Fluid and Hemodynamics II (trans 6)

Question 1

Thrombosis

• Thrombosis is a formation of a solid clotted mass (thrombus/antemortem clot) derived from blood elements (vessel, platelets, CF) intravascularly in a living person.
• *Also known as antemortem clot, it is a solid clotted mass that is attached to the vessel wall.

Answer 1

It is to be differentiated from post-mortem clot:
o Formed extravascularly
o Involves clotting factors only
o Clotting after death
o “Currant jelly” or “chicken fat” clot
**Post-mortem Clots. They are rubbery and gelatinous that form perfect cast on vessel walls, and have no attachment to the vessel wall/endothelium.

Question 2

Thrombus
Consistency: Dry and friable
Surface: Granular and rough
Color: White or buff
Attachment: Attached to vessel wall
Endothelium: Damaged/ injured
Composition: Platelets primarily
Rapidity of blood flow: Formed in flowing stream of blood
Organization: May be partially organized

Answer 2

Postmortem Clot
Consistency: Moist and jelly-like
Surface: Smooth and glistening
Color: Intense red or yellow
Attachment: Not attached to vessel wall
Endothelium: Undamaged
Composition: Fibrin primarily
Rapidity of blood flow: Formed in stagnant column of blood
Organization: No organization

Question 3

Normal Hemostasis

Functions (2)

Answer 3

o Maintenance of blood in a fluid, clot-free state

o Ability to rapidly form a localized hemostatic plug at the site of vascular injury

Question 4

Normal Hemostasis

Factors/Elements (3)

Answer 4

o Blood vessel wall/endothelium
o Platelets
o Coagulation system

Question 5

Normal Hemostasis

Sequence of events (4)

Answer 5

o Vasoconstriction
- Stimulated by vascular injury
- Mediated by sympathetic NS and endothelin secretion
o Primary hemostatic plug
- Easily dislodged, platelet response
- Unstable, friable so there is a need to add fibrin
o Secondary hemostatic plug
- Cross-linkage of fibrin
- More stable, firmer
- Produces thrombus, which can occlude blood flow if formed excessively
o Thrombosis and anti-thrombotic events
- Significant in the prevention of excessive thrombus formation

Question 6

Primary Hemostasis.
Platelets adhere to von Willebrand factor (vWF), located on exposed extracellular matrix (ECM), via glycoprotein 1b (GpIb) receptors leading to their activation. Thus, activated platelets undergo a conformational change and granular release. Released adenosine diphosphate (ADP) and thromboxane A2 (TxA2) induce additional platelet aggregation through binding of platelet GpIIb-IIIa receptors to fibrinogen. This platelet aggregate then fills the vascular defect, forming the primary hemostatic plug.

Answer 6

Secondary Hemostasis.
Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, “cementing” the platelets into a definitive secondary hemostatic plug that is larger and more stable than the primary plug and contains entrapped red cells and leukocytes

Question 7

Roles of the Three Elements of Hemostasis

Blood vessel wall

Answer 7

1. Elaboration of pro-thrombotic factors/substances:
   - vWF-platelet binding co-factor (Factor VIII)
   - Extrinsic tissue factor activates extrinsic pathway
   - Plasminogen activator inhibitors - inhibits fibrinolysis
2. Insulation of platelets from subendothelial collagen
3. Elaboration of humoral factors (endothelin) => vasoconstriction
4. Elaboration of anti-thrombotic substances
   - Platelet aggregator inhibitors (prostacyclin, ADPase, nitric oxide “NO”)
   - Anti-thrombin inhibitors (thrombomodulin, heparinlike molecule)
   - Fibrinolytic (tissue plasminogen activator “t-PA”)

Question 8

Roles of the Three Elements of Hemostasis

Platelet

Answer 8

o Maintain the integrity of the vascular endothelium
o Participate in endothelial repair through the contribution of platelet-derived growth factor (PDGF)
o Form platelet plugs
o Promote the coagulation cascade through platelet
phospholipid complex

Question 9

Roles of the Three Elements of Hemostasis

Platelet: Adhesion - Activation-Aggregation

Answer 9

Platelet adhesion
- Attachment to site of injury and exposed collagen
- Needs vWF to bridge platelet and collagen
Platelet secretion and release
- Platelet activation leads to the appearance of negatively charged phospholipids (phosphatidylserine) on their surface which binds calcium and serves as critical nucleation sites for the assembly of complexes containing various coagulation factors.
- Platelet secretory products:
 Alpha granules (fibrinogen, fibronectin, PDGF, platelet factor-4)
 Dense bodies (ADP, Ca, histamine, serotonin)
Platelet aggregation (platelet-to-platelet interaction)
- Formation of temporary (primary) hemostatic plug
- Stimulated by ADP, TXA2, thrombin
Platelet contraction
- Viscous metamorphosis
- Formation of secondary hemostatic plug
- Mediated by octomyosin

Question 10

Roles of the Three Elements of Hemostasis
Coagulation System
- Coagulation Cascade. The coagulation cascade is a successive series of amplifying enzymatic reactions. At each step in the process, a proenzyme is proteolyzed to become an active enzyme, which in turn proteolyzes the next proenzyme in the series, eventually leading to the activation of thrombin and the formation of fibrin.

Answer 10

o Conversion of thrombin to fibrinogen and formation of fibrin => thrombus
o May be stimulated by extrinsic and intrinsic pathway
**Fibrinogen – large protein that forms bridging interactions between platelets that promote aggregation
**Thrombin converts fibrinogen to fibrin, functionally cementing the platelets in place

Question 11

Anti-Clotting Mechanism

Answer 11

 Depletion of clotting factors
 Clearance of clotting factors by liver
 Fibrinolysis: plasmin and plasminogen
 Proteases
 Anti-thrombin

Question 12

Predisposing Factors to thrombosis
 Injury to endothelium
 Alteration in normal blood flow
 Alteration in the blood (hypercoagulable state)

Answer 12

**Virchow’s Triangle - The predisposing factors as illustrated by Rudolf Virchow. These factors can work either independently or in combination. Ex. Endothelial injury can alter local blood flow and coagulation.

Question 13

Predisposing Factors to thrombosis: Endothelial Injuries

Answer 13

1. Acute Myocardial Infarction
   - Injury due to ischemia to heart muscles
2. Atherosclerosis
   - Formed fibrinolytic plaques
3. Cigarette smoking
   - Contain endotheliotoxic chemicals that trigger clot formation
4. Vasculitis
5. Hypertension
6. Hypercholesterolemia

Question 14

Predisposing Factors to thrombosis: Alterations in Blood Flow

Answer 14

1. Stasis
    A major factor in development of venous thrombi
    Can be prevented post-surgery by asking patients to immediately ambulate
2. Aneurysm
    Arterial and cardiac thrombi
    Abnormal dilation of blood vessels => irregular blood flow
3. Valvular stenosis/regurgitation
    Rheumatic mitral valve stenosis causes left atrial dilatation
4. Vascular obstructions
5. Turbulence
    Causes endothelial injury or dysfunction
    Forms counter-currents and local pockets of stasis

Question 15

Predisposing Factors to thrombosis: Hypercoagulability (Thrombophilia)

Answer 15

1. Immobilization
    Stagnation or Post-Surgery
2. Malignancy
   E.g. point mutations in Factor V and prothrombin gene
3. APAS (Anti-Platelet Antibody Syndrome)
4. DIC (Disseminated Intravascular Coagulopathy)
5. Nephrotic syndrome
   o Oral contraceptive use

Question 16

Morphology of thrombosis

Answer 16

Lines of Zahn
o Gross and microscopic linear laminations
o Distinguishes antemortem from post-mortem thrombosis
o Alternating dark and light regions
- Dark/Red: RBCs, some leukocytes, fibrin (venous system)
- Light/Pale: Clotting factors, degranulated platelets, fibrin (Arterial System)

Question 17

Types of Thrombus

Answer 17

1. Mural Thrombus
2. Vegetation Thrombus
3. Arterial Thrombi (Occlusive/White/Conglutination)
4. Venous Thrombi (Phlebothrombosis/Red/Coagulative)

Question 18

Types of Thrombus:

Mural Thrombus

Answer 18

o Attached to walls of large capacitance vessels

o Found in aorta, surface of heart, ventricle, and atria

Question 19

Types of Thrombus:

Vegetation Thrombus

Answer 19

o Found on heart valves
o Infective endocarditis – blood-born bacteria or fungi can adhere to previously damaged valves or can directly damage valves
o Nonbacterial thrombotic endocarditis – sterile vegetations on non-infected valves in persons with hypercoagulable states

Question 20

Types of Thrombus:
Arterial Thrombi (Occlusive/White/Conglutination)

Answer 20

o Occur at site of injury/turbulence
o Has retrograde growth
o Prone to occlusion
o Gray/White thrombi
o More platelets and fibrin, less RBC

Question 21

Types of Thrombus:
Venous Thrombi (Phlebothrombosis/Red/Coagulative)

Answer 21

o Occurs at the site of stasis
o Has forward propagation
o Prone to occlusion and fragmentation
o Red, stasis thrombi
o More RBCs

Question 22

REMEMBER

One of the following can occur to the thrombi if a patient survives initial thrombosis

Answer 22

 Propagation – Platelets grow in dimension & number
 Lysis and Resolution – The major outcome; due to fibrinolysis
 Embolization– The thrombi dislodge and can travel to other sites of vasculature
 Organization– The thrombus becomes part of the wall; fibroblastic reparative process
1. Mechanical
2. Recanalized – formation of secondary or tertiary vessels (to compensate); mainly occur in deep veins of the lower extremities.

Question 23

Disseminated Intravascular Coagulopathy (DIC)
 An acute, subacute, or chronic thrombo-embolic disorder
 Occurs as 2° cluster of variety of clinical disorders
 Presenting with: thrombotic ischemia, consumption coagulopathy, shock
Also known as:
o Defibrination syndrome
o Microcirculatory thrombosis
o Consumption coagulopathy

Answer 23

Clinical associations
o Sepsis
o Snake bites
o Abruption placenta
o Retained dead fetus
o Carcinomatosis
o Burns
o Shock
o Amniotic fluid embolism (AFE)
Morphology
o Multiple microthrombi in different organs (brain, heart, lungs, kidneys, adrenals)
o 2° ischemic necrosis or hypoxic injury to tissues
o Paradoxical multiple hemorrhages. Due to consumption of clotting factors

Question 24

EMBOLISM
- Process by which a detached intravascular solid, liquid or gaseous mass (embolus) is carried via blood stream to a site distant to its point of origin.

Answer 24

Types
o Thrombo-embolism
o Systemic embolism
o Amniotic fluid embolism
o Air embolism
o Fat/cholesterol embolism

Question 25

Types of Embolism:
Pulmonary Thrombo-Embolism (PTE)
 95% arise from deep veins of leg
 Passes from the deep veins of the leg to the inferior vena cava entering the right atrium then the right ventricle, which shunts blood to the pulmonary arteries where the thromboembolus lodges.
 Majority lodges at large and medium sized pulmonary arteries

Answer 25

Associated diseases/states: immobilization, cardiac disease, recent surgery, carcinoma
o These conditions all contain the predisposing Virchow’s triad
o To prevent thrombo-embolism, ambulate to prevent hemostasis

Question 26

Types of Embolism:

Pulmonary Thrombo-Embolism (PTE) - Morphology

Answer 26

1. Saddle embolus (thrombo-emboli in the pulmonary artery)
   - Occlude the main pulmonary artery, straddle the pulmonary artery bifurcation
2. Paradoxical embolus
   - A venous type of thrombus that gained entry into the systemic circulation
   - It is “paradoxical” how it entered systemic circulation
   - Pathway is through a hole in the heart usually in an interatrial or interventricular defect and bypass the pulmonary circulation
   * *May have hemorrhagic infarction of lung – minority will have this complication

Question 27

Types of Embolism:

Pulmonary Thrombo-Embolism (PTE) - Clinical Sequelae

Answer 27

o Acute RV failure
o Sudden cardiac death
- Because there will be complete stoppage of circulation of the blood to the lungs and to the left side of the heart leading to the reduction of cardiac output
o Pulmonary hypertension
- Sudden precipitous elevation of the pulmonary wedge pressure related to the obstruction of pulmonary blood flow
- Chronic pulmonary hypertension: slow stepwise increase if there is repeated pulmonary thrombo-embolism
o Resolution/organization
- Majority of the cases, the clot lyse by the process of fibrinolysis and therefore there will be complete resolution; it will heal
- Part of the thrombus will reside in the pulmonary arteries and become resident thrombi by the process of organization
**Pulmonary infarction and hemorrhage: Minority of cases (10%) pulmonary infarction will occur wherein there is cell death, an irreversible damage

Question 28

Types of Embolism:
Systemic Embolism
 Emboli travels within arterial circulation
 Almost always occlusive and therefore produce infarction

Answer 28

Sources:
80% arise from the heart, called a mural thrombus
 Left ventricle from AMI
 Left atrium from RHD
 Others: aorta (due to aortic aneurysm), valves
 10-15 % unknown primary
Sites of Lodgment:
o 75% Lower extremities
o 10% Brain (cerebral arteries) => may lead to stroke
o Rest: Viscera (spleen, kidney, heart), upper extremities

Question 29

REMEMBER
In contrast with venous embolus that tends to lodge primarily in one vascular bed (the lung), arterial thrombus can travel to a wide variety of sites.

Answer 29

Common sites of infarction from arterial emboli

o Brain, retina, heart (left ventricle), spleen, kidney, small intestine

Question 30

Types of Embolism:
Air Embolism (AKA barotrauma)
 Embolic substances are dissolved gases
 Common complication of deep sea divers who are not properly decompressed
 Significant volume of air embolus that will produce clinical manifestation will be 100ml to produce obstruction
 Produce complete obstruction and distal ischemic injury

Answer 30

Causes
o Rupture of blood vessel during difficult delivery
- Especially when there is suction procedure and a vessel ruptures, air can gain entry via the vagina to the maternal circulation
o Rupture during thoracotomy secondary to pneumothorax (iatrogenic)
- When a vessel is hit and air gains entry in the circulation
- Thoracotomy: needle insertion on the pleural to remove air from pneumothorax or fluid from pleural effusion
o Lung trauma
o Rapid decompression among deep sea divers

Question 31

Types of Embolism:
Air Embolism (AKA barotrauma) - Decompression Sickness
o Result of sudden changes in atmospheric pressures
o Associated with deep sea divers, rapid descent in unpressurized aircraft
o Dissolving of nitrogen in blood and tissues

Answer 31

Causes
Acute decompression
- Sudden
- “the bends” – air embolism in joints/skeletal muscles
- “the chokes” – air embolism in lungs
Chronic decompression (Caisson’s Ds)
- Long standing process of ischemic injury
- Chronic air embolism that may enter skeletal system and lead to multiple ischemic necrosis of bone

Question 32

Types of Embolism:
Amniotic Fluid (AF) Embolism/Infusion
 Amniotic fluid material from the gestational sac that gains access to the maternal circulation
 Embolic materials are fetal skin, lanugo hair, vernix caseosa, mucin, bile, amniotic fluid debris – which lodge in the pulmonary vessels resulting in many patients presenting with respiratory difficulty
 Patients who pushed too much, had arrested vaginal delivery - cause the blood vessels to dilate, and AF can gain entry to the maternal circulation which may go to the lungs
 80-90% high mortality rate - because amniotic fluid is highly thrombogenic

Answer 32

Complications
o DIC
 Aka microcirculatory thrombosis
 Stimulation of the extrinsic pathway causes microclots
to lodge in small arteries
 High mortality – 90% of the time, death
o Diffuse alveolar damage
o Pulmonary edema
o Adult respiratory distress syndrome (ARDS)

Question 33

Types of Embolism:
Fat Embolism
 Embolic material: fat/marrow
 Complication of fracture, trauma, burns
- Marrow fat can be dislodged and enter venouscirculation.
 Only 10% will have clinical signs and symptoms
 Associated with pulmonary, neurologic symptoms and petechial skin rashes
 10% fatality rate (good prognosis)

Answer 33

Pathogenesis:
o Mechanical vascular obstruction
o Endothelial injury from free FA with platelet and RBC aggregation
**Requires Sudan, Oil-red-O stain to demonstrate fat globules within the blood vessels

Question 34

INFARCT
 An area of ischemic necrosis of organ/tissue as a result of arterial or venous occlusion
 99% of infarcts result from thrombotic or thrombo embolic occlusion of arteries (arterial in nature)
 End product of ischemia
 Irreversible

Answer 34

*NOTE: Nearly all (99%) infarcts result from thrombotic or embolic arterial occlusions. Venous occlusions can cause infarction but the more common outcome is just congestion.

Question 35

Causes of Infarction

Answer 35

 Thrombotic occlusion (thrombus completely occludes a blood vessel)
 Embolic occlusion
 Thrombo-embolic occlusion
 Atherosclerotic plaque that may form an embolus and clog the vessel lumen
 Extrinsic compression of blood vessels (ex. tumor hinging on a vessel)
 Twisting of blood vessels
 Mechanical compression (tumor or hernia)
 Trapping of viscous material
 Vasospasms

Question 36

Types of Infarction

Answer 36

A. Anemic (White) Infarcts
B. Hemorrhagic (Red) Infarcts
C. Septic Infarcts (Bacterial infection) - Infected cardiac valve embolize, infarct is converted into an abscess with a greater inflammatory response
D. Bland Infarcts - Without bacterial infection (sterile)

Question 37

Types of Infarction: Anemic (White) Infarcts

Answer 37

 Arterial occlusion
 Occurs in solid tissues (heart, spleen, kidney) with a single blood supply (end artery)
 Can lead to irreversible gangrene

Question 38

Types of Infarction: Hemorrhagic (Red) Infarcts

Answer 38

 Venous occlusion
 Generally affects the loose/spongy organs (lungs)
 Tissues served by double circulation (testis, ovary, small intestines)
 Previously congested tissue
 Re-vascularization of arterial occlusion
 Consists more RBC and fibrin strands

Question 39

INFARCT: Morphology

Answer 39

 Wedged-shaped with apex pointing to occlusion
 Pale or hemorrhagic
 Sharp or poorly defined margins (generally sharply delimited)
 Zone of Inflammatory response at periphery of infarction
 Coagulation necrosis in most organs (dominant histologic characteristic)
 Liquefaction necrosis in brain
 Most of the infarcts are replaced by scar tissue
 Loss of perfusion in the blood vessels, loss of vitality in the organ
 Ischemic injury and necrosis

Question 40

Factors That Affect the Development of an Infarct

Answer 40

1. Nature of blood supply
2. Rate of development of occlusion
3. Vulnerability of tissue to hypoxia
4. Blood oxygen content

Question 41

Factors That Affect the Development of an Infarct: Nature of blood supply

Answer 41

o Organs with dual blood supply are resistant to infarction while organs with single blood supply (end-arterial) can be damaged and result to tissue death

Question 42

Factors That Affect the Development of an Infarct: Rate of development of occlusion

Answer 42

o Slowly developing occlusions are less likely to cause infarction because there is still time to develop alternate perfusion pathways

Question 43

Factors That Affect the Development of an Infarct: Vulnerability of tissue to hypoxia

Answer 43

o Neurons – 3-4 minutes deprived of blood can be irreversibly damaged
o Myocardial cells – die at 20 to 30 minutes of ischemia (higher incidence of infarction)
o Fibroblasts – viable even after many hours of ischemia

Question 44

Infarction: Diseases

Answer 44

 Acute myocardial infarction
 Cerebral infarction (stroke)
 Gangrene

Question 45

SHOCK
 Systemic hypoperfusion (a problem in the circulation of blood) of tissues secondary to reduction of cardiac output or effectivecirculating blood volume.
 Produces hypotension, anoxia, and cellular death
 High mortality rate

Answer 45

Types of Shock

1. Cardiogenic
2. Hypovolemic/Hemorrhagic
3. Septic
4. Neurogenic
5. Anaphylactic
   * *Septic, Neurogenic and Anaphylactic exhibit the same mechanism: Widespread peripheral dilatation => pooling in periphery => reduced venous return => reduced cardiac output => decreased circulating blood volume => shock

Question 46

Types of Shock: Cardiogenic

Answer 46

 Due to low cardiac output from myocardial pump failure

 Results from intrinsic myocardial damage

Question 47

Types of Shock: Hypovolemic/Hemorrhagic

Answer 47

 Reduction of the circulating blood volume due to severe blood/fluid loss
 Inadequate blood/plasma volume
 Due to puncture wounds, significant fluid loss due to massive diarrhea (e.g. cholera)

Question 48

Types of Shock: Septic

Answer 48

Septic
 Due to bacteremia/septicemia (presence of organisms circulating in blood)
 Endotoxins released by bacteria stimulate peripheral vasodilation => pooling of blood into periphery => reduced venous return to heart => affect cardiac output
 Endotoxemia => peripheral vasodilatation

Question 49

Types of Shock: Neurogenic

Answer 49

 Sympathetic Nervous System stimulation => peripheral vasodilatation
 Due to anesthetic accident or spinal cord injury

Question 50

Types of Shock: Anaphylactic

Answer 50

 Ig-E-mediated hypersensitivity reaction => vasodilatation

Question 51

Stages of Shock

Answer 51

1. Nonprogressive / Compensated
2. Progressive Stage
3. Irreversible Stage

Question 52

Stages of Shock:
1. Nonprogressive / Compensated
 CO and BP are maintained via reflex activation

Answer 52

Primary compensatory mechanism: secretion of
o baroreceptors
o catecholamines
o ADH
o Symathetic Nervous System (SNS)
o Renin-Angiotensin-Aldosterone
Secondary compensatory mechanism:
o Tachycardia (if you increase heart rate, CO will also increase to maintain BP)
o peripheral vasoconstriction (of organs not necessarily used,vasoconstriction of peripheral arteries to conserve and maintain adequate BP)
o skin pallor (dermal vasoconstriction)
**If underlying cause is not corrected, it goes to
progressive stage

Question 53

Stages of Shock:

2. Progressive Stage

Answer 53

 persistence of shock and reduction of BP, CO
 onset of tissue hypo-perfusion/anoxia => metabolic acidosis => decreased vasomotor response => vasodilatation
 increased levels of lactic acid (metabolic acidosis) promotes vasodilation, so hypoperfusion becomes more progressive.
 Clinical presentation: hypotension, oliguria (increased volume of urine), cerebral depression

Question 54

Stages of Shock:

Irreversible Stage

Answer 54

 Results in severe cellular/tissue injury
 marked reduction of BP, CO
 renal shutdown
 worsening of metabolic acidosis
 coma and death

Question 55

NOTE: For the treatment of shock, it is very essential to recognize that there is shock. Hence, know the clinical manifestations, which are:

Answer 55

 Lowering of BP (most important!)
 Cold, clammy skin
 Perspiration

Question 56

Shock: Morphology: Widespread Hypoxic Injury

Answer 56

 Brain - ischemic encephalopathy
 Heart - contraction band and subendocardial necrosis
 Kidney - acute tubular necrosis
 Lungs - ARDS, shock lung
 Adrenals - cortical cell lipid depletion
 GIT- hemorrhagic enteropathy (necrosis of the GIT)
 Liver - fatty change, central hemorrhagic necrosis

Question 57

Hemostasis
• Arteriolar vasoconstriction occurs immediately and markedly reduces blood flow to the injured area. It is mediated by reflex neurogenic mechanisms and augmented by the local secretion of factors such as endothelin, a potent endothelium-derived vasoconstrictor.
• Primary hemostasis: the formation of the platelet plug. Disruption of the endothelium exposes subendothelial von Willebrand factor (vWF) and collagen, which promote platelet adherence and activation. Activation of platelets results in a dramatic shape change (from small rounded discs to flat plates with spiky protrusions that markedly increased surface area), as well as the release of secretory granules. Within minutes the secreted products recruit additional platelets, which undergo aggregation to form a primary hemostatic plug

Answer 57

• Secondary hemostasis: deposition of fibrin. Tissue factor is also exposed at the site of injury. Tissue factor is a membrane-bound procoagulant glycoprotein that is normally expressed by subendothelial cells in the vessel wall, such as smooth muscle cells and fibroblasts. Tissue factor binds and activates factor VII, setting in motion a cascade of reactions that culiminates in thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork, and also is a potent activator of platelets, leading to additional platelet aggregation at the site of injury.
• Clot stabilization and resorption. Polymerized fibrin and platelet aggregates undergo contraction to form a solid, permanent plug that prevents further hemorrhage. At this stage, counterregulatory mechanisms (e.g., tissue plasminogen activator, t-PA) are set into motion that limit clotting to the site of injury and eventually lead to clot resorption and tissue repair.

Question 58

Platelets
α-Granules: adhesion molecule P-selectin on their membranes and contain proteins involved in coagulation, such as fibrinogen, coagulation factor V, and vWF, as well as protein factors that may be involved in wound healing, such as fibronectin, platelet factor 4 (a heparin-binding chemokine), platelet-derived growth factor (PDGF), and transforming growth factor-β

Answer 58

Dense (or δ) granules: adenosine diphosphate (ADP) and adenosine triphosphate, ionized calcium, serotonin, and epinephrine.

Question 59

Platelet adhesion
- mediated largely via interactions with vWF, which acts as a bridge between the platelet surface receptor glycoprotein Ib (GpIb) and exposed collagen

Answer 59

Notably, genetic deficiencies of vWF or GpIb (Bernard-Soulier syndrome) result in bleeding disorders, attesting to the importance of these factors.

Question 60

Platelet activation

• Platelets rapidly change shape
• Secretion (release reaction)

Answer 60

• Platelets rapidly change shape following adhesion, being converted from smooth discs to spiky “sea urchins” with greatly increased surface area. This change is accompanied by alterations in glycoprotein IIb/IIIa that increase its affinity for fibrinogen, and by the translocation of negatively charged phospholipids (particularly phosphatidylserine) to the platelet surface. These phospholipids bind calcium and serve as nucleation sites for the assembly of coagulation factor complexes.

Question 61

Platelet aggregation
- The conformational change in glycoprotein IIb/IIIa that occurs with platelet activation allows binding of fibrinogen, a large bivalent plasma polypeptide that forms bridges between adjacent platelets, leading to their aggregation. Predictably, inherited deficiency of GpIIb-IIIa results in a bleeding disorder called Glanzmann thrombasthenia).

Answer 61

The initial wave of aggregation is reversible, but concurrent activation of thrombin stabilizes the platelet plug by causing further platelet activation and aggregation, and by promoting irreversible platelet contraction. Platelet contraction is dependent on the cytoskeleton and consolidates the aggregated platelets. In parallel, thrombin also converts fibrinogen into insoluble fibrin, cementing the platelets in place and creating the definitive secondary hemostatic plug. Entrapped red cells and leukocytes are also found in hemostatic plugs, in part due to adherence of leukocytes to P-selectin expressed on activated platelets.

Question 62

Coagulation cascade
Based on assays carried out in clinical laboratories, the coagulation cascade has traditionally been divided into the extrinsic and intrinsic pathways

Answer 62

• The prothrombin time (PT) assay assesses the function of the proteins in the extrinsic pathway (factors VII, X, V, II, and fibrinogen). In brief, tissue factor, phospholipids, and calcium are added to plasma and the time for a fibrin clot to form is recorded.
• The partial thromboplastin time (PTT) assay screens the function of the proteins in the intrinsic pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen). In this assay, clotting of plasma is initiated by addition of negativecharged particles (e.g., ground glass) that activate factor XII (Hageman factor) together with phospholipids and calcium, and the time to fibrin clot formation is recorded.

Question 63

Fibrinolysis is largely accomplished through the enzymatic activity of plasmin, which breaks down fibrin and interferes with its polymerization.

Answer 63

Plasmin is generated by enzymatic catabolism of the inactive circulating precursor plasminogen, either by a factor XII–dependent pathway (possibly explaining the association of factor XII deficiency and thrombosis) or by plasminogen activators. The most important plasminogen activator is t-PA;

Question 64

Hypercoagulable States
Primary (Genetic)
1. Factor V mutation (Arg to Glu substitution in amino acid residue 506 leading to resistance to activated protein C; factor V Leiden)
2. Prothrombin mutation (G20210A noncoding sequence variant leading to increased prothrombin levels)
3. Fibrinolysis defects
4. Homozygous homocystinuria (deficiency of cystathione β-synthetase)

Answer 64

Secondary (Acquired)
Prolonged bed rest or immobilization
Myocardial infarction
Atrial fibrillation
Tissue injury (surgery, fracture, burn)
Cancer
Prosthetic cardiac valves
Disseminated intravascular coagulation
Heparin-induced thrombocytopenia
Antiphospholipid antibody syndrome

Question 65

Most venous thrombi occur in the superficial or deep veins of the leg. Superficial venous thrombi typically occur in the saphenous veins in the setting of varicosities. Such thrombi can cause local congestion, swelling, pain, and tenderness, but rarely embolize

Answer 65

Deep venous thrombosis (DVT) involving one of the large leg veins—at or above the knee (e.g., the popliteal, femoral, and iliac veins)—is more serious because such thrombi more often embolize to the lungs and give rise to pulmonary infarction