Exam IV: Hemodynamic Disorders and Thromboembolic Diseases II

Question 1

Coagulation Cascade

Answer 1

Third arm of the hemostatic process
Amplifying series of enzymatic conversions
Each step proteolytically cleaves an inactive proenzyme into an activated enzyme
Culminates in thrombin formation
Thrombin is the most important coagulation factor because it can act at numerous stages in the process

Question 2

Proteolytic Cascade

Answer 2

Thrombin converts the soluble plasma protein fibrinogen into fibrin monomers that polymerize into an insoluble gel converting the primary hemostatic plug into a secondary plug
Fibrin gel encases platelets and other circulating cells in the definitive secondary hemostatic plug
Fibrin polymers are covalently cross-linked and stabilized by factor XIIIa (which itself is activated by thrombin)

Question 3

Clinical Assessments of Coagulation Dysfunction

Answer 3

Assess the function of the two arms of the coagulation pathway
Two standard assays:
1. Prothrombin time (PT)
2. Partial thromboplastin time (PTT)

Question 4

PT Assay

Answer 4

Assesses the function of the proteins in the extrinsic pathway
Factors II, V, VII, X, and fibrinogen (2, 5, 7, 10)
Accomplished by adding tissue factor and phospholipids to citrated plasma (sodium citrate chelates calcium and prevents spontaneous clotting)
Coagulation is initiated by the addition of exogenous calcium and the time for a fibrin clot to form is recorded

Question 5

PTT Assay

Answer 5

Partial thromboplastin time (PTT)
Screens for the function of the proteins in the intrinsic pathway
Factors II, V, VIII, IX, X, XI, XII, and fibrinogen (2, 5, 8, 9, 10, 11, 12)
Clotting is initiated through the addition of negative charged particles (ground glass)
Activates factor XII (Hageman factor), phospholipids, and calcium, and the time to fibrin clot formation is recorded

Question 6

Thrombin

Answer 6

Exerts a wide variety of pro-inflammatory effects
Most effects of thrombin occur through its activation of a family of protease activated receptors (PARs)
PARs are expressed on endothelium, monocytes, dendritic cells, T lymphocytes, and other cell types

Thrombin Effects: neutrophil adhesion, monocyte activation, platelet aggregation with fibrin and TxA2, lymphocyte activation, endothelial activation

Question 7

Anticoagulation Restriction

Answer 7

Coagulation cascade must be restricted to the site of vascular injury to prevent runaway clotting of the entire vascular tree

Question 8

Three Categories of Endogenous Anticoagulants

Answer 8

1. Antithrombins (antithrombin III): inhibit the activity of thrombin and other serine proteases, including factors IXa, Xa, XIa, and XIIa (9, 10, 11, and 12)
   Antithrombin III is activated by binding to heparin-like molecules on endothelial cells
   Clinical usefulness of administering heparin to minimize thrombosis since heparin is an anti-coagulant
2. Proteins C and S: vitamin K-dependent proteins that act in a complex that proteolytically inactivates factors Va and VIIIa
3. Tissue Factor Protein Inhibitor (TFPI) is a protein produced by endothelium that inactivates tissue factor-factor VIIa complexes

Question 9

Endothelial Cells

Answer 9

Fine-tune the coagulation/anticoagulation balance
Releasing plasminogen activator inhibitor (PAI)
Blocks fibrinolysis by inhibiting t-PA binding to fibrin
Confers an overall procoagulant effect
Production is increased by thrombin as well as certain cytokines

Question 10

Fibrinolytic System: Fibrin Degradation Products

Answer 10

Endothelial cells release plasminogen activator inhibitors (PAI) to cause clot degradation; if you block PAI via tPA it won’t break down
What happens: “syrup” hardens and pieces flake off to get fibrin degradation products, which can be measured in the lab
Fibrin degradation products = indicate a clot was formed
Disseminated intravascular coagulation: disease where you see lots of clots and when they break down you see a lot of breakdown products

Question 11

Virchow’s Triad

Answer 11

Three primary abnormalities that lead to thrombus formation (called Virchow’s triad):

1. Endothelial injury
2. Stasis or turbulent blood flow
3. Hypercoagulability of the blood

When you have stasis, the blood is slowing down
Turbulent blood flow, fast moving, but there are spots that are slowed down = spots of clot formation

Question 12

Endothelial Injury

Answer 12

Particularly important for thrombus formation in the heart or the arterial circulation
Normally high flow rates might otherwise impede clotting by preventing platelet adhesion and washing out activated coagulation factors

Thrombus is not a normal occurrence unless injury present (anywhere in vasculature)
Thrombus formation within cardiac chambers (i.e. after endocardial injury due to myocardial infarction)
Over ulcerated plaques in atherosclerotic arteries
Sites of traumatic or inflammatory vascular injury (vasculitis)

Question 13

Endothelial Dysfunction

Answer 13

Endothelium does not need to be denuded or physically disrupted to contribute to the development of thrombosis
Any perturbation in the dynamic balance of the prothombotic and antithrombotic activities of endothelium can influence local clotting events

Induced by a wide variety of insults:
Hypertension
Turbulent blood flow
Bacterial endotoxins
Radiation injury
Metabolic abnormalities: homocystinemia or hypercholesterolemia
Toxins absorbed from cigarette smoke

Question 14

Turbulence

Answer 14

Alteration of normal blood flow
Contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction
Forming countercurrents and local pockets of stasis
Stasis is a major contributor in the development of venous thrombi

Arteries: most common cause of thrombosis is endothelial injury whereas in veins it is stasis

Question 15

Normal Blood Flow

Answer 15

Normal flow is laminar
Platelets (and other blood cellular elements) flow centrally in the vessel lumen
Separated from endothelium by a slower moving layer of plasma

Question 16

Stasis and Turbulence

Answer 16

Stasis and Turbulence:
Promote endothelial activation enhancing pro-coagulant activity
Disrupt laminar flow
Bring platelets into contact with the endothelium
Prevent washout and dilution of activated clotting factors via fresh flowing blood and inflow of clotting factor inhibitors

Question 17

Hypercoagulability

Answer 17

also called thrombophilia- something is missing in the coagulation pathway
Less frequent contributor to thrombotic states
Any alteration of the coagulation pathways that predisposes to thrombosis
Divided into primary (genetic) and secondary (acquired) disorders which are a result of the primary disease

Question 18

Inherited Hypercoagulation Diseases

Answer 18

Inherited causes (most common):
Point mutations in the factor V gene
Prothrombin gene

Question 19

Homocysteine and Thrombosis

Answer 19

Elevated levels of homocysteine contribute to arterial and venous thrombosis
Prothrombotic effects of homocysteine due to thioester linkages

Question 20

Rare Inherited Causes of Primary Hypercoagulability

Answer 20

Deficiencies of anticoagulants: antithrombin III, protein C, or protein S

Clinical presentation:
Begins in adolescence or early adulthood
Venous thrombosis
Recurrent thromboembolism

Question 21

HIT Syndrome

Answer 21

Acquired thrombophilic states
Heparin-induced thrombocytopenia (HIT) syndrome
Occurs following the administration of unfractionated heparin
May induce the appearance of antibodies
Recognize complexes of heparin and platelet factor 4 on the surface of endothelial cells causing binding of antibodies to platelets and results in their activation, aggregation, and consumption
Prothrombotic state, even in the face of heparin administration and low platelet counts

Question 22

Anti-Phospholipid Antibody Syndrome

Answer 22

AKA lupus anticoagulant syndrome
Autoantibodies induce a hypercoagulable state causing endothelial injury
Directly activates platelets and complement

Clinical manifestations:

1. Recurrent thrombosis, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia
2. Pulmonary embolism, pulmonary hypertension, stroke, bowel infarction, or renovascular hypertension
3. Fetal loss

Typical of younger patient that has lots of clots
Young adult who has had several miscarriages

Question 23

Secondary Antiphospholipid Syndrome

Answer 23

Individuals with a well-defined autoimmune disease

Systemic lupus erythematosus

Question 24

Primary Antiphospholipid Syndrome

Answer 24

Exhibit only the manifestations of a hypercoagulable state
Lack evidence of other autoimmune disorders
Association with certain drugs or infections

Question 25

Morphology of Thrombi

Answer 25

Can develop anywhere in the cardiovascular system Size and shape of thrombi depend on the site of origin and the cause Arterial or cardiac thrombi: begin at sites of turbulence or endothelial injury Venous thrombi: occur at sites of stasis

Question 26

Arterial vs. Venous Thrombi

Answer 26

Focally attached to the underlying vascular surface Arterial thrombi: grow retrograde from the point of attachment Venous thrombi: extend in the direction of blood flow

Question 27

Lines of Zahn

Answer 27

Represent pale platelet and fibrin deposits alternating with darker red cell-rich layers Signify that a thrombus has formed in flowing blood Presence can therefore distinguish antemortem thrombosis from the bland nonlaminated clots that occur postmortem **Indicate clot occurred over time/before death

Question 28

Post-Mortem Clots

Answer 28

Post mortem: lacking inter-digitation of cells from attaching to thrombus because no moving blood flow and RBCs will follow gravity and be on the bottom of vessels and WBCs that aren’t as heavy will be on top of the RBCs = buffy coat on top

Question 29

Mural Thrombi

Answer 29

Thrombi occurring in heart chambers or in the aortic lumen Abnormal myocardial contraction Arrhythmias, dilated cardiomyopathy, or myocardial infarction Endomyocardial injury (myocarditis or catheter trauma) Part of the wall isn’t moving and get stasis – mural thrombus develops Can get outpouching of the aorta

Question 30

Arterial Thrombi

Answer 30

Frequently occlusive Most common sites: coronary, cerebral, and femoral arteries Friable meshwork of platelets, fibrin, red cells, and degenerating leukocytes Superimposed on a ruptured atherosclerotic plaque Atherosclerotic: below the surface and breakdown of tissue underneath because of lack of blood supply (tunica media especially) When plaques ruptures = thrombus on top of it Straw from Panera – glued cornflakes along the inside = atherosclerosis

Question 31

Venous Thrombosis (Phlebothrombosis)

Answer 31

Invariably occlusive Thrombus forming a long cast of the lumen (takes shape of lumen from which it came from) Thrombi form in the sluggish venous circulation Contain more enmeshed red cells: red, or stasis, thrombi Veins of the lower extremities are most commonly involved (90% of cases)

Question 32

Post-Mortem vs. Venous Thrombi

Answer 32

Postmortem clots: mistaken for antemortem venous thrombi Gelatinous with a dark red dependent portion Red cells have settled by gravity Yellow "chicken fat" upper portion Usually not attached to the underlying wall Red/Venous thrombi: firmer, focally attached, gross and/or microscopic lines of Zahn

Question 33

Vegetations

Answer 33

Thrombi on heart valves Blood-borne bacteria or fungi Adhere to previously damaged valves (rheumatic heart disease) to directly cause valve damage and sometimes infective endocarditis Sterile vegetations: nonbacterial thrombotic endocarditis Sterile, verrucous endocarditis: Libman-Sacks endocarditis in SLE (lupus)

Question 34

Fate of Thrombus

Answer 34

Survival of the initial thrombosis ensues days to weeks Thrombi undergo some combination of the following four events: 1. Propagation: thrombi accumulate additional platelets and fibrin 2. Embolization: thrombi dislodge and travel to other sites in the vasculature 3. Dissolution: result of fibrinolysis and leads to shrinkage and total disappearance of recent thrombi 4. Organization and recanalization: older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts

Question 35

DVT

Answer 35

Deep venous thrombosis (DVT) Larger leg veins-at or above the knee Thrombi more often embolize to the lungs and give rise to pulmonary infarction Venous obstructions from DVTs can be rapidly offset by collateral channels DVTs are asymptomatic in approximately 50% of affected individuals Recognized only in retrospect after embolization

Question 36

Disseminated Intravascular Coagulation

Answer 36

Obstetric complications to advanced malignancy Sudden or insidious onset of widespread fibrin thrombi in the microcirculation Not grossly visible Diffuse circulatory insufficiency, particularly in the brain, lungs, heart, and kidneys Tear in maternal vasculature somehow and amniotic fluid containing fetal dead cells and debris gets in maternal circulation and the body recognizes the foreign substances causing the coagulation cascade to occur so eventually clotting off all the mother’s organs = multi system failure All coagulation elements are being consumed and they become exhausted and used up = body will begin fibrinogenolysis and the mother will just hemorrhage to death with multi system failure

Question 37

Embolus

Answer 37

Detached intravascular solid, liquid, or gaseous mass Carried by the blood to a site distant from its point of origin Thromboembolism Rare forms of emboli: fat droplets, nitrogen bubbles, atherosclerotic debris (cholesterol emboli), tumor fragments, bone marrow, or foreign bodies Unless otherwise specified, emboli should be considered thrombotic in origin

Question 38

Embolic Occlusions

Answer 38

Occlusions usually embolic, not thrombotic, as pulmonary vasculature is low pressure 95% of emboli are from deep leg veins; also indwelling central venous lines cause right atrial thrombi

Question 39

Large vs. Small Emboli

Answer 39

Large emboli= sudden death Lodging in major branches of pulmonary arteries or saddle emboli Acute cor pulmonale- right side heart failure Small emboli: usually have minimal symptoms, except if bronchial circulation is inadequate, then have shortness of breath, tachycardia, pain, fever, cough, hemoptysis, fibrinous pleuritis, friction rub Small emboli can go undetected, then go on plane and then goes into vasculature In younger population: perfusion is better Elderly: not as much bronchial circulation When in full body cast: need to give patient heparin because stasis is bad for veins

Question 40

Causes of Emboli

Answer 40

Causes of emboli: Immobilized individuals Hypercoagulable state (primary vs. secondary) Heart failure Emboli originate from leg or pelvic veins, often in immobilized individuals; other risk factors are trauma, hypercoagulable state, carcinoma and Trousseau’s syndrome, protein C/S deficiency, oral contraceptives, heart failure, pregnancy, older age

Question 41

Pathophysiologic Response and Clinical Significance of Pulmonary Embolism

Answer 41

Depend on the extent to which the pulmonary artery blood flow is obstructed Size of the occluded vessel(s) Number of emboli Overall status of the cardiovascular system Release of vasoactive factors such as thromboxane A2 from platelets that accumulate at the site of the thrombus

Question 42

Emboli Result in Two Main Pathophysiologic Consequences

Answer 42

1. Respiratory Compromise due to the nonperfused, though ventilated, segment 2. Hemodynamic Compromise due to increased resistance to pulmonary blood flow engendered by the embolic obstruction.

Question 43

Compensation for Pulmonary Emboli

Answer 43

If cardiovascular function is adequate, bronchial artery may compensate for pulmonary emboli, leading to hemorrhage without infarction Lungs can recover from hemorrhage but not from infarction Emboli cause infarction only when circulation is already inadequate, so rare in young

Question 44

Cardiopulmonary Resuscitation Aftermath

Answer 44

A large pulmonary embolus is one of the few causes of virtually instantaneous death, but if the patient survives they have clinical symptoms that mimic a MI Electromechanical dissociation: electrocardiogram has a rhythm, but no pulses are palpated Pulmonary hemorrhages due to small emboli induce only transient chest pain

Question 45

Pulmonary Embolism Dx

Answer 45

Spiral CT= best imaging Other diagnostic methods: Ventilation perfusion scanning Pulmonary angiography Duplex ultrasonography for DVT

Question 46

Pulmonary Embolism Prevention and Treatment

Answer 46

Prevention: Major clinical problem that does not constitute an easy solution Prophylactic therapy: early ambulation, stockings, anticoagulation, filter Treatment: thrombolysis and anticoagulation

Question 47

Pulmonary Embolism: Gross Examination

Answer 47

``` 1. Parenchyma: 75% of all infarcts affect the lower lobes Greater than 50%--multiple lesions Wedge shaped and hemorrhagic 2. Fibrinous pleural exudate 3. Scar 4. Embolus ```

Question 48

Pulmonary Embolism: Microscopic Examination

Answer 48

Ischemic necrosis of lung substance around the hemorrhage area affecting the alveolar walls, bronchioles, and vessels If infarct caused by an infected embolus there is intense neutrophilic inflammatory reaction (acute) = septic infarct

Question 49

Fat and Marrow Embolism

Answer 49

Microscopic fat globules-with or without associated hematopoietic marrow elements Fractures of long bones (which have fatty marrow) Soft tissue trauma and burns Common incidental findings after vigorous cardiopulmonary resuscitation No clinical consequence

Question 50

Air Embolism

Answer 50

Gas bubbles within the circulation: Coalesce to form frothy masses and obstruct vascular flow (causes distal ischemic injury) More than 100 cc of air is required to have a clinical effect in the pulmonary circulation

Question 51

Air Embolism: Decompression Sickness

Answer 51

Sudden decreases in atmospheric pressure At risk: scuba and deep sea divers, underwater construction workers, and individuals in unpressurized aircraft in rapid ascent

Question 52

Air Embolism: The Bends

Answer 52

Rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints

Question 53

Air Embolism: The Chokes

Answer 53

Gas bubbles in the vasculature | Causes edema, hemorrhage, and focal atelectasis or emphysema, leading to a form of respiratory distress

Question 54

Caisson Disease

Answer 54

Chronic form of decompression sickness Named for the pressurized vessels used in the bridge construction Workers in these vessels suffered both acute and chronic forms of decompression sickness Persistence of gas emboli in the skeletal system Leads to multiple foci of ischemic necrosis More common sites Femoral heads, tibia, and humeri

Question 55

Amniotic Fluid Embolism

Answer 55

Ominous complication of labor and the immediate postpartum period Sudden severe dyspnea, cyanosis, and shock Followed by neurologic impairment ranging from headache to seizures and coma If the patient survives the initial crisis, pulmonary edema typically develops, along with (in half the patients) DIC, as a result of release of thrombogenic substances from the amniotic fluid DIC – massive tear in maternal blood supply and get particles from amniotic fluid creating shock and seizures and then DIC

Question 56

Amniotic Fluid Embolism: Underlying Cause and Classic Findings

Answer 56

Underlying cause Infusion of amniotic fluid or fetal tissue into the maternal circulation via a tear in the placental membranes or rupture of uterine veins Classic findings Presence of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract in the maternal pulmonary microvasculature

Question 57

Shock

Answer 57

Final common pathway for several potentially lethal clinical events Severe hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism, and microbial sepsis Clinical findings Systemic hypotension Due to reduced cardiac output or to reduced effective circulating blood volume Consequences: impaired tissue perfusion and cellular hypoxia

Question 58

Shock Categories

Answer 58

Three general categories: 1. Cardiogenic shock 2. Hypovolemic shock 3. Septic shock

Question 59

Consequences of Hypovolemic, Cardiogenic, and Septic Shock

Answer 59

Hypovolemic and cardiogenic shock: Patient presents with hypotension Weak, rapid pulse; tachypnea Cool, clammy, cyanotic skin Septic shock: Skin may initially be warm and flushed because of peripheral vasodilation Cardiac, cerebral, and pulmonary changes secondary to shock worsen the problem Electrolyte disturbances and metabolic acidosis