A/16-21 HEMODYNAMIC DISORDERS (Leiel)

Question 1

What is shock?

Answer 1

Is the final common pathway of a number of potentially lethal clinical events

• At any case, shock leads to a systemic hypoperfusion, which is caused by:
  
  • reduced cardiac output
  • reduced effective circulating blood volume

Question 2

What is the end result of shock?

Answer 2

The end result of a shock:

• Hypotension
• Impaired tissue perfusion
• Hypoxia

Question 3

What are the consequences of shock?

Answer 3

Consequences of a shock- 2 stages:

• Reversible cell injury: tissue hadn’t reached yet the point of no return.
• Irreversible cell injury: necrosis. Can culminate in the death of the patient.

Question 4

List the types of shock

Answer 4

1. Cardiogenic shock
2. Hypovolemic shock
3. Anaphylactic shock
4. Neurogenic shock
5. Septic shock

Question 5

What are the reasons for cardiogenic shock

Answer 5

1. Systolic failure
   
   • AMI: the necrosis in the tissue impaires the pumping function
   • Arrhythmia: the conductive system impaired the pumping effect
2. Diastolic (filling) failure
   
   • MI: rupture of myocardium → cardiac tampnade
3. Outflow failure:
   
   • Pulmonary embolism → blood cannot be ejected from the right side
   • Thrombus in the left atrium → it is “hard” for the blood to enter the ventricle

Question 6

What are the reasons for hypovolemic shock

Answer 6

• Loss of blood
• Loss of plasma volume

Caused by hemorrhage, severe burns or trauma

Question 7

What are the main events that occur in anaphylactic shock?

Answer 7

• Vasodilation
• Increased vascular permeability: caused by an IgE hypersensitivity reaction
• The severe vasodilation might lead to tissue hypoperfusion and cellular anoxia.

Question 8

What are the events that occur in neurogenic shock?

Answer 8

Spinal lesion → loss of vessel tone → vasodilation

Question 9

Describe the development of septic shock

Answer 9

20-25% mortality rate.

most cases of septic shock are caused by endotoxin-producing gram negative bacterium (endotoxic shock).

The endotoxin is a part of the LPS, which consist of a toxic lipid A, core and a polysaccharide coat called O-antigen.

Free LPS binds to circulating LPS-binding protein, forming a complex → recognized by CD14 present on macrophages, monocytes and neutrophils → Toll like receptor signaling cascade that leads to the production of TNF and IL-1 which have the following effects:

• reduce the synthesis of anticoagulant factors → bleeding
• activation of the complement system → cell lysis
• activation of monocytes
• act on endothelial cells to produce IL-6 and IL-8 (IL-cascade) which have the following effects:
  
  • Systemic vasodilatation
  • Decreased contractility
  • Endothelial damage → makes a damage to the lung → ARDS
  • Activation of coagulation system → DIC

The final result is MOF that affects the kidney, liver, CNS

Question 10

What are the fucking stages of shock?

Answer 10

1. non-progressive stage:
   
   • compensatory neurohumoral mechanisms are activated:
     
     • renin system, secretion of catecholamines to maintain tone and contractility, ADH release, generalized sympathetic stimulation.
   • The net effect is tachycardia, vasoconstriction, renal conservation of fluid.
   • Perfusion of vital organs is maintained
2. progressive stage:
   
   • tissue hypoperfusion and onset of worsening and metabolic imbalances.
   • hypoxia, anaerobic glycolysis → lactic acidosis → vasomotor response: arterioles dilate leading to pooling of blood in the arterial side and worsening of cardiac output, ischemic injuries
3. irreversible stage:
   
   • leakage of lysosomal enzymes
   • contractility worsens
   • ischemic bowel may let intestinal flora to enter the circulation and developing endotoxic shock
   • renal failure due to tubular necrosis

Question 11

Define edema

Answer 11

increase of the H₂O content in the interstitial spaces.

Question 12

What are the medical terms of:

1. excess of fluid in the pleural cavity
2. excess of fluid in the pericardial sac
3. excess of fluid in the abdominal cavity
4. excess of fluid in the subcutaneous tissue

Answer 12

1. hydrothorax: excess of fluid in the pleural cavity
2. hydropericardium: excess of fluid in the pericardial sac.
3. ascites/hydroperitoneum: excess of fluid in the abdominal cavity
4. anasarca: excess of fluid in the subcutaneous tissue

Question 13

What are the 2 types of edema fluids? how do they differ?

Answer 13

• Transudate: low protein content. Gravity < 1.012. occurs with volume or pressure overload or reduced plasma protein content.
• Exudate: protein-rich fluid. Gravity > 1.012. related to inflammation and the increased vascular permeability.

Question 14

What are the 4 pathophysiologic forms of edema?

Answer 14

1. Increased hydrostatic pressure
2. Reduced plasma osmotic pressure
3. Lymphatic obstruction
4. Increased vascular permeability

Question 15

What are the forms and reasons of edema caused by Increased hydrostatic pressure? give examples.

Answer 15

Local:

impaired venous return.

For example:

• Deep venous thrombus in the lower extremities (femoral vein) → backflow from the leg is impaired
• Increased resistance of the liver (cirrhosis) → blood cannot pass through the liver → ascites

Systemic: is due to an increased venous pressure. Occurs mostly in congestive heart failure.

• CO reduced → stasis→ pulmonary edema.
• CO reduced → reduced renal perfusion → renin→ increased plasma volume.

​The heart is not able to increase the output, so that the extra fluid load increases the venous pressure and leads to edema formation.

Question 16

How’s osmotic pressure usually maintained? what can cause it’s defficiency?

What is the result of reduced plasma osmotic pressure?

Answer 16

• This pressure is mostly maintained by albumin.
• Reasons for decreased serum albumin:
  
  • Nephrotic syndrome: glomerular capillary wall is leaky
  • Diffused liver disease-cirrhosis: there is a decreased albumin synthesis
  • Protein malnutrition
• Result: decreased plasma osmotic pressure → movement of fluid into the interstitium → decrease in plasma volume → renal hypoperfusion → renin system → Na and H₂O retention.
  
  • Since the primary defect is the low serum albumin, this fluid and salt retention will not solve the problem - the fluid will keep on leaking and the edema becomes even more severe.

Question 17

Which cases will result in lymphatic obstruction?

Answer 17

Impaired lymphatic drainage and consequent lymphedema

1. Post-irradition: breast cancer is treated by irradiation of associated axillary lymph nodes → fibrosis of lymphatic channels → leakage → upper extremity edema
2. Neoplastic: carcinoma → obstruction of lymphatics → leakage
3. Post-surgical: removal of the axillary lymph nodes.

Question 18

Where is the most common site for increased vascular permeability?

What are some common causes for increased vascular permeability?

Answer 18

Is very common in the lung.

• the capillaries surrounding the alveoli are very thin due to their role in gas exchange.

Toxins as in sepsis/pneumonia due to bacterial damage/inflammation in any organ → increased leakage from the vessels → edema

Question 19

Morphology of Subcutaneous edema

Answer 19

Subcutaneous edema (anasarca): the most obvious feature.

1. Dependent:
   
   • gravity-dependent distribution
   • typical for cardiac failure
   • Visible in the lower extremities
2. Diffused:
   
   • oncotic pressure related edema
   • generalized
   • in tissues with loose connective tissue matrix, like the eyelids.

• Pitting edema: finger pressure displaces the fluid and leaves a finger-shaped depression.

Question 20

Morphology of pulmonary edema

Answer 20

related to left ventricular failure, ARDS, pulmonary infections.

Fluid fills-up the alveolar spaces → no proper gas exchange → hypoxia

*The lung is heavy (2 or 3 times the normal weight), when squeezing: a clear fluid or fluid stained by blood is washed out.

Question 21

Morphology of Cerebral edema

Answer 21

localized to the site of injury

(infarct, absecesses, neoplasma)

or

generalized as in encephalitis.

• normal brain weight: 1200gr → (1300-1400gr)
• brain is pressed into the foramen magnum → tonsils of the cerebellum are pressed and damaged → death
• narrowed sulci, distended gyri
• softening of brain tissue

Question 22

Clinical correlations of edema

Answer 22

• Subcutaneous edema may indicate an underlying disease (cardiac, renal)
• Can impair wound healing or the clearance of infection
• Pulmonary edema leads to impaired gas exchange
• Favorable environment for bacterial infection

Question 23

What is Hemostasis?

What is Thrombosis?

What things are involved in both?

Answer 23

• Hemostasis: normal coagulation of the blood
• Thrombosis: pathological coagulation of the blood
• Both involve 3 components:
  
  • vascular wall
  • platelets
  • the coagulation cascade

Question 24

What is sequence of events in hemostasis at the site of injury?

Answer 24

1. arteriolar vasoconstriction: due to reflex neurogenic mechanisms and release of factors such as endothelin
2. primary hemostasis:

ECM→AAA
3. secondary hemostasis:
TF + factor 7 →thrombin → cleavage of fibrinogen → fibrin
4. anti-thrombotic counter-regulation: this stage occurs after a plug was formed and includes several mechanisms aimed to stop the propagation of the thrombus:
* heparin like molecule: allow antithrombin 3 to inactivate thrombin, factor 10 and other coagulation factors.
* thrombomodulin: binds to thrombin and converting it to an anticoagulant factor (it activates protein C → proteolysis of factor 5a and 8a)
* tissue plasminogen activator: promote fibrinolytic activity

Question 25

What are the 3 primary influences on thrombus formation?

Answer 25

together called “Virchow’s triad”

1. Endothelial injury
2. Alteration in normal blood flow
3. Hypercoagulability

Question 26

What are the types of endothelial injury?

Give some examples of thrombus formation due to endothelial injury.

Answer 26

• denuding injury:
  endothelium is lost→exposure of the ECM →coagulation cascade
• non-denuding injury: dysfunctional endothelium,

too much procoagulant factors (TF, PAI)
or
fewer anticoagulant factors (t-PA, TM).

The following are examples of thrombus formation due to endothelial injury:

• Myocardial infarction → necrotic area is replaced by a scar tissue that favors thrombus formation
• Ulcerated plaques in atherosclerotic arteries
• Endocardities: inflammation of the endocardium which effects heart valves. Called “vegetation of the endocardium”
• Vasculities: antibodies against endothelial cells

Question 27

Alteration in normal blood flow what means that?

Answer 27

normal blood flow is laminar.

thrombocytes are kept away from the endothelium

clotting factors from endothelium can be washed by the plasma.

Turbulence and stasis:

• disrupt laminar flow and bring platelets into contact with the endothelium
• prevent dilution of activated clotting factors by fresh-flowing blood
• retard the inflow of clotting factor inhibitors and permit the build up of thrombi
• promote endothelial cell activation

The two contribute to thrombosis in several clinical correlations:

• atherosclerotic plaques: cause turbulency and expose the ECM
• aneurysm: create stasis
• acute MI: result in focally noncontractile myocardium
• long bed rest → stasis → thrombus
• mitral valve stenosis → stasis in the atrium → thrombosis
• left sided HF: backward failure → stasis in the atrium → thrombosis
• arrhythmia absoluta: atrial fibrillation

Question 28

What are the hypercoagulability states?

Answer 28

• _Primary (inherited)_:
  
  • mutation in factor 5, which is normally anti-thrombotic (Leiden mutation).
  • Also can be mutation in prothrombin gene, protein C and S.
• _Secondary (Acquired)_: associated with oral contraceptive pills, MI, cancer and
  
  • Heparin induced thrombocytopenia: administration of heparin induces the formation of autoantibodies that bind to complexes that are present on platelets activation and endothelial injury

Question 29

Generally what causes arterial/cardiac thrombi and what causes venous thrombi?

Answer 29

Arterial or cardiac thormbi typically begin at sites of endothelial injury or turbulence

Venous thrombi occurs at sites of stasis

Question 30

What are the different morphology possibilities of thrombus?

Answer 30

White thrombus (sedimentation thrombus) - fibrin + platelets. Characterizes arteries. There is endothelial lesion → aggregation of platelets → secondary fibrin deposition

Red thrombus - characteristic or vein. Is the result of activated coagulation cascade and it contains more enmeshed erythrocytes, therefor it appears red.

Composite thrombus: white + red. In the arteries. Related to endothelial injury which generates the white thrombus which changes the circulation → Behind the thrombus there is a stasis. The head of the thrombus will appear white and the rest will be red.

Laminated thrombus:

• altered endothel
• generated in the heart
• At the beginning there is precipitation of platelets and fibrin (white layer), and the altered circulation coagulates the blood (red layer). If we cut the surface we will see that is has a laminated appearance called “lines of Zahn”. It represents thrombosis in the setting of flowing blood.
• precipitation of → several factors are released

Disseminated intravascular coagulation: platelets and fibrins.

The propagation portion of the thrombus tends to be poorly attached and is therefore prone to fragmentation and embolus formation.

Question 31

Localization of the thrombi

Answer 31

1. Mural: occur in the heart chambers or in the aortic lumen.
   
   • In the ventricle- due to MI
   • On the valves- due to endocarditis (vegetation)
   • In the atrium- due to mitral stenosis, left sided HF, arrhythmia absoluta
2. Arterial: usually on ulcerated AT plaque or based on aneurysm
3. Venous: also called phlebothrombosis.

lower extremities.
* femoral vein:
superficial →varicosites- curely veins,

deep( long bed rest) →pulmonary embolism
* Parametric vein thrombus:
baby presses the vein → stasis → thrombus
* Periprostatic:
prostate enlarged presses the plexus
* Pulle thrombus:
increased liver resistance due to cirrhosis→​thrombosis in portal vein.

Question 32

Fate of the thrombus

Answer 32

1. Propagation: the thrombi accumulated additional platelets and fibrin, eventually causing vessel obstruction
2. Embolization: thrombi dislodge or fragment and are transported in the vasculature
3. Dissolution: the thrombi are removed by fibrinolytic activity
4. Organization and recanalization: the thrombi induces inflammation and fibrosis. Pluripotent stem cells make new endothelial channels → neuvascularization → opening

Question 33

What is DIC?

Answer 33

Disseminated Intravascular Coagulation

Thrombohemorrhagic disorder caused by systemic activation of the coagulation pathway, leading to the formation of thrombi throughout the microcirculation.

As a result of the widespread thrombosis, there is a consumption of platelets and coagulation factors and secondarily, activation of fibrinolysis.

Question 34

What can DIC cause?

Answer 34

1. microinfarcts
   (mostly in organs with intensive blood supply)
2. Pathologic activation of fibrinolysis and depletion of elements required for hemostasis (coagulopathy)

Question 35

What are the causes of DIC?

Answer 35

• TF in circulation+endothelial injury
  (causes the release of TF and exposure of ECM)

1. Obstetric:

placenta previa

fetus mortus
2. Infection:
gram negative and gram positive sepsis;

meningococcus

malaria
3. Trauma:

crash syndrome;
burning
surgery
4. Neoplastic disease: Carcinoma (can release procoagulant substances);

APL (acute promyelocytic leukemia)

Question 36

Organ morphology of DIC

Answer 36

The microthrombi are found principally in the kidney, adrenals, brain and heart (the lung, GI mucosa and liver can be affected).

1. Kidney: glomeruli contain small fibrin thrombi which can lead to damage of various the degrees:
   
   • swelling of the endothelial cells
   • glomerulitis
   • infarcts/destruction of renal cortex
2. Adrenal gland:

Waterhouse Friderichsen syndrome
3. Brain:
focal hemorrhage+ neurologic signs

The bleeding tendency is seen as hemorrhages near the site of infarction and as diffused petechiae and ecchymoses

Question 37

Clinical course of DIC

• What are the forms of DIC
• What are the laboratory findings in the case of DIC

Answer 37

Depends on the balance between clotting and bleeding tendencies.

• Acute DIC (for example in obstetric complications) is dominated by bleeding
• Chronic DIC (cancer) is dominated by thrombosis

The manifestation might be very mild or extensive

ARDS ,

Laboratory findings: thrombocytopenia, prolongation of PT and PTT

Question 38

What is embolus?

What is the most common form of embolus?

Answer 38

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.

99% of emboli are thrombemboli = a dislodged thrombus

Question 39

What are the different types of Emboli

Answer 39

• Pulmonary thrombemboli
• Systemic thrombemboli
• Fat emboli
• Air embolism
• Tumor embolism
• Amniotic fluid embolism

Question 40

Explain Pulmonary thrombemboli

• Common origin
• Site of the embolus
• Consequences

Answer 40

In more than 95% of the cases it is originated from deep leg vein thrombi above the level of the knee (parametric, periprostatic).

• It passes through the right side of the heart and then into the pulmonary vasculature.

According to the site of the embolus:

• Total pulmonary embolus: occlusion of the main pulmonary artery
• saddle embolus: impact across the bifurcation
• subtotal: effects only one side of the lung
• partial: in the smaller vessels

Consequences:

• most are clinicaly silent because they are small
• when 60% or more are obstructed, sudden death, right ventricular failure or cardiovascular collapse occurs
• if a medium-sized arteries are obstructed, pulmonary hemorrhage occurs but not infarction due to the dual blood supply of the lung.
  
  • If left sided HF is present, the bronchial circulation is impaired and an infarct might occur.
• Emboli in a small end-artery leads to infarct.

Question 41

Explain systemic thrombemboli

• Origin
• Affected organs
• Consequence

Answer 41

80% from heart.

(2/3 of the cases are due to infarction in the left ventricular wall and 1/4 due to dilated atria which is the result of mitral stenosis).

Other causes
aneurysm, thrombi of ulcerated atherosclerotic plaques

or fragmentation of valvular vegetations.

affects the extremities ,brain

(to a lesser extent the kidney, spleen, intestine).

The consequence depends on the effected organ -> generally infarction.

Question 42

Fat emboli

• Origin
• affected organs

Answer 42

Is generated by fractures to long bones (contain fatty marrow) or after soft tissue trauma.

Pathogenesis:

• mechanical obstruction of microvasculature
• FFAS→toxic effect on endothelium

It usually effects the kidney, brain and the lung.

• Characterized by pulmonary insufficiency, neurologic symptoms, anemia and thrombocytopenia

Question 43

Explain air embolism

• Amount needed to produce clinical effect
• Explain Decompression sickness

Answer 43

Gas bubbles can obstruct vascular flow.

• More than 100mL of air are required to produce clinical effects.
• It can result from obstetric procedure or chest wall injury.

Decompression sickness: when individuals are exposed to sudden changes in atmospheric pressure. When air is breathed at high pressure, increased amount of gas becomes dissolved in the blood and tissue. If the person ascends too rapidly, the N expands in the tissues and bubbles out of solution in the blood to form gas emboli.

Question 44

Tumor embolism what means that?

Answer 44

Neoplastic disease interrupts vessels → ischemic injury

Question 45

Explain amniotic fluid embolism pathomechanism

Answer 45

Entry of amniotic fluid and its content into the maternal circulation via tear in the placental membranes and rupture of the uterine veins.

There is pulmonary edema and diffuse alveolar damage with the pulmonary microcirculation containing squamous cells shed from fetal skin, lanugo hair, mucin from fetal respiratory of GI tracts.

Question 46

Define Hemorrhage

Define Hematoma

Answer 46

Hemorrhage: extravasation of blood from the vessel into the extravascular space

Hematoma: accumulation of blood inside the tissue

Question 47

What are pathways to develop hemorrhage?

Answer 47

1. Hemorrhage per rhexin (rupture)
2. Hemorrhage per arrosionem (Erosions)
3. Hemorrhage per diapedesim (vascular wall disturbance)

Question 48

Give 3 examples of vessel ruptures that lead to hemorrhage

Answer 48

Apoplexia

• Hypertension in brain →

Aneurysm “charot badrout” → rupture → intracranial pressure increase → cerebral tonsils → Resp/Card centers failure -> Death

Hematoma epidurale

• Trauma to the head -> M.Meningeal artery -> pressure on the brain
• Lucidum intervalum

Esophageal ravix

• Liver hypertension -> periesophageal shunt -> rupture

Question 49

Causes for hemorrhage per arrosionem

Answer 49

• Bacteria -> stomach ulcer -> hole -> bleeding
• Cancer -> vessel wall interruption

Question 50

What are the possible morphologies of hemorrhage per diapedesim (vascular wall disturbance)

Answer 50

Possible morphologies

• Petechiae - 1-2mm
• Purpura - 3-5mm
• Suphosio / ecchymoses - Huge / large

Question 51

What are the thrombopathies causes for hemorrhage per diapedesim (vascular wall disturbance)

Answer 51

Anaplastic anemia - bone marrow failure

Disseminated cancer - penetrate to bone marrow

ITP - Antibodies against platelets

Sepsis - toxins targeting platelets

Question 52

What are the Coagulopathies causes for hemorrhage per diapedesim (vascular wall disturbance)

Answer 52

Hepatic failure - no factors 2, 7, 9, 10

DIC - depletion of coagulation factors

Hemophilia - A -> f8 deficiency B -> f9 deficiency

Question 53

What are the vasculopathies causes for hemorrhage per diapedesim (vascular wall disturbance)

Answer 53

• Hypoxia - results in leaky vessels (CO poisoning)
• Infection - toxic effect on endothel
• Vit C deficiency - collagen synthesis decrease
• Vasculitis - antibodies against endothelial cells