Hemodynamic Disorders,

Thromboembolic Disease,
and Shock

Nam Deuk Kim, Ph.D.

Pusan National University

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 Contents
1. Edema and Effusions
II. Hyperemia and Congestion
III. Hemostasis, Hemorrhagic Disorders, and Thrombosis
1. Hemostasis
2. Hemorrhagic Disorders
3. Thrombosis
4. Disseminated Intravascular Coagulation
IV. Embolism  Disorders of Hemodynamics
1. Pulmonary Embolism : edema, effusions, congestion,
shock
2. Systemic Thromboembolism
3. Fat and Marrow Embolism
 Disorders of Bleeding & Clotting
4. Air Embolism : hemorrhagic disorders,
5. Amniotic Fluid Embolism thrombosis, embolism
V. Infarction
VI. Shock
1. Pathogenesis of Septic Shock
2. Stages of Shock
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I. Edema and Effusions
- Disorders that perturb cardiovascular, renal, hepatic function are often marked
by the accumulation of fluid in tissues (edema) or body cavities (effusions)
- Factors influencing fluid movement across capillary walls
1) hydrostatic pressure, 2) osmotic pressure

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4
 I. Edema and Effusions
 Edema fluids and effusions may be inflammatory or
noninflammatory
1) Inflammation-related edema and effusions
- protein-rich exudates usually accumulate due to increases in vascular
permeability caused by inflammatory mediators
- local edema (국소성 부종), localized to one or a few tissues, is usual.
- generalized edema (전신성 부종) may appear in systemic inflammatory
states, such as sepsis, that produce widespread endothelial injury and
dysfunction

2) Noninflammatory edema and effusions

- protein-poor fluids called transudates
- common in many diseases, including heart failure, liver failure, renal
disease, and severe nutritional disorders (Fig. 4-2)

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 I. Edema and Effusions
 Various causes of edema
1) increased hydrostatic P.
- impaired venous return
- arteriolar dilation
2) reduced plasma osmotic P.
3) lymphatic obstruction
4) sodium and water retention
5) inflammation
: increased vascular permeability

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Severe edema of arm resulting from
long-standing lymphatic obstruction

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I. Edema and Effusions
Mechanisms of systemic edema

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I. Edema and Effusions
 Clinical features
- the consequences of edema range from merely annoying to rapidly fatal
1) Subcutaneous edema
- signals potential underlying cardiac or renal disease
- when significant, it can impair wound healing or clearance of infections
2) Pulmonary edema
- frequently seen in left ventricular failure, can occur with renal failure, acute
respiratory distress syndrome, and pulmonary inflammation or infection
- impediment of oxygen diffusion
- creation of a favorable environment for bacterial infection
- pulmonary effusions often accompany lung edema, and can further
compromise gas exchange by compressing pulmonary parenchyma
3) Peritoneal effusions (ascites )
- resulting most commonly from portal hypertension
- prone to seeding by bacteria, leading to serious or fatal infections
4) Brain edema
- life threatening; if severe, brain substance can herniate (extrude) through
foramen magnum, or the brain stem vascular supply can be compressed.
- either condition can injure the medullary centers and cause death

Pulmonary
edema

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II. Hyperemia and Congestion
- Hyperemia and congestion both stem from increased blood volumes within
tissues, but have different underlying mechanisms and consequences.

 Hyperemia (충혈)
- active process in which arteriolar dilation leads
to increased blood flow to a tissue
- at sites of inflammation
: endothelial damage & increased capillary
permeability  edema, RBC extravasation
- in skeletal muscle and heart during exercise
- affected tissues turn red (erythema) due to
increase in oxygenated blood

 Congestion (울혈)
- passive process resulting from reduced outflow
of blood from a tissue
- systemic in cardiac failure (congestive heart
failure) which is secondary to coronary artery
disease, hypertension, right-sided failure
- localized in isolated venous obstruction

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II. Hyperemia and Congestion
Liver with congestion and hemorrhagic necrosis

향신료. 갈아서 가루로 만들어 사용함. 단맛과 매우 강한 맛이 남. 우

유나 크림이 들어가는 음식, 또는 케이크나 푸딩 등에 넣는다 11
Nutmeg(육두구)
III. Hemostasis, Hemorrhagic Disorders, and Thrombosis
1. Hemostasis
- can be defined simply as the process by which blood clots form at sites of
vascular injury
- is essential for life and is deranged to varying degrees in a broad range of
disorders, which can be divided into two groups, hemorrhagic disorders
and thrombotic disorders

2. Hemorrhagic disorders
: characterized by excessive bleeding, hemostatic mechanisms are either
blunted or insufficient to prevent abnormal blood loss

3. Thrombotic disorders
: blood clots (often referred to as thrombi ) form within intact blood vessels
or within the chambers of the heart. Thrombosis has a central role in the
most common and clinically important forms of cardiovascular disease

4. Disseminated intravascular coagulation (DIC)

: activation of clotting produces bleeding due to the consumption of
coagulation factors

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1. Hemostasis
- a precisely orchestrated process involving platelets, clotting factors, and
endothelium
- occurs at the site of vascular injury and culminates in the formation of a
blood clot, which serves to prevent or limit the extent of bleeding

 Sequence of events in hemostasis

1) Arteriolar vasoconstriction
2) Primary hemostasis: the formation of the platelet plug
3) Secondary hemostasis: deposition of fibrin
4) Clot stabilization and resorption

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1. Hemostasis
1) Arteriolar vasoconstriction
2) Primary hemostasis: the formation of the platelet plug

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1. Hemostasis

3) Secondary hemostasis: deposition of fibrin

4) Clot stabilization and resorption

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1. Hemostasis
 Platelets
- play a critical role in hemostasis by forming the primary plug that initially seals
vascular defects and by providing a surface that binds and concentrates activated
coagulation factors

• Sequence of reactions of platelets after a traumatic vascular injury

1) platelet adhesion: to collagen mediated via interaction with vWF

2) shape change of platelet: rapidly follows adhesion

- alteration in GpIIb/IIIa  increase of platelet affinity for fibrinogen

3) granule (ADP, TxA2) secretion (release): occurs along with shape change
* platelet activation: shape change and granule secretion

4) platelet aggregation
- altered GpIIb/IIIa binds fibrinogen forming bridges between adjacent
platelets leading to platelet aggregation

• Glanzmann thrombasthenia
: bleeding disorder results from inherited deficiency of GpIIb/IIIa
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1. Hemostasis
Platelet adhesion an aggregation

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1. Hemostasis
 Coagulation cascade

- series of amplifying enzymatic reactions leading to the deposition of

an insoluble fibrin clot.

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1. Hemostasis

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1. Hemostasis
• The prothrombin time (PT) assay
- assesses the function of the proteins in the extrinsic pathway
(factors VII, X, V, II, and fibrinogen)
- in brief, tissue factor, phospholipids, and calcium are added to
plasma and the time for a fibrin clot to form is recorded

• The partial thromboplastin time (PTT) assay

- screens the function of the proteins in the intrinsic pathway
(factors XII, XI, IX, VIII, X, V, II, and fibrinogen)
- in this assay, clotting of plasma is initiated by addition of negative-
charged particles (e.g., ground glass) that activate factor XII
(Hageman factor) together with phospholipids and calcium, and
the time to fibrin clot formation is recorded

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1. Hemostasis

 Activities of thrombin (the most important coagulation factors) in

coagulation cascade

- Conversion of fibrinogen into crosslinked fibrin

- Platelet activation
- Pro-inflammatory effects
- Anticoagulant effects

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1. Hemostasis
 Fibrinolytic cascade
- limits the size of the clot
- contributes to its later dissolution

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1. Hemostasis
 Endothelium

Antithrombotic properties of endothelium

1) Platelet inhibitory effects

: PGI2, NO, ADP

2) Anticoagulant effects
: thrombomodulin-mediated
activation of protein C

3) Fibrinolytic effects
: tPA

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2. Hemorrhagic Disorders

 Defects of primary hemostasis (platelet defects or von Willebrand disease)

- often present with small bleeds in skin or mucosal membranes

- bleeds typically take the form of petechiae (점출혈), minute 1- to 2-mm
hemorrhages, or purpura (자색반) , which are slightly larger ( ≥ 3 mm) than
petechiae
- mucosal bleeding as the form of epistaxis (nosebleeds), gastrointestinal bleeding,
or excessive menstruation (menorrhagia)
- a feared complication of very low platelet counts (thrombocytopenia) is
intracerebral hemorrhage, which may be fatal

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2. Hemorrhagic Disorders
 Defects of secondary hemostasis (coagulation factor defects)
- often present with bleeds into soft tissues (e.g., muscle) or joints
- bleeding into joints (hemarthrosis) following minor trauma is particularly
characteristic of hemophilia
- as with severe platelet defects, intracranial hemorrhage, sometimes fatal,
may also occur

 Generalized defects involving small vessels

- often present with “palpable purpura” and ecchymoses
- Ecchymoses (반상출혈, sometimes simply called bruises) are
hemorrhages of 1 to 2 cm in size.
- in both purpura and ecchymoses, the volume of extravasated blood is
sufficient to create a palpable mass of blood known as a hematoma
- Purpura and ecchymoses are particularly characteristic of systemic
disorders that disrupt small blood vessels (e.g., vasculitis, Chapter 11) or
that lead to blood vessel fragility (e.g., amyloidosis, Chapter 6 ; scurvy,
Chapter 9).

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3. Thrombosis
Virchow triad: the primary abnormalities that lead to thrombosis
1) endothelial injury
2) stasis or turbulent blood flow
3) hypercoagulability of the blood

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3. Thrombosis

 Endothelial Injury
- endothelial injury leading to platelet activation almost inevitably underlies
thrombus formation in the heart and the arterial circulation, where the high
rates of blood flow impede clot formation.

• prothrombotic alterations of endothelial cells

- Procoagulant changes
: endothelial activation by cytokines  downregulate the expression of
thrombomodulin  sustained activation of thrombin  stimulate platelets
and inflammation through PARs on platelets and inflammatory cells
: downregulates the expression of protein C and tissue factor protein
inhibitor

- Antifibrinolytic effects
: activated endothelial cells secrete plasminogen activator inhibitors (PAIs)
 limit fibrinolysis and downregulate the expression of t-PA  favor
development of thrombi

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3. Thrombosis
 Alternations in Normal Blood Flow

- promote endothelial activation, enhancing procoagulant activity and leukocyte

adhesion

- disrupt laminar flow and bring platelets into contact with the endothelium

- prevent washout and dilution of activated clotting factors by fresh flowing blood
and the inflow of clotting factor inhibitors

 Hypercoagulability

- hypercoagulability (also called thrombophilia) can be loosely defined as

any disorder of the blood that predisposes to thrombosis

- particularly important role in venous thrombosis

- divided into primary (genetic) and secondary (acquired) disorders

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3. Thrombosis

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3. Thrombosis
- Among the acquired thrombophilic states,
the heparin-induced thrombocytopenia and the antiphospholipid antibody
syndromes are particularly important clinical problems

1) Heparin-Induced Thrombocytopenia (HIT) Syndrome

- occurs following the administration of unfractionated heparin
 induce antibodies recognizing 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
 bnding of Abs to platelets  Plt activation, aggregation, consumption
 hence the thrombocytopenia in the syndrome name

2) Antiphospholipid Antibody Syndrome

- previously called the lupus anticoagulant syndrome
- protean clinical manifestations: recurrent thromboses, repeated miscarriages,
cardiac valve vegetations, and thrombocytopenia
- depending on the vascular bed involved, the clinical presentations can
include pulmonary embolism (PE) (following lower extremity venous
thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary
emboli), stroke, bowel infarction, or renovascular hypertension

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3. Thrombosis

 Fate of the Thrombus

- If a patient survives the initial thrombosis, in the ensuing days to weeks

thrombi undergo some combination of the following four events:

1) Propagation: thrombi accumulate additional platelets and fibrin

2) Embolization: thrombi dislodge and travel to other sites in the

vasculature

3) Dissolution: dissolution is the result of fibrinolysis, which can lead to the

rapid shrinkage and total disappearance of recent thrombi

4) Organization and recanalization

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3. Thrombosis

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3. Thrombosis
 Clinical features
- Thrombi come to clinical attention when they obstruct arteries or veins, or give
rise to emboli
1) Venous Thrombosis (Phlebothrombosis): superficial or deep veins of leg
- Superficial venous thrombi: typically occur in the saphenous veins
: cause local congestion, swelling, pain, and tenderness, but rarely embolize
- Deep venous thrombosis (DVT) involving one of the large leg veins - at or
above the knee (e.g., the popliteal, femoral, and iliac veins)- is more serious
because more often embolize to the lungs and give rise to pulmonary
infarction
2) Arterial and Cardiac Thrombosis: atherosclerosis is a major cause
- associated with loss of endothelial integrity and with abnormal blood flow
- myocardial infarction can predispose to cardiac mural thrombi by causing
dyskinetic myocardial contraction and endocardial injury, and rheumatic heart
disease may engender atrial mural thrombi by causing atrial dilation and
fibrillation

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4. Disseminated Intravascular Coagulation (DIC)

- DIC is not a specific disease but rather a complication of a large number of

conditions associated with systemic activation of thrombin

- widespread microvascular thrombi can cause diffuse circulatory insufficiency and

organ dysfunction, particularly of the brain, lungs, heart, and kidneys

- the runaway thrombosis “uses up” platelets and coagulation factors (hence the
synonym consumptive coagulopathy) and often activates fibrinolytic mechanisms

- symptoms initially related to thrombosis can evolve into a bleeding catastrophe,

such as hemorrhagic stroke or hypovolemic shock (Chapter 14)

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IV. Embolism
- an embolus is a detached intravascular solid, liquid, or gaseous mass that is carried
by the blood from its point of origin to a distant site, where it often causes tissue
dysfunction or infarction
- Thromboembolism: majority of emboli are dislodged thrombi
- Others: fat droplets, nitrogen bubbles, atherosclerotic debris (cholesterol emboli),
tumor fragments, bone marrow, foreign bodies

1. Pulmonary Embolism (PE)

- Pulmonary emboli originate from deep venous thrombosis and are the most
common form of thromboembolic disease
- >95% of cases, PE originate from leg DVTs
- Fragmented thrombi from DVTs
 carried through larger veins and
the right side of the heart
 slam into the pulmonary arterial vasculature
- can occlude main pulmonary artery, straddle
pulmonary artery bifurcation (saddle embolus),
or pass out into the smaller branching arteries
Figure 4-14. Embolus from a lower extremity DVT,
lodged at a pulmonary artery branchpoint
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36
IV. Embolism
2. Systemic Thromboembolism
- Most systemic emboli (80%) arise from intracardiac mural thrombi, two thirds of
which are associated with left ventricular wall infarcts and another one fourth with
left atrial dilation and fibrillation, the remainder originates from aortic aneurysms,
atherosclerotic plaques, valvular vegetations, or venous thrombi (paradoxical
emboli)

3. Fat and Marrow Embolism

- Microscopic fat globules—sometimes with associated hematopoietic bone
marrow—can be found in the pulmonary vasculature after fractures of long bones
or, rarely, in the setting of soft tissue trauma and burns

- fat embolism occurs in some 90% of individuals with severe skeletal injuries, but
less than 10% of such patients have any clinical findings

- Fat embolism syndrome: the minority of patients who become symptomatic.

: characterized by pulmonary insufficiency, neurologic symptoms, anemia, and
thrombocytopenia
: fatal in about 5% to 15% of cases
: 1 to 3 days after injury, sudden onset of tachypnea, dyspnea, tachycardia;
irritability and restlessness can progress to delirium or coma.
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IV. Embolism
Bone marrow embolus in pulmonary circulation

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IV. Embolism
4. Air Embolism

- Gas bubbles within the circulation can coalesce to form frothy masses that
obstruct vascular flow and cause distal ischemic injury

• Decompression sickness
- occurs when individuals experience sudden decreases in atmospheric pressure.
- scuba and deep sea divers, underwater construction workers, and individuals in
unpressurized aircraft in rapid ascent are all at risk
- when air is breathed at high pressure (e.g., during a deep sea dive), 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

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IV. Embolism
5. Amniotic Fluid Embolism
- Amniotic fluid embolism is the fifth most common cause of maternal mortality
worldwide; it accounts for roughly 10% of maternal deaths in the United States
and results in permanent neurologic deficit in as many as 85% of survivors.

Amniotic fluid embolism

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V. Infarction
- an infarct is an area of ischemic necrosis caused by
occlusion of either the arterial supply or the venous
drainage
- the vast majority of causes: arterial thrombosis or
arterial embolism
- less common causes of arterial obstruction: local Spleen infarcts
vasospasm, hemorrhage into atheromatous plaque or
extrinsic vessel compression (e.g., by tumor)

 Factors That Influence Development of an Infarct

- Anatomy of the vascular supply
- Rate of occlusion
- Tissue vulnerability to hypoxia
Acute myocardial infarcts
- Hypoxemia

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V. Infarction
 Red infarcts (hemorrhagic) and White infarcts (anemic)
• Red infarct occur;
1) with venous occlusions (e.g., testicular torsion)
2) in loose spongy tissues (e.g. lung)
3) in tissues with dual circulations (e.g. lung and small intestine)
4) in tissues previously congested by sluggish venous outflow
5) When flow is reestablished to occlusion site (e.g. angioplasty)
• White infarct occur;
with arterial occlusions in solid organs with end-arterial circulation (e.g., heart,
spleen, and kidney), and where tissue density limits the seepage of blood from
adjoining capillary beds into the necrotic area

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Red infarct in the lung
V. Infarction

- In stable or labile tissues, parenchymal regeneration can occur at the

periphery where underlying stromal architecture is preserved. However,
most infarcts are ultimately replaced by scar.

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 VI. Shock
- Shock is defined as a state of systemic tissue hypoperfusion due to reduced cardiac
output and/or reduced effective circulating blood volume, and can leads to hypoxic
tissue injury if nor corrected

 Three general categories

• Cardiogenic shock: results from low cardiac output due to heart failure
• Hypovolemic shock: results from low cardiac output due to low blood volume
• Shock associated with systemic inflammation: triggered by a variety of insults,
microbial infections (septic shock), burns, trauma, and or pancreatitis

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VI. Shock
SHOCK

Cardiogenic Hypovolemic Septic Anaphylactic Neurogenic

• Myocardial • Hemorrhage Severe Type 1 Brain damage

infarction infection Hypersensitivity Spinal cord injury
• Diarrhea reaction
• Myocarditis
• Dehydration
• Cardiac
tamponade • Burns

• Pulmonary
embolus

Myocardial Pump Failure Blood Volume Vasodilation Vascular Permeability

Classification of shock

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VI. Shock
1. Pathogenesis of Septic Shock

- Septic shock is caused by the host response to bacterial, viral or fungal infections;
it is a systemic inflammatory condition characterized by endothelial cell activation,
tissue edema, disseminated intravascular coagulation, and metabolic
derangements that often lead to organ failure and death

 Factors in the pathophysiology of septic shock

1) Inflammatory and counter-inflammatory responses

2) Endothelial activation and injury

3) Induction of a procoagulant state

4) Metabolic abnormalities

5) Organ dysfunction

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VI. Shock Pathogenesis of Septic Shock

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VI. Shock

2. Stages of Shock

1) an initial nonprogressive phase

: reflex compensatory mechanisms are activated and perfusion of vital organs is
maintained

2) a progressive stage
: characterized by tissue hypoperfusion and onset of worsening circulatory and
metabolic imbalances, including lactic acidosis

3) an irreversible stage
: 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

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VI. Shock
 Clinical Consequences

- In hypovolemic and cardiogenic shock: the patient presents with hypotension; a

weak, rapid pulse; tachypnea; and cool, clammy, cyanotic skin

- In septic shock: the skin may initially be warm and flushed because of peripheral
vasodilation

- The initial threat to life stems from the underlying catastrophe that precipitated
the shock (e.g., myocardial infarct, severe hemorrhage, or sepsis). Rapidly, however,
shock begets cardiac, cerebral, and pulmonary dysfunction, and eventually
electrolyte disturbances and metabolic acidosis exacerbate the dire state of the
patient further.

- The prognosis varies with the origin of shock and its duration
: greater than 90% of young, otherwise healthy patients with hypovolemic shock
survive with appropriate management
: septic shock, or cardiogenic shock associated with extensive myocardial
infarction, are associated with substantially worse mortality rates, even with
state-of-the-art care.

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