Download Mech41-HemodynamicDisorders

MOD #41
Thursday 5/01/03 11am
Dr. Wasson
Scribe: Jennifer Elmore
Page 1 of 9
Hemodynamic Disorders, Thrombosis, and Shock (part 1)
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You are responsible for pages 113-137 in Robbins
Know learning objectives on the Interactive Case Study Companion CD-ROM
Review interactive cases (1-2) under fluid and hemodynamic disorders
Objectives:
1. Understand and be able to discuss edema, its mechanism of production and
differences between transudate and exudate.
2. Know the difference between active and passive hyperemia and the consequences
of chronic passive congestion.
3. Be conversant with the mechanism of both hemostasis and thrombosis, fate of a
thrombus and the clinical spectrum of disseminated intravascular coagulopathy.
4. List and be able to discuss different types of embolic phenomena including:
- Pulmonary thromboembolism
- Systemic thromboembolism
- Fat embolism
- Air embolism
- Amniotic fluid embolism
5. Be able to define an infarct, to describe the difference between a red infarct and
white infarct and list factors that influence the development of infarcts.
6. Understand and be able to describe the pathogenesis, stages, morphology and
clinical course of shock including cardiogenic shock, hypovolemic shock, and
septic shock.
EDEMA
Water Content: 60% of lean body weight is water.
- Intracellular = 2/3
- Extra cellular = 1/3; of extracellular 95% is interstitial and only 5% is in the
plasma (in vessels).
Definitions:
Edema: increased fluid in interstitial tissue
Hydro: when collection of fluid is in any body cavity
Hydrothorax: increased fluid in chest cavity
Hydropericardium: increased fluid in pericardium
Hydroperitoneum: increased fluid in abdominal cavity (aka ascites)
Hydrosalphinx: increased fluid in fallopian tube
Anasarca: severe and generalized edema with profound subcutaneous tissue swelling.
Often caused by Nephrotic Syndrome.
Pathophysiology of Edema: two mechanisms
1. Inflammatory edema: increased vascular permeability, which leads to localized
edema (as seen in previous lectures).
2. Non-Inflammatory edema: due to alterations of Starling’s forces.
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Starling’s hypothesis: The relationship between hydrostatic pressure and oncotic
pressure and the role of these forces in regulating fluid passage across the capillary
endothelium constitute the Starling hypothesis. (1896)
Capillary hydrostatic pressure vs. oncotic pressure:
- Capillary hydrostatic pressure pushes fluid out and is variable within the same
tissue. Pressure higher in vessel and pushes fluid out.
- Oncotic pressure – pulls fluid in and is mostly due to presence of albumin in the
plasma. More albumin in vessel than in interstitium, water will go into vessel.
Normal movement of fluid across vascular bed: see figure 5-1 pg.114
- Arteriolar end: capillary hydrostatic pressure is higher and pushes fluid out into
interstitium
- Venular end: oncotic pressure is higher and pulls most of the fluid back into the
microcirculation.
- The outflow is normally balanced by the inflow back in, but a small amount of
fluid may be leftover and is usually removed by the lymphatics (because pressure
is higher in interstitium than in lymphatics and pushes fluid out), which will then
drain into the thoracic duct and into the blood stream (left subclavian vein).
Oncotic Pressure (average pressure = 25 mm Hg)
The key factor that results in permanent fluid loss from the capillaries is the low
oncotic pressure.
- 65 % of oncotic pressure is derived from albumin (4.5 gm%, charge, mol wt.)
- 15% is from globulin (2.5 gm%)
- Rest is ill defined.
Causes of Non-Inflammatory Edema:
1. Increased hydrostatic pressure:
a. Impaired venous return (focus on these)
- Congestive heart failure (for example if right heart not pumping, blood will back
up in the venous system and increase pressure.) See figure 5-2 pg. 115
- Constrictive pericarditis – heart not pumping
- Liver cirrhosis (ascites) - portal hypertension
- Venous obstruction (thrombosis) – for example, DVT (deep vein thrombosis) get
a clot in the leg and the blood can no longer move up leg.
b. Arteriolar dilation:
- Heat
- Neurohormonal dysregulation
2. Reduced Plasma Oncotic Pressure: means you have hypoproteinemia (hypo
albuminemia)
a. Protein losing Glomerulonephropathy (Nephrotic Syndrome) – loose
protein in urine (> 3gm/day) no protein in blood because leaky
glomerular capillary wall and so protein is higher in interstitium and
pulls fluid out of vessel.
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b. Liver cirrhosis – because liver makes albumin
c. Malnutrition – no building blocks to make albumin
d. Protein losing gastroenteropathy – don’t absorb protein
3. Lymphatic Obstruction: aka Lymphedema
a. Inflammatory – filariasis is a disorder where there is lymph node
fibrosis in the inguinal area causing distal limb and external genitalia
edema (legs look like elephant trunks so sometimes called
elephantiasis)
b. Neoplastic – large mass in lymphatics
c. Post Surgical/Irradiation: mastectomy where the patient will get
axillary node resection leading to severe edema in the arm.
4. Sodium retention:
a. Excessive salt intake (with renal insufficiency)
b. Increased tubular resorption of sodium: renal hypoperfusion, which
leads to activation of rennin-angiotensin-aldosterone axis.
Characteristics of Edema Fluid
- Non-inflammatory edema = transudate
- Clear fluid, low specific gravity (less than 1.012), low protein, few cells and if
any will see lymphocytes
- Inflammatory edema = exudate (think excess everything)
- Cloudy, high specific gravity (greater than 1.2), high protein, high neutrophils
Edema Morphology
- Gross: More readily apparent; for example the lungs will be very heavy and you
can wring them out.
- Micro: subtle cell swelling with clearing and separation of extra-cellular matrix
(there will be spaces between cells because edema in interstitium)
- Target for edema include subcutaneous tissues, the lungs, and the brain.
Subcutaneous Tissue
- CHF with RVF (right ventricular failure) – right heart not moving fluid forward
and produces dependent edema (legs/sacrum)
- Nephrotic Syndrome – edema in nephritic syndrome is more severe and more
generalized (anasarca) than in CHF. Initially involves loose CT matrix (such as
the eyelids)
Pulmonary Edema
- Major cause is Left Ventricular Failure (LVF) because can’t get fluid out of lungs
- Other causes include: ARDS (Acute Respiratory Distress Syndrome), Pulmonary
infections (exudative), hypersensitivity reactions.
- Gross: lungs are 2-3 times their normal weight, and there is a purging of frothy,
bloody fluid.
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Brain Edema
- Localized at site of injury or inflammation (abscess or trauma) have peripheral
edema with a tumor in the brain
- Generalized: as in encephalitis, hypertensive crisis, and obstruction to venous
flow.
- Gross appearance is swollen, narrow sulci and flattened gyrii because brain matter
has nowhere to go because of confining skull bones.
Figure 5-2 pg. 115
This figure shows edema secondary to heart failure. It is not only due to
increased hydrostatic pressure, but also because there is a decrease in cardiac output,
which leads to decreased renal perfusion and results in activation of the renninangiotensin aldosterone reaction. This induces retention of Na+ and H20 (since water
follows sodium). Also ADH secretion is increased and this also leads to increased water
retention in the kidneys. All these factors together are what lead to edema in congestive
heart failure.
Hyperemia and Congestion
1. Hyperemia: active process with arteriolar dilatation or augmentation
(increase) of blood flow (exercise, inflammation). The affected tissue is
“redder” and “warmer” because engorgement with oxygenated blood.
2. Congestion: Passive process with impaired outflow of blood flow.
Congestion may be localized (as in isolated venous obstruction), or systemic
(as in CHF). Affected tissue is “blue-red” (cyanosis) because accumulation of
deoxygenated hemoglobin in the veins.
Unlike hyperemia, congestion of capillary beds is closely related to development of
edema, therefore edema and congestion occur together.
Congestion Morphology:
- Hyperemic or congestive tissues are hemorrhagic and wet on cut surfaces.
- Acute Pulmonary Congestion: develops in someone who has an acute MI today
and develop into heart failure this afternoon. The capillaries are engorged with
blood (rbcs), there may be alveolar septal edema, and may see transudate in
alveolar spaces.
- Chronic Pulmonary Congestion: Occurs in patients who have had several MI
over a span of years, possibly they haven’t come in and they have increased
fibrosis in the heart so heart not pumping as it should.) Get hemorrhage over time
and this occurs in the alveolar spaces, and are a dark red blood that gets taken up
by numerous hemosiderin-laden macrophages (aka heart failure cells) The septa
are thickened and fibrotic because the fibroblast come in and lay down collagen.
These septa have problems with normal respiration functions. Can have Mitral
valve stenosis or regurgitation, as a cause of pulmonary edema, but classic cause
is congestive heart failure.
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Acute Hepatic Congestion: caused by right heart failure. The veins and
sinusoids distended with blood, possible central hepatocyte degeneration,
periportal hepatocytes may show fatty change
Chronic Passive Congestion of Liver: Also caused by right heart failure.
Central regions of the hepatic lobules are grossly red-brown and slightly
depressed “nutmeg liver”, microscopically centrilobular necrosis with hepatoctye
dropout and hemorrhage including hemosiderin laden macrophages, severe long
standing congestion leads to hepatic fibrosis or “cardiac cirrhosis” see figure 5-3
pg. 117
Consequences of longstanding congestion:
Chronic passive congestion leads to tissue hypoxia, which leads to parenchymal
cell damage or death, which leads to microscopic or gross scarring.
- Seen in lungs – widening of the septa is a type of fibrosis, and with longstanding
will see denser fibrosis.
- Also seen in liver – cardiac cirrhosis (resulting from heart failure)
- All cirrhosis looks the same; only differentiate by looking at where it came from.
Cirrhosis is the term for fibrosis of the liver.
Hemorrhage: “extravasation of blood due to vessel injury”
- Caused by:
1. Capillary bleeding: acute and chronic congestion because vessels are so
congested and stuffed with blood cells.
2. “Insignificant” injury in the setting of “hemorrhagic diathesis”
3. Rupture of arteries or veins, for example injury, artherosclerosis or
inflammatory/neoplastic vessel wall erosion.
- Sites of hemorrhage:
1. External – skin, GI – only bleed externally
2. Enclosed – “hematoma,” which may be insignificant (such as a bruise) or life
threatening (as in a CNS hematoma).
- Sizes of hemorrhages: see figure 5-4 pg. 117
1. Petechiae = 1-2 mm in diameter; small punctate
- Location is on skin, mucous membranes or serosa
- Causes include: locally increased intravascular pressure, low platelet count
(thrombocytopenia), defective platelets (uremia), or clotting factor deficiency.
2. Purpura = > or equal to 3 mm in diameter
- Location is on skin, mucous membranes or serosa
- Causes include those for petechiae and trauma, vasculitis, and increased
vascular fragility.
3. Eccymosis = 1-2 cms or greater in diameter
- Location can be anywhere
- Major cause is trauma. Often seen as a bruise on the leg.
- Clinical Consequences
1. Acute loss: fast (up to 20% of blood volume) or slow loss even greater than
20 % of blood volume often have no major consequences because body can
adjust. Greater than 20 % acutely and you can go into shock.
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2. Hematoma: depends on location, a hematoma may be fatal (if in brain).
3. Chronic slow loss: iron deficiency anemia because bleed iron out and can’t
reuse it.
Normal Hemostasis: Keeps blood in a fluid, clot-free state in the vessels, but can induce
rapid and localized platelet clot formation when injury occurs.
Consists of three components:
1. Endothelium (has antithrombotic and prothrombotic properties)
2. Platelets
3. Coagulation Cascade
Thrombosis: the pathologic opposite to hemostasis. Inappropriate activation of normal
hemostatic processes and therefore you get thrombus formation.
Sequence of events in normal hemostasis: figure 5-5 pg. 118
1. Reflex Vasoconstriction:
- After initial injury, there is brief arteriolar vasoconstriction due to reflex
neurogenic mechanisms. It is augmented by the local secretion of
endothelin (potent endothelium derived vasoconstrictor). This
vasoconstriction is transient and bleeding would occur again if platelets
are not activated.
2. Primary hemostasis:
- Platelets come in and adhere exposed EC matrix (where collagen is
exposed) via vWF (von Willebrand Factor), which is a bridge between the
platelets and endothelial collagen. The platelets become activated
(undergo shape change and secrete granules with ADP and TXA2
(thromboxane). The release of these two substances leads to further
platelet recruitment and formation of the primary hemostatic plug.
3. Secondary hemostasis:
- Now membrane bound tissue factor (thromboplastin or factor VII) is
exposed. This activates the coagulation cascade (through the extrinsic
pathway), which will ultimately activate thrombin. Thrombin converts
fibrinogen into fibrin to be deposited on plug “cementing” the platelets
into a secondary hemostatic plug.
4. Factor XIII is used for the polymerization of fibrin, also keeping clot only at
site of injury where there are trapped RBCs and neutrophils making permanent plug.
Counter-Regulatory mechanisms are set into motion to restrict plug formation to site of
injury. Examples include the release of tPA (tissue plasminogen activator), which
induces fibrinolysis, and thrombomodulin, which blocks the coagulation cascade.
Endothelium Role in Clot formation: see figure 5-6 p. 119
- Antithrombotic properties:
1. Antiplatelet: intact endothelium prevents platelets and coagulation
factors from meeting the subendothelial EC matrix (platelets won’t
adhere to intact endothelium). But after injury, platelets are activated
and prohibited from binding to uninjured endo. By Prostacyclin (PGI2)
and nitric oxide (NO), which are potent vasodilators (inhibit platelet
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aggregation). Also adenosine diphosphatase degrades ADP, and
inhibits platelet aggregation.
2. Anticoagulant: two ways
i. Membrane associated heparin-like molecules, which allow
antithrombin III to inactivate thrombin, factor Xa, and factor
IXa inhibiting the coagulation cascade.
ii. Thrombomodulin binds to thrombin and converts it from its
procoagulant form to an anticoagulant from capable of
activating protein C. Protein C (with protein S as cofactor) will
inhibit clotting by proteolytic cleavage of factors Va and VIIIa.
These will also inhibit the coagulation cascade.
iii. Antithrombin III, Protein C and Protein S are naturally
occurring anticoagulants.
3. Fibinolytic – endothelial cells make tPA, which promotes fibrinolytic
activity to clear fibrin deposits.
- ProThrombotic properties:
1. Endothelium produces vWF when injured, which is essential cofactor
for platelet binding, thus allowing platelet adherence.
2. Synthesis of tissue factor, which will activate the extrinsic clotting
cascade.
3. Secretes PAIs (plasminogen activator inhibitors), which inhibit
fibrinolylsis (breaking down the clot).
Platelet Role in Clot formation:
- Adhesion to extracellular matrix aka subendothelial collagen by vWF.
- Secretion (release reaction) of Ca++, ADP, and TXA2, which will cause platelet
aggregation. Ca is important for the coagulation cascade.
- Aggregation – form primary hemostatic plug, and then with addition of thrombin
(ultimately fibrin) and platelet contraction, the secondary hemostatic plug is
formed.
Figure 5-7 pg. 120 is a schematic of platelet adhesion and aggregation.
- See platelets adhering to subendothelium by Glycoprotein Ib (GpIb) on the
platelet, which adheres to the vWF. Platelet aggregation at site of injury by
fibrinogen linkage through the GpIIb-IIIa complex. If any of these factors, vWF,
GpIb, or GpIIb-IIIa complex are deficient, you will see prolonged bleeding
because the platelets aren’t functioning and adherence in impeded. The important
one to know is von Willebrand disease, a deficiency in vWF. Patients present
fairly young with history of prolonged bleeding with minor/insignificant injuries.
There are also disorders of deficiency of GpIIb-IIIa complex, called Glanzmann’s
Thrombasthenia, and deficiency of GpIb, which is Bernard-Soulier Disease.
Coagulation Cascade figure 5-8 pg. 121
Know general principles.
- There is an intrinsic pathway and an extrinsic pathway, which converge at Factor
X, forming the common pathway. In the lab, we measure these separately, but in
the body they don’t occur separately, but simultaneously. Remember the kinin
system and complement are also related.
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We can measure the intrinsic pathway using the PTT (partial thromboplastin
time).
- We can measure the extrinsic pathway using the PT (prothrombin time).
- Both the PT and the PTT will measure the common pathway as well as their
respective pathway. So if deficiency in common pathway (starting at factor X)
you will see a prolonged PT and PTT.
- Example – Pt. Comes in with DVT and you need to anticoagulate them, you are
going to put them on heparin. Monitor heparin therapy by measuring the PTT
because heparin inhibits the intrinsic pathway. For prolonged anticoagulation, put
them on coumadin (which will monitor the extrinsic pathway). Coumadin affects
vitamin K factors (II, VII, IX, and X). So monitor coumadin therapy by
measuring the PT. If give patient too much coumadin, can give Vit. K. to stop
bleeding.
- Common pathway starts with factor X converting prothrombin into thrombin.
Thrombin then converts fibrinogen into fibrin. With the addition of factor XIII to
fibrin, we see cross-linking of the fibrin monomers making the permanent platelet
plug.
Fibrinolytic System figure 5-11 pg. 124
Now we break down the clot by fibrinolysis. Break down the fibrin.
- Plasminogen is converted to plasmin by tPA. Plasmin then breaks down the fibrin
and we get fibrin degradation products (FDP) or fibrin split products. Test used
to measure the FDPs is called the d-dimer test. In normal small injuries (cut on
finger) you won’t see increased FDPs.
- tPA can also be a pharmacologic agent. Urokinase and Streptokinase are also
pharmacologic agents.
- Example, when a patient comes in with an MI, who have a thrombus in their
coronary artery, give tPA or urokinase to break down the fibrin clot.
- PAI – endothelium makes these, which will block the action of tPA and inhibits
fibrinolysis.
Figure 5-9 pg. 123
Just wanted us to get the idea that Thrombin has a central role in many things. Its most
important role is the conversion of fibrinogen into fibrin.
Thrombosis
Has three influences for its formation (known as Virchow’s Triad):
1. Endothelial Injury
2. Abnormal Blood Flow (aka Stasis)
3. Hypercoagulability
It is a balance between these three factors that prevents us from forming a thrombus.
A thrombus may develop anywhere in the cardiovascular system:
1. Within cardiac chambers
2. In arteries, veins and capillaries.
The size and shape depends upon the site where it is generated.
- In heart: Mural thrombi
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Caused by: endothelial injury is dominant cause and endothelial damage is
caused by arrhythmia, cardiomyopahty, myocardial infarction (probably primary
cause), or endocarditis.
In arteries:
Caused by: endothelial injury also (endothelial injury is primarily caused by
artherosclerosis). Endo. Injury may also be caused by vasculitis or trauma.
Common sites for injury include Coronary (from MI), cerebral (stroke) or femoral
(thrombus).
Dr. Wasson will finish this lecture tomorrow (May 2, 2003) in the morning.