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 body’s water = intracellular compartment

1/3 of the body’s 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


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


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)


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

factor–factor 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

α-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-β

(TGF-β)

Dense (δ) 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)


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 γ-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)


o Activated by binding to heparin-like molecules on

endothelial cells (heparin – minimize thrombosis)

Proteins C and S

o Vitamin K–dependent 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 factor–factor 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

α2-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


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

βsynthetase

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


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 cell–rich 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


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.


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)


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


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 IgE–mediated 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-γ, 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


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.

Documents

Hemodynamic Disorders, Thromboembolic Disease and Shock