Hemodynamic Changes,

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Hemodynamic Changes, Thrombosis and
Embolism Wayne L. Chandler, MD Laboratory
Medicine
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Microvasculature
Capillary
Vein
Artery
Hydrostatic Pressure
Extravascular Fluid Flow
Lymphatics
Proteins-Osmotic Pressure
Sodium
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EDEMA
EDEMA increase in the amount of fluid in the
interstitial spaces (e.g. connective tissue),
free spaces in tissue (e.g. pulmonary
alveoli), and body cavities (e.g. pleural,
pericardial or abdominal). - increased
hydrostatic pressure - decrease osmotic
pressure - lymphatic obstruction - sodium
retention (water follows sodium)
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EDEMA
EDEMA can be localized (acute inflammation,
tumor, parasites, scar) or generalized (congestiv
e heart failure). Transudate (low protein
content, SG non-inflammatory Exudate (high protein content,
SG 1.020) often seen with inflammation
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Where Fluid Accumulates
Hydrothorax chest cavity (pleural
space) Hydropericardium heart cavity
(pericardial space) Ascites abdominal cavity
(peritoneal
space) Subcutaneous space Congestive Heart
Failure -- pitting and dependent Renal
Protein Loss -- non-pitting, non-dependent
(around eyes) Anasarca All tissues
and spaces
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EDEMA - Mechanisms
Increased hydrostatic pressure Congestive heart
failure with elevated venous pressure Dependent
edema (ankles, lower extremities) Pulmonary
edema (orthopnea) Decreased colloid osmotic
pressure Liver disease or malnutrition -
diminished protein synthesis Nephrotic renal
disease - losing protein in the urine
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Microvasculature
Capillary
Vein
Artery
Hydrostatic Pressure
Extravascular Fluid Flow
Lymphatics
Proteins-Osmotic Pressure
Sodium
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Hyperemia and Congestion
Hyperemia increased blood flow Active process,
secondary to arterial dilation and
enhanced blood flow to the tissue - tissue
appears red Emotional response facial
flushing Inflammation wound redness Heat
loss all skin red Congestion impaired
outflow Passive process, secondary to
obstruction of blood flow out of the tissue -
tissue appears cyanotic (blue) Left
ventricular heart failure pulmonary
congestion Right ventricular heart failure
liver congestion
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Hemorrhage
Loss of blood from blood vessels Hematoma
mass of extravasated blood Blood in a body
cavity Hemothorax blood in the chest
cavity Hemopericardium blood in the heart
cavity Hemoperitoneum blood in the abdominal
cavity Petechiae tiny hemorrhages (1 mm)
Purpura moderate, confluent areas of
hemorrhage Ecchymoses large areas of
hemorrhage, bruise, may be extensive
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Hematoma
Collection of blood in tissue outside of a vessel
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Petechiae
Multiple small hemorrhages, in this case on the
surface of the heart
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Ecchymoses
Larger areas of hemorrhage
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Hemostasis - Two Goals
1. PLUG THE HOLE FAST! Speed counts - 5 min vs
5 hours vs 5 days How? - clot only on the
injured surface, have each step accelerate
the next in line 2. DONT PLUG THE
VESSEL! Limit clotting to the injured
site How? - inhibit clotting in flowing blood,
regulate the size of the clot by lysing
superficial fibrin
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Hemostatic System - 4 Parts
1. Vessel Wall - endothelium Contract, expose
and secrete proteins to trigger clotting 2.
Platelets - primary hemostasis Bind to wound,
clump together to plug hole 3. Coagulation
System - secondary hemostasis Amplifier system
of enzymes, form fibrin to stabilize clot 4.
Fibrinolytic System - prevent occlusion Limits
the size of thrombus to keep vessel open
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Vascular System
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Vascular Injury
1. Endothelial damage Change from
anti-thrombotic to pro-thrombotic 2. Collagen
Exposure Activates platelets 3. Tissue Factor
Exposure Activates coagulation system
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Example Cutaneous Wound

• Damage opens vessels and removes endothelial
  cells exposing blood to subendothelial proteins
  including collagen and tissue factor (TF)

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Normal Hemostatic System
Thrombin
Coag Activation
D-dimer
Lysis
Fibrin
Fibrin
Plt
Plt
Plt
Plt
Plt
Plt
Plt
TF
TF
Collagen
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Endothelium
Normal endothelium - antithrombotic Inhibit
platelets Inhibit coagulation Stimulate
fibrinolysis (dissolving the clot) Activated or
injured endothelium - prothrombotic Activate
platelets Stimulate coagulation Block
fibrinolysis
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Platelets
RBC
WBC
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Platelets
Membrane-bound fragments of cytoplasm released
from megakaryocytes in the bone marrow that
circulate in blood. Damage to a vessel leads to
exposure of extracellular matrix (collagen)
which along with von Willebrand factor attaches
and activates platelets, causing them to
aggregate, plugging the wound - termed primary
hemostasis. When activated (triggered) platelets
release granules that stimulate the other
platelets and the coagulation system.
Coagulation factors bind to the platelet surface
where they ultimately form fibrin that
stabilizes the platelet plug - termed secondary
hemostasis.
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Platelet Adhesion
E N D O
C O L L A G E N
vWF
E N D O
vWF von Willebrand Factor
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Platelets bind to wound

• Adhesion of platelets to the wound, through von
  Willebrand factor, results in a monolayer of
  platelets that anchors the forming platelet plug
  to the tissue

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Platelet Activation and Aggregation

• The first platelets to bind to the wound are
  activated by collagen.
• GPIaIIa and GPVI receptors
• 2. Activated platelets change their shape to
  cover the wound and release granules containing
• ADP, serotonin to activate other platelets
• Calcium and coagulation factors to accelerate
• formation of fibrin, stabilizing the clot

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Platelet Aggregation
Activated platelets expose fibrinogen binding
sites on GPIIbIIIa receptors. This causes
platelets to stick together or aggregate through
fibrinogen.
Fibrinogen
Activated Platelet
Activated Platelet
GPIIbIIIa
GPIIbIIIa
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Platelet Function - 3 As
1. Adhesion Bind through von Willebrand factor
to wound 2. Activation Release granules ADP
to stimulate other platelets Calcium and
coagulation factors to accelerate formation
of fibrin, to stabilize the clot 3.
Aggregation Cause multiple platelets to bind to
the wound plugging the hole
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Platelet aggregation

• Release of activation factors by bound platelets
  stimulates other platelets to bind or aggregate,
  forming the initial platelet hemostatic plug

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Coagulation
Coagulation is a linked set of enzyme reactions
that end in the formation of fibrin, a mesh like
polymer the forms over platelets and red cells,
stabilizing the clot. Without coagulation and
fibrin formation, the platelet clot will
breakdown in minutes to hours resulting in
re-bleeding.
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Coagulation
F VII Tissue Factor (Wound) Platelet surface
F IX F VIII Platelet surface
F IX
F X F V Platelet surface
Thrombin
Fibrin
F VIII deficiency hemophilia A F IX deficiency
hemophilia B
Stable Plug
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Fibrinolytic System
The final part of the hemostatic system is
fibrinolytic (fibrin dissolving) system. This
system dissolves superficial fibrin on the
forming clot preventing the clot from becoming to
big and occluding the vessel. tPA tissue
plasminogen activator PAI-1 plasminogen
activator inhibitor 1
Fibrin Degradation
D
D
tPA Plasminogen ? Plasmin
D
E
D
E
D
E
D
D
D
D
D
D
E
D
E
D
E
D
D
Polymerized Fibrin
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Fibrinolytic System
E N D O
Plasminogen
tPA
Fibrin
PAI-1
Plasmin
E N D O
Antiplasmin
tPA/PAI-1
Fibrin Degradation Products
Plasmin/Antiplasmin
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Thrombin and fibrin formation

• The platelet plug alone is not stable, the
  coagulation system generates thrombin which in
  turn forms a fibrin meshwork over and around
  platelets that strengthens the clot until wound
  healing can occur
• Fibrinolysis prevents the clot from becoming too
  large

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Platelet contraction, fibrin stabilization

• Platelets contract, shrinking clot size
• Fibrin is stabilized by factor XIII crosslinks

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Wound healing

• Collagen formation, angiogenesis, tissue
  remodeling
• Removal of platelet remnants, fibrin, cellular
  debris

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Normal Hemostasis
1. Arteriolar vasoconstriction 2. Endothelial
injury, collagen exposure, rapid formation of
a primary platelet plug 3. Activation of the
coagulation, fibrin formation, secondary
stabilization of the clot 4. Superficial lysis
of the fibrin once the wound is sealed to
prevent occlusion of the vessel
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Causes of Hemorrhage
1. Physical Trauma - motor vehicle accident,
gunshot wound, stabbing. 2. Inadequate or
abnormal hemostasis too few or poorly
functioning platelets reduced coagulation
factors increased fibrinolysis
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Hemostasis vs Thrombosis
Hemostasis - normal process maintain an adequate
volume of liquid (non-clotted) blood flowing,
yet create a clot to prevent blood loss when
needed Thrombosis - pathologic
process inappropriate clotting in an
undamaged vessel, or excessive size of clot
occluding damaged vessel
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Types of Thrombosis
1. Venous thrombosis - red thrombus, RBCs,
fibrin Usually occur near valves in the deep leg
or pelvic veins Associated with stasis (bed
rest, long flight), hereditary and acquire
abnormalities of coagulation 2. Arterial
thrombosis - white thrombus, platelets Associated
with atherosclerosis 3. Mural thrombosis
Thrombus on the inside wall of the heart
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Mural Thrombi
Heart Ventricular Acute myocardial infarction
- injured wall Old myocardial infarction -
ventricular aneurysm Cardiomyopathy - dilated
heart due to chronic damage Auricular Atrial
fibrillation Aorta Ulcerated atherosclerotic
plaque
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Thrombosis - Pathogenesis
Dysregulation of normal hemostasis Virchows
Triad 1 - Endothelial injury atherosclerosis
trauma infection 2 - Flow abnormality stasis
turbulence 3 - Hypercoagulability
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Coagulation Regulation
F VII Tissue Factor
F IX F VIII
F X F V
Thrombin
Antithrombin Accelerated by Heparin Destroys
Proteases (FIX,FX,thrombin)
Fibrin
Stable Plug
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Coagulation Regulation
F VII Tissue Factor
F IX F VIII
F X F V
Protein C and S PC Activated by Thrombin PS
Cofactor for activated PC Destroys Cofactors Va
and VIIIa
Thrombin
Fibrin
Stable Plug
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Thrombophilia or Hypercoagulation
THROMBOPHILIA Thrombus loving Characterized by
an increased tendency to thrombose May be
hereditary or acquired HEREDITARY CAUSES
Abnormalities of the regulating systems
including Elevated coagulation factor levels
(prothrombin, VIII) Reduced Antithrombin
(inhibits active enzymes) Reduced Protein C and
Protein S (inhibits cofactors) Reduced
Fibrinolysis (unable to degrade fibrin in clot)
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Clinical History Venous Thrombophilia

• Family history of venous thrombosis
• Thrombosis at a young age (venous arterial
• Unusual venous thrombosis sites (i.e. mesenteric,
  renal or hepatic veins)
• Recurrent venous thrombosis or thrombophlebitis
• Thrombosis with little provocation (i.e. After
  long airplane flight, long car ride, or
  antepartum)
• Thrombosis while on apparent therapeutic dosage
  of anticoagulant

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Hereditary ThrombophiliaVenous thrombosis

• Antithrombin deficiency
• Protein C deficiency
• Protein S deficiency
• Mutation in Factor V (blocks protein C activity)
• Mutation in Prothrombin (increases prothrombin
  levels in blood)
• Increased production of factor VIII

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Fate of Thrombi
Normal hemostasis leaves no clot behind. With
thrombosis, pathologic healing may
occur Propagation or extension enlargement
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Fate of thrombi 2
Organization - conversion of a thrombus
into connective tissue, usually associated
with some degree of Recanalization -
establishment of new blood channels
through the thrombus and forming
connective tissue
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Emboli
Fragment of material that moves through the
vascular system until it is stopped by a vessel
smaller than the embolus Emboli can be solid,
liquid or gas Fragment of thrombus - most
common Air Amniotic fluid Fat Bone
marrow Tumor fragment Cholesterol from
atheroma
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Pulmonary Embolus
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Acute Cor Pulmonale
Sudden death secondary to right heart failure and
asphyxia. Most frequently associated with
large saddle thrombo-emboli originating in the
deep leg or pelvic veins No time for infarct to
develop
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Other Emboli
Heart valve vegetations arterial emboli -
systemic dissemination Fat and bone marrow
long bone fracture Amniotic fluid small amount
all deliveries, large amount with placental
abruption Air delivery, chest or neck injury,
decompression sickness (bends)
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Arterial Thrombosis and Infarction
1. Vascular occlusion - loss of blood
supply partial or complete 2. Loss of blood
supply leads to Tissue damage Tissue
death Necrosis of tissue - tissue decay
while still in the living organism
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Infarction
1. Ischemic necrosis - arterial
occlusion Myocardial infarction - heart
attack Cerebral infarction - stroke 2. Gangrene
- necrosis of an extremity 3. Pulmonary infarct -
need occlusion of pulmonary arterial supply and
reduced flow in the systemic circuit
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Shock - Low Blood Pressure
Impaired perfusion of critical end
organs Heart Brain Kidneys Causes Cardiogenic
shock - massive myocardial infarct Hemorrhagic
shock - massive blood loss Septic shock -
complex form relating to severe
infection Neurogenic shock - marked dilated
vascular bed Anaphylactic shock -
hypersensitivity reaction
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Clinical Presentation - Shock
Hemorrhagic (hypovolemic) shock Cardiogenic
shock Inadequate blood flow weak pulse rapid
pulse (tachycardia) rapid breathing
(tachypnea) cool, clammy skin (diaphoretic)
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Clinical Presentation - Shock
Sepsis host systemic inflammatory response
to infection and release of endotoxin
(lipopolysacchride). Septic shock severe
response, multiorgan failure Peripheral
dilation - warm skin, flushed Myocardial
dysfunction Endothelial injury Coagulation
activation Lung injury - pulmonary edema Liver
and renal injury
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Prognosis of Shock
1. Hypovolemic shock - otherwise well e.g. motor
vehicle accident (MVA) 80 survival with
treatment 2. Cardiogenic and septic
shock 70-80 mortality with treatment
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Disseminated Intravascular Coagulation (DIC)
Normal hemostasis activation of coagulation
only at the site of a wound. DIC secondary
syndrome due to release or exposure of large
amounts of tissue factor and other coagulation
activating substances and widespread injury of
endothelial cells throughout (disseminated) the
vascular system (intravascular) secondary to
some other process.
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Causes of DIC
Shock - widespread organ damage Sepsis - organ
damage and pathogen products Obstetric
complications - amniotic fluid embolism,
placental abruption, dead fetus,
toxemia Neoplasms - carcinomas (pancreas,
prostate, lung, stomach), acute promyelocytic
leukemia Tissue injury - trauma, burns, extensive
surgery Acute intravascular hemolysis - drowning,
hemolytic transfusion reaction
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Clinical Implications of DIC
THROMBOSIS systemic coagulation activation and
fibrin formation, microvascular thrombi. May
result in thrombosis at multiple sites or move
from site to site (Trousseaus syndrome), organ
ischemia. BLEEDING increased consumption of
coagulation factors and inhibitors (decreased
platelets, fibrinogen antithrombin, protein C).
Activation of fibrinolytic system dissolves
clots. Must treat underlying cause to stop DIC
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Markers of Fibrin Degradation in blood
FPA
FPA
D-dimers
D
D
E
D
D
Fibrinogen
Coagulation Activation
Fibrin Degradation
D
D
E
D
E
D
D
D
D
E
D
E
D
Polymerized Fibrin
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Laboratory Findings in DIC

• Falling platelet count
• Falling fibrinogen
• Rising fibrin degradation - D-dimer

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Spectrum of DIC
Normal Hemostasis
Acute DIC
Chronic DIC
Increased Factor Synthesis
Suppression by inhibitors
D-dimer
Fibrinogen synthesis
Fibrinogen
Increasing tissue factor release