Robbins - Chapter 4

Question 1

Differentiate between Edema and Effusions.

Answer 1

1. Edema –> Accumulation of fluid in tissues
2. Effusions –> Accumulation of fluid in body cavities

*** Both are protein-poor fluids can TRANSUDATES

Question 2

Be familiar with the Pathological Categories of Edema.

Answer 2

Table 4-1; Pg. 114

Question 3

Describe the various causes of edema:

Answer 3

1. Increased Hydrostatic Pressure –> Mainly caused by disorders that impair (decrease) venous return
2. Reduced Plasma Osmotic Pressure –> Inadequate synthesis of Albumin can lead to a reduction in the Plasma Osmotic Pressure (LIVER disease); NEPHROTIC SYNDROME is when Albumin leaks into the urine due to a defect in glomerular filtration; Kidneys are going to see that the protein levels in the blood are going to be low so they will excrete Aldosterone to try and fix it (This will only exacerbate the edema)
3. Sodium and Water Retention –> Causes an increase in Hydrostatic Pressure (due to more fluid in the capillary) and a decrease in Vascular Colloid Osmotic Pressure due to the proteins being more diluted; Most commonly seen with Renal Problems; Congestive Heart Failure (CHF) results in the activation of the Renin-Angiotensin-Aldosterone axis which will be okay in early heart failure (increase vascular tone, elevated levels of ADH, and an increase in cardiac output); In late CHF, the RAAS axis is going to cause extreme Edema and Effusions due to the increase in Hydrostatic Pressure

Figure 4-2; Pg. 115

4. Lymphatic Obstruction –> LYMPHEDEMA is a result of the inability to clear interstitial fluid from the lymph system; ELEPHANTIASIS is caused by parasitic organisms that induce obstructive fibrosis of lymphatic channels and lymph nodes

Question 4

Describe the morphology of Edema:

1. Subcutaneous Edema
2. Renal Edema
3. Pulmonary Edema
4. Brain Edema

Answer 4

1. Subcutaneous Edema –> Its distribution is often dependent on Gravity (“Dependent Edema” - Standing up edema is in legs, but while lying down edema is in the Sacrum); Can end up with “Pitting Edema” where finger pressure over an Edema to us subcutaneous structure will leave a depression
2. Edema from RENAL Dysfunction –> Appears in parts of the body that contain LOOSE connective tissue (i.e. PERIORBITAL EDEMA)
3. Pulmonary Edema –> Lungs are often two to three times their normal weight and suctioning will yield “Frothy, Blood-tinged fluid”; Brought on by a problem in the left ventricle that is going to back up into the lungs! Commonly seen with CHF!
4. Brain Edema –> Swollen brain shows Narrow Sulci and Distended Gyri

Question 5

Describe the morphology of effusions.

Answer 5

1. Transudative effusions – Typically “Protein-Poor”, translucent and straw colored (Seen in Noninflammatory Pleural and Pericardial Effusions); *** Exception: Peritoneal Effusions may be milky due to the presence of lipids absorbed from the gut because there is “lymphatic blockage”!
2. Exudative Effusions –> “Protein-Rich” and often cloudy due to the presence of white cells

Different types of Effusions:

1. Hydrothorax: Pleural Cavity
2. Hydropericardium: Pericardial Cavity
3. Hydroperitoneum or ascites: Peritoneal Cavity

Question 6

Discuss some of the clinical features that are involved in edema and effusions.

Answer 6

1. Subcutaneous Edema –> Important because it can show an underlying cardiac or renal (Periorbital Edema) disease; when significant it can also impair wound healing
2. Pulmonary Edema –> Present with LEFT VENTRICULAR failure that you see in CONGESTIVE HEART FAILURE (also can occur with renal failure, acute respiratory distress syndrome and pulmonary inflammation)
3. Pulmonary Effusions –> Can compromise Gas exchange
4. Ascites (Peritoneal Effusions) –> Results from Portal Hypertension (LIVER failure)
5. Brain Edema –> SERIOUS! If severe, brain substance can herniate through the foramen magnum, or the brain stem vascular supply can be compressed

Question 7

Differentiate between Hyperemia and Congestion.

Answer 7

1. Hyperemia –> ACTIVE PROCESS in which Arteriolar Dilation leads to increased BLOOD FLOW; Affected tissues turn RED (erythema) because of increased delivery of oxygenated blood
2. Congestion –> PASSIVE PROCESS from reduced OUTFLOW of blood from a tissue; Can be systemic (i.e. Cardiac Failure) or localized (i.e. Isolated Venous Obstruction)

Question 8

Describe the morphology of tissues that are in the process of Congestion.

Answer 8

*** Take on a DUSKY reddish-blue color (cyanosis) due to red cell stasis and the presence of deoxygenated Hemoglobin

1. Acute Pulmonary Congestion –> Engorged alveolar capillaries, alveolar septal edema and focal intraaveolar hemorrhage
2. Chronic Pulmonary Congestion –> Often cause by Congestive Heart Failure, Septa are thickened and Fibrotic and the alveoli often contain number outs HEMOSIDERIN-laden (broken down form of iron from hemoglobin) macrophages called “Heart Failure Cells”
3. Acute Hepatic Congestion –> Central vein and sinusoids are distended; Centrilobar areas (far away from blood supply may undergo ischemic necrosis) and Perilobar Areas (around blood supply will undergo fatty change)
4. Chronic Passive Hepatic Congestion –> Centrilobar areas are red-brown and slightly depressed (because of cell death) “NUTMEG LIVER” –> Dark areas are the spots with Congestion

Question 9

Define Hemostasis and the various stages:

1. Arteriolar Vasoconstriction
2. Primary Hemostasis
3. Secondary Hemostasis
4. Clot stabilization and resorption

Answer 9

Process involving Platelets, Clotting Factors, and Endothelium that occurs at the site of vascular injury and culminates in the formation of a blood clot

1. Arteriolar Vasoconstriction –> Mediated by Neurogenic Mechanisms (reflex) and augmented by ENDOTHELIN
2. Primary Hemostasis –> von Willebrand Factor (vWF) will be exposed with disruption of the endothelium; Platelets come in, change their shape, release TxA2 to recruit more Platelets and form a Primary Hemostatic Plug
3. Secondary Hemostasis –> Tissue Factor is exposed beneath the endothelium and that is going to activate the Coagulation Cascade (activates Factor VII); Fibrin polymerization will stabilize the Initial Platelet Plug
4. Clot Stabilization and Resorption –> Polymerized Fibrin and Platelet Aggregates will undergo contraction to form a permanent platelet plug that prevents further hemorrhage; t-PA (fibrinolysis) and THROMBOMODULIN (blocks coagulation cascade) will limit clotting to the site of injury and eventually leads to repair

Figure 4-4; Pg. 117

Question 10

Differentiate between the structures within platelets:

1. Alpha-Granules
2. Dense Granules

Answer 10

1. Alpha-Granules –> Contain P-Selectin on their membranes; Contain proteins involved in the Coagulation Cascade (i.e. Fibrinogen, coagulation factor V, and vWF); Contains proteins involved in wound healing (i.e. Fibronectin, Platelet Factor 4, PDGF, and TGF-Beta)
2. Dense Granules –> ADP and ATP, Ca2+, Serotonin and epinephrine

Question 11

Describe the various phases involving platelets:

1. Platelet Adhesion
2. Platelets Rapidly changing shape
3. Secretion of Granule contents
4. Platelet Aggregation

Answer 11

1. Platelet Adhesion –> vWF is going to be the connection between the Platelet surface receptor GLYCOPROTEIN (GpIb) and exposed collagen. GpIIb-IIIa is going to mediate the adhesion of Platelets with one another through FIBRINOGEN. If you are missing these by way of genetic diseases, you will have bleeding disorders
   - - Missing vWF –> von Willebrand Disease
   - - Missing GpIb –> Bernard-Soulier Syndrome
   - - Missing GpIIb-IIIA –> Glanzmann thrombasthenia
2. Platelets Rapidly change shape –> Alterations in Glycoproteins IIb/IIIa that increase its affinity for fibrinogen and by translocation of NEGATIVELY charged phospholipids (i.e. Phosphatidylserine) to the platelet surface
3. Secretion of Granule contents –> Occurs along with changes in shape and together this is referred to as “Platelet Activation”; Platelet activation is triggered by THROMBIN and ADP; Thrombin Activates platelets through a special type of GPCR referred to as PROTEASE-ACTIVATED RECEPTOR (PAR); Dense-granules are going to release ADP and that will cause RECRUITMENT of more Platelets; Activated platelets will also produce THROMBOXANE A2 (Potent inducer of platelet aggregation); ASPIRIN is going to inhibit COX which is necessary to make TxA2 and that will decrease the ability to form blood clots
4. Platelet Aggregation –> Conformational change in GpIIb-IIIa will cause a higher affinity to Fibrinogen and that will cause the cross-linking of additional platelets; If you do not have GpIIb-IIIa you will have “Glanzmann Thrombasthemia”; Initial wave of aggregation is REVERSIBLE but thrombin is going to stabilize the platelet plug and cause IRREVERSIBLE Platelet Contraction (dependent on the cytoskeleton); Thrombin also converts fibrinogen into insoluble fibrin which will created the definitive Secondary Hemostatic Plug; RBCs and Leukocytes will get trapped in the plug due to the presence of P-SELECTINS on the outer surface of the platelets!

Figure 4-5; Pg. 118

Question 12

Differentiate between the Clotting cascade in the Laboratory and In Vivo.

Answer 12

Figure 4-6; Pg. 118

Question 13

Which factors are dependent on Calcium?

Where does Calcium bind?

Which drug will block these factors?

Answer 13

X, IX, VII, II (1972)

Binds to gamma-carboxylated Glutamic Acid residues

COUMADIN –> Blocks the factors because they use a Vitamin K cofactor

Question 14

Differentiate between the function of:

1. Prothrombin Time (PT)
2. Partial Thromboplastin Time (PTT)

Answer 14

1. Prothrombin Time (PT) –> Looks @ the function of the EXTRINSIC PATHWAY (Factors VII, X, V, II, and Fibrinogen); ADD: Tissue Factor, Phospholipids and Ca2+ are added to plasma and the time for a fibrin clot is recorded
2. Partial Thromboplastin Time (PTT) –> Looks @ the function of the INTRINSIC PATHWAY (Factors XII, XI, VIII, X, II, and Fibrinogen); ADD Negatively Charged surface, Phospholipids and Ca2+
   - - Deficiencies of Factors V, VII, VIII, IX, and X are associated with moderate - severe bleeding disorders
   - - Prothrombin Deficiency –> Likely incompatible with life
   - - Factor XI Deficiency –> Mild Bleeding (Explained by the ability of THROMBIN to activate factor XI in a feedback mechanism that amplifies the coagulation cascade)
   - - Factor XII Deficiency –> Can be more susceptible to Thrombosis

Question 15

Which of the Coagulation Factors is the most important?

List and describe the functions of this factor.

Answer 15

THROMBIN

Functions:
1. Conversion of Fibrinogen to cross linked Fibrin –> Also causes Amplification of the coagulation cascade by activating Factors XI, V, VIII and XIII (which will covalently cross-link fibrin)

2. Platelet Activation –> Able to activate PARs
3. Pro-inflammatory Effects
4. Anticoagulant Effects –> Changes from a pro coagulant to an anticoagulant outside of the damaged portion to protect from excessive clotting

Figure 4-8; Pg. 120

Question 16

Describe the various factors that are going to limit Coagulation.

Answer 16

1. Simple Dilution –> Blood washing by the clot will wash away the coagulation factors
2. Requirement of Negatively Charged Phospholipids
3. Fibrinolytic Cascade –> Activated when the Coagulation Cascade has been activated; Primarily accomplished through PLASMIN; tPA and urokinase are going to activate PLASMINOGEN in the presence of Fibrin (Good drug target for sites of recent thrombosis); “Alpha2-antiplasmin” is going to bind and INHIBIT free plasmin in the blood stream; PAI (Plasminogen Activator Inhibitor; Inhibits t-PA and urokinases)

– An elevated levels of breakdown products of fibrinogen (often called fibrin split products), most notably fibrin-derived-“D-DIMERS”; They are used for clinical markers of Several Thrombotic States.

Figure 4-9; Pg. 120

Question 17

Describe the various effects that the Endothelium has to decrease clotting:

1. Platelet Inhibitory Effects
2. Anticoagulant Effects
3. Fibrinolytic Effects

Answer 17

1. Platelet Inhibitory Effects –> An intact Endothelium is going to hide vWF and Collagen from platelets; Prostacyclin (PGI2), NO and ADPase will all inhibit Platelet Aggregation; Bind to THROMBIN and will alter its activity
2. Anticoagulant Effects –> Thrombomodulin and Endothelial Protein C receptor (bind Thrombin and Protein C respectively); Protein C is a Vitamin-K dependent Protease that requires the cofactor Protein S (Potent inhibitor of Factor Va and VIIIa); Heparin-Like molecules on the surface of endothelium bind and activate ANTITHROMBIN III which then inhibits THROMBIN and factors IXa, Xa, XIa, and XIIa
3. Firbinolytic Effects –> Normal endothelium produces t-PA (which is going to activate Plasminogen)

Figure 4-10; Pg. 121

Question 18

Describe the different types of Hemorrhagic Disorders:

1. Defects of Primary Hemostasis
2. Defects of Secondary Hemostasis
3. Generalized defects involving small vessels

Answer 18

1. Defects of Primary Hemostasis –> Platelet defects of vWF disease present with small bleeds in the SKIN or MUCOSAL membranes (MUCOCUTANEOUS BLEEDING); Take the form of Petechiae (Minute 1- to 2-mm hemorrhages) or Purpura (Slightly larger than Petechiae >3-mm)
   - - Aspirin: Inhibits COX - Decrease TxA2 - Decrease Platelet aggregation
   - Renal Failure - uremia - reduced platelet function
   - - Present as EPISTAXIS (nose bleeds) GI bleeding or menorrhagia (excessive menstruation)
   - - Thrombocytopenia (low Platelet counts) can result in a fatal intracerebral bleed
2. Defects of Secondary Hemostasis –> Problems with coagulation factors; Hemophilia typically has hemarthrosis (bleeding in joints) following minor trauma
3. Generalized defects in vessels –> Present with Ecchymosis (bruises that are 1-2 cm in size) and that can present with a palpable mass called a Hematoma

Question 19

List and describe the three components that are involved in the Virchow Triad of Thrombosis.

Answer 19

1. Endothelial Injury –> CAN lead to Abnormal blood flow AND HYPERCOAGUABLE; Can lead to Chronic Inflammation, Hypertension, Hyperlipidemia, and Circulating Toxins; Results in: DECREASE in Procoagulant (Thrombomodulin, protein C, TF inhibitor) and Antifibrinolytic (t-PA) effects
2. Hypercoagulability –> Predisposition that is going cause people to be more susceptible to Thrombosis; 1. HEREDITARY Factor V Leiden (resistant to protein C), “Arg –> GLU” substitution results in an increased risk for venous thrombosis; 2. Prothrombin Gene Mutation (Increase circulating Prothrombin) is the 2nd most common inherited cause of hypercoagulability in the US; 3. Homocysteinuria (deficiency of Cystanthione Beta-synthetase); 4. Deficiencies of anticoagulant proteins
3. Abnormal Blood flow –> Turbulence (Arteries and in the heart) and Stasis (veins) can both contribute to Clot Formation and lead to Endothelial Injury; Clinical examples: Ulcerated atherosclerotic plaques, Aneurysms, Infarcted Myocardial Tissue, Prolonged immobilization (Long Airline flights)

Figure 4-12

Question 20

Differentiate between the various Hypercoagulable States.

Answer 20

Table 4-2; Pg. 123

– Heparin-Induced Thrombocytopenia (HIT) syndrome –> Platelets will actually be low because you are making so many clots; Abs to complexes of “unfractionated heparin” and platelet factor 4 (if you give “Low Molecular Weight Heparin” the incidence of Thrombosis is lower); can cause rapid necrosis

– Antiphospholipid Antibody Syndrome –> Recurrent thrombosis, thrombocytopenia or recurrent fetal loss; Elevated levels of antibodies to anionic phospholipids (i.e. anticardiolipin antibody) might give a FALSE positive test for SYPHILIS; Clinical presentation includes: Pulmonary Embolism, Stroke, MI, Bowel Infarction

Question 21

Describe the morphology of a Thrombus.

Answer 21

Arterial Thrombi (clot will grow in the retrograde direction) arise at sites of turbulence (aka Branch points in major vessels), Venous Thrombi (clot will grow in the anterograde direction) occur at sites of stasis

LINES OF ZAHN –> Indicates that the thrombus formed in the presence of flowing blood (Clue to figure out if there is a pathologic clot or a clot if the body is just sitting there after death)

Common Sites for Arterial Thrombi: 1. Coronary Arteries (MI), 2. Cerebral Arteries (Stroke), 3. Femoral Arteries

Common Sites for Venous Thrombi: 1. Veins of Legs (superficial and deep), upper extremities

MURAL THROMBI –> Thrombus that occurs in the heart or within the aorta (i.e. Myocardial Infarction or aortic aneurysm)

Figure 4-13; Pg. 125

Question 22

Describe the Fate of the Thrombus.

Answer 22

1. Propagation - Grows until it runs out of space
2. Embolize - Piece of the thrombus is going to break off and travel downstream
3. Dissolution by Fibrinolysis
4. Organization (Thrombus is replaced by fibroblasts, smooth muscle and endothelial cells) and recanalization (new capillaries and small vessels grow through the structure)

Figure 4-14; Pg. 126

Question 23

Describe Pulmonary Embolisms.

Answer 23

Originate from DVTs and are the MOST COMMON form of thromboembolic disease!

*** Fragmented thrombi from DVTs are carried through progressively larger veins and the right side of the heart before slamming into the pulmonary arterial vasculature.

Types:

1. Saddle Embolus –> Straddles the Pulmonary Artery bifurcation
2. Paradoxical Embolism –> Venous Embolus gains access to the systemic arterial circulation (rare)

Facts:

• Most pulmonary emboli (60-80%) are clinically silent because they are small and will eventually incorporate into the vessel wall
• COR PULMONALE (right heart failure)
• Medium sized Emboli in the Pulmonary arteries typically does not end up in an infarction because the supply to the lungs by the BRONCHIAL ARTERIES is sufficient to keep the lungs alive; LEFT-SIDED heart failure is going to cause INFARCTIONS due to the decrease output of the Bronchial Arteries
• Embolic obstruction of small end-arteriolar pulmonary branches often will cause Hemorrhage or Infarction
• Multiple emboli over time may cause pulmonary hypertension and right ventricular failure

Question 24

Describe Systemic Thromboembolism.

Answer 24

80% arise from INTRACARDIAC Mural Thrombi (2/3 are associated with Left Ventricular Wall infarcts and 1/4 with Left atrial dilation and fibrillation)

• ** Where it will occlude depends on the blood flow that downstream tissues receive
• • Most come to rest in the Lower Extremities (75%) or Brain (10%)

Question 25

Describe Fat and Marrow Embolism.

Answer 25

Figure 4-16; Pg. 128

Microscopic Fat globules can be found in the pulmonary vasculature after fractures of long bones or in the setting of soft tissue trauma and burns

Can occur after vigorous CPR

FAT EMBOLISM SYNDROME –> Term applied to the minority of patients who become symptomatic

• • Pulmonary insufficiency, neurological symptoms, anemia, and thrombocytopenia
• • Presentation: 1-3 Days after injury, there is a sudden onset of tachypnea, dyspnea and tachycardia; irritability and restlessness can progress to delirium or coma
• • Release of free fatty acids can exacerbate the injury because that will cause the recruitment of platelet activating factors

Question 26

Describe Air Embolisms.

Answer 26

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

At least 100 cc of air is necessary to produce clinical symptoms

DECOMPRESSION SICKNESS –> If you ascend too quickly while diving, Nitrogen go into the tissues!

Question 27

Describe Amniotic Fluid Embolism.

Answer 27

Figure 4-17; Pg. 129

Question 28

Describe an infarction.

Answer 28

Area of ischemic necrosis caused by occlusion of either the arterial supply or venous drainage.

MORPHOLOGY
– Red Infarcts: Occur with Venous conclusions; In loose spongy tissues (lungs); In tissues with dual circulations (lung and small intestine); When flow is reestablished to a site of previous arterial occlusion and necrosis (i.e. Following angioplasty of an arterial obstruction)

– White Infarcts: Occur with arterial occlusions in SOLID ORGANS with end-arterial circulation (i.e. Heart, Spleen, and kidney)

– Tend to be wedged shape with the occluded area @ the APEX and the periphery of the organ @ the BASE