Hemodynamic Disorders,Thromboembolism and Shock

Krisna Murti

Department of Anatomical Pathology, Faculty of Medicine,

University of Sriwijaya

Fluids—Water

total water

intracellular

interstitial

intravascular

0 10 20 30 40 50 60 70 80 90 100

Percentage lean body mass

Approximately 60% of lean body weight is water

Two thirds of the body's water is intracellular

The remainder is in extracellular compartments, mostly the interstitium (or third space) that lies between cells; only about 5% of total body water is in blood plasma.

Edema and Effusions

Edema: accumulation of fluid in the interstitial

tissue spaces Effusions is accumulation of fluid in body

cavities Depending on the site, fluid collections are

variously designated hydrothorax,

hydropericardium, and

hydroperitoneum (ascites) Anasarca: severe, generalized edema with

profound subcutaneous tissue swelling.

Pulmonary edema

Elephantiasis--Lymphedema

Peau d’orange and Post-Mastectomy Lymphedema

Ascites is the accumulation of excess fluid within the peritoneal cavity

It is most frequently encountered in patients with cirrhosis and other forms of severe liver disease

Ascites due to Portal Congestion

Pleural Effusions and Edema

Pleural Effusion

Dilated Lymphatic Vessels

Normal:

balance of vascular hydrostatic presure to push water and salt out of capillaries into the interstitial spaces – plasma colloid osmotic pressure to pull water and salts back into vessels

Edema:

Elevated hydrostatic pressure or diminished colloid osmotic pressure disrupts this balance—results in increased movement of fluid out of vessels—to the interstitial and accumulate

Transportation of Fluid

Pathologies Categories of Edema

Mechanisms of Systemic Edema in Heart Failure, Renal Failure, Malnutrition, Hepatic Failure

and Nephrotic Syndrome

Types of Edema

• Transudate: protein poor (<3 gm/dl) fluid with specific gravity of <1.012 due to imbalances in normal hemodynamic forces

e.g. congestive heart failure, liver and renal disease etc.

• Exudate: protein rich (>3 gm/dl) fluid with a specific gravity of >1.020 results from endothelial damage and alteration of vascular permeability

e.g. inflammatory and immunologic pathology

Hyperemia and Congestion

• Hyperemia

An active process resulting from tissue inflow because of arteriolar dilation e.g. skeletal muscle during exercise or at sites of inflammation.

The affected tissue is redder because of the engorgement of vessels with oxygenated blood.

• Congestion

A passive process resulting from impaired outflow from a tissueSystemic: e.g. cardiac failure, Local: e.g. an isolated venous obstruction The tissue has a blue-red color

(cyanosis) due to accumulation of deoxygenated hemoglobin in the affected tissues.

Nutmeg Liver

Hepatic congestion

Morphology: Lung

• The cut surfaces are hemorrhagic and wet

• LUNGS: Microscopically, acute pulmonary congestion is characterized by alveolar capillaries engorged with blood,alveolar septal edema and/or focal intra-alveolar hemorrhage

• In chronic pulmonary congestion, the septa are thickened and fibrotic, and the alveolar spaces may contain numerous hemosiderin-laden macrophages (heart failure cells)

Morphology: Liver

• In acute hepatic congestion: central vein and sinusoids are distended with blood with or without central hepatocyte degeneration.

• In chronic passive congestion of the liver: on cut surface central regions of the hepatic lobules are red-brown and surrounded by zones of uncongested tan liver (nutmeg liver).

Microscopically: centrilobular necrosis with loss of hepatocytes, hemorrhage and hemosiderin-laden macrophages

Long-standing cases (most commonly associated with heart failure), hepatic fibrosis (cardiac cirrhosis) may developed

Hemorrhage

• Hemorrhage generally indicates extravasation of blood due to vessel rupture

• Hematoma: accumulation of blood within tissue

• Petechiae: Minute 1- to 2-mm hemorrhages into skin, mucous membranes, or serosal surfaces

• Purpura: Slightly larger (≥3 mm) hemorrhages

• Ecchymoses: Larger (>1 to 2 cm) subcutaneous hematomas (i.e., bruises).

• Large accumulations of blood in one or another of the body cavities are called hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis (in joints)

Thrombosis

• Represents hemostasis in the intact vascular system

• A process by which a thrombus is formed

• A thrombus is a solid mass of blood constituents which developes in artery or vein

• Is intravascular coagulation of blood often causing sinificant interuption to blood flow

Thrombi come to clinical attention when they obstruct arteries or veins, or give rise to emboli

Pathogenesis of Thrombosis

Three primary influences predispose to thrombus formation,

the so-called Virchow triad:

(1) endothelial injury

(2) stasis or turbulence of blood flow

(3) blood hypercoagulability

Thrombus results from interaction: Platelets Damaged endothelial cells Coagulation cascade

Thrombus (arrow)

Virchow Triad in Thrombosis

Endothelial integrity is the single most important factor

Note that injury to endothelial cells can affect local blood flow and/or coagulability; abnormal blood flow (stasis or turbulence) can, in turn, cause endothelial injury

The elements of the triad may act independently or may combine to cause thrombus formation

Primary (Genetic) Hypercoagulable States

• Mutation in factor V gene (factor V Leiden)

• Mutation in prothrombin gene

• Mutation in methyl tetrahydrofolate gene

• Antithrombin III deficiency

• Protein C deficiency

• Protein S deficiency

• Fibrinolysis defects

)

Secondary(Acquired) Hypercoaguable States

High risk for thrombosis

• Prolonged bed rest or immobilization

• Myocardial infarction, Atrial fibrillation

• Tissue damage (surgery, fracture, burns)

• Cancer

• Prosthetic cardiac valves

• Disseminated intravascular coagulation

• Heparin-induced thrombocytopenia

• Antiphospholipid antibody syndrome

(lupus anticoagulant syndrome)

Lower risk for thrombosis

Cardiomyopathy

Nephrotic syndrome

Hyperestrogenic states (pregnancy)

Oral contraceptive use

Sickle cell anemia

Smoking

Pathogenesis cont …

1) Platelets

• Maintain the integrity of the vascular endothelium

• Participate in endothelial repair through the contribution of PDGF

• Form platelet plugs

• Promote the coagulation cascade through the platelet phospholipid complex.

Pathogenesis cont… 2) Endothelial cells

• Resistant to the thrombogenic influence of platelets and coagulation

proteins

• Intact endothelial cells act to modulate several aspects of hemostasis and

oppose coagulation after injury by thrombo-resistance

Pathogenesis cont… 3) Coagulation Cascade

• The coagulation cascade constitutes the third component of the hemostatic process and is a major contributor to thrombosis

• The coagulation cascade is essentially a series of enzymatic conversions, turning inactive proenzymes into activated enzymes and culminating in the formation of thrombin

• Thrombin then converts the soluble plasma protein fibrinogen precursor into the insoluble fibrous protein fibrin

• Intrinsic pathway

• Extrinsic pathway

Pathogenesis cont…

3) Coagulation Cascade cont…

• Besides inducing coagulation, activation of the clotting cascade also sets into motion a fibrinolytic cascade that limits the size of the final clot

• This is primarily accomplished by the generation of plasmin

• Plasmin is derived from enzymatic breakdown of its inactive circulating precursor plasminogen, either by a factor XII-dependent pathway or by two distinct types of plasminogen activators

Fibrinolysis (thrombus dissolution)

• Runs concurrently with thrombogenesis

• Restores blood flow in vessels occluded by a thrombus and facilitates healing after inflammation and injury

• The proenzyme plasminogen is converted by proteolysis to plasmin, the most important fibrinolytic protease

• Plasmin split fibrin

Thrombotic Disorders

• Can be anti-thrombotic (hemorrhagic), leading to pathologic bleeding states such as hemophilia, Christmas disease and von Willebrand disease

• Can also be prothrombotic, leading to hypercoagulability with pathologic thrombosis

Hereditary Thrombophilia

• Is a prothrombotic familial syndrome

• Charecterized by recurrent venous thrombosis and thromboembolism

• Can be caused by deficiency of antithrombotic proteins including antithrombin 3, protein C, and protien S

Antiphospholipid Antibody Syndrome

• Is a prothrombotic disorder characterized by autoantibodies directed against a number of protein antigens complexed to phospholipids

• Is further characterized by recurrent venous and arterial thromboembolism, fetal loss, thrombocytopenia and a variety of neurological manifestations

• It is most often diagnosed because of an incidental finding of prolonged PTT

• It is sometimes associated Systemic Lupus Erythematosus and so this antibody is also known as lupus anticoagulant

Disseminated Intravascular Coagulation (DIC)

• Is both prothrombotic and antithrombotic disorder characterized by widespread thrombosis and hemorrhage resulting from the consumption of platelets and coagulation factors

Morphology of Thrombus

• Thrombi may develop anywhere in the cardiovascular system, the cardiac chambers, valve cusps, arteries, veins, or capillaries. They vary in size and shape, depending on the site of origin

• Arterial or cardiac thrombi usually begin at a site of endothelial injury (e.g., atherosclerotic plaque) or turbulence (vessel bifurcation)

• Venous thrombi characteristically occur in sites of stasis

Arterial and Venous Thrombi

• Arterial thrombi grow in a retrograde direction from the point of attachment

• Venous thrombi extend in the direction of blood flow (i.e., toward the heart)

• The propagating tail of either thrombi may not be well attached (particularly in veins) is prone to fragmentation, creating an embolus

Thrombi cont…

• When formed in the heart or aorta, thrombi may have grossly (and microscopically) apparent laminations, called lines of Zahn; these are produced by alternating pale layers of platelets admixed with some fibrin and darker layers containing more red cells

• When arterial thrombi arise in heart chambers or in the aortic lumen, they usually adhere to the wall of the underlying structure and are termed mural thrombi

Arterial Thrombi

• Usually occlusive

• The most common sites in descending order, are coronary, cerebral, and femoral arteries

• Usually superimposed on an atherosclerotic plaque and are firmly adherent to the injured arterial wall and are gray-white and friable, composed of a tangled mesh of platelets, fibrin, erythrocytes, and degenerating leukocytes

Atherosclerosis is the major causative factor

Venous Thrombosis

• Also called phlebothrombosis, is almost invariably occlusive

• the thrombus often takes the shape of the vein

• Because these thrombi form in a relatively static environment, they contain more enmeshed erythrocytes and are therefore known as red, or stasis thrombi

• Phlebothrombosis most commonly affects the veins of the lower extremities (90% of cases)

Postmortem Clots

• At autopsy, postmortem clots may be confused for venous thrombi

• Postmortem clots are gelatinous with a dark red dependent portion where red cells have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat. They are not attached to the underlying wall

• Red thrombi are firmer, almost always have a point of attachment, and on transection reveal vague strands of pale gray fibrin

Thrombi on Heart Valves

• Bacterial or fungal blood-borne infections may result in the development of large thrombotic masses on heart valves, called as vegetations (infective endocarditis)

• Sterile vegetations can also develop on noninfected valves in patients with hypercoagulable states, so-called nonbacterial thrombotic endocarditis

• Less commonly, noninfective, verrucous (Libman-Sacks) endocarditis attributable to elevated levels of circulating immune complexes may occur in patients with systemic lupus erythematosus

Potential Outcomes of Venous Thrombosis.

Fate of Thrombus

Embolization

Embolism

• An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin

• Almost all emboli represent some part of a dislodged thrombus, hence the commonly used term thromboembolism

• The emboli ultimately lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion leading to ischemic necrosis of distal tissue, (infarction)

• Depending on the site of origin, emboli may lodge in the pulmonary or systemic circulations

Pulmonary Thromboembolism

• Depending on size of embolus, it may occlude main pulmonary artery, or impact across the bifurcation (saddle embolus), or pass out into the smaller, branching arterioles

• Rarely, embolus may pass through an interatrial or interventricular defect to gain access to the systemic circulation (paradoxical embolism)

• Most pulmonary emboli (60% to 80%) are clinically silent because they are small

• Sudden death, right heart failure (cor pulmonale), or CVS occurs when 60% or more of the pulmonary circulation is obstructed with emboli

• Embolic obstruction of small end-arteriolar pulmonary branches may result in infarction

Systemic Thromboembolism

• Refers to emboli traveling within the arterial circulation

• Most (80%) arise from intracardiac mural thrombi

• The major sites for arteriolar embolization are the lower extremities (75%) and the brain (10%)

• The consequences of systemic emboli depend on the extent of collateral vascular supply in the affected tissue, the tissue's vulnerability to ischemia, and the caliber of the vessel occluded; in general, arterial emboli cause infarction of tissues supplied by the artery

Fat Embolism

• Microscopic fat globules may be found in the circulation after fractures of long bones (which have fatty marrow) or, rarely, in soft tissue trauma and burns

• Fat is released by marrow or adipose tissue injury and enters the circulation through rupture of the blood vessels

• Less than 10% of patients with fat embolism have any clinical findings

• Fat embolism syndrome is characterized by pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia

Air Embolism

• Gas bubbles within the circulation can obstruct vascular flow (and cause distal ischemic injury) acting as thrombotic masses. Bubbles may coalesce to form frothy masses sufficiently large to occlude major vessels

• Air may enter the circulation during obstetric procedures or as a consequence of chest wall injury

• An excess of 100 cc is required to have a clinical effect

Decompression Sickness

• Occurs when individuals are exposed to sudden changes in atmospheric pressure

• Scuba and deep sea divers, underwater construction workers, and individuals in unpressurized aircraft in rapid ascent are all at risk

• When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) become dissolved in the blood and tissues

• If the diver then ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles out of solution in the blood to form gas emboli

• ‘Bends’ and ‘chokes’

Decompression Sickness cont…

• Treatment: placing the individual in a compression chamber where the barometric pressure may be raised, thus forcing the gas bubbles back into solution followed by subsequent slow decompression

• A more chronic form of decompression sickness is called caisson disease in which, persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis; the more common sites are the heads of the femurs, tibia, and humeri

Amniotic Fluid Embolism

• A grave and uncommon complication of labor and the immediate postpartum period, characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma

• If the patient survives the initial crisis, pulmonary edema develops, along with DIC, owing to release of thrombogenic substances from amniotic

• Caused by infusion of amniotic fluid or fetal tissue into the maternal circulation via a tear in the placental membranes or rupture of uterine veins.

• Microscopy: presence in the pulmonary microcirculation of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract

• Marked pulmonary edema and diffuse alveolar damage are also present• Systemic fibrin thrombi indicative of DIC can also be seen

Infarction

• An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage in a particular tissue e.g. myocardial, cerebral, pulmonary and bowel infarction

• Most infarcts result from thrombotic or embolic events, and almost all result from arterial occlusion

• Venous thrombosis may cause infarction, it more often merely induces venous obstruction and congestion

Morphology

• Infarcts are classified on the basis of their color (reflecting the amount of hemorrhage) and the presence or absence of microbial infection

• Therefore, infarcts may be either red (hemorrhagic) or white (anemic) and may be either septic or bland

Red Infarcts

Red (hemorrhagic) infarcts occur

• with venous occlusions (such as in ovarian torsion)

• in loose tissues (such as lung), and in tissues with dual circulations (e.g., lung and small intestine), permitting flow of blood from the unobstructed vessel into the affected zone

White Infarct

• White (anemic) infarcts occur with arterial occlusions in solid organs with end-arterial circulation (such as heart, spleen, and kidney)

• where the solidity of the tissue limits the amount of hemorrhage that can seep into the area of ischemic necrosis from adjoining capillary beds

Morphology

• Gross: Most infarcts are wedge-shaped, with the occluded vessel at the apex and the periphery of the organ forming the base

• Micro: An inflammatory response begins along the margins of infarcts within a few hours and is usually well defined within 1 or 2 days, followed by gradual degradation of the dead tissue with phagocytosis of the cellular debris by neutrophils and macrophages

• Most infarcts are ultimately replaced by scar tissue

Septic Infarct

• Septic infarctions may develop when embolization occurs by fragmentation of a bacterial vegetation from a heart valve or when microbes seed an area of necrotic tissue

• The septic infarct is converted into an abscess, with a correspondingly greater inflammatory response

Infarct (cont.)

• The consequences of a vascular occlusion can range from no or minimal effect, all the way up to death of a tissue or even the individual.

• The major determinants include:

(1) the nature of the vascular supply

(2) the rate of development of the occlusion

(3) the vulnerability of a given tissue to hypoxia

(4) the blood oxygen content

Defect due to Infarc

Shock

• or cardiovascular collapse

• is the final common pathway for a number of potentially lethal clinical events: including

severe hemorrhage extensive trauma or burns large myocardial infarction massive pulmonary embolism microbial sepsis

Events in Schock

• Systemic hypoperfusion caused by reduction either in cardiac output or in the effective circulating blood volume

• The end results are hypotension, followed by impaired tissue perfusion and cellular hypoxia

• Initially the cellular injury is reversible, persistence of shock eventually causes irreversible tissue injury

Types of Shock

• Cardiogenic s: results from myocardial pump failure e.g intrinsic myocardial infarction, ventricular arrhythmias

• Hypovolemic s: results from loss of blood or plasma volume e.g. hemorrhage, fluid loss from severe burns, or trauma

• Septic shock is caused by systemic microbial infection. Most commonly due to gram-negative infections (endotoxic shock), but it can also occur with gram-positive and fungal infections

• Neurogenic s: anesthetic accident or spinal cord injury can lead to loss of vascular tone and peripheral pooling of blood.

• Anaphylactic s: initiated by a generalized IgE-mediated hypersensitivity response, is associated with systemic vasodilation and increased vascular permeability.

Major Pathogenic Pathway in Septic Shock

PAMPs: pathogen-associated molecular patternsHMGB1: Hihg mobility group box 1 proteinNO: Nitric oxidePAF: Platelet activating factorPAI-1: plasminogen activator inhibitor 1TF: Tissue factorTFPI: Tissue factor pathway inhibitor

Septic/Endotoxic Shock

• Septic shock results from spread and expansion of an initially localized infection (e.g., abscess, peritonitis, pneumonia) into the bloodstream

• Most cases of septic shock (approximately 70%) are caused by endotoxin-producing gram-negative bacilli

• Endotoxins are bacterial wall lipopolysaccharides (LPSs) that are released when the cell walls are degraded (e.g., in an inflammatory response)

Stages of Shock

If uncorrected, leads to death. Unless insult is massive and lethal (e.g. a massive hemorrhage), shock tends to evolve through three general phases

• A nonprogressive phase: reflex compensatory mechanisms are activated and perfusion of vital organs is maintained

• A progressive stage: tissue hypoperfusion and onset of worsening circulatory and metabolic imbalances, including acidosis

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

Morphology

• The cellular and tissue changes induced by shock are essentially those of hypoxic injury, since shock is characterized by failure of multiple organ systems, the cellular changes may appear in any tissue

• They are particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract

• Heart - coagulation necrosis, may exhibit subendocardial hemorrhage and/or contraction band necrosis

• Kidneys - tubular ischemic injury (acute tubular necrosis, therefore oliguria, anuria, and electrolyte disturbances constitute major clinical problems.

Liver: centrilobular sinusoidal congestion (grossly visible) with hepatocellular vacuolar degeneration and necrosis (may be grossly apparent)

Stomach and intestines: congestion, edema (particularly severe in the equine colon), and mucosal necrosis with hemorrhage (all of these changes are grossly visible)

Lungs are seldom affected in pure hypovolemic shock because they are resistant to hypoxic injury. When shock is caused by bacterial sepsis or trauma, however, changes of diffuse alveolar damage may appear, the so-called shock lung

Brain - ischemic encephalopathy

Morphology…cont…

Clinical Course

• In hypovolemic and cardiogenic shock, the patient presents with hypotension; a weak, rapid pulse; tachypnea; and cool, clammy, cyanotic skin. In septic shock, the skin may initially be warm and flushed because of peripheral vasodilation

• As shock progresses, electrolyte disturbances and metabolic acidosis (lactic acidosis) complicate the situation followed by progressive fall in urine output

Prognosis

• The prognosis varies with the origin of shock and its duration

• 80% to 90% of young, otherwise healthy patients with hypovolemic shock survive with appropriate management

• Cardiogenic shock associated with extensive myocardial infarction and gram-negative shock carry mortality rates of up to 75%, even with the best care currently available