Pathology 5/14 Fluid And Haemodynamic

Front 1

Causes of edema

Back 1

Increased Hydrostatic Pressure
Reduced Oncotic Pressure
Lymphatic Obstruction
Sodium/Water Retention

Front 2

Edema (def)

Back 2

Increased fluid in the interstitial tissue spaces.
In different body cavities:
- hydrothorax
- hydropericardium
- hydroperituneum (ascites)
- anscara: severe, generalized edame with subcutaenous tissue swelling

Front 3

Transudate

Back 3

Protein-poor, specific gravity less than 1.012. (Fluid leakage)

Front 4

Exudate

Back 4

In inflammatoy edema. Protein rich, specific gravity greater than 1.020. (Fluid and protein leakage)

Front 5

INCREASED HYDROSTATIC PRESSURE

Back 5

Impaired venous return
Congestive heart failure  
Constrictive pericarditis  
Ascites (liver cirrhosis)  
Venous obstruction or compression
Thrombosis    
External pressure (e.g., mass)
Lower extremity inactivity with prolonged dependency
Arteriolar dilation
Heat  
Neurohumoral dysregulation

Front 6

REDUCED PLASMA ONCOTIC
PRESSURE (HYPOPROTEINEMIA)

Back 6

Protein-losing glomerulopathies (nephrotic syndrome)
Liver cirrhosis (ascites)
Malnutrition
Protein-losing gastroenteropathy

Front 7

LYMPHATIC OBSTRUCTION
(LYMPHEDEMA)

Back 7

Inflammatory
Neoplastic
Postsurgical
Postirradiation

Front 8

Na+ RETENTION

Back 8

Excessive salt intake with renal insufficiency
Increased tubular reabsorption of sodium
Renal hypoperfusion --> Increased renin-angiotensin-aldosterone secretion

Front 9

Congestive heart failure edema

Back 9

INCREASED VENOUS PRESSURE DUE TO FAILURE

DECREASED RENAL PERFUSION, triggering of RENIN-ANGIOTENSION-ALDOSTERONE complex, resulting ultimately in SODIUM RETENTION (secondary aldosteronism)

Front 10

Nephrotic vc nephrotic syndroms

Back 10

Both leads to hypoalbuminemia.

NephrOtic: proteins move into urine

NephrItic: small pores in podocytes leads to loss of RBC and proteins, cause hematuria.

Front 11

Peu d'orange

Back 11

In breast carcinoma infiltration and obstruction of superficial lymphatics can cause edema ov overlying skin.

Front 12

Subcutaneous dependent edema

Back 12

Gravity dependent. Typical for cardiac failure, particularly RV.

Front 13

Edema due to renal sysfunction or nephrotic syndrome

Back 13

More severe than cardiac edema, and affects all parts of the body equally.

Front 14

Pulmonary edema

Back 14

Seen most frequently in left ventricular failure, but also in renal failure, ARDS, pulmonary infections and hypersensitivity reactions.
Weigh 2-3 times normal, on section: frothy, blood-tingled fluid (air, edema fluid and extravasated red cells)

Front 15

Edema of the brain

Back 15

May be localized to places of focal injury (infarct, abcsess, neoplasm) or generalized (encephalitis, hypertensive crisis, obstruction of venous outflow).
Generalized: swollen, narrowed sulci, distended gyri.
May cause herniation throug foramen magnum.

Front 16

Hyperemia and congestion

Back 16

Local increased volume of blood in a particular tissue.

Front 17

Hyperemia

Back 17

Active process resulting form augmented blood flow due to arteriolar dilation. Eg: infl, excercise

Front 18

Congestion

Back 18

Passice process resulting form impaired venous return out of a tissue. May be systemic (heart failure), or local (isloated venous obstruction). Leads to cyanosis. Commonly occure together with edema.
Chronic passive congestion: hypoxia, death of tissue, fibrosis. If capillary rupture --> hemociderin-laden macroph.

Front 19

Morphology acute pulmonary congestion

Back 19

Alveolar capillaries engorged with blood, septal edema and/or focal minute intra-alveolar hemorrhage.

Front 20

Morphology chronic pulmonary congestion

Back 20

Septa become thickened and fibroticHemociderin-laden macrophages (heart failure cells) in alveolar spaces

Front 21

Morphology acute hepatic congestion

Back 21

Central vein and sinusoids are distended with blood, mey be central hepatocyte degeneration. Periportal hepatocytes have less hypoxia, only fatty change is seen.

Front 22

Morphology chronic passive congestion of the liver

Back 22

Nutmeg liver: central regions of hepatic lobules are red-brown, surrounding zones are uncongested tan, sometimes fatty.
Micro: centrilobular necrosis, , hemorrhage, hemociderin-laden macroph.

Front 23

Brain herniation due to edema

Back 23

1. Subfalcine herniation
2. Transtenrorial herniation
3. Tonsillar herniation

Front 24

Hemorrhage

Back 24

Extravasation of blood from vessles into the extravascular space

Front 25

Hematoma

Back 25

Accumulation of blood. Insignificant; bruise. Significant; massive retriperitoenal hematoma resulting form ruptupe of a dissecting aortic aneurysm

Front 26

Petechiae

Back 26

Minute (1-2 mm) hemorrhages into the skin, mucous membr, serosal surf.
Associated with:
- local increase IV pressure,
- thrombocytopenia,
- defevtiv platelet function or
- clotting factor deficiencies

Front 27

Purpura

Back 27

3-5 mm hem
Associated with:
(- same as peteciae pluss:)
- vasculitis
- trauma
- increased vascular fragility

Front 28

Ecchymoses

Back 28

1-2 cm, subcutaneous (brusies)
Colour changes in hematoma due to phagocytises and degradation of RBC:
1. hemoglobin: red-blue
2. bilirubin: blue-green
3. hemosiderin: golden-brown

Front 29

Large accumulations of blood in body cavities

Back 29

- hemothorax
- hemopericardium
- hemoperitoneum
- hemarthrosis

Front 30

Normal hemostasis(def)

Back 30

Consequence of thightly regulated processes that maintain blood in a fluid, clot-free state in normal vessels while inducing tha rapid formation of a localized hemostatic plug at the site of vascular injury.
Pathologic form: thrombosis.
Involve three components: vascular wall, platelets, coagulation cascade.

Front 31

Steps of normal hemostasis

Back 31

A. Vasoconstriciton: after vascular injury, local neurohumoral factors (endothelin) induce transient vasoconstr.
B. Primary haemostasis: platelet adhere (via Gplb receptor) to exposed ECM by binding to vWF and are activated, undergoing shape change and granule release.

Released ADP and TXA2 lead to further platelet aggregation (binding fibrinogen to platelet GpIIb-IIIa rec), to form primary hemostatic plug.

C. Local activation of coagulation cascade (involving tissue factor and platelet phospholipid) results in polymerization, "cementing" the platelets to definitive secondary hemostatic plug.
D. Counter-regulatory mechanism, such as release of t-PA and thrombomodulin, limit hemostatic process to the site of injury.

Front 32

PLATELET ADHESION

Back 32

Primarily to the subendothelial ECM
Regulated by vWF, which bridges platelet surface receptors to ECM collagen

Front 33

Platelet secretion

Back 33

Both granules. Agonist binds to surface receptors and initiate an IC phosphorulation cascade which leads to degranulation. Dense bodies are spesially important; ADP for platelet aggregation, calcium for coagulation cascade.

Front 34

Platelet aggregation

Back 34

ADP
TxA2 (Thromboxane A2)
THROMBIN from coagulation cascade also
FIBRIN further strengthens and hardens and contracts the platelet plug

Front 35

Platelet events

Back 35

1. ADHERENCE to ECM
2. SECRETION of ADP and TxA2
3. EXPOSE phospholipid complexes
4. Express TISSUE FACTOR
5. PRIMARY -> SECONDARY PLUG
6. STRENGTHENED by FIBRIN

Front 36

Cofactors in coagulation cascade

Back 36

Ca++
Phospholipid (from platelet membranes)
Vit-K dep.
Prot. S, C, Z

Front 37

Vit K dependent factors in coagulation cascade

Back 37

II
VII
IX
X

Front 38

Virchow's triad

Back 38

Three primary influences on thrombus formation
1) endothelial injury
2) stasis or turbulence of flow
3) blood hypercoagulability

Front 39

Primary (genetic) hypercoagulable states

Back 39

Common
- mutaion in factor V gene (Leiden)
- mut in prothrombin gene
- mut in methyltetrahydrofolate gene
Rare
- antithrobin III deficiency
- protein C def
- protein S def
Very rare
- fibrinolysis defects

Front 40

Secondary (acquired) hypercoagulable states

Back 40

High risk for throbosis
- prolonged immonilization
-MI
-atrial fibrillation
- tissue damage
-cancer
- prosthetic cardiac valve
- DIC
- heparin-induced thrombocytopenia
- antiphospholipid ab syndrome (lupus anticoagulant sy)
Lower risk:
- cardiomyopathy
- nephrotic sy
- hyperestrogenic states (pregnancy)
- oral contraceprive use
- sickle cell anemia
- smoking

Front 41

Properties of endothelium related to thrombus formation

Back 41

1. ANTI-Platelet PROPERTIES
- Protection from the subendothelial ECM
- Degrades ADP (inhib. Aggregation)
2. ANTI-Coagulant PROPERTIES
- Membrane HEPARIN-like molecules
- Makes THROMBOMODULIN --> Protein-C
- TISSUE FACTOR PATHWAY INHIBITOR
3. FIBRINOLYTIC PROPERTIES (TPA)

Front 42

Arterial thrombi characteristics

Back 42

- Arterial and cardiac thrombi typically begins at sites of endothelial injury or turbulence
- arterial thrombi grow retrograde

Front 43

Venous thrombi characteristics

Back 43

- Venous thrombi occure at sites of stasis
- extend in the direction of the blood flow

Front 44

Lines of Zahn:

Back 44

laminations, pale platelet and fibrin layers alternating with darker erythrocyte rich layers. Antemortem.

Front 45

Mural thrombi:

Back 45

in heart chambers or in the aortic lumen. Abnormal myocardial contraction or endomyocardial injury promotes cardial mural thrombi. Ulcerated atherosclerotic plaques and aneurysmal dilation promote aortic thrombosis.

Front 46

Arteral thrombi:

Back 46

frequently occlusive, produced by platelet and coagulation ativation. Meshwork of platelets, fibrin, erythrocytes, and degenerating leukocytes. White "flux" thrombus in arteries. Mixed "coral" thrombus with changing layers in big arteries, heart and aneurisms. Hyaline thrombus in capillaries.

Front 47

Venous thrombosis:

Back 47

(phlebothrombosis): occlusive, can create a long cast of the lumen. It is largely the result of activation of the coagulation cascade, and platelets play a secondary role. Contain more erythrocytes; red or stasis thrombi. Strands of grey fibrin.

Front 48

Postmortem clots:

Back 48

gelatinous with a dark red dependent portion where red cells have setteled by gravity, and a yellow supernatant. They are not attached to the vessel wall.

Front 49

Vegetations

Back 49

thrombi on heart valves. Bacterial or fungal blood born infecions can cause valve damage, leading to thrombothic masses (infective endocarditis). Nonbacterial thrombotic endocarditis; sterile hypercoagulative states. Sterile verrucous endocarditis (Libman-Sacks endocarditis) can occure in the setting of SLE (uncommon).

Front 50

Fate of thrombus

Back 50

- Propagation: thrombi accumulate platelets and fibrin, eventually causing vessel obstruction
- Embolization: Thrombi dislodge or fragment and are transported elsewhere in the vasculature
- Dissolution: Thrombi are removed by fibrinolytic activity
- Organization and recanalization;: Thrombi induce inflammation and fibrosis. These can eventually recanalize, or they can be incorporated into a thickened vessel wall.

Front 51

Trousseau's syndrom

Back 51

=migratory thromboplebitis
Increased risk of thromboembolic phenomena seen in disseminated cancers due to tumour-assosiated procoagulant release.

Front 52

Paradoxial emboli

Back 52

A small fraction of systemic emboli arise in the veins, but end up in the arterial circulations, through interatrial or interventricular defects.

Front 53

Saddle embolus

Back 53

Emboli in the pulmonary artery branchin point.

Front 54

Types of emboli

Back 54

99% dislodged from thrombi.
Fat droplets,
bubbles of nitrogen,
atherosclerotic debris (cholesterol emboli),
tumor fragments,
bits of bone marrow,
foreign bodies such as bullets

Front 55

Pulmonary emboli

Back 55

60-80% are clinically silent
When 60% or more of pulm circ is obstructed: Cor pulmonale (RV failure), CV collapse or sudden death.
In medium size a: Lead to hemorrhage, but normally not infarct (left-sided heart failure leads to massive infarct)
In small arterioles: infarct
Many emboli over time: pulm hypertension, RV failure

Front 56

Systemic emboli

Back 56

80% cardiac/20% aortic aneurysm
Embolization lodging site is proportional to the degree of flow (cardiac output) that area or organ gets, i.e., brain, kidneys, legs

Limbs – 75% Brain – 10%

Front 57

Other emboli; fat, air, amniotic

Back 57

FAT (long bone fx’s ): Occurs in 90% of those with severe trauma, only 10% develop fat embolism syndrome

Pathogenesis: Mechanical obstruction
Platelet aggregation
Local endothelial injury

Fat embolism syndrome: typically begins 1-3 days after injury (fatal in 10%) and is characterized by:
Tachycardia
Tachypnoea Irritability
Diffuse petechial rash in 20-50% (not due to thrombocytopenia)
Thrombocytopenia

AIR (SCUBA bends)

AMNIOTIC FLUID, very prolonged or difficult delivery, high mortality
1 in 50 000 deliveries Mortality >80%

Pathogenesis:
Tear in placental membrane results in leakage
of amniotic fluid into systemic circulation
Clinically:
Shock, seizures, coma
Pulmonary oedema
DIC

Diagnosed by finding fetal epithelial cells in the maternal pulmonary vasculature

Front 58

Infarct def

Back 58

area of necrosis secondary to decreased blood flow

All infarcts wedge shaped with irregular margins. All have some degree of haemorrhage but in white infarcts, few extravasated red cells are rapidly lysed to form haemosiderin, therefore they become more pale with time.
Ischaemic coagulative necrosis is the dominant histological change with liquefactive necrosis occurring in CNS. Some parenchymal regeneration may occur but most infarcts are replaced by scar

Front 59

Anemic infartct

Back 59

White/pale infarct.
Caused by arterial occlusions in the heart, spleen, kidney

Front 60

Hemorrhagic infarct

Back 60

Red infarcts; red cells goes in to necrotic tissue.
In lungs and GIT form arterial occlusion. Tissues are loose and have double blood supplies.
Can also be venous occlusion

Front 61

Types of shock

Back 61

1. CARDIOGENIC: (Acute, Chronic Heart Failure)
2. HYPOVOLEMIC: (Hemorrhage or Leakage)
3. SEPTIC: (“ENDOTOXIC” shock, #1 killer in ICU)
4. NEUROGENIC: (loss of vascular tone)
5. ANAPHYLACTIC: (IgE mediated systemic vasodilation and increased vascular permeability)

Front 62

Septic shock events

Back 62

SYSTEMIC VASODILATION (hypotension) -->
↓ MYOCARDIAL CONTRACTILITY -->
DIFFUSE ENDOTHELIAL ACTIVATION -->
LEUKOCYTE ADHESION -->
ALVEOLAR DAMAGE --> (ARDS)
DIC
VITAL ORGAN FAILURE --> CNS

Caused by gram-negative bacilli that produce endotoxins Endotoxins are bacterial wall lipopolysaccharides (LPS).

LPS binds and activates leucocytes and endothelial cells causing release of mediators. At low doses, TNF, IL1, IL6 and IL8 predominate (note that they peak in this order, preceded by the peak of endotoxin)

At high doses NO and PAF become significant and endothelial injury may result. LPS also directly activates complement.

Front 63

Clinical stages of shock

Back 63

1. NON-PROGRESSIVE
- COMPENSATORY MECHANISMS
- CATECHOLAMINES
- VITAL ORGANS PERFUSED
2. PROGRESSIVE
- HYPOPERFUSION
- EARLY “VITAL” ORGAN FAILURE
- OLIGURIA
- ACIDOSIS
3. IRREVERSIBLE
- HEMODYNAMIC CORRECTIONS of no use

Front 64

Clinical progression of symproms in shock

Back 64

Hypotension -->
Tachycardia -->
Tachypnea -->
Warm skin --> Cool skin --> Cyanosis
Renal insufficiency -->
Obtundance
Death

Front 65

Describe the intrinsic clotting cascade?

Back 65

Slow pathway – takes 1-6 minutes to cause clotting Trigger – exposure to collagen fibres (or any electronegative surface), or trauma to blood

Activation of factor XII is catalysed by Kallikrein and HMW kininogen

Activated factor XII activates factor XI.
Activated factor XI activates factor IX.
Activated factor IX forms a complex with factor VIII, which activates factor X (prothrombin activator)

Calcium and phospholipids from platelets are also required.

Front 66

Describe the extrinsic clotting system?

Back 66

Rapid pathway – takes 15 seconds to cause clotting Trigger – release of tissue thromboplastin – a protein and phospholipid mixture that activates factor VII. Tissue thromboplastin and activated factor VII activate factor IX and X.

Calcium, phopholipids and factor V also required.

Front 67

What are the anticoagulant factors produced by endothelium?

Back 67

Prostacyclin and NO which are vasodilators and antiaggregators. Tissue plasminogen activator (and TPA inhibitors) – activates plasminogen Thrombomodulin – binds thrombin, complex activates protein C
Protein S

Front 68

What are the procoagulant factors produced by endothelium?

Back 68

Von Willebrand Factor – essential for binding of platelets to extracellular matrix. Tissue thromboplastin – activates extrinsic clotting cascade.

Front 69

Describe thromboxane A2 and prostacyclin?

Back 69

Thromboxane A2 has an aggregating effect that is counteracted by prostacyclin that has an antiaggregating effect.

Front 70

What is antithrombin III?

Back 70

Circulating protease inhibitor that binds to serine proteases in clotting cascade and blocks their action. Affects thrombin, factors IX, X, XI and XII. Other proteases include alpha1 antiprotease, alpha2 macroglobulin, alpha2 antiplasmin.

Front 71

What is heparin?

Back 71

Mixture of sulfated polysaccharides which facilitates binding of antithrombin III.

Front 72

Describe the fibrinolytic system?

Back 72

Thrombomodulin is a thrombin binding protein produced by endothelial cells (except cerebral microcirculation). Thrombomodulin-thrombin complex activates protein C.

Activated protein C inactivates factor VIII and V and inactivates inhibition of TPA.
Plasmin formed from plasminogen by action of thrombin, TPA and kallikrein Plasminogen is also activated by binding to endothelium. Plasmin lyses fibrin.