Thrombosis, and Shock Flashcards
Thrombosis
The primary abnormalities that lead to thrombosis are (1) endothelial injury, (2) stasis or turbulent blood flow, and (3) hypercoagulability of the blood (the so-called Virchow triad)
Virchow’s Triad
Endothelian injury (Hypercholesterolemia)
Abnormal Blood Flow (Stasis, turbulence)
hypercoaguability (Inherited- V leiden, disemminated cancer)
Endothelial Injury
Endothelial injury leading to platelet activation almost inevitably underlies thrombus formation in the heart and the arterial circulation, where the high rates of blood flow impede clot formation
cardiac and arterial clots are
rich in platelets, and it is believed that platelet adherence and activation is a necessary prerequisite for thrombus formation under high shear stress, such as exists in arteries.
Why use aspirin in MI and CAD?
cardiac and arterial clots are typically rich in platelets, and it is believed that platelet adherence and activation is a necessary prerequisite for thrombus formation under high shear stress, such as exists in arteries. This insight provides part of the reasoning behind the use of aspirin and other platelet inhibitors in coronary artery disease and acute myocardial infarction
severe endothelial injury may trigger thrombosis by
exposing vWF and tissue factor. However, inflammation and other noxious stimuli also promote thrombosis by shifting the pattern of gene expression in endothelium to one that is “prothrombotic.
endothelial activation or dysfunction and can be produced by
including physical injury, infectious agents, abnormal blood flow, inflammatory mediators, metabolic abnormalities, such as hypercholesterolemia or homocystinemia, and toxins absorbed from cigarette smoke. Endothelial activation is believed to have an important role in triggering arterial thrombotic events.
Procoagulant changes.
Endothelial cells activated by cytokines downregulate the expression of thrombomodulin, already described as a key modulator of thrombin activity. This may result in sustained activation of thrombin, which can in turn stimulate platelets and augment inflammation through PARs expressed on platelets and inflammatory cells. In addition, inflamed endothelium also downregulates the expression of other anticoagulants, such as protein C and tissue factor protein inhibitor, changes that further promote a procoagulant state
Antifibrinolytic effects
Activated endothelial cells secrete plasminogen activator inhibitors (PAIs), which limit fibrinolysis, and downregulate the expression of t-PA, alterations that also favor the development of thrombi.
Turbulence
contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents that contribute to local pockets of stasis.
Stasis is a major contributor in the development of
venous thrombi
Alternations in Normal Blood Flow
Promote endothelial activation, enhancing procoagulant activity and leukocyte adhesion, in part through flow-induced changes in the expression of adhesion molecules and pro-inflammatory factors
• Disrupt laminar flow and bring platelets into contact with the endothelium •
Prevent washout and dilution of activated clotting factors by
Ulcerated atherosclerotic plaques
xpose subendothelial vWF and tissue factor but also cause turbulence
Aortic and arterial dilations called aneurysms result in
local stasis and are therefore fertile sites for thrombosis
Acute myocardial infarctions result in areas of noncontractile myocardium and sometimes in cardiac aneurysms;
both are associated with stasis and flow abnormalities that promote the formation of cardiac mural thrombi
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 thrombosis
Hyperviscosity
(such as is seen with polycythemia vera; Chapter 13) increases resistance to flow and causes small vessel stasis, and the deformed red cells in sickle cell anemia (Chapter 14) impede blood flow through small vessels, with the resulting stasis also predisposing to thrombosis.
Hypercoagulability
Hypercoagulability (also called thrombophilia) can be loosely defined as any disorder of the blood that predisposes to thrombosis
Hypercoagulability has a particularly important role in
venous thrombosis and can be divided into primary (genetic) and secondary (acquired) disorders
. Of the inherited causes of hypercoagulability, point mutations
in the factor V gene and prothrombin gene are the most common
• Approximately 2% to 15% of Caucasians carry a
single-nucleotide mutation in factor V that is called the factor V Leiden, after the city in The Netherlands where it was discovered
Among individuals with recurrent DVT, the frequency of this mutation is considerably higher, approaching 60%. The mutation results in a glutamine to arginine substitution at amino acid residue 506 that renders factor V resistant to cleavage and inactivation by protein C. As a result, an important antithrombotic counterregulatory pathway is lost (Fig. 4-10)
another common mutation (1% to 2% of the population) associated with hypercoagulability. It leads to elevated prothrombin levels and an almost three-fold increased risk of venous thrombosis.
A single nucleotide change (G20210A) in the 3′-untranslated region of the prothrombin gene
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. Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione β-synthetase
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 in adolescence or early adulthood
factor V Leiden heterozygosity may trigger
DVT
inherited causes of hypercoagulability must be considered in patients younger than
age 50 years who present with thrombosis—even when acquired risk factors are present.
Unlike hereditary disorders, the pathogenesis of acquired thrombophilia is
frequently multifactorial
Hypercoagulability due to oral contraceptive use or the hyperestrogenic state of pregnancy is probably caused by
increased hepatic synthesis of coagulation factors and reduced anticoagulant synthesis. In disseminated cancers, release of various procoagulants from tumors predisposes to thrombosis
hypercoagulability seen with advancing age may be due to
Reduced Endothelial PGI2
Heparin-Induced Thrombocytopenia (HIT) Syndrome
has a distinctive pathogenesis and is of particular importance because of its potential for severe clinical consequences. Thrombocytopenia occurs in about 5% of persons receiving heparin and is of two types: • Type I thrombocytopenia occurs rapidly after the onset of therapy and is of little clinical importance, sometimes resolving despite the continuation of therapy. It most likely results from a direct platelet-aggregating effect of heparin. • Type II thrombocytopenia is less common but of much greater clinical significance. It occurs 5 to 14 days after therapy begins
This severe form of HIT is caused by
antibodies that recognize complexes of heparin and platelet factor 4, which is a normal component of platelet granules. Binding of antibody to these complexes activates platelets and promotes thrombosis, even in the setting of thrombocytopenia. Unless therapy is immediately discontinued and an alternative nonheparin anticoagulant instituted, clots within large arteries may lead to vascular insufficiency and limb loss, and emboli from deep venous thrombosis can cause fatal pulmonary thromboembolism
The risk of severe HIT is lowered, but not completely eliminated, by the use of
low-molecular-weight heparin preparations. Unfortunately, once severe HIT develops even low-molecular-weight heparins exacerbate the thrombotic tendency and must be avoided.
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome
Depending on the vascular bed involved, the clinical presentations can include
PE
LOWER EX THROMB
PUL HYP
Stroke
BOwel infarct
Renovascular Hypertension
Fetal loss does not appear to be explained by thrombosis, but rather seems to stem from
antibody-mediated interference with the growth and differentiation of trophoblasts, leading to a failure of placentation.
Antiphospholipid antibody syndrome is also a cause of renal microangiopathy,
resulting in renal failure associated with multiple capillary and arterial thromboses
Suspected antibody targets include
e β2-glycoprotein I, a plasma protein that associates with the surfaces of endothelial cells and trophoblasts, and thrombin. In vivo, it is suspected that these antibodies bind to these and perhaps other proteins, thereby inducing a hypercoagulable state through uncertain mechanisms
The antibodies also frequently give a false-positive serologic test for syphilis because
the antigen in the standard assay is embedded in cardiolipin
Antiphospholipid antibody syndrome has primary and secondary forms. Individuals with a well-defined autoimmune disease, such as
systemic lupus erythematosus (
Morphology Thrombi
can develop anywhere in the cardiovascular system and vary in size and shape depending on the involved site and the underlying cause
Arterial or cardiac thrombi vs venous Thrombi
usually begin at sites of turbulence or endothelial injury, whereas venous thrombi characteristically occur at sites of stasis.
arterial thrombi tend to grow
retrograde, while venous thrombi extend in the direction of blood flow; thus both propagate toward the heart.
The propagating portion of a thrombus is often poorly attached and therefore prone to
fragmentation and embolization
lines of Zahn
which are 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 clots from the bland nonlaminated clots that occur postmortem (see later).
Thrombi occurring in heart chambers or in the aortic lumen are designated
Mural thrombi
promotes cardiac mural thrombi
Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) or endomyocardial injury (myocarditis or catheter trauma)
ulcerated atherosclerotic plaque and aneurysmal dilation are the precursors of
aortic thrombi
Arterial thrombi are frequently
occlusive; the most common sites in decreasing order of frequency are the coronary, cerebral, and femoral arteries. They typically consist of a friable meshwork of platelets, fibrin, red cells, and degenerating leukocytes
Venous thrombosis (phlebothrombosis)
almost invariably occlusive, with the thrombus forming a long luminal cast. 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
Venous thrombi are firm, are focally attached to the vessel wall, and contain
lines of Zahn, features that help distinguish them from postmortem clots
The veins of the lower extremities are most commonly involved (90% of cases)
Venous Thrombi
Postmortem clots
can sometimes be mistaken for antemortem venous thrombi. However, clots that form after death are gelatinous and have a dark red dependent portion where red cells have settled by gravity and a yellow “chicken fat” upper portion, and are usually not attached to the underlying vessel wall.
Thrombi on heart valves are called
Vegetations
Bloodborne bacteria or fungi can adhere to previously damaged valves (e.g., due to rheumatic heart disease) or can directly cause valve damage; in either case, endothelial injury and disturbed blood flow can induce the formation of large thrombotic masses
infective endocarditis;
Sterile vegetations can also develop on noninfected valves in persons with hypercoagulable states, so-called
Sterile vegetations can also develop on noninfected valves in persons with hypercoagulable states, so-called
Less commonly, sterile verrucous endocarditis
(Libman-Sacks endocarditis) can occur in the setting of systemic lupus erythematosus
Fate of the Thrombus
If a patient survives the initial thrombosis, in the ensuing days to weeks thrombi undergo some combination of the following four events:
- Propagation
- Embolization
- Dissolution
- Organization and Recanalization
Propagation.
hrombi accumulate additional platelets and fibrin (discussed earlier).
Embolization
Thrombi dislodge and travel to other sites in the vasculature
Dissolution
Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi. In contrast, the extensive fibrin deposition and crosslinking in older thrombi renders them more resistant to lysis.
This distinction explains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in the setting of acute coronary thrombosis)
is generally effective only when given during the first few hours of a thrombotic event
Organization and recanalization
Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts (Fig. 4-14). Capillary channels eventually form that reestablish the continuity of the original lumen, albeit to a variable degree. Continued recanalization may convert a thrombus into a smaller mass of connective tissue that becomes incorporated into the vessel wall. Eventually, with remodeling and contraction of the mesenchymal elements, only a fibrous lump may remain to mark the original thrombus.
of lysosomal enzymes from trapped leukocytes and platelets. In the setting of bacteremia, such thrombi may become infected, producing an inflammatory mass that erodes and weakens the vessel wall. If unchecked, this may result in a
mycotic aneurysm
, although arterial thrombi can also embolize and cause downstream infarctions, the chief clinical problem is more often related to
occlusion of a critical vessel (e.g., a coronary or cerebral artery), which can have serious or fatal consequences.
Venous Thrombosis (Phlebothrombosis)
Most venous thrombi occur in the superficial or deep veins of the leg. Superficial venous thrombi typically occur in the saphenous veins in the setting of varicosities. Such thrombi can cause local congestion, swelling, pain, and tenderness, but rarely embolize. Nevertheless, the associated edema and impaired venous drainage predispose the overlying skin to the development of infections and ulcers (varicose ulcers). Deep venous thrombosis (DVT) involving one of the large leg veins—at or above the knee (e.g., the popliteal, femoral, and iliac veins)— is more serious because such thrombi more often embolize to the lungs and give rise to pulmonary infarction
Tumor-associated inflammation and coagulation factors (tissue factor, factor VIII), as well as 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. Regardless of the specific clinical setting, advanced age also increases the risk of DVT.
Arterial and Cardiac Thrombosis
Atherosclerosis is a major cause of arterial thromboses because it is associated with loss of endothelial integrity and with abnormal blood flow (Fig. 4-13B). Myocardial infarction can predispose to cardiac mural thrombi by causing dyskinetic myocardial contraction and endocardial injury (Fig. 4-13A), and rheumatic heart disease may engender atrial mural thrombi by causing atrial dilation and fibrillation. Both cardiac and aortic mural thrombi are prone to embolization. Although any tissue can be affected, the brain, kidneys, and spleen are particularly likely targets because of their rich blood supply
Disseminated Intravascular Coagulation
DIC is not a specific disease but rather a complication of a large number of conditions associated with systemic activation of thrombin.
Disorders ranging from obstetric complications to advanced malignancy can be complicated by
DIC
runaway thrombosis
“uses up” platelets and coagulation factors (hence the synonym consumptive coagulopathy) and often activates fibrinolytic mechanisms. Thus, symptoms initially related to thrombosis can evolve into a bleeding catastrophe, such as hemorrhagic stroke or hypovolemic shock.
DIC is discussed in greater detail along with other bleeding diatheses
Ch 14
Embolism
An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction.
The vast majority of emboli are
dislodged thrombi, hence the term thromboembolism
Other rare emboli are composed of fat droplets, nitrogen bubbles, atherosclerotic debris (cholesterol emboli), tumor fragments, bone marrow, or even foreign bodies.
Pulmonary Embolism
Pulmonary emboli originate from deep venous thromboses and are the most common form of thromboembolic disease.
Fragmented thrombi from DVTs are
carried through progressively larger veins 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
l, the patient who has had one PE is at high risk for more. Rarely, a venous embolus passes through an interatrial or interventricular defect and gains access to the systemic arterial circulation
paradoxical embolism
paradoxical embolism
Rarely, a venous embolus passes through an interatrial or interventricular defect and gains access to the systemic arterial circulation
Most pulmonary emboli (60% to 80%) are clinically silent
because they are small. 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.
Sudden death, right heart failure (cor pulmonale), or cardiovascular collapse occurs when emboli obstruct
60% or more of the pulmonary circulation.
Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in
pulmonary hemorrhage but usually does not cause pulmonary infarction
Understandably, if the bronchial arterial flow is compromised
by left-sided cardiac failure), infarction may occur.
Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in pulmonary hemorrhage but usually does not cause pulmonary infarction.
because the lung is supplied by both the pulmonary arteries and the bronchial arteries, and the intact bronchial circulation is usually sufficient to perfuse the affected area
Embolic obstruction of small end-arteriolar pulmonary branches often does produce
Embolic obstruction of small end-arteriolar pulmonary branches often does produce
Multiple emboli over time may cause
pulmonary hypertension and right ventricular failure
Systemic Thromboembolism
Most systemic emboli (80%) arise from intracardiac mural thrombi, two thirds of which are associated with left ventricular wall infarcts and another one fourth with left atrial dilation and fibrillation
The remainder originates from (Systemic Thromboembolism)
m aortic aneurysms, atherosclerotic plaques, valvular vegetations, or venous thrombi (paradoxical emboli); 10% to 15% are of unknown origin.
In contrast to venous emboli, the vast majority of which lodge in the lung, arterial emboli can travel to a wide variety of sites
he point of arrest depends on the source and the relative amount of blood flow that downstream tissues receive. Most come to rest in the lower extremities (75%) or the brain (10%), but other tissues, including the intestines, kidneys, spleen, and upper extremities, may be involved on occasion. The consequences of systemic emboli depend on the vulnerability of the affected tissues to ischemia, the caliber of the occluded vessel, and whether a collateral blood supply exists; in general, however, the outcome is tissue infarction
Fat and Marrow Embolism
Microscopic fat globules—sometimes with associated hematopoietic bone marrow—can be found in the pulmonary vasculature after fractures of long bones or, rarely, in the setting of soft tissue trauma and burns.
Soft tissue trauma and burns. Presumably these injuries
rupture vascular sinusoids in the marrow or small venules, allowing marrow or adipose tissue to herniate into the vascular space and travel to the lung. Fat and marrow emboli are very common incidental findings after vigorous cardiopulmonary resuscitation and are probably of no clinical consequence
fat embolism occurs in some 90% of individuals with
severe skeletal injuries (Fig. 4-16), but less than 10% of such patients have any clinical findings.
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.
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.
The pathogenesis of fat emboli syndrome probably involves
both mechanical obstruction and biochemical injury
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 typically requires specialized techniques, including frozen sections and stains for fat.
Air Embolism
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,”
A larger volume of air, generally more than
100 cc, Fatal- 300-500ml
this volume of air can be inadvertently introduced during
obstetric or laparoscopic procedures, or as a consequence of chest wall injury.
A particular form of gas embolism, called decompression sickness
occurs when individuals experience sudden decreases in atmospheric pressure. 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
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. 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 (so named in the 1880s because it was noted that those afflicted characteristically arched their backs in a manner reminiscent of a then-popular women’s fashion pose called the Grecian bend)
In the lungs, gas bubbles in the vasculature cause edema, hemorrhage, and focal atelectasis or emphysema, leading to a form of respiratory distress called
chokes
A more chronic form of decompression sickness is called
Caisson disease (named for the pressurized vessels used in bridge construction; workers in these vessels suffered both acute and chronic forms of decompression sickness)
In caisson disease
ersistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis; the more common sites are the femoral heads, tibia, and humeri.
Individuals affected by acute decompression sickness are treated by
being placed in a chamber under sufficiently high pressure to force the gas bubbles back into solution. Subsequent slow decompression permits gradual resorption and exhalation of the gases, which prevents the obstructive bubbles from reforming.
Amniotic Fluid Embolism
Amniotic fluid embolism is 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
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%.
The onset is characterized by (Amniotic embolism)
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, frequently accompanied by disseminated intravascular coagulation
much of the morbidity and mortality in amniotic fluid embolism may stem from the
biochemical activation of coagulation factors and components of the innate immune system by substances in the amniotic fluid, rather than the mechanical obstruction of pulmonary vessels by amniotic debris
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 at autopsy include the presence of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract in the maternal pulmonary microvasculature (Fig. 4-17). Other findings include marked pulmonary edema, diffuse alveolar damage (Chapter 15), and the presence of fibrin thrombi in many vascular beds due to disseminated intravascular coagulation
Infarction
An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage
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.
Arterial thrombosis or arterial embolism underlies
vast majority of infarctions. Less common causes of arterial obstruction leading to infarction include local vasospasm, hemorrhage into an atheromatous plaque, or extrinsic vessel compression (e.g., by tumor). Other uncommon causes of tissue infarction include torsion of a vessel (e.g., in testicular torsion or bowel volvulus), traumatic vascular rupture, or vascular compromise by edema (e.g., anterior compartment syndrome) or by entrapment in a hernia sac
Although venous thrombosis can cause infarction, the more common outcome is just
congestion; in this setting, bypass channels rapidly open and permit vascular outflow, which then improves arterial inflow. Infarcts caused by venous thrombosis are thus more likely in organs with a single efferent vein (e.g., testis and ovary).
Morphology Infarcts are classified according to color and the presence or absence of infection; they are either
red (hemorrhagic) or white (anemic) and may be septic or bland
Red infarcts
(1) with venous occlusions (e.g., testicular torsion, Chapter 19),
(2) in loose, spongy 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 to flow from an unobstructed parallel supply into a necrotic zone,
(4) in tissues previously congested by sluggish venous outflow, and
(5) when flow is reestablished to a site of previous arterial occlusion and necrosis (e.g., following angioplasty of an arterial obstruction).
White infarcts
occur with arterial occlusions in solid organs with end-arterial circulation (e.g., heart, spleen, and kidney), and where tissue density limits the seepage of blood from adjoining capillary beds into the necrotic area.
nfarcts tend to be wedge-shaped, with the occluded vessel at the apex and the periphery of the organ forming the base (Fig. 4-18); when the base is a serosal surface there may be an overlying fibrinous exudate resulting from an acute inflammatory response to mediators release from injured and necrotic cells.
Fresh infarcts are poorly defined and slightly hemorrhagic, but over a few days the margins tend to become better defined by a
narrow rim of congestion attributable to inflammation. With further passage of time, infarcts resulting from arterial occlusions in organs without a dual blood supply typically become progressively paler and more sharply defined (Fig. 4-18B). In comparison, in the lung hemorrhagic infarcts are the rule
Extravasated red cells in hemorrhagic infarcts are
phagocytosed by macrophages, which convert heme iron into hemosiderin; small amounts do not grossly impart any appreciable color to the tissue, but extensive hemorrhage can leave a firm, brown hemosiderin-rich residuum
The dominant histologic characteristic of infarction is
ischemic coagulative necrosis
the vascular occlusion has occurred shortly (minutes to hours) before the death of the person, histologic changes may be absent
it takes 4 to 12 hours for the dead tissue to show microscopic evidence of frank necrosis. Acute inflammation is present along the margins of infarcts within a few hours and is usually well defined within 1 to 2 days. Eventually a reparative response begins in the preserved margins
In stable or labile tissues
parenchymal regeneration can occur at the periphery where underlying stromal architecture is preserved. However, most infarcts are ultimately replaced by scar (Fig. 4-19). The brain is an exception to these generalizations, in that central nervous system infarction results in liquefactive necrosis
Septic infarctions
occur when infected cardiac valve vegetations embolize or when microbes seed necrotic tissue. In these cases the infarct is converted into an abscess, with a correspondingly greater inflammatory response (Chapter 3). The eventual sequence of organization, however, follows the pattern already described.
Factors That Influence Development of an Infarct.
A vascular occlusion can cause effects ranging from virtually nothing to tissue dysfunction and necrosis sufficient to result in death.
Anatomy of the vascular supply
The availability of an alternative blood supply is the most important determinant of whether vessel occlusion will cause tissue damage. As mentioned, the lungs have a dual pulmonary and bronchial artery blood supply that protects against thromboembolisminduced infarction. Similarly, the liver, with its dual hepatic artery and portal vein circulation, and the hand and forearm, with their dual radial and ulnar arterial supply, are all relatively resistant to infarction. In contrast, renal and splenic circulations are end-arterial, and vascular obstruction generally causes tissue death
Rate of occlusion.
Slowly developing occlusions are less likely to cause infarction, because they provide time for development of collateral pathways of perfusion. 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 occluded slowly (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.
Tissue vulnerability to hypoxia
Neurons undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes. Myocardial cells, although hardier than neurons, are also quite sensitive and die after only 20 to 30 minutes of ischemia (although, as mentioned, changes in the appearance of the dead cells take 4-12 hours to develop). In contrast, fibroblasts within myocardium remain viable even after many hours of ischemia (Chapter 12).
Hypoxemia
Understandably, abnormally low blood O2 content (regardless of cause) increases both the likelihood and extent of infarction
Shock
Shock is a state in which diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to cellular hypoxia
t the outset the cellular injury is reversible; however
prolonged shock eventually leads to irreversible tissue injury and is often fatal. Shock may complicate severe hemorrhage, extensive trauma or burns, myocardial infarction, pulmonary embolism, and microbial sepsis
Its causes fall into three general categories
- Cardiogenic
- hypovolemic
- Shock-associated with systemic inflammation
Cardiogenic shock
results from low cardiac output due to myocardial pump failure. This can be due to intrinsic myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac tamponade; Chapter 11), or outflow obstruction (e.g., pulmonary embolism).
Hypovolemic shock
k results from low cardiac output due to low blood volume, such as can occur with massive hemorrhage or fluid loss from severe burns
Shock associated with systemic inflammation
may be triggered by a variety of insults, particularly microbial infections, burns, trauma, and or pancreatitis. The common pathogenic feature is a massive outpouring of inflammatory mediators from innate and adaptive immune cells that produce arterial vasodilation, vascular leakage, and venous blood pooling. These cardiovascular abnormalities result in tissue hypoperfusion, cellular hypoxia, and metabolic derangements that lead to organ dysfunction and, if severe and persistent, organ failure and death. It should be noted that diverse triggers of shock (microbial and non-microbial) associated with inflammation produce a similar set of clinical findings, which are referred to as the systemic inflammatory response syndrome. The pathogenesis of shock caused by microbial infection (septic shock) is discussed in detail below
neurogenic shock
Less commonly, shock can occur in the setting of an anesthetic accident or a spinal cord injury
an IgE– mediated hypersensitivity reaction
Anaphylactic shock
Pathogenesis of Septic Shock
Its incidence is rising, ironically due to improvements in life support for critically ill patients, as well as the growing ranks of immunocompromised hosts (due to chemotherapy, immunosuppression, advanced age or HIV infection) and the increasing prevalence of multidrug resistant organisms in the hospital setting.
Septic shock is most frequently triggered by
gram-positive bacterial infections, followed by gram-negative bacteria and fungi. Hence, an older synonym, “endotoxic shock”, is no longer appropriate
Factors believed to play major roles in the pathophysiology of septic shock include the following:
Inflammatory and counter-inflammatory responses\
Endothelial activation and injury
Induction of a procoagulant state
Metabolic abnormalities
Organ dysfunction
WaterhouseFriderichsen syndrome
This may stem from depression of the synthetic capacity of intact adrenal glands or frank adrenal necrosis due to disseminated intravascular dissemination
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; and the 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 failed to be effective and may even have had deleterious effects in some cases.
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).
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, suggesting that organ failure secondary to edema and the attendant tissue hypoxia has a central role
initial nonprogressive phase
during which reflex compensatory mechanisms are activated and perfusion of vital organs is maintained
A progressive stage
characterized by tissue hypoperfusion and onset of worsening circulatory and metabolic imbalances, including lactic acidosis
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
Clinical Consequences.
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. 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, shock begets cardiac, cerebral, and pulmonary dysfunction, and eventually electrolyte disturbances and metabolic acidosis exacerbate the dire state of the patient further
a variety of neurohumoral mechanisms help to maintain
cardiac output and blood pressure. These include baroreceptor reflexes, catecholamine release, activation of the renin-angiotensin axis, ADH release, and generalized sympathetic stimulation. The net effect is tachycardia, peripheral vasoconstriction, and renal conservation of fluid.
Cutaneous vasoconstriction,
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
ersistent oxygen deficit, intracellular aerobic respiration is replaced by anaerobic glycolysis with excessive production of lactic acid. The resulting 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 endothelial cells at risk for developing anoxic injury with subsequent disseminated intravascular coagulation
Widespread cell injury is reflected in
lysosomal enzyme leakage, further aggravating the shock state. If ischemic bowel allows intestinal flora to enter the circulation, bacteremic septic shock may be superimposed.
At this point the patient may develop anuria as a result of acute tubular necrosis and renal failure (Chapter 20), and despite heroic measures the downward clinical spiral almost inevitably culminates in death
