Hemodynamic Disorders, Thromboembolic Disease and Shock

PATHOLOGY Robbins and Cotran: Chapter 4 Hemodynamic Disorders, Thromboembolic Diseases, and Shock 1
Guia, Alexa M. 2D
CHAPTER 4 HEMODYNAMIC DISORDERS, THROMBOEMBOLIC DISEASE,
AND SHOCK

Hemodynamic Disorders
Edema
Congestion
Shock
Hemostatic Disorders
Hemorrhage
Thrombosis
Embolism

EDEMA
Water = 60% of lean body weight
2/3 of the bodys water = intracellular compartment
1/3 of the bodys water = extracellular compartment
5% of total body water = blood plasma
*** The movement of water and low molecular weight solutes is controlled
primarily by the opposing effect of vascular hydrostatic pressure and plasma
colloid osmotic pressure.
Increased Interstitial Fluid
Due to either increased capillary pressure or diminished colloid
osmotic pressure.
Edema
An abnormal increase in interstitial fluid within tissues
Fluid collections in different body cavities:
Hydrothorax
Hydropericardium
Hydroperitoneum (Ascites)
Anasarca
Severe and generalized edema with wide spread subcutaneous
tissue swelling.
Transudate
Protein poor edema (increased hydrostatic pressure or reduced
plasma protein)
Individuals suffering from heart failure, renal failure, hepatic failure,
malnutrition
Exudate
Protein rich edema (increased vascular permeability)

Pathophysiologic Categories of Edema
INCREASED HYDROSTATIC PRESSURE

Impaired venous return

Congestive heart failure

Constrictive pericarditis

Ascites (liver cirrhosis)

Venous obstruction or compression

Thrombosis

External pressure (e.g., mass)

Lower extremity inactivity with prolonged dependency

Arteriolar dilation

Heat

Neurohumoral dysregulation

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

Renal hypoperfusion

Increased renin-angiotensin-aldosterone secretion

INFLAMMATION

Acute inflammation

Chronic inflammation

Angiogenesis

Increased Hydrostatic Pressure
Regional increases HP from focal impairment in venous return
o Deep venous thrombosis (lower extremity) may cause
localized edema in the affected leg
Generalized increases VP
o Congestive Heart Failure compromised right ventricular
function leads to pooling of blood on the venous side of
the circulation
Reduced Plasma Osmotic Pressure
Albumin is not synthesized in adequate amounts or is lost from the
circulation
Nephrotic Syndrome
o Important cause of albumin loss
o Glomerular capillaries = leaky
o Generalized edema
Severe liver diseases
Protein Malnutrition
Leads to a net movement of fluid into the interstitial tissues with
subsequent plasma volume contraction.
Reduced intravascular volume decreased renal perfusion
Sodium Water Retention
Guia, Alexa M. 2D
Increased salt retention with obligate assoc. water
o Causes both increased hydrostatic pressure
(intravascular fluid volume expansion) and diminished
vascular colloid osmotic pressure (dilution)
Renal function is compromised
Congestive Heart Failure
o One of the most important causes of renal hypoperfusion
results in the activation of the renin-angiotensin-
aldosterone axis.
o Early (sodiunm and water retention, increased vascular
tone, elevated levels of ADH) improve cardiac output
and restore normal renal perfusion
o Worse (CO diminish) retained fluid increases the
venous pressure (major cause of edema in this disorder)
Primary water retention produced by the release of ADH from the
posterior pituitary
Increase ADH (malignancies, lung and pituitary disorders)
o Lead to hyponatremia and cerebral edema
Lymphatic Obstruction
Lymphedema
o Due to impaired lymphatic drainage
o Localized
o Caused by:
Chronic inflammation with fibrosis
Invasive malignant tumors
Physical disruption
Radiation damage
Infectious agents
Parasitic filariasis
o Lymphatic obstruction due to extensive inguinal lymphatic
and lymph node fibrosis edema of the external
genitalia and lower limbs (massive) = ELEPHANTIASIS
Morphology
Edema
o Most commonly seen in subcutaneous tissues, the lungs
and the brain.
Subcutaneous Edema
o Diffuse or more conspicuous in regions with high
hydrostatic pressure.
o Dependent edema - distribution is influenced by gravity
o Pitting Edema - finger pressure displaces the interstitial
fluid and leaves a depression
Periorbital Edema
o Seen in severe renal disease
Pulmonary Edema
o Lungs 2 to 3x their normal weight
o Frothy, blood-tinged fluid (mixture of air, edema,
extravasated red cells)
Brain Edema
o Localized or generalized
o Generalized grossly swollen with narrow sulci and
distended gyri
Clinical Consequences
Subcutaneous Tissue Edema
o Signals potential underlying cardiac or renal disease
o Can also impair wound healing or the clearance of
infection
Pulmonary Edema
o Most frequently seen in the setting of left ventricular
failure.
o Can also occur in renal failure, acute respiratory
syndrome and pulmonary inflammation or infection
Brain Edema
o Brain substance can herniate through the foramen
magnum or the brain stem vascular supply can be
compressed.

HYPEREMIA AND CONGESTION
Hyperemia
Active process in which arteriolar dilation leads to increased blood
flow.
Affected tissues turn red (erythema) because of the engorgement of
vessels with oxygenated blood.
Congestion
Passive process resulting from reduced outflow of blood from a tissue
Systemic cardiac failure
Local isolated venous obstruction
Congested tissues dusky reddish-blue color (cyanosis)
o Due to red cell stasis and the accumulation of
deoxygenated hemoglobin.
Long Standing Chronic Passive Congestion
o Lack of blood flow causes chronic hypoxia ischemic
tissue injury and scarring
Capillary rupture in chronic congestion
o Small hemorrhagic foci
o Subsequent catabolism of extravasated red cells leave
residual telltale clusters of hemosiderin-laden
macrophages.
Morphology
Acute pulmonary congestion
o Exhibits engorged alveolar capillaries often with alveolar
septal edema and focal intra-alveolar hemorrhage
Chronic pulmonary congestion
o Septa: thickened and fibrotic
o Alveoli: numerous hemosiderin-laden macrophages (heart
failure cells)
Acute hepatic congestion
o Central vein and sinusoids: distended
o Centrilobular hepatocytes: ischemic
o Periportal hepatocytes: develop fatty change
Chronic passive hepatic congestion
Centrilobular regions: grossly red-brown and slightly depressed
(because of cell death) and are accentuated against the surrounding
zones of uncongested tan liver (nutmeg liver)
Centrilobular hemorrhage
Hemosiderin-laden macrophages
Degeneration of hepatocytes

HEMORRHAGE
Hemorrhage
Extravasation of blood into the extravascular space
Capillary bleeding chronic congestion
Increased tendency to hemorrhage hemorrhagic diatheses
Rupture of large artery or vein severe hemorrhage
Guia, Alexa M. 2D
o Due to vascular injury, including trauma, atherosclerosis,
or inflammatory or neoplastic erosion of the vessel wall.
Distinct patterns:
Hematoma
o Hemorrhage in external or contained within a tissue
Petechiea
o Minute 1- to 2-mm hemorrhages
o Skin, mucous membranes, serosal surfaces
o Most commonly associated with:
Locally increased intravascular pressure
Low platelet counts (thrombocytopenia)
Defective platelet function (uremia)
Purpura
o Slightly larger (3 mm)
o Associated with same disorders that cause petechiae or
secondary to:
Trauma
Vascular inflammation (vasculitis)
Increased vascular fragility (amyloidosis)
Ecchymoses
o Larger (>1 to 2 cm) subcutaneous hematomas (bruises)
o Red cells: degraded and phagocytized by macrophages
o Hemoglobin (red-blue color) bilirubin (blue-green color)
hemosiderin (gold-brown color)
*** Depending on the location, a large accumulation of blood in a body cavity is
denoted as a hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis
(in joints). Patients with extensive bleeding can develop jaundice from the
massive breakdown of red cells and hemoglobin.
Clinical significance of hemorrhage
Depends on the volume and rate of bleeding
o Rapid loss of up to 20% of the blood volume or slow
losses of even larger amounts may have little impact in
healthy adults
o Greater losses
hemorrhagic (hypovolemic) shock
Site of hemorrhage
o Brain
Intracranial hemorrhage increase in
pressure that is sufficient to compromise the
blood supply or to cause the herniation of the
brainstem
Chronic or recurrent external blood loss
o Causes a net loss in iron iron deficiency anemia
Red cells are retained
o Iron is recovered and recycled for use in the synthesis of
hemoglobin

HEMOSTASIS AND THROMBOSIS
Normal hemostasis
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
Thrombosis
Pathologic counterpart of hemostasis
It involves blood clot (thrombus) formation within intact vessels
Three components (Hemostasis and Thrombosis):
Vascular wall (particularly the endothelium)
Platelets
Coagulation cascade

NORMAL HEMOSTASIS
General sequence of events in hemostasis at a site of vascular injury:
Arteriolar Vasoconstriction
o Mediated by reflex neurogenic mechanisms
o Augmented by local secretion of factors (endothelin a
potent endothelium-derived vasoconstrictor)
o Effect: transient
Primary hemostasis
o Platelet adherence and activation
Highly thrombogenic subendothelial ECM
o Activation of platelets (dramatic shape change and
release of secretory granules) within minutes,
aggregation (recruit additional platelets) Hemostatic
plug
Secondary hemostasis
o Tissue factor (factor III and thromboplastin)
Exposed at the site of injury
Membrane bound procoagulant glycoprotein
synthesized by endothelial cells
Acts in conjunction with factor VII: major in
vivo initiator of the coagulation cascade
o Thrombin
Cleaves circulating fibrinogen into insoluble
fibrin (fibrin meshwork)
Induces additional platelet recruitment and
activation
o Consolidates the initial platelet plug
Permanent Plug
o Polymerized fibrin and platelet aggregates form a solid to
prevent further hemorrhage
o Counter-regulatory mechanisms are set in motion to limit
hemostatic plug to the site of injury
I. Endothelium
Endothelial cells
o 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
o Exhibit antiplatelet, anticoagulant, and fibrinolytic
properties
o After injury or activation they acquire numerous
procoagulant activities
o Activated by infectious agents, hemodynamic forces,
plasma mediators, and cytokines
Antithrombotic Properties
Prevent thrombosis
Antiplatelet effects
Intact endothelium prevents platelets from engaging the highly
thrombogenic subendothelial ECM
Prostacyclin (PGI2) and Nitric oxide
o Produced by endothelial cells
o Impede platelet adhesion
o Potent vasodilators
o Inhibitors of platelet aggregation
o Synthesis is stimulated by several factors produced
during coagulation (e.g., thrombin and cytokines)
Guia, Alexa M. 2D
Adenosine diphosphatase
o Degrades adenosine diphosphate (ADP)
o Further inhibits platelet aggregation
Anticoagulant effects
Mediated by:
o Endothelial membrane-associated heparin-like molecules
Act indirectly
cofactors that greatly enhance the inactivation
of thrombin and several other coagulation
factors by the plasma protein antithrombin III
o Thrombomodulin
Binds to thrombin and converts it from a
procoagulant into an anticoagulant via its
ability to activate protein C (inhibits clotting by
inactivating factors Va and VIIIa)
o Tissue factor pathway inhibitor
Cell surface protein that directly inhibits tissue
factorfactor VIIa and factor Xa activities
Protein S
o Co-factor for protein C and tissue factor pathway inhibitor
(TFPI)
Fibrinolytic effects
Tissue-type plasminogen activator (t-PA)
o Protease that cleaves plasminogen to form plasmin
(cleaves fibrin to degrade thrombi)
Prothrombotic Properties
Induce a prothrombotic state that alters the activities of platelets,
coagulation proteins, and the fibrinolytic system
Platelet effects
von Willebrand factor (vWF)
o Subsequent adhesion occurs
o Product of normal endothelial cells
o Essential cofactor for platelet binding to matrix elements
Procoagulant effects
Tissue factor
o Synthesized by endothelial cells in response to cytokines
(TNF or IL-1) or bacterial endotoxin
o Major activator of the extrinsic clotting cascade
Activated endothelial cells
o augment the catalytic function of activated coagulation
factors IXa and Xa
Antifibrinolytic effects
Plasminogen activator inhibitors (PAIs)
o Limit fibrinolysis
o Favor thrombosis
*** Intact, nonactivated endothelial cells inhibit platelet adhesion and blood
clotting. Endothelial injury or activation results in a procoagulant phenotype that
enhances thrombus formation.

II. Platelets
Platelets
o Disc-shaped
o Anucleate cell fragments
o Shed from megakaryocytes in the bone marrow into the
blood stream
o Critical role in normal hemostasis by:
Forming hemostatic plug that initially seals
vascular defects
Providing a surface that recruits and
concentrates activated coagulation factors
o Function depends on several glycoprotein receptors, a
contractile cytoskeleton, and two types of cytoplasmic
granules
-Granules
- Adhesion molecule P-selectin on
their membranes
- Fibrinogen
- Fibronectin
- Factors V and VIII
- Platelet factor 4 (a heparin-binding
chemokine)
- Platelet-derived growth factor
(PDGF)
- Transforming growth factor-
(TGF-)
Dense () granules
- ADP and ATP
- Ionized calcium
- Histamine
- Serotonin
- Epinephrine
ECM constituents
Collagen
Adhesive glycoprotein vWF
On contact with these proteins, platelets undergo:
o Adhesion and shape change
o Secretion (release reaction)
o Aggregation
Platelet Adhesion
Mediated largely via interactions with:
o vWF
acts as a bridge between platelet surface
receptors (glycoprotein Ib [GpIb]) and
exposed collagen
o vWF-GpIb associations
necessary to overcome the high shear forces
of flowing blood
o genetic deficiencies of vWF (von Willebrand disease) or
its receptor (Bernard-Soulier syndrome) bleeding
disorders
Secretion (release reaction)
Calcium
o Required in the coagulation cascade
ADP
o Potent activator of platelet aggregation
o Also begets additional ADP release amplifying the
aggregation process
Negatively charged phospholipids (phosphatidylserine)
o Bind calcium
o Serve as critical nucleation sites for the assembly of
complexes containing the various coagulation factors
Platelet aggregation
Vasoconstrictor thromboxane A2 (TxA2)
Important platelet-derived stimulus that amplifies platelet aggregation
formation of the primary hemostatic plug.
Initial wave of aggregation (reversible)
Guia, Alexa M. 2D
Concurrent activation of the coagulation cascade generates thrombin
(stabilizes the platelet plug via two mechanisms)
o (1) Thrombin binds to a protease-activated receptor
(PAR) on the platelet membrane and in concert with ADP
and TxA2 further platelet aggregation
o Platelet contraction
Dependent on the platelet cytoskeleton
(irreversibly fused mass of platelets)
secondary hemostatic plug.
o (2) Thrombin converts fibrinogen to fibrin platelet plug
(functionally cementing the platelets in place)
Noncleaved fibrinogen
o Important component of platelet aggregation.
Platelet activation by ADP
o Triggers a conformational change in the platelet GpIIb-IIIa
receptors that induces binding to fibrinogen, a large
protein that forms bridging interactions between platelets
that promote platelet aggregation
Glanzmann thrombasthenia
o inherited deficiency of GpIIb-IIIa results in a bleeding
disorder
Block platelet aggregation by:
o Interfering with thrombin activity
o Blocking ADP binding (clopidogrel)
o Binding to the GpIIb-IIIa receptors (synthetic antagonists
or monoclonal antibodies)
Leukocytes
o Adhere to platelets via P-selectin and to endothelium
using several adhesion receptors
o Contribute to the inflammation that accompanies
thrombosis.
Thrombin
o Drives thrombus-associated inflammation by:
Directly stimulating neutrophil and monocyte
adhesion
Generating chemotactic fibrin split products
during fibrinogen cleavage
Platelet-Endothelial Cell Interactions
Endothelial cell-derived prostaglandin PGI2 (prostacyclin)
Inhibits platelet aggregation
Potent vasodilator
Platelet-derived prostaglandin TxA2
Activates platelet aggregation
Vasoconstrictor
Aspirin
An irreversible cyclooxygenase inhibitor in persons at risk for
coronary thrombosis resides in its ability to permanently block platelet
TxA2 synthesis
Endothelial PGI2 production is also inhibited
*** Endothelial cells can resynthesize active cyclooxygenase and thereby
overcome the blockade.
Endothelial-derived nitric oxide
Acts as a vasodilator
Inhibitor of platelet aggregation

III. Coagulation Cascade
Coagulation Cascade
o Third arm of the hemostatic process
o An amplifying series of enzymatic conversions
o Each step proteolytically cleaves an inactive proenzyme
into an activated enzyme thrombin formation
Thrombin
o Most important coagulation factor
o Converts the soluble plasma protein fibrinogen into fibrin
monomers that polymerize into an insoluble gel
Factor XIIIa
o Fibrin polymers are covalently cross-linked and stabilized
o Activated by thrombin
Each reaction in the pathway results from the assembly of a complex
composed:
o Enzyme (activated coagulation factor)
o Substrate (proenzyme form of coagulation factor)
o Cofactor (reaction accelerator)
o Assembled on a phospholipid surface
o Held together by calcium ions
Binding of coagulation factors II, XII, IX, and X to calcium depends on
the addition of -carboxyl groups to certain glutamic acid residues on
these proteins
o Cofactor (Vitamin K)
o Antagonized by drugs (Coumadin) widely used
anticoagulant
Classificattion of Blood Coagulation
Extrinsic pathways
o Required the addition of an exogenous trigger (tissue
extracts)
o Most physiologically relevant pathway for coagulation
occurring when vascular damage has occurred
o Activated by tissue factor (thromboplastin or factor III) a
membrane-bound lipoprotein expressed at sites of injury
Intrinsic pathways
o Required exposing factor XII (Hageman factor) to
thrombogenic surfaces (even glass would suffice).
Two standard assays:
Prothrombin time (PT)
o Assesses the function of the proteins in the extrinsic
pathway (factors VII, X, II, V, and fibrinogen).
o Accomplished by adding tissue factor and phospholipids
to citrated plasma (sodium citrate chelates calcium and
prevents spontaneous clotting)
Partial thromboplastin time (PTT)
o Screens for the function of the proteins in the intrinsic
pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen)
o Clotting is initiated through the addition of negative
charged particles (ground glass) activates factor XII
(Hageman factor), phospholipids, and calcium
Protease activated receptors (PARs)
Expressed on endothelium, monocytes, dendritic cells, T
lymphocytes, and other cell types
Receptor activation is initiated by cleavage of the extracellular end of
the PAR (generates a tethered peptide that binds to the clipped
receptor conformational change that triggers signaling)
Three categories of endogenous anticoagulants (control clotting)
Antithrombins (Antithrombin III)
o Inhibit the activity of thrombin and other serine proteases
(factors IXa, Xa, XIa, and XIIa)
Guia, Alexa M. 2D
o Activated by binding to heparin-like molecules on
endothelial cells (heparin minimize thrombosis)
Proteins C and S
o Vitamin Kdependent proteins that act in a complex that
proteolytically inactivates factors Va and VIIIa
o Thrombomodulin activates Protein C
TFPI
o Protein produced by endothelium (and other cell types)
o Inactivates tissue factorfactor VIIa complexes
Fibrinolytic cascade
Fibrinolysis
o Largely accomplished through the enzymatic activity of
plasmin (breaks down fibrin and interferes with its
polymerization)
Fibrin split products (FSPs or fibrin degradation products)
o Also act as weak anticoagulants
o Elevated levels (most notably fibrin-derived D-dimers) can
be used in diagnosing abnormal thrombotic states:
Disseminated intravascular coagulation (DIC)
Deep venous thrombosis
Pulmonary embolism
Plasmin
o Generated by enzymatic catabolism of the inactive
circulating precursor plasminogen (either by a factor XII
dependent pathway or by plasminogen activators)
t-PA
o Most important of the Pas
o Synthesized principally by endothelium
o Most active when bound to fibrin
o Largely confines fibrinolytic activity to sites of recent
thrombosis
Urokinase-like PA (u-PA)
o Another PA present in plasma and in various tissues
o Activate plasmin in the fluid phase
Streptokinase
o Bacterial enzyme that cleaves plasminogen to
2-plasmin inhibitor
o Prevent excess plasmin from lysing thrombi
indiscriminately elsewhere in the body
o Free plasmin is rapidly inactivated
Plasminogen activator inhibitor (PAI)
o Blocks fibrinolysis by inhibiting t-PA binding to fibrin and
confers an overall procoagulant effect
o Production is increased by thrombin as well as certain
cytokines
o Plays a role in the intravascular thrombosis
accompanying severe inflammation

THROMBOSIS
Virchow's triad:
I. Endothelial injury
Particularly important for thrombus formation in the heart or the
arterial circulation
Normally high flow rates might otherwise impede clotting by
preventing platelet adhesion and washing out activated coagulation
factors
Largely consequence of endothelial injury
o Thrombus formation within cardiac chambers
o Over ulcerated plaques in atherosclerotic arteries or at
sites of traumatic or inflammatory vascular injury
(vasculitis)
Endothelium need not be denuded or physically disrupted to
contribute to the development of thrombosis
o Any perturbation in the dynamic balance of the
prothombotic and antithrombotic activities of endothelium
can influence local clotting events
Dysfunctional endothelial cells
o Produce more procoagulant factors (platelet adhesion
molecules, tissue factor, PAIs)
o Synthesize less anticoagulant effectors (thrombomodulin,
PGI2, t-PA)
o Induced by hypertension, turbulent blood flow, bacterial
endotoxins, radiation injury, metabolic abnormalities
(homocystinemia or hypercholesterolemia) and toxins
absorbed from cigarette smoke.

II. Stasis or turbulent blood flow
Turbulence
o Contributes to arterial and cardiac thrombosis by
Causing endothelial injury or dysfunction
Forming countercurrents and local pockets
stasis
Stasis
o Major contributor in the developments of venous thrombi.
Laminar
o Normal blood flow such that platelets flow centrally in the
vessel lumen
Stasis and Turbulence
o Promote endothelial activation, enhancing procoagulant
activity, leukocyte adhesion
o Disrupt laminar flow and bring platelets into contact with
the endothelium
o Prevent washout and dilution of activated clotting factors
by fresh flowing blood and the inflow of clotting factor
inhibitors
Turbulence and stasis contribute to thrombosis in several clinical settings:
Ulcerated atherosclerotic plaques
o Expose subendothelial ECM
o Cause turbulence
Aortic and arterial dilations
o Aneurysms
o Result in local stasis
o Fertile sites for thrombosis
Acute myocardial infarctions
o result in areas of noncontractile myocardium and
sometimes cardiac aneurysms
o Associated with stasis and flow abnormalities that
promote the formation of cardiac mural thrombi
Rheumatic mitral valve stenosis
o Results in left atrial dilation
o Conjunction with atrial fibrillation
Dilated atrium is a site of profound stasis and
a prime location for developing thrombi
Hyperviscosity (polycythemia vera)
o Increases resistance to flow
Guia, Alexa M. 2D
o Causes small vessel stasis
Deformed red cells in sickle cell anemia
o Cause vascular occlusions
o Resulting stasis

III. Hypercoagulability of the blood
Hypercoagulability (thrombophilia)
o Less frequent contributor to thrombotic states
o Loosely defined as any alteration of the coagulation
pathways that predisposes to thrombosis
o Divided into primary (genetic) and secondary (acquired)
disorders
o Inherited causes of hypercoagulability
Point mutations in the factor V gene and
prothrombin gene (most common)
Leiden Mutation
o Caucasians
o single-nucleotide mutation in factor V
o Mutations results in glutamine to arginine substitution at
position 506 that renders factor V resistant to cleavage by
protein C important antithrombotic counter-regulatory
pathway is lost
o Five-fold increased relative risk ovenous thrombosis
(heterozygotes); 50-gold increase (homozygotes)
Single nucleotide change (G20210A) in the 3-untranslated region of
the prothrombin gene
o another common mutation in individuals with
hypercoagulability (1% to 2% of the population)
o Associated with elevated prothrombin levels
o Almost threefold increased risk of venous thrombosis
Elevated levels of homocysteine
o contribute to arterial and venous thrombosis and
development of atherosclerosis
o Prothrombotic effects of homocysteine
Due to thioester linkages formed between
homocysteine metabolites and a variety of
proteins, including fibrinogen
o Caused by an inherited deficiency of cystathione
synthetase
Variant form of the enzyme 5,10-methylenetetrahydrofolate reductase
o Much more common
o Causes mild homocysteinemia in 5% to 15% of
Caucasian and eastern Asian populations
o As common as factor V Leiden
Folic acid, pyridoxine, and/or vitamin B12 supplements
o Can reduce plasma homocysteine concentrations (by
stimulating its metabolism)
o Fail to lower the risk of thrombosis
Deficiencies of anticoagulants (antithrombin III, protein C, or protein
S)
o Rare inherited causes of primary hypercoagulability
o Venous thrombosis and recurrent thromboembolism
beginning in adolescence or early adulthood
Acquired thrombophilic states:
Heparin-induced thrombocytopenia (HIT) syndrome.
Administration of unfractionated heparin
o Induce the appearance of antibodies that recognize
complexes of heparin and platelet factor 4 on the surface
of platelets as well as complexes of heparin-like
molecules and platelet factor 4-like proteins on
endothelial cells
Binding of these antibodies to platelets results in their activation,
aggregation, and consumption
Effect on platelets and endothelial damage combine = prothrombotic
state
Newer low-molecular weight heparin preparations
o Induce antibody formation less frequently
o Still cause thrombosis if antibodies have already formed
Fondaparinux
o Pentasaccharide inhibitor of factor X
o Cause a HIT-like syndrome on rare occasions
Antiphospholipid antibody syndrome
Lupus anticoagulant syndrome
Protean clinical manifestations
o Recurrent thrombosis
o Repeated miscarriages
o Cardiac valve vegetations
o Thrombocytopenia
Fetal loss
o Attributable to antibody-mediated inhibition of t-PA activity
necessary for trophoblastic invasion of the uterus
Cause of renal microangiopathy renal failure associated with
multiple capillary and arterial thromboses
Most important pathologic effects are mediated through binding of the
antibodies to epitopes on plasma proteins (prothrombin) that are
somehow induced or unveiled by phospholipids
In vivo induce a hypercoagulable state (endothelial injury,
activating platelets and complement directly and through interaction
with the catalytic domains of certain coagulation factors)
In vitro (in the absence of platelets and endothelial cells)
autoantibodies interfere with phospholipids and thus inhibit
coagulation
Antibodies frequently give a false-positive serologic test for syphilis
because the antigen in the standard assay is embedded in
cardiolipin.
Primary and secondary forms:
Primary antiphospholipid syndrome
o Patients exhibit only the manifestations of a
hypercoagulable state and lack evidence of other
autoimmune disorders
o Association with certain drugs or infections
Secondary antiphospholipid syndrome
o Individuals with a well-defined autoimmune disease
(systemic lupus erythematosus)
Catastrophic antiphospholipid syndrome
o Aggressive form
o Widespread small-vessel thrombi
o Multi-organ failures
Therapy involves anticoagulation and immunosuppression.
Antiphospholipid antibodies
o clearly associated with thrombotic diatheses and
identified in 5% to 15% of apparently normal individuals
implying that they are necessary but not sufficient to
cause the full-blown syndrome.
Morphology
Thrombi
Guia, Alexa M. 2D
o Can develop anywhere in the cardiovascular system
o Size and shape of thrombi depend on the site of origin
and the cause
o Focally attached to the underlying vascular surface
Lines of Zahn
o Grossly and microscopically apparent laminations
o Represent pale platelet and fibrin deposits alternating with
darker red cellrich layers
o Signify that a thrombus has formed in flowing blood
o Their presence can distinguish antemortem thrombosis
from the bland nonlaminated clots that occur postmortem
Mural thrombi
o Thrombi occurring in heart chambers or in the aortic
lumen
o Abnormal myocardial contraction (arrhythmias, dilated
cardiomyopathy, or myocardial infarction) or
endomyocardial injury (myocarditis or catheter trauma)
Ulcerated atherosclerotic plaque and aneurysmal dilation
o Precursors of aortic thrombus
Arterial thrombi
o Usually begin at sites of turbulence or endothelial injury
o Tend to grow retrograde from the point of attachment
o Occlusive
o Most common sites in decreasing order of frequency
Coronary arteries
Cerebral arteries
Femoral arteries
o Typically cosist of a friable meshwork of platelets, fibrin,
red cells, and degenerating leukocytes
Venous thrombosis (phlebothrombosis)
o Characteristically occur at sites of stasis
o Extend in the direction of blood flow
o Invariably occlusive with the thrombus forming a long cast
of the lumen
o Form in the sluggish venous circulation tend to contain
more enmeshed red cells (and relatively few platelets)
red or stasis, thrombi
o Veins of the lower extremities (most commonly involved)
o Upper extremities, periprostatic plexus, or the ovarian and
periuterine veins
o Can also occur in the dural sinuses, portal vein, or hepatic
vein.
Postmortem clots
o Sometimes mistaken for antemortem venous thrombi
o Gelatinous with a dark red dependent portion where red
cells have settled by gravity and a yellow chicken fat
upper portion
o Usually not attached to the underlying wall
Red thrombi
o Firmer and are focally attached
o Sectioning: gross and/or microscopic lines of Zahn
Vegetations
o Thrombi on heart valves
o Blood-borne bacteria or fungi
Adhere to previously damaged valves or can
directly cause valve damage
o Endothelial injury and disturbed blood flow
Induce the formation of large thrombotic
masses (infective endocarditis)
o Sterile vegetations
Develop on noninfected valves in persons with
hypercoagulable states (nonbacterial
thrombotic endocarditis)
o Libman-Sacks endocarditis
Less commonly, sterile, verrucous
endocarditis can occur in the setting of
systemic lupus erythematosuss
Fate of the Thrombus
Propagation
o Thrombi accumulate additional platelets and fibrin
Embolization
o Thrombi dislodge and travel to other sites in the
vasculature
Dissolution
o Result of fibrinolysis
o Lead to the rapid shrinkage and total disappearance of
recent thrombi
o t-PA
Generally effective only when given in the first
few hours of a thrombotic episode
Organization and recanalization
o Older thrombi become organized (ingrowth of endothelial
cells, smooth muscle cells, and fibroblasts)
o Capillary channels eventually form that re-establish the
continuity of the original lumen, albeit to a variable
degree.
*** Thrombi are significant because they cause obstruction of arteries and veins,
and are sources of emboli.
Venous Thrombosis (Phlebothrombosis)
Most occur in the superficial or deep veins of the leg
Superficial venous thrombi
o Occur in the saphenous veins in the setting of varicosities
rarely embolize.
Deep venous thrombosis (DVT) in the larger leg veins
o At or above the knee (popliteal, femoral, and iliac veins)
o More serious because such thrombi more often embolize
to the lungs and give rise to pulmonary infarction
o Can be rapidly offset by collateral channels
o Asymptomatic in approximately 50% of affected
individuals
o Recognized only in retrospect after embolization
Lower extremity DVTs (associated with hypercoagulable states)
o Common predisposing factors:
Bed rest
Immobilization (reduce the milking action of
the leg muscles, resulting in reduced venous
return)
Congestive heart failure (cause of impaired
venous return)
o Trauma, surgery, and burns associated with:
Vascular insults
Procoagulant release from injured tissues
Increased hepatic synthesis of coagulation
factors
Guia, Alexa M. 2D
Altered t-PA production
o Late pregnancy and the postpartum period (systemic
hypercoagulability)
o Tumor-associated inflammation and coagulation factors
(tissue factor, factor VIII) and procoagulants (mucin)
released from tumor cells
Contribute to the increased risk of
thromboembolism in disseminated cancers
(migratory thrombophlebitis or Trousseau
syndrome)
Advanced age also increases the risk of DVT.
Arterial and Cardiac Thrombosis
Atherosclerosis
o Major cause of arterial thrombosis
o Associated with loss of endothelial integrity and with
abnormal vascular flow
Myocardial infarction
o Predispose to cardiac mural thrombi by causing
dyskinetic myocardial contraction as well as damage to
the adjacent endocardium
Rheumatic heart disease
o Engender atrial mural thrombi

DISSEMINATED INTRAVASCULAR COAGULATION
Sudden or insidious onset of widespread fibrin thrombi in the
microcirculation
Can cause diffuse circulatory insufficiency (brain, lungs, heart, and
kidneys)
Widespread microvascular thrombosis in platelet and coagulation
protein consumption (consumption coagulopathy), and at the same
time, fibrinolytic mechanisms are activated
Not a primary disease but rather a potential complication of any
condition associated with widespread activation of thrombin

EMBOLISM
Embolus
Detached intravascular solid, liquid, or gaseous mass that is carried
by the blood to a site distant from its point of origin
Term is coined by Rudolf Virchow
Should be considered thrombotic in origin
Thromboembolism
Almost all emboli represent some part of a dislodged thrombus
Rare forms of emboli
Fat droplets
Nitrogen bubbles
Atherosclerotic debris (cholesterol emboli)
Tumor fragments
Bone marrow
Foreign bodies
*** Emboli lodge in vessels too small to permit further passage, causing
partial or complete vascular occlusion; a major consequence is ischemic
necrosis (infarction) of the downstream tissue.

PULMONARY EMBOLISM
Originate from leg deep vein thromboses (DVTs) although it is
important to realize that DVTs occur roughly two to three times more
frequently than PEs
Fragmented thrombi from DVTs are carried through progressively
larger channels and the right side of the heart before slamming into
the pulmonary arterial vasculature.
Size of the embolus: occlude the main pulmonary artery, straddle the
pulmonary artery bifurcation (saddle embolus), or pass out into the
smaller, branching arteries
High risk of having more smaller emboli
Paradoxical embolism
o embolus can pass through an interatrial or interventricular
defect and gain access to the systemic circulation
Most are clinically silent because they are small
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 pulmonary hemorrhage but usually does not
cause pulmonary infarction
*** This is because the lung has a dual blood supply, and the intact
bronchial circulation continues to perfuse the affected area.
Embolic obstruction of small end-arteriolar pulmonary branches
hemorrhage or infarction
Multiple emboli over time cause pulmonary hypertension and right
ventricular failure

SYSTEMIC THROMBOEMBOLISM
Refers to emboli in the arterial circulation
Most (80%) arise intracardiac mural thrombi
Two thirds left ventricular wall infarcts
25% left atrial dilation and fibrillation
Also 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
Venous emboli
o tend to lodge primarily in one vascular bed the lung
Arterial emboli
o Cause infarction of the affected tissues
o Can travel to a wide variety of sites
Point of arrest depends on source and relative amount of blood flow
that downstream tissues receive
Major sites for arteriolar embolization:
o Lower extremities (75%)
o Brain (10%)
o Intestines, kidneys, spleen, and upper extremities
involved to a lesser extent
Consequences of embolization in a tissue depend on:
o Its vulnerability to ischemia
o Caliber of the occluded vessel
o Whether there is a collateral blood supply

FAT AND MARROW EMBOLISM
Fat globules (with or without associated hematopoietic marrow
elements)
o 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.
Guia, Alexa M. 2D
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
Fat and marrow PEs
o Very common incidental findings after vigorous
cardiopulmonary resuscitation and are probably of no
clinical consequence
Fat embolism syndrome
o Characterized by pulmonary insufficiency, neurologic
symptoms, anemia, and thrombocytopenia, and is fatal in
about 5% to 15% of cases
o 1 to 3 days after injury (sudden onset of tachypnea,
dyspnea, and tachycardia)
o Irritability and restlessness delirium or coma
o Thrombocytopenia
Attributed to platelet adhesion to fat globules
and subsequent aggregation or splenic
sequestration
o Anemia
From similar red cell aggregation and/or
hemolysis
o Diffuse petechial rash (seen in 20% to 50% of cases)
Related to rapid onset of thrombocytopenia
Useful diagnostic feature
Pathogenesis of fat emboli syndrome
o Involves both mechanical obstruction and biochemical
injury
Fat microemboli and associated red cell and platelet aggregates
o Occlude the pulmonary and cerebral microvasculature

AIR EMBOLISM
Gas bubbles within the circulation
Coalesce to form frothy masses that obstruct vascular flow (and
cause distal ischemic injury)
More than 100 cc of air are required to have a clinical effect in the
pulmonary circulation this volume of air can be inadvertently
introduced during obstetric or laparoscopic procedures, or as a
consequence of chest wall injury
Decompression sickness
o Form of gas embolism occurs when individuals
experience sudden decreases in atmospheric pressure
o Scuba and deep sea divers, underwater construction
workers, and individuals in unpressurized aircraft in rapid
ascent are all at risk
o 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.
Bends
o Painful condition due to rapid formation of gas bubbles
within skeletal muscles and supporting tissues in and
about joints
Chokes (lungs)
Respiratory distress due to gas bubbles in the vasculature cause
edema, hemorrhage, and focal atelectasis or emphysema
Caisson Disease
o A more chronic form of decompression sickness
o Persistence of gas emboli in the skeletal system leads to
multiple foci of ischemic necrosis
o More common sites: femoral heads, tibia, and humeri.
Acute decompression sickness
o Treated by placing the individual in a high pressure
chamber which serves to force the gas bubbles back
into solution.

AMNIOTIC FLUID EMBOLISM
Ominous complication of labor and the immediate postpartum period
Fifth most common cause of maternal mortality worldwide
Results in permanent neurologic deficit in as many as 85% of
survivors
Onset: sudden severe dyspnea, cyanosis, and shock, followed by
neurologic impairment ranging from headache to seizures and coma
Cause: 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: 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
Other findings: marked pulmonary edema, diffuse alveolar damage
and the presence of fibrin thrombi in many vascular beds due to DIC

INFARCTION
Infarct
An area of ischemic necrosis caused by occlusion of either the
arterial supply or the venous drainage
Tissue infarction
Common and extremely important cause of clinical illness
Pulmonary infarction
Common complication in many clinical settings
Bowel infarction
Frequently fatal
Ischemic necrosis of the extremities (gangrene)
Serious problem in the diabetic population
*** All infarcts result from thrombotic or embolic arterial occlusions. Although
venous thrombosis can cause infarction, the more common outcome is just
congestion.
Infarcts caused by venous thrombosis
More likely in organs with a single efferent vein (testis and ovary)
Morphology
Red infarcts
o Venous occlusions (ovary)
o Loose tissues (lung) where blood can collect in the
infarcted zone
o Tissues with dual circulations (lung and small intestine)
that allow blood flow from an unobstructed parallel supply
into a necrotic zone
o Tissues previously congested by sluggish venous outflow
o When flow is re-established to a site of previous arterial
occlusion and necrosis (following angioplasty of an
arterial obstruction)
White infarcts
o Arterial occlusions in solid organs with end-arterial
circulation (heart, spleen, and kidney)
Guia, Alexa M. 2D
o Where tissue density limits the seepage of blood from
adjoining capillary beds into the necrotic areas
Infarcts
o Wedge-shaped, with the occluded vessel at the apex and
the periphery of the organ forming the base
o Base (serosal surface): overlying fibrinous exudate
o Acute infarcts
Poorly defined and slightly hemorrhagic With
time the margins tend to become better
defined by a narrow rim of congestion
attributable to inflammation
o Resulting from arterial occlusions in organs without a dual
blood supply progressively paler and more sharply
defined with time
Extravasated red cells in hemorrhagic infarcts
o Phagocytosed by macrophages (convert heme iron into
hemosiderin
o Small amounts do not grossly impart any appreciable
color to the tissue
Extensive hemorrhage firm, brown residuum.
Ischemic coagulative necrosis
o Dominant histologic characteristic of infarction
o vascular occlusion occurred shortly
o Minutes to hours no demonstrable histologic changes
o 4 to 12 hours frank necrosis
o 1 to 2 days acute inflammation (well defined)
In stable or labile tissues, parenchymal regeneration can occur at the
periphery where underlying stromal architecture is preserved.
Most infarcts are ultimately replaced by scar
Central nervous system infarction liquefactive necrosis
Septic infarctions
o Occur when infected cardiac valve vegetations embolize
or when microbes seed necrotic tissue
o Infarct is converted into an abscess, with a
correspondingly greater inflammatory response
Factors That Influence Development of an Infarct.
Nature of the vascular supply
o The availability of an alternative blood supply is the most
important determinant of whether vessel occlusion will
cause damage
o Lungs (dual pulmonary and bronchial artery blood supply)
Provides protection from thromboembolism-
induced infarction
o All relatively resistant to infarction
Liver (dual hepatic artery and portal vein
circulation)
Hand and forearm (dual radial and ulnar
arterial supply)
o Renal and splenic circulations are end-arterial, and
vascular obstruction generally causes tissue death
Rate of occlusion development
o Slowly developing occlusions
Less likely to cause infarction
Provide time to develop alternate perfusion
pathways
Small interarteriolar anastomoses normally
with minimal functional flow interconnect the
three major coronary arteries in the heart
Vulnerability to hypoxia
o Neurons
undergo irreversible damage when deprived
of their blood supply for only 3 to 4 minutes
o Myocardial cells
Hardier than neurons
Quite sensitive and die after only 20 to 30
minutes of ischemia
o Fibroblasts within myocardium
Remain viable even after many hours of
ischemia
Oxygen content of blood
o Partial obstruction of a small vessel that would be without
effect in an otherwise normal individual might cause
infarction in an anemic or cyanotic patient.

SHOCK
Shock
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
Characterized by systemic hypotension due either to reduced cardiac
output or to reduced effective circulating blood volume
Consequences: impaired tissue perfusion and cellular hypoxia
Cellular injury reversible
Prolonged shock irreversible tissue injury that often proves fatal
Three Major Types of Shock
Cardiogenic shock
o Low cardiac output due to myocardial pump failure
o Can be due to intrinsic myocardial damage (infarction),
ventricular arrhythmias, extrinsic compression (cardiac
tamponade), or outflow obstruction (pulmonary embolism)
Hypovolemic shock
o Low cardiac output due to the loss of blood or plasma
volume can occur with massive hemorrhage or fluid loss
from severe burns
Septic shock
o Vasodilation and peripheral pooling of blood as part of a
systemic immune reaction to bacterial or fungal infection
Type of Shock Clinical Example Principal Mechanisms
CARDIOGENIC

Myocardial
infarction

Ventricular rupture

Arrhythmia

Cardiac
tamponade

Pulmonary
embolism

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

Fluid loss (e.g.,
hemorrhage, vomiting,
diarrhea, burns, or
trauma)
Inadequate blood or plasma
volume
Guia, Alexa M. 2D
SEPTIC

Overwhelming
microbial
infections
(bacterial and
fungal)

Superantigens
(e.g., toxic shock
syndrome)

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

Neurogenic shock
o Shock occur in the setting of anesthetic accident or a
spinal cord injury as a result of loss of vascular tone and
peripheral pooling of blood.
Anaphylactic shock
o Denotes systemic vasodilation and increased vascular
permeability caused by an IgEmediated hypersensitivity
reaction
PATHOGENESIS OF SEPTIC SHOCK
Septic shock
Associated with severe hemodynamic and hemostatic derangements
Most frequently triggered by gram-positive bacterial infections,
followed by gram-negative bacteria and fungi
Systemic vasodilation and pooling of blood in the periphery
leads to tissue hypoperfusion accompanied by widespread
endothelial cell activation and injury hypercoagulable state that
can manifest as DIC
Associated with changes in metabolism that directly suppress cellular
function
Net effect of these abnormalities is hypoperfusion and dysfunction of
multiple organs
Major factors contributing to its pathophysiology:
Inflammatory mediators
o Various microbial cell wall constituents engage receptors
on neutrophils, mononuclear inflammatory cells, and
endothelial cells
o Toll-like receptors (TLRs)
Recognize microbial elements and trigger the
responses that initiate sepsis.
o Inflammatory cells
Produce TNF, IL-1, IFN-, IL-12, and IL-18
High mobility group box 1 protein (HMGB1)
o Reactive oxygen species and lipid mediators
(prostaglandins and platelet activating factor)
Activate endothelial cells (and other cell types)
adhesion molecule expression, a
procoagulant phenotype, and secondary
waves of cytokine production
o Complement cascade is also activated
Anaphylotoxins (C3a, C5a), chemotactic
fragments (C5a), and opsonins (C3b) pro-
inflammatory state
o Endotoxin
Activate coagulation directly (factor XII) and
indirectly (altered endothelial function)
Endothelial cell activation and injury
o Thrombosis
o Increased vascular permeability
o Vasodilation
o 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
o Tissue factor pathway inhibitor, thrombomodulin, and
protein C production are diminished
o 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
o Endothelium also increases its expression of inducible
nitric oxide synthetase and the production of nitric oxide
(NO)
Metabolic abnormalities
o Septic patients exhibit insulin resistance and
hyperglycemia
o Gluconeogenesis
Cytokines (TNF and IL-1)
Stress-induced hormones (glucagon, growth
hormone, and glucocorticoids)
Catecholamines
o Pro-inflammatory cytokines
suppress insulin release while simultaneously
promoting insulin resistance in the liver and
other tissues, likely by impairing the surface
expression of GLUT-4
o Hyperglycemia
Decreases neutrophil function suppressing
bactericidal activity and causes increased
adhesion molecule expression on endothelial
cells
o Adrenal insufficiency and a functional deficit of
glucocorticoids
Waterhouse-Friderichsen syndrome
Immune suppression
o Hyperinflammatory state initiated by sepsis
Activate counter-regulatory
immunosuppressive mechanisms (innate and
adaptive immunity)
o Shift from pro-inflammatory (TH1) to anti-inflammatory
(TH2) cytokines
o Production of anti-inflammatory mediators (soluble TNF
receptor, IL-1 receptor antagonist, and IL-10)
o Lymphocyte apoptosis
o Immunosuppressive effects of apoptotic cells
o Induction of cellular anergy
Organ dysfunction
o Systemic hypotension, interstitial edema, and small
vessel thrombosis
Decrease the delivery of oxygen and nutrients
to the tissues
o High levels of cytokines and secondary mediators
Diminish myocardial contractility and cardiac
output
Increased vascular permeability
Guia, Alexa M. 2D
Endothelial injury adult respiratory distress
syndrome
Cause the failure of multiple organs (kidneys,
liver, lungs, and heart)
Severity and outcome of septic shock dependent upon:
Extent and virulence of the infection
Immune status of the host
Presence of other co-morbid conditions
Pattern and level of mediator production
Standard of care
Treatment with appropriate antibiotics
Intensive insulin therapy for hyperglycemia
Fluid resuscitation to maintain systemic pressures
Physiologic doses of corticosteroids to correct relative adrenal
insufficiency
Superantigens
Cause a syndrome similar to septic shock
Polyclonal T-lymphocyte activators that induce the release of high
levels of cytokines

STAGES OF SHOCK
Shock
Progressive disorder that, if uncorrected, leads to death
Three general (albeit somewhat artificial) phases:
Nonprogressive phase
o Reflex compensatory mechanisms are activated and
perfusion of vital organs is maintained
Progressive stage
o Characterized by tissue hypoperfusion and onset of
worsening circulatory and metabolic imbalances,
including 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

Early nonprogressive phase of shock
Neurohumoral mechanisms help to maintain cardiac output and blood
pressure
o Baroreceptor reflexes
o Catecholamine release
o Activation of the renin-angiotensin axis
o ADH release
o Generalized sympathetic stimulation
= The net effect is tachycardia, peripheral vasoconstriction, and
renal conservation of fluid.
Cutaneous vasoconstriction
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
Less sensitive to the sympathetic response and thus maintain
relatively normal caliber, blood flow, and oxygen delivery
Setting of persistent oxygen deficit
Intracellular aerobic respiration is replaced by anaerobic glycolysis
with excessive production of lactic acid.
Metabolic lactic acidosis lowers the tissue pH and blunts the
vasomotor response; arterioles dilate, and blood begins to pool in the
microcirculation.
Peripheral pooling
Worsens the cardiac output
Puts EC at risk for developing anoxic injury with subsequent DIC
With widespread tissue hypoxia, vital organs are affected and begin
to fail.

Myocardial contractile function
Worsens in part because of nitric oxide synthesis
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 and despite heroic measures the downward
clinical spiral almost inevitably culminates in death.
Morphology
Adrenal
o Changes in shock seen in all forms of stress
o Cortical cell lipid depletion
o Conversion of the relatively inactive vacuolated cells to
metabolically active cells that utilize stored lipids for the
synthesis of steroids
Kidneys
o Exhibit acute tubular necrosis
Lungs
o Seldom affected in pure hypovolemic shock resistant
to hypoxic injury
o Shock is caused by bacterial sepsis or trauma,
changes of diffuse alveolar damage may develop (shock
lung)
Septic shock
o Development of DIC leads to widespread deposition of
fibrin-rich microthrombi (brain, heart, lungs, kidney,
adrenal glands, and gastrointestinal tract)
Consumption of platelets and coagulation factors appearance of
petechial hemorrhages on serosal surface and the skin
Clinical manifestations of shock depend on the precipitating insult:
Hypovolemic and cardiogenic shock
o Hypotension
o A weak, rapid pulse
o Tachypnea
o Cool, clammy, cyanotic skin
Septic shock
o Skin may initially be warm and flushed because of
peripheral vasodilation
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.

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PATHOLOGY Robbins and Cotran: Chapter 4 Hemodynamic Disorders, Thromboembolic Diseases, and Shock 1

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