clinical findings.
209
What is Fat embolism syndrome?
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 can result from similar red cell aggregation and/or hemolysis. A diffuse petechial rash (seen in 20%to 50% of cases) is related to rapid onset of thrombocytopenia and can be a useful diagnosticfeature.
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WHat is the pathogenesis of fat emboli syndrome?
The pathogenesis of fat emboli syndrome probably involves both mechanical obstruction andbiochemical injury. [52]Fat microemboli and associated red cell and platelet aggregates can occlude the pulmonary and cerebral microvasculature.Release of free fatty acids from the fatglobules exacerbates the situation by causing local toxic injury to endothelium, and platelet activation and granulocyte recruitment (with free radical, protease, and eicosanoid release) complete the vascular assault.Because lipids are dissolved out of tissue preparations by thesolvents routinely used in paraffin embedding, the microscopic demonstration of fat microglobules (in the absence of accompanying marrow) typically requires specializedtechniques, including frozen sections and stains for fat.
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How does Air embolism occurs?
Gas bubbles within the circulation can coalesce to form frothy masses that obstruct vascular flow (and cause distal ischemic injury). For example, a very small volume of air trapped in acoronary artery during bypass surgery, or introduced into the cerebral circulation by neurosurgery in the “sitting position,” can occlude flow with dire consequences.
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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.
100 cc
213
What is decompression sickness?
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 are all at risk. When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) are dissolved in the blood and tissues. If the diver then ascends (depressurizes) too rapidly, the nitrogen comes out of solution in the tissues and theblood.
214
What are bends?
The rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints is responsible for the painful condition called the bends
215
What are chokes?
In the lungs, gas bubbles in thevasculature cause edema, hemorrhage, and focal atelectasis or emphysema, leading to a formof respiratory distress called the chokes.
216
What is caisson's disease?
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).
217
In caisson disease, persistence of gas emboli in the skeletal system leads to multiple foci ofischemic necrosis; the more common sites are the ____________
femoral heads, tibia, humeri.
| FTH
218
How is acute decompression sickness treated?
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.
219
What is amniotic embolism?
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 is up to 80%, making amniotic fluid embolism the fifth most common cause of maternal mortality worldwide; it accounts for roughly 10% of maternal deaths in the United States and results in permanent neurologic deficit in as many as 85% of survivors. [56]
220
What is the characteristic amniotic embolism?
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
221
What is the pathophysiology of amniotic embolsm?
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 pulmonary microvasculature ( 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.
222
What is an infarction?
An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage. Tissue infarction is a common and extremely important cause of clinical illness. Roughly 40% of all deaths in 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.
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Nearly all infarcts result from______________
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 include torsion 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.
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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).
congestion
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Morphology.Infarcts are classified according to color and the presence or absence ofinfection;they are either
red (hemorrhagic) or white (anemic) and may be septic or bland.
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Red infarcts ( Fig. 4-18A ) occur
(1) with venous occlusions (e.g., ovary), (2) in loose tissues (e.g., lung) where blood can collect in the infarcted zone, (3) in tissues with\ dual circulations (e.g., lung and small intestine) that allow blood flow from an unobstructed parallel supply into a necrotic zone, (4) in tissues previously congested by sluggish venous outflow, and (5) when flow is re-established to a site of previous arterial occlusion and necrosis (e.g., following angioplasty of an arterial obstruction).
227
White infarcts ( Fig. 4-18B ) occur with arterial occlusions in
solid organs with endarterialcirculation (e.g., heart, spleen, and kidney), and where tissue density limits the seepage of blood from adjoining capillary beds into the necrotic area.
228
Infarcts tend to be___________
wedge-shaped,
with the occluded vessel at the apex and the periphery of the organ forming the base (see Fig. 4-18 );
when the base is a serosal surface there can be an overlying fibrinous exudate.
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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.
230
Infarcts resulting from arterial occlusions in organs without a dual blood supply typically Extravasated 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.
become progressively paler and more sharply defined with time (see Fig. 4-18B ). By comparison, in the lung hemorrhagic infarcts are the rule (see Fig. 4-18A ).
231
The dominant histologic characteristic of infarction is__________
ischemic coagulative necrosis ( Chapter 1 ).
232
It is important to recall that if the vascular occlusion has occurred shortly (minutes to hours) before the death of the person, no demonstrable histologic changes maybe evident;it takes _____________- for the tissue to show frank necrosis.
4 to 12 hours
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 (
1 to2 days.
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What are septic infarctions?
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.
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FIGURE 4-19 Remote kidney infarct, now replaced by a large fibrotic scar.
FIGURE 4-19 Remote kidney infarct, now replaced by a large fibrotic scar.
236
Factors That Influence Development of an Infarct.
The effects of vascular occlusion can range from no or minimal effect to causing the death of a tissue or person.The major determinants of the eventual outcome are:
* (1) the nature of the vascular supply,
* (2) the rate at which an occlusion develops,
* (3) vulnerability to hypoxia, and
* (4) the oxygen content of the blood .
237
Factors That Influence Development of an Infarct. Explain the Nature of the vascular supply when it comes to influencing the development of infarct.
The availability of an alternative blood supply is the most important determinant of whether vessel occlusion will cause damage. As alreadymentioned, the lungs have a dual pulmonary and bronchial artery blood supply that provides protection from thromboembolism-induced infarction.Similarly, the liver, with itsdual hepatic artery and portal vein circulation, and the hand and forearm, with their dual radial and ulnar arterial supply, are all relatively resistant to infarction.In contrast, renaland splenic circulations are end-arterial, and vascular obstruction generally causestissue death.
238
What organns have dual blood supply that are resistant to infarction?
the lungs have a dual pulmonary and bronchial artery blood supply that provides protection from thromboembolism-induced infarction. Similarly, the liver, with its dual hepatic artery and portal vein circulation,
and the hand and forearm, with their dual radial and ulnar arterial supply, are all relatively resistant to infarction.
239
In the factors the influenec development of infatct, discuss rate of occlusion development.
Rate of occlusion development. Slowly developing occlusions are less likely to causeinfarction, because they provide time to develop alternate perfusion pathways. For example, small interarteriolar anastomoses—normally with minimal functional flow —interconnect the three major coronary arteries in the heart. If one of the coronaries isonly slowly occluded (i.e., by an encroaching atherosclerotic plaque), flow within this collateral circulation may increase sufficiently to prevent infarction, even though thelarger coronary artery is eventually occluded.
240
In line with the factors that influence the development of an infarct, discuss the vulnerability to hypoxia.
Vulnerability to hypoxia. Neurons undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes. Myocardial cells, though hardier than neurons, are also quite sensitive and die after only 20 to 30 minutes of ischemia. In contrast, fibroblasts within myocardium remain viable even after many hours of ischemia (
* Chapter 12 ).
241
In line with the factors that influence the development of an infarct, discuss the Oxygen content of blood.
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.
242
What is Shock?
Shock is the final common pathway for several potentially lethal clinical events, including severe hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism, and microbial sepsis.
243
What is the characteristic of SHOCK?
Shock is characterized by: systemic hypotension due either to reduced cardiac output or to reduced effective circulating blood volume.
244
The consequences of SHOCK are:
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.
245
The causes of shock fall into three general categories
* Cardiogenic
* Hypovolemic
* Septic
246
Explain Cardiogenic Shock.
Cardiogenic shock results from low cardiac output due to myocardial pump failure.
247
Cardiogenic shock can be due to:
This can be due to:
* intrinsic myocardial damage (infarction),
* ventricular arrhythmias,
* extrinsic compression (cardiac tamponade; Chapter 12 ),
* or outflow obstruction (e.g., pulmonary embolism).
* Myocardial infarction
* Ventricular rupture
* Arrhythmia
* Cardiac tamponade
* Pulmonary embolism
248
What is the principal mechanism of Cardiogenic shock?
Failure of myocardial pump resulting from intrinsic myocardialdamage, extrinsic pressure, or obstruction to outflow
249
Define Hypoveolemic Shock.
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.
250
Give an example of Hypovolemic Shock
Fluid loss (e.g.,hemorrhage, vomiting,diarrhea, burns, ortrauma)
251
What is the principal mechanism of Hypovolemic shock?
Inadequate blood or plasma volume
252
Define Septic Shock.
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.
253
What are example of clinical setting of Septic Shock.
Overwhelming microbial infections (bacterial and fungal) Superantigens (e.g., toxic shock syndrome)
254
What is the principal mechanism of Septic Shock?
Peripheral vasodilation and pooling of blood;
* endothelial activation/injury; leukocyte-induced damage, disseminated intravascular coagulation;
* activation of cytokine cascades
255
Define neurogenic shock and when does it mostly occur.
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.
256
What is anaphylactic shock?
Anaphylactic shock denotes systemic vasodilation and increased vascular permeability causedby an IgE–mediated hypersensitivity reaction ( Chapter 6 ). In these situations, acute widespread vasodilation results in tissue hypoperfusion and hypoxia.
257
What is the pathogenesis of Septic Shock?
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 of immunocompromised hosts (due to chemotherapy, immunosuppression, or HIV infection).
258
What is the most currently triggering factor of septic shock?
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.
259
Discuss what happens in septic shock.
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 leading to a hypercoagulable state that can manifest as DIC. In addition, septic shock is associated withchanges in metabolism that directly suppress cellular function.
260
What is the net effect of the pathogenesis of Septic shock?
The net effect of theseabnormalities is hypoperfusion and dysfunction of multiple organs—culminating in the extraordinary morbidity and mortality associated with sepsis.
261
The ability of diverse microorganisms to cause septic shock (sometimes even when the infection is localized to one area of the body) [58] is consistent with the idea that 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 that respond to a variety of substances derived from microorganisms. Once activated, these cells release inflammatory mediators, as well as a variety of immunosuppressive factors that modifythe host response. In addition, microbial constituents also activate humoral elements of innate immunity, 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]
262
The major factorscontributing to its pathophysiology include the following:
* Inflammatory mediators
* Endothelial cell activation and injury .
* Metabolic abnormalities
* Immune suppression
* Organ dysfunction
263
How do inflammatory mediators contribute to the pathophysiology of septic shock?
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 and trigger 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 also involved 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 1 protein (HMGB1). [62 ] Reactive oxygen species and lipid mediators such asprostaglandins and platelet activating factor (PAF) are also elaborated.These effector molecules activate endothelial cells (and other cell types) resulting in adhesion molecule expression, a procoagulant phenotype, and secondary waves of 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 and indirectly 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 on inflammatory cells.
264
Explain how Endothelial cell activation and injury contribute to the pathophysio of Septic Shock.
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 derangement in coagulation is sufficient to produce the fearsome complication of DIC in up to half of septic patients. [60] Sepsis alters the expression of many factors so as to favorcoagulation. Pro-inflammatory cytokines result in increased tissue factor production by endothelial cells (and monocytes as well), while at the same time reining in fibrinolysis by increasing PAI-1 expression (see Fig. 4-6B and Fig. 4-8 ). The production of other endothelial anti-coagulant factors, such as tissue factor pathway inhibitor, thrombomodulin, and protein C (see Fig. 4-6 and Fig. 4-8 ), are diminished. [60,] [61,] [64] The procoagulant tendency is further exacerbated bydecreased blood flow at the level of small vessels, producing stasis and diminishing the washout of activated coagulation factors. Acting in concert, these effects promote thedeposition of fibrin-rich thrombi in small vessels, often throughout the body, which also contributes to the hypoperfusion of tissues. [60] In full-blown DIC, the consumption of coagulation factors and platelets is so great that deficiencies of these factors appear, leading to concomitant bleeding and hemorrhage ( Chapter 14 ).The increase in vascular permeability leads to exudation of fluid into the interstitium, causing edema and an increase in interstitial fluid pressure that may further impede blood flow into tissues, particularly following resuscitation of the patient with intravenous fluids. The endothelium also increases its expression of inducible nitric oxide synthetase and the production ofnitric oxide (NO). These alterations, along with increases in vasoactive inflammatory mediators (e.g., C3a, C5a, and PAF), cause the systemic relaxation of vascular smooth muscle, leading to hypotension and diminished tissue perfusion.
265
Explain how metabolic abnormalitiies contribute to Septic Shock.
Metabolic abnormalities. Septic patients exhibit insulin resistance and hyperglycemia.Cytokines such as TNF and IL-1, stress-induced hormones (such as glucagon, growth hormone, and glucocorticoids), and catecholamines all drive gluconeogenesis.At the same time, the pro-inflammatory cytokines suppress insulin release while simultaneously promoting insulin resistance in the liver and other tissues, likely by impairing the surface expression of GLUT-4, [65] a glucose transporter. Hyperglycemia decreases neutrophil function—thereby suppressing bactericidal activity—and causes increased adhesion molecule expression on endothelial cells. [65] Although sepsis is initially associated with an acute surge in glucocorticoid production, this phase is frequently followed by adrenal insufficiency and a functional deficit of glucocorticoids. This may stem from depression of the synthetic capacity of intact adrenal glands or frank adrenal necrosis due to DIC(Waterhouse-Friderichsen syndrome, Chapter 24 ).
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How does immune suppression contribute to Septic shock pathology?
Immune suppression.The hyperinflammatory state initiated by sepsis can activate counter-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 effects of apoptotic cells, and the induction of cellular anergy. [59] [60] [61] It is still debated whether immunosuppressive mediators are deleterious or protective in sepsis
267
How does organ dysfunciton contribute to the pathophysiology of Septic shock?
Systemic hypotension, interstitial edema, and small vesselthrombosis all decrease the delivery of oxygen and nutrients to the tissues, which fail to properly utilize those nutrients that are delivered due to changes in cellular metabolism. High levels of cytokines and secondary mediators may diminish myocardial contractility and cardiac output, and increased vascular permeability and endothelial injury can 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.
268
The severity and outcome of septic shock are likely dependent upon the:
* extent and virulence of the infection;
* the immune status of the host;
* the presence of other co-morbid conditions;
* andthe pattern and level of mediator production.
The multiplicity of factors and the complexity of theinteractions that underlie sepsis explain why most attempts to intervene therapeutically with antagonists of specific mediators have been of very modest benefit at best, and may even have had deleterious effects in some cases. [59]
269
What is the standard of care for septic shock?
The standard of care remains treatment with: appropriate antibiotics, intensive insulin therapy for hyperglycemia, fluid resuscitation to maintain systemic pressures, and “physiologic doses” of corticosteroids to correct relative adrenal insufficiency. [59] Administration of activated protein C (to prevent thrombin generation and thereby reduce coagulation and inflammation) may have some benefit in cases of severe sepsis, but this remains controversial. Suffice it to say, even in the best of clinical centers, septic shock remains an obstinate clinical challenge
270
How do superantigens cause a syndrome similar to septic shock?
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 of cytokines that result in a variety of clinical manifestations, ranging from a diffuse rash tovasodilation, hypotension, and death.
271
STAGES OF SHOCK Shock is a progressive disorder that, if uncorrected, leads to death.The exact mechanism(s) of death from sepsis are still unclear; aside from increased lymphocyte and enterocyte apoptosis there is only minimal cell death, and patients rarely have refractory hypotension. [61] For hypovolemic and cardiogenic shock, however, the pathways to death are reasonably wellunderstood. Unless the insult is massive and rapidly lethal (e.g., a massive hemorrhage from a ruptured aortic aneurysm), shock in those settings tends to evolve through three general (albeit somewhat artificial) phases:
An initial nonprogressive phase A progressive stage
| •An irreversible stage
272
Describe the initial progressive phase.
An initial nonprogressive phase during which reflex compensatory mechanisms are activated and perfusion of vital organs is maintained
273
Discuss the progressive stage.
A progressive stage characterized by tissue hypoperfusion and onset of worseningcirculatory and metabolic imbalances, including acidosis
274
Discuss the irreversible stage.
An irreversible stage that sets in after the body has incurred cellular and tissue injury so severe that even if the hemodynamic defects are corrected, survival is not possible
275
In the early nonprogressive phase of shock, a variety of neurohumoral mechanisms help tomaintain cardiac output and blood pressure.These include
baroreceptor reflexes, catecholamine release, activation of the renin-angiotensin axis, ADH release, and generalized sympathetic stimulation.
276
What is the net effect of the neurohormonal mechanism of the nonprogressive stage?
The net effect is:
* tachycardia,
* peripheral vasoconstriction,
* and renal conservation of fluid.
* Cutaneous vasoconstriction, for example, is responsible for the characteristic coolness and pallor of the skin in well-developed shock (although septic shock can initially cause cutaneous vasodilation and thus present with warm, flushed skin).
* Coronary and cerebral vessels are less sensitive to the sympathetic response and thus maintain relatively normal caliber, blood flow, and oxygen delivery.
277
Explain the coolness and pallor of the skin in well developed shocked.
Cutaneous vasoconstriction, for example, is responsible for the characteristic coolness and pallor of the skin in well-developed shock.
278
although septic shock can initially cause cutaneous vasodilation and thus present with warm, flushed skin T or F
T
279
If the underlying causes are not corrected, shock passes imperceptibly to the progressive phase, during which there is ____________.
widespread tissue hypoxia In the setting of persistent oxygen deficit, intracellular aerobic respiration is replaced by anaerobic glycolysis with excessiveproduction of lactic acid.The resultant metabolic lactic acidosis lowers the tissue pH and blunts the vasomotor response; arterioles dilate, and blood begins to pool in the microcirculation.Peripheral pooling not only worsens the cardiac output, but also puts EC at risk for developing anoxic injury with subsequent DIC. With widespread tissue hypoxia, vital organs are affectedand begin to fail.
280
Without intervention, the process eventually enters an irreversible stage. Widespread cell injuryis reflected in ________
lysosomal enzyme leakage, further aggravating the shock state. Myocardialcontractile function worsens in part because of nitric oxidesynthesis. If ischemic bowel allows intestinal flora to enter the circulation, bacteremic shock may be superimposed. At this point the patient has complete renal shutdown as a result of acute tubular necrosis ( Chapter 20 ), anddespite heroic measures the downward clinical spiral almost inevitably culminates in death.
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The cellular and tissue changes induced by cardiogenic or hypovolemic shock are essentially those of __________ ( Chapter 1 );
hypoxic injury changes can manifest in any tissue although they are particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract.
282
The adrenal changes in shock are those seen in all forms of _____________
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 that utilize stored lipids for the synthesis of steroids. The kidneys typically exhibit acute tubularnecrosis ( Chapter 20 ).
283
What is a shock lung?
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 ) may develop, the so-called shock lung.
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 serosal surface and the skin.
brain, heart, lungs, kidney, adrenal glands, and gastrointestinal tract.
285
With the exception of _________ ischemic loss, virtually all of these tissues may revert to normal if the individual survives. Unfortunately, most patients with irreversiblechanges due to severe shock die before the tissues can recover.
neuronal and myocyte
286
The clinical manifestations of shock depend on the precipitating insult.In hypovolemic and cardiogenic shock the patient presents
with hypotension;
a weak,rapid pulse;
tachypnea; and cool, clammy, cyanotic skin.
287
What is the clinical presentation in septic shock?
In septic shock the skin may initially be warm and flushed because of peripheral vasodilation.The initial threat to life stems from the underlying catastrophe that precipitated the shock (e.g., myocardial infarct, severe hemorrhage, or sepsis).Rapidly, however, the cardiac, cerebral, and pulmonary changes secondary to shock worsen theproblem.Eventually, electrolyte disturbances and metabolic acidosis also exacerbate thesituation.Individuals who survive the initial complications may enter a second phase dominated by renal insufficiency and marked by a progressive fall in urine output as well as severe fluidand electrolyte imbalances.
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The prognosis varies with the origin of shock and its duration. Thus, greater than 90% ofyoung, otherwise healthy patients with hypovolemic shock survive with appropriate management; in comparison, septic shock, or cardiogenic shock associated with extensivemyocardial infarction, can have substantially worse mortality rates, even with optimal care.
RIP mama :(
