Chapter 4 – Hemodynamic Disorders, Thromboembolic Disease, and Shock Flashcards

Question

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

Answer 1

**wellin****clearing and separation of the extracellular matrix** and subtle cell sg. Any organ or tissue can be involved, but **edema is most commonly seen in subcutaneous tissues, the lungs, and the brain.**

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

renal dysfunction periorbital edema is thus a characteristic finding in severe renal disease.

Answer 6

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

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

**Slightly larger (≥3 mm) hemorrhages** are called purpura. These may be associated with many of the same disorders that cause petechiae or can be secondary to trauma, vascular inflammation (vasculitis), or **increased vascular fragility (e.g., in amyloidosis).**

Answer 15

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

Answer 16

volume and rate of bleeding

Answer 17

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

Answer 18

The pathologic counterpart of hemostasis is thrombosis; it **involves blood clot (thrombus) formation _within intact vessels_.**

Answer 19

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

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

**Activation of platelets results in a dramatic shape change** (from small rounded discs to flat plates with markedly increased surface area), as well as the **release of secretory granules.** Within minutes the secreted products recruit additional platelets (aggregation) to form a **hemostatic plug**; this process is referred to as primary hemostasis

Answer 24

factor III and thromboplastin

Answer 25

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

Answer 26

Tissue factor is also exposed at the site of injury. Also known as factor III andthromboplastin, tissue factor is a membrane-bound procoagulant glycoprotein synthesized by endothelial cells. I**t acts in conjunction with factor VII** (see below) as the **major in vivo initiator of the coagulation cascade**, eventually culminating in thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork, and also induces additional platelet recruitment and activation. This sequence, secondary hemostasis, consolidates the initial platelet plug

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

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

Answer 32

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

Answer 33

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

Answer 34

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

Answer 35

* Antiplatelet effects * Anticoagulant effects. * Fibrinolytic effects

Answer 36

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 a**denosine diphosphate (ADP) and further inhibits platelet aggregation**

Answer 37

prostacyclin (PGI2) and nitric oxide

Answer 38

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

Answer 39

These effects are mediated by endothelial tmembraneassociated heparin-like molecules, **thrombomodulin, and tissue factor pathway inhibitor** (see Fig. 4-6 ). The heparin-like molecules act indirectly; they are cofactors that greatly enhance the inactivation of thrombin and several other coagulation factors by the plasma protein antithrombin III (see later). Thrombomodulin binds to thrombin and converts it from a procoagulant into an anticoagulant via its ability to activate protein C, which inhibits clotting by inactivating factors Va and VIIIa. [9] Endothelium also produces **protein S, a co-factor for protein C, and tissue factor pathway inhibitor (TFPI)** , a cell surface protein that directly inhibits tissue factor–factor VIIa and factor Xa activities

Answer 40

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

Answer 41

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

Answer 42

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

Answer 43

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

Answer 44

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

Answer 45

Procoagulant effects. In response to c**ytokines (e.g., tumor necrosis factor [TNF] or interleukin-1 [IL-1]) or bacterial endotoxin, endothelial cells synthesize tissue factor , the major activator of the extrinsic clotting cascade**. [10,] [12] In addition, activated endothelial cells **augment the catalytic function of activated coagulation factors IXa and Xa.**

Answer 46

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

Answer 47

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

Answer 48

* 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.

Answer 49

* 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).

Answer 50

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

Answer 51

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

Answer 52

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

Answer 53

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

Answer 54

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

Answer 55

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

Answer 56

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

Answer 57

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

Answer 58

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

Answer 59

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

Answer 60

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

Answer 61

Predictably, inherited deficiency of GpIIb-IIIa results in a bleeding disorde NOTE: The recognition of the central role of the various receptors and mediators in platelet cross-linking has led to the development activity, [17] by blocking ADP binding (clopidogrel), or by binding to the GpIIb-IIIa receptors (synthetic antagonists or monoclonal antibodies). [18] Antibodies against GpIb are on the horizon. of therapeutic agents that block platelet aggregation—for example, by interfering with thrombin

Answer 62

**directly stimulating neutrophil and monocyte adhesion and by generating chemotactic fibrin split products during fibrinogen cleavage.** Red cells and leukocytes are also found in hemostatic plugs. Leukocytes adhere to platelets via **P-selectin and to endothelium** using several adhesion receptors ( Chapter 2 ); they contribute to the inflammation that accompanies thrombosis.

Answer 63

* **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 ).

Answer 64

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

Answer 65

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

Answer 66

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

Answer 67

vitamin K 1972

Answer 68

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

Answer 69

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

Answer 70

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.

Answer 71

extrinsic pathway

Answer 72

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

Answer 73

protease activated receptors (PARs)

Answer 74

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

Answer 75

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

Answer 76

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

Answer 77

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

Answer 78

**i**ntrinsic pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen) PITT

Answer 79

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

Answer 80

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

Answer 81

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

Answer 82

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

Answer 83

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

Answer 84

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

Answer 85

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

Answer 86

plasmin **PILAS!!!!! PILASMIN**

Answer 87

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

Answer 88

it largely confines **fibrinolytic activity to sites of recent thrombosis**

Answer 89

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

Answer 90

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

Answer 91

α2-plasmin inhibitor

Answer 92

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

Answer 93

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

Answer 94

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

Answer 95

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

Answer 96

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

Answer 97

Clearly, physical loss of endothelium can lead to **exposure of the subendothelial ECM, adhesion of platelets, release of tissue 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 the development of thrombosis_***; *_any perturbation in the dynamic_* balance of the prothombotic and antithrombotic activities of endothelium *can influence local clotting events (*see Fig. 4-6 ). Thus,***_dysfunctional endothelial cells can produce more procoagulant factors_*** (e.g., platelet adhesion molecules, tissue factor, PAIs) or may synthesize less anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA).

Answer 98

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

Answer 99

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

Answer 100

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

Answer 101

* 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

Answer 102

* 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.

Answer 103

Hypercoagulability (also called thrombophilia) is a less frequent contributor to thrombotic states but is **nevertheless an important component in the equation, and in some situations can predominate**. *_**It is loosely defined as any alteration of the coagulation pathways that predisposes to thrombosis**;_*

Answer 104

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

Answer 105

point mutations in the factor V gene and prothrombin gen

Answer 106

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).

Answer 107

The mutation results in a **glutamine to** * *arginine substitution at position 506 that renders factor V resistant to cleavage by** * *protein C**. As a result, an important antithrombotic counter-regulatory pathway is lost (see Fig. 4-6 ). Indeed, heterozygotes have a five-fold increased relative risk of venous thrombosis, and homozygotes have a 50-fold increase

Answer 108

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

Answer 109

Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as the development of atherosclerosis ( Chapter 11 ). The prothrombotic effects of homocysteine may be due to **thioester linkages formed between homocysteine** **metabolites** and a variety of proteins, including fibrinogen. [32] Marked elevations of homocysteine may be caused by an inherited deficiency of **cystathione βsynthetase.** Much more common is a variant form of the enzyme 5,10-methylenetetrahydrofolate reductase that causes mild homocysteinemia in 5% to 15% of Caucasian and eastern Asian populations; this possible etiology for hypercoagulability is therefore as common as **factor V Leiden**. [27] However, while folic acid, pyridoxine, and/or vitamin B12 supplements can reduce plasma homocysteine concentrations (by stimulating its metabolism), they fail to lower the risk of thromboses, raising questions about the significance of modest homocysteinemia.

Answer 110

deficiencies of anticoagulants such as **antithrombin III, protein C, or protein S;** affected individuals typically present with venous thrombosis and recurrent thromboembolism beginning in adolescence or early adulthood. [27 ] Various polymorphisms in coagulant factor genes can result in increased synthesis and impart an elevated risk of venous thrombosis

Answer 111

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)

Answer 112

**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

Answer 113

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

Answer 114

factor V and prothrombin

Answer 115

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

Answer 116

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

Answer 117

to reduced endothelial PGI2.

Answer 118

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

Answer 119

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

Answer 120

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

Answer 121

(previously called the **lupus anticoagulant syndrome**). This syndrome has protean clinical manifestations, including recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia.

Answer 122

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

Answer 123

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

Answer 124

Antiphospholipid antibody syndrome has **primary and secondary form**s

Answer 125

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.**

Answer 126

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

Answer 127

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

Answer 128

of turbulence or endothelial injury

Answer 129

underlying vascular surface

Answer 130

* *arterial thromb**i tend to grow **retrograde** from the point of attachment, while **venous thrombi extend in the direction of blood** * *flow (thus both propagate toward the heart)**. a**R**terial : **R**etrogade The propagating portion of a thrombus is often poorly attached and therefore prone to fragmentation and embolization

Answer 131

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 thrombosi**s from the bland nonlaminated clots that occur postmortem (see below).

Answer 132

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).

Answer 133

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

Answer 134

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

Answer 135

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

Answer 136

``` Venous thrombosis (phlebothrombosis) is almost **invariably****occlusive**, with the thrombus **forming a long cast of the lumen.** ``` Because these thrombi **form in the sluggish venous** * *circulation**, they tend to **contain more enmeshed red cells (and relatively few platelets)** and * *are therefore known as red, or stasis, thrombi.**

Answer 137

``` The **veins of the lower extremities** are most commonly involved (90% of cases); however, upper extremities, periprostatic plexus, or the ovarian and periuterine veins can also develop venous thrombi. ``` Under special circumstances, they **can also occur in the dural sinuses, portal vein, or hepatic vein.**

Answer 138

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

Answer 139

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

Answer 140

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

Answer 141

**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**

Answer 142

FIGURE 4-13 Mural thrombi. A, Thrombus in the left and right ventricular apices, overlying white fibrous scar. B, Laminated thrombus in a dilated abdominal aortic aneurysm. Numerous friable mural thrombi are also superimposed on advanced atherosclerotic lesions of the more proximal aorta (left side of picture) .

Answer 143

* Propagation * Embolization * Dissolution. * Organization and recanalization

Answer 144

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

Answer 145

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

Answer 146

Dissolution. Dissolution is the **result of fibrinolysis,** which can lead to the **rapid shrinkage and total disappearance of recent thrombi.** **I**n contrast, the extensive fibrin deposition and crosslinking in older thrombi renders them more resistant to lysis. This distinction explains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in the setting of acute coronary thrombosis) is **generally effective only when given in the first** **few hours of a thrombotic episode.**

Answer 147

the extensive fibrin deposition and crosslinking in older thrombi renders them more resistant to lysis. This distinction explains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in the setting of acute coronary thrombosis) is generally effective only when given in the first few hours of a thrombotic episode.

Answer 148

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

Answer 149

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

Answer 150

superficial or deep veins of the leg.

Answer 151

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

Answer 152

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.

Answer 153

hypercoagulable states

Answer 154

* 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]

Answer 155

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

Answer 156

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

Answer 157

Disorders ranging from **obstetric complications to advanced malignancy c**an 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 .

Answer 158

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

Answer 159

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

Answer 160

ischemic necrosis (infarction)

Answer 161

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

Answer 162

leg deep vein thromboses (DVTs),

Answer 163

Fragmented thrombi from DVTs are carried through progressively larger channels and the right side of the heart before slamming into the pulmonary arterial vasculature. Depending on the size of the embolus, it can occlude the main pulmonary artery, straddle the pulmonary artery bifurcation (saddle embolus), or pass out into the smaller, branching arteries ( Fig. 4-15 ). Frequently there are multiple emboli, perhaps sequentially or as a shower of smaller emboli from a single large mass; in general, the patient who has had one PE is at high risk of having more. Rarely, an embolus can pass through an interatrial or interventricular defect and gain access to the systemic circulation (paradoxical embolism) . A more complete discussion of PEs is presented in Chapter 15 ; an overview is offered here

Answer 164

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

Answer 165

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

Answer 166

clinically silent because they are small.

Answer 167

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

Answer 168

60% or more

Answer 169

pulmonary hemorrhage

Answer 170

This is because the **lung has a dual blood supply**, and **the intact bronchial circulation** continues to perfuse the affected area. ## Footnote ``` *_**However, a similar embolus in the setting of left-sided cardiac failure (and compromised bronchial artery flow) can result in infarction.**_* ```

Answer 171

hemorrhage or infarction

Answer 172

**pulmonary** hypertension and right ventricular failure.

Answer 173

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

Answer 174

Systemic thromboembolism refers to **emboli in the arterial circulation**

Answer 175

* **Most (80%)** arise f**rom 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**.

Answer 176

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

Answer 177

* 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.

Answer 178

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

Answer 179

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

Answer 180

after vigorous cardiopulmonary resuscitation and are probably of no clinical consequence

Answer 181

severe skeletal injuries

Answer 182

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

Answer 183

Fat embolism syndrome is the term applied to the **minority of patients who become symptomatic.** It is characterized by **pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia,**and is fatal in about 5% to 15% of cases. [52,] [53] Typically, **1 to 3 days after injury there is a sudden onset of tachypnea, dyspnea, and tachycardia;** irritability and restlessness can progress to delirium or coma. Thrombocytopenia is attributed to platelet adhesion to fat globules and subsequent aggregation or splenic sequestration; anemia can result from similar red cell aggregation and/or hemolysis. **A diffuse petechial rash (seen in 20%** to 50% of cases) is related to rapid onset of thrombocytopenia and can be a useful diagnostic feature.

Answer 184

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

Answer 185

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

Answer 186

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

Answer 187

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

Answer 188

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

Answer 189

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

Answer 190

* femoral heads, * tibia, * humeri. FTH

Answer 191

Acute decompression sickness is treated by placing the individual in a high pressure chamber, which serves to force the gas bubbles back into solution. Subsequent slow decompression theoretically permits gradual resorption and exhalation of the gases so that obstructive bubbles do not re-form.

Answer 192

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

Answer 193

The onset is characterized by sudden **severe dyspnea, cyanosis, and shock,** followed by **neurologic impairment ranging** from headache to seizures and coma. If the patient survives the initial crisis, **pulmonary edema** typically develops, **along with (in half the patients) DIC**, as a result of release of thrombogenic substances from the amniotic fluid

Answer 194

The underlying cause is the **infusion of amniotic fluid or fetal tissue** **into the maternal circulation** **via a tear in the placental membranes** or **rupture of uterine veins.** **Classic findings include the presence of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract in the maternal pulmonary microvasculature**( Fig. 4-17 ). Other findings includ**e marked pulmonary edema, diffuse alveolar damage**( Chapter 15 ), and the**presence of fibrin thrombi in many vascular beds due to DIC.**

Answer 195

FIGURE 4-17 Amniotic fluid embolism. Two small pulmonary arterioles are packed with **laminated swirls of fetal squamous cells**. There is marked edema and congestion, and elsewhere in the lung were small organizing thrombi consistent with disseminated intravascular coagulation.

Answer 196

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

Answer 197

**thrombotic or embolic arterial occlusions.** Occasionally infarctions are caused by other mechanisms, **including local vasospasm, hemorrhage** into an **atheromatous plaque,** or **extrinsic vessel compression** (e.g., by tumor). Rarer causes include torsion of a vessel (e.g., in testicular torsion or bowel volvulus), traumatic rupture, or vascular compromise by edema (e.g., anterior compartment syndrome) or by entrapment in a hernia sac.

Answer 198

congestion

Answer 199

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

Answer 200

* (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).

Answer 201

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

Answer 202

* **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.**

Answer 203

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

Answer 204

ischemic coagulative necrosis ( Chapter 1 ).

Answer 205

4 to 12 hours

Answer 206

1 to 2 days.

Answer 207

Septic infarctions occur when i**nfected cardiac valve vegetations embolize or when** **microbes seed necrotic tissue.** In these cases the infarct is converted into an abscess, with a correspondingly greater inflammatory response ( Chapter 2 ). The eventual sequence of organization, however, follows the pattern already described.

Answer 208

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

Answer 209

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

Answer 210

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 .

Answer 211

The **availability of an alternative blood supply is the most important determinant of whether vessel occlusion will cause damage.** As already mentioned, **the lungs have a dual pulmonary and bronchial artery blood supply** that provides protection from thromboembolism-induced infarction. Similarly, the **liver, with its dual hepatic artery and portal vein circulatio**n, and the **hand and forearm,** with **their dual radial and ulnar arterial supply,** are all relatively resistant to infarction. In contrast, **renal and splenic circulations are end-arterial, and vascular obstruction generally causes tissue death.**

Answer 212

* 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.

Answer 213

Rate of occlusion development. * *Slowly developing occlusions are less likely to cause** * *infarction**, **because they provide time to develop alternate perfusion pathwa**ys. For example, small interarteriolar anastomoses—normally with minimal functional flow —interconnect the three major coronary arteries in the heart. If one of the coronaries is only slowly occluded (i.e., by an encroaching atherosclerotic plaque), flow within this collateral circulation may increase sufficiently to prevent infarction, even though the larger coronary artery is eventually occluded.

Answer 214

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 ).

Answer 215

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

Answer 216

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.**

Answer 217

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

Answer 218

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.

Answer 219

1. Cardiogenic 2. Hypovolemic 3. Septic

Answer 220

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

Answer 221

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

Answer 222

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

Answer 223

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

Answer 224

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

Answer 225

Inadequate blood or plasma volume

Answer 226

Septic shock results from **vasodilation and peripheral pooling of blood as part of a systemic immune reaction to bacterial or fungal infection**. Its complex pathogenesis is discussed in further detail below.

Answer 227

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

Answer 228

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

Answer 229

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.**

Answer 230

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

Answer 231

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

Answer 232

Currently, septic shock is most frequently triggered by **gram-positive bacterial infections,** followed by gram-negative bacteria and fungi. [57] Hence, the older synonym of “endotoxic shock” is not appropriate.

Answer 233

In septic shock, **systemic vasodilation and pooling of blood** in the **periphery leads to tissue hypoperfusion**,**even though cardiac output may be preserved or even increased early in the course.** This is accompanied by **widespread endothelial cell activation and injury,** often leading **to a hypercoagulable state** that c**an manifest as DIC**. In addition**, septic shock is associated with** **changes in metabolism that directly suppress cellular function**.

Answer 234

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

Answer 235

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

Answer 236

Various microbial cell wall constituents engage receptors on neutrophils, mononuclear inflammatory cells, and endothelial cells**, leading to cellularactivation.** Toll-like receptors (TLRs, Chapter 2 ) recognize microbial elements and trigger the responses that initiate sepsis. However, mice genetically deficient in TLRs still succumb to sepsis, [59,] [60] and it is believed that other pathways are probably also involved in the initiation of sepsis in humans (e**.g., G-protein coupled receptors that detect bacterial peptides and nucleotide oligomerization domain proteins 1 and 2 [NOD1, NOD2]).** [62] Upon activation, inflammatory cells produce **TNF, IL-1, IFN-γ, IL-12, and IL-18**, as well as other inflammatory mediators such as **high mobility group box 1 protein (HMGB1**). [62 ] **Reactive oxygen species and lipid mediators** such as prostaglandins and platelet activating factor (PAF) are also elaborated. These effector molecules **activate endothelial cells (and other cell types)** **resulting in adhesion molecule expression**, a procoagulant phenotype, and secondary waves of cytokine production. [61] The **complement cascade is also activated by microbial components, both directly and through the proteolytic activity of plasmin (** Chapter 2 ), **resulting in the production of anaphylotoxins (C3a, C5a),****chemotactic fragments (C5a), and opsonins (C3b**) that contribute to the pro-inflammatory state. [63] In addition, **microbial components such as endotoxin**can activate coagulation directly through factor XII and indirectly through altered endothelial function (discussed below). The systemic procoagulant state induced by sepsis not only leads to thrombosis, but also augments inflammation through effects mediated by protease-activated receptors (PARs) found on inflammatory cells.

Answer 237

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

Answer 238

Metabolic abnormalities. Septic patients **exhibit insulin resistance and hyperglycemia.** Cytokines such as **TNF and IL-1, stress-induced hormone**s (such as glucagon, growth hormone, and glucocorticoids), and catecholamines all drive gluconeogenesis. At the same time, the **pro-inflammatory cytokines suppress insulin r**elease 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 ).

Answer 239

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

Answer 240

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

Answer 241

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

Answer 242

* extent and virulence of the infection; * the immune status of the host; * the presence of other co-morbid conditions; * andthe pattern and level of mediator production. The multiplicity of factors and the complexity of the interactions that underlie sepsis explain why most attempts to intervene therapeutically with antagonists of specific mediators have been of very modest benefit at best, and may even have had deleterious effects in some cases. [59]

Answer 243

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

Answer 244

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

Answer 245

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

Answer 246

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

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A progressive stage characterized by **tissue hypoperfusion and onset of worsening circulatory and metabolic imbalances**,***_including acidosis_***

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

Answer 249

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

Answer 250

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.

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

Answer 252

widespread tissue hypoxia In the setting of persistent oxygen deficit, intracellular aerobic respiration is replaced by anaerobic glycolysis with excessive production of lactic acid. The resultant metabolic lactic acidosis lowers the tissue pH and blunts the vasomotor response; arterioles dilate, and blood begins to pool in the microcirculation. Peripheral pooling not only worsens the cardiac output, but also puts EC at risk for developing anoxic injury with subsequent DIC. With widespread tissue hypoxia, vital organs are affected and begin to fail.

Answer 253

**lysosomal enzyme leakage**, further aggravating the shock state. Myocardial contractile function worsens in part because of nitric oxidesynthesis. If ischemic bowel allows intestinal flora to enter the circulation, bacteremic shock may be superimposed. At this point the patient has complete renal shutdown as a result of acute tubular necrosis ( Chapter 20 ), and despite heroic measures the downward clinical spiral almost inevitably culminates in death.

Answer 254

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

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

Answer 256

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

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

Answer 258

neuronal and myocyte

Answer 259

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

Answer 260

In septic shock the **skin may initially be warm and flushed because of peripheral vasodilation**. The initial threat to life stems from the underlying catastrophe that precipitated the shock (e.g., myocardial infarct, severe hemorrhage, or sepsis). Rapidly, however, **the cardiac, cerebral, and pulmonary changes secondary to shock worsen the problem**. Eventually, electrolyte disturbances and metabolic acidosis also exacerbate the situation. Individuals who survive the initial complications may enter a second phase dominated by renal insufficiency and marked by a progressive fall in urine output as well as severe fluid and electrolyte imbalances.

Answer 261

RIP mama :(

Chapter 4 – Hemodynamic Disorders, Thromboembolic Disease, and Shock Flashcards

(307 cards)