4 Hemodynamic Disorders, Thromboembolic Disease, and Shock

Richard N. Mitchell
As a group, cardiovascular diseases are the most important cause of morbidity and mortality in
Western society. In the year 2005, it was estimated that 81 million people in the United States
had one or more forms of cardiovascular disease, which were responsible for 35% to 40% of
deaths. Included in this category are diseases that primarily affect one of the three major
components of the cardiovascular system: the heart; the blood vessels; and the blood itself,
which is composed of water, salts, a wide variety of proteins, elements that regulate clotting (the
coagulation factors and platelets), and other formed elements (red cells and white cells). For the
sake of simplicity we will consider disorders affecting each component of the cardiovascular
system separately, recognizing that disturbances affecting one component often lead to
adaptations and abnormalities involving others. Here, we focus on disorders of hemodynamics
(edema, congestion, and shock) and hemostasis (hemorrhage and thrombosis), as well as various
forms of embolism. Diseases that primarily affect the blood vessels and the heart will be
discussed in Chapters 11 and 12, respectively.
Edema
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Approximately 60% of lean body weight is water. Two thirds of the body's water is intracellular,
and the remainder is in extracellular compartments, mostly the interstitium (or third space) that
lies between cells; only about 5% of total body water is in blood plasma. The movement of water
and low molecular weight solutes such as salts between the intravascular and interstitial spaces is
controlled primarily by the opposing effect of vascular hydrostatic pressure and plasma colloid
osmotic pressure. Normally the outflow of fluid from the arteriolar end of the microcirculation
into the interstitium is nearly balanced by inflow at the venular end; a small residual amount of
fluid may be left in the interstitium and is drained by the lymphatic vessels, ultimately returning
to the bloodstream via the thoracic duct. Either increased capillary pressure or diminished
colloid osmotic pressure can result in increased interstitial fluid (Fig. 4-1). If the movement of
water into tissues (or body cavities) exceeds lymphatic drainage, fluid accumulates. An abnormal
increase in interstitial fluid within tissues is called edema, while fluid collections in the different
body cavities are variously designated hydrothorax, hydropericardium, and hydroperitoneum
(the last is more commonly called ascites). Anasarca is a severe and generalized edema with
widespread subcutaneous tissue swelling.
Table 4-1. Pathophysiologic Categories of Edema
INCREASED HYDROSTATIC PRESSURE

Impaired venous return

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

Neurohumoral dysregulation

REDUCED PLASMA OSMOTIC PRESSURE (HYPOPROTEINEMIA)

Protein-losing glomerulopathies (nephrotic syndrome)

Liver cirrhosis (ascites)
Malnutrition
Protein-losing gastroenteropathy
LYMPHATIC OBSTRUCTION

Inflammatory
Neoplastic
Postsurgical
Postirradiation
SODIUM RETENTION

Excessive salt intake with renal insufficiency

Increased tubular reabsorption of sodium
o Renal hypoperfusion
o Increased renin-angiotensin-aldosterone secretion
INFLAMMATION

Acute inflammation
Chronic inflammation
Angiogenesis

Modified from Leaf A, Cotran RS: Renal Pathophysiology, 3rd ed. New York, Oxford
University Press, 1985, p 146.

Figure 4-1 Factors influencing fluid transit across capillary walls. Capillary hydrostatic and
osmotic forces are normally balanced so that there is no net loss or gain of fluid across the
capillary bed. However, increased hydrostatic pressure or diminished plasma osmotic pressure
will cause extravascular fluid to accumulate. Tissue lymphatics remove much of the excess
volume, eventually returning it to the circulation via the thoracic duct; however, if the capacity
for lymphatic drainage is exceeded, tissue edema results.
There are several pathophysiologic categories of edema (Table 4-1). Edema caused by increased
hydrostatic pressure or reduced plasma protein is typically a protein-poor fluid called a
transudate. Edema fluid of this type is seen in patients suffering from heart failure, renal failure,

hepatic failure, and certain forms of malnutrition, as described below and outlined in Figure 4-2.
In contrast, inflammatory edema is a protein-rich exudate that is a result of increased vascular
permeability. Edema in inflamed tissues is discussed in Chapter 2; noninflammatory causes of
edema (see Fig. 4-2) are described below.
Increased Hydrostatic Pressure
Regional increases in hydrostatic pressure can result from a focal impairment in venous return.
Thus, deep venous thrombosis in a lower extremity may cause localized edema in the affected
leg. On the other hand, generalized increases in venous pressure, with resulting systemic edema,
occur most commonly in congestive heart failure (Chapter 12), where compromised right
ventricular function leads to pooling of blood on the venous side of the circulation.
Reduced Plasma Osmotic Pressure
Reduced plasma osmotic pressure occurs when albumin, the major plasma protein, is not
synthesized in adequate amounts or is lost from the circulation. An important cause of albumin
loss is the nephrotic syndrome (Chapter 20), in which glomerular capillaries become leaky;
patients typically present with generalized edema. Reduced albumin synthesis occurs in the
setting of severe liver diseases (e.g., cirrhosis, Chapter 18) or protein malnutrition (Chapter 9). In
each case, reduced plasma osmotic pressure leads to a net movement of fluid into the interstitial
tissues with subsequent plasma volume contraction. The reduced intravascular volume leads to
decreased renal perfusion. This triggers increased production of renin, angiotensin, and
aldosterone, but the resulting salt and water retention cannot correct the plasma volume deficit
because the primary defect of low serum protein persists.
Sodium and Water Retention
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Figure 4-2 Pathways leading to systemic edema from primary heart failure, primary renal failure,
or reduced plasma osmotic pressure (e.g., from malnutrition, diminished hepatic synthesis, or
protein loss from nephrotic syndrome).
Salt and water retention can also be a primary cause of edema. Increased salt retention-with
obligate associated water-causes both increased hydrostatic pressure (due to intravascular fluid
volume expansion) and diminished vascular colloid osmotic pressure (due to dilution). Salt
retention occurs whenever renal function is compromised, such as in primary disorders of the
kidney and disorders that decrease renal perfusion. One of the most important causes of renal
hypoperfusion is congestive heart failure, which (like hypoproteinemia) results in the activation
of the renin-angiotensin-aldosterone axis. In early heart failure, this response tends to be
beneficial, as the retention of sodium and water and other adaptations, including increased
vascular tone and elevated levels of antidiuretic hormone (ADH), improve cardiac output and
restore normal renal perfusion.1,2 However, as heart failure worsens and cardiac output
diminishes, the retained fluid merely increases the venous pressure, which (as already
mentioned) is a major cause of edema in this disorder. Unless cardiac output is restored or renal
sodium and water retention is reduced (e.g., by salt restriction, diuretics, or aldosterone
antagonists), a downward spiral of fluid retention and worsening edema ensues. Salt restriction,
diuretics, and aldosterone antagonists are also of value in managing generalized edema arising

from other causes. Primary retention of water (and modest vasoconstriction) is produced by the
release of ADH from the posterior pituitary, which normally occurs in the setting of reduced
plasma volumes or increased plasma osmolarity.2 Inappropriate increases in ADH are seen in
association with certain malignancies and lung and pituitary disorders and can lead to
hyponatremia and cerebral edema (but interestingly not to peripheral edema).
Lymphatic Obstruction
Impaired lymphatic drainage results in lymphedema that is typically localized; causes include
chronic inflammation with fibrosis, invasive malignant tumors, physical disruption, radiation
damage, and certain infectious agents. One dramatic example is seen in parasitic filariasis, in
which lymphatic obstruction due to extensive inguinal lymphatic and lymph node fibrosis can
result in edema of the external genitalia and lower limbs that is so massive as to earn the
appellation elephantiasis. Severe edema of the upper extremity may also complicate surgical
removal and/or irradiation of the breast and associated axillary lymph nodes in patients with
breast cancer.
Hyperemia and Congestion
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Hyperemia and congestion both stem from locally increased blood volumes. Hyperemia is an
active process in which arteriolar dilation (e.g., at sites of inflammation or in skeletal muscle
during exercise) leads to increased blood flow. Affected tissues turn red (erythema) because of
the engorgement of vessels with oxygenated blood. Congestion is a passive process resulting
from reduced outflow of blood from a tissue. It can be systemic, as in cardiac failure, or local, as
in isolated venous obstruction. Congested tissues take on a dusky reddish-blue color (cyanosis)
due to red cell stasis and the accumulation of deoxygenated hemoglobin.
As a result of the increased volumes and pressures, congestion commonly leads to edema. In
long-standing chronic passive congestion, the lack of blood flow causes chronic hypoxia,
potentially resulting in ischemic tissue injury and scarring. Capillary rupture in chronic
congestion can also cause small hemorrhagic foci; subsequent catabolism of extravasated red
cells can leave residual telltale clusters of hemosiderin-laden macrophages
Hemorrhage
Hemorrhage is defined as the extravasation of blood into the extravascular space. As described above,
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.

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

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.

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

Hemostasis and Thrombosis

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
NORMAL HEMOSTASIS
The general sequence of events in hemostasis at a site of vascular injury is shown in Figure 45.3,4

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

reflex neurogenic mechanisms and augmented by the local secretion of factors such as
endothelin (a potent endothelium-derived vasoconstrictor; Fig. 4-5A). The effect is
transient, however, and bleeding would resume if not for activation of the platelet and
coagulation systems.
Endothelial injury exposes highly thrombogenic subendothelial extracellular matrix
(ECM), facilitating platelet adherence and activation. 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 (Fig. 4-5B).
Tissue factor is also exposed at the site of injury. Also known as factor III and
thromboplastin, tissue factor is a membrane-bound procoagulant glycoprotein
synthesized by endothelial cells. It acts in conjunction with factor VII (see below) as the
major in vivo initiator of the coagulation cascade, eventually culminating in thrombin
generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin
meshwork, and also induces additional platelet recruitment and activation. This sequence,
secondary hemostasis, consolidates the initial platelet plug (Fig. 4-5C).
Polymerized fibrin and platelet aggregates form a solid, permanent plug to prevent any
further hemorrhage. At this stage, counter-regulatory mechanisms (e.g., tissue
plasminogen activator, t-PA) are set into motion to limit the hemostatic plug to the site of
injury

THROMBOSIS
three 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.

Endothelial Injury
Endothelial injury is particularly important for thrombus formation in the heart or the arterial
circulation, 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. 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). Endothelial dysfunction can be induced by a wide variety of
insults, including hypertension, turbulent blood flow, bacterial endotoxins, radiation injury,
metabolic abnormalities such as homocystinemia or hypercholesterolemia, and toxins absorbed
from cigarette smoke.
Alterations in Normal Blood Flow
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Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or
dysfunction, as well as by forming countercurrents and local pockets of stasis; stasis is a major
contributor in the development of venous thrombi.25 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. Stasis and turbulence therefore:

Promote endothelial activation, enhancing pro-coagulant 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 endothelium26
Prevent washout and dilution of activated clotting factors by fresh flowing blood and the
inflow of clotting factor inhibitors

Hypercoagulability
Table 4-2. Hypercoagulable States
PRIMARY (GENETIC)
Common

Factor V mutation (G1691A mutation; factor V Leiden)

Prothrombin mutation (G20210A variant)
5,10-Methylenetetrahydrofolate reductase (homozygous C677T mutation)
Increased levels of factors VIII, IX, XI, or fibrinogen
Rare

Antithrombin III deficiency

Protein C deficiency
Protein S deficiency
Very Rare

Fibrinolysis defects
Homozygous homocystinuria (deficiency of cystathione -synthetase)

SECONDARY (ACQUIRED)

High Risk for Thrombosis

Prolonged bedrest or immobilization

Myocardial infarction
Atrial fibrillation
Tissue injury (surgery, fracture, burn)
Cancer
Prosthetic cardiac valves
Disseminated intravascular coagulation
Heparin-induced thrombocytopenia
Antiphospholipid antibody syndrome
Lower Risk for Thrombosis

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

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

Propagation. Thrombi accumulate additional platelets and fibrin. This process was
discussed earlier.
Embolization. Thrombi dislodge and travel to other sites in the vasculature. This process
is described below.
Dissolution. Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkage
and total disappearance of recent thrombi. In contrast, the extensive fibrin deposition and
crosslinking in older thrombi renders them more resistant to lysis. This distinction
explains why therapeutic administration of fibrinolytic agents such as t-PA (e.g., in the
setting of acute coronary thrombosis) is generally effective only when given in the first
few hours of a thrombotic episode.
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 re-establish the continuity of the original lumen, albeit to a variable
degree.
Although the earliest capillary channels may not restore significant flow to obstructed
vessels, 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. Occasionally the centers of thrombi undergo
enzymatic digestion, presumably as a result of the release 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