Flashcards in Venous Thrombosis, PE and Shock Deck (94):
How does it differ from a clot?
A thrombus is a solid, intravascular mass formed from circulating blood elements DURING LIFE.
A clot is formed intravascularly post mortum or extravascularly in the presence of hemorrhage (like in a test tube or body cavity)
What are the four major circulating elements that compose a thrombi?
1. fibrin (from polymerization of fibrinogen)
What is Virchow's Triad?
These are the three things that would predispose a person to thrombus.
1. endothelial damage
2. disruption of normal blood flow
3. hypercoagulability of circulating blood
Endothelial abnormalities can occur anywhere in the circulatory system, although they are most important for thrombi formation when they occur in what two places?
2. Cardiac chambers
What are the three main ways that endothelial cells maintain blood in normal fluid state?
1. prevent platelet adhesion and aggregation (blocking ECM and secreting NO and prostacyclin)
2. inactivate thrombin and other parts of the coagulation cascade, activating protein C (via thrombomodulin and heparin-like molecules respectively)
3. breaking down local fibrin deposits (synthesis of tissue plasminogen activator TPA that has fibrinolytic effects)
What are the two ways endothelial cells prevent platelet adhesion and aggregation under normal circumstances?
1. Block platelets from subendothelial ECM
2. Inhibiting local adhesion via elaboration of anti-platelet effects (NO and prostacyclin)
How do normal endothelial cells inactivate thrombin and other coagulation cascade components?
1. inactivate thrombin via heparin-like molecules
2. activating protein C (anticoagulant) via thrombomodulin
How do normal endothelial cells ensure the break down of local fibrin deposits?
They synthesize tissue plasminogen activator TPA which has fibrinolytic effects
How does endothelial damage promote thrombus formation?
1. Damage exposes the subendothelial ECM which allows binding of platelets to it via vWF
2. Procoagulant molecules are synthesized like tissue factor (activator or coagulation cascade) and inhibitors of TPA
What allows platelets to bind to the subendothelial ECM after endothelial cell damage?
von Willebrand Factor (vWF)
What procoagulant molecules are synthesized when endothelial cells are damaged?
1. tissue factor- an initiator of coagulation cascade
2. inhibitors of TPA
What are the two ways that normal laminar blood flow can be interrupted? Which one is the biggest cause of thrombus?
1. stasis- biggest cause of thrombus
2. abnormal tubulence
Endothelial abnormalities play a large role in thrombi in ________ and ________ whereas stasis plays a large role in _________ thrombi.
Endothelial abnormalities- arteries, cardiac chambers
Stasis- venous thrombi
What are the four most important consequences of stasis interrupting normal laminar blood flow?
1. platelets are brought in contact with endothelial surface
2. Activated coagulation factors reach high local concentrations
3. Inflow of factors that inhibit coagulation cascade decrease
4. endothelial cells are activated due to increased contact with platelets
What are the two main types of hypercoagulability?
1. Primary- hereditary
2. Secondary- acquired
Although _____________ states are less commonly responsible for thrombi, they should be considered in any thrombotic episode and carefully excluded in patients with _______________.
Hypercoagulability; recurrent thrombi
What is the most important cause of arterial thrombosis?
atherosclerosis- by virtue of its association with endothelial injury and in many cases disruption of normal blood flow
What accounts for most cases of venous thrombosis?
Hypercoagulability and stasis (together or alone)
What specific clinical condition causes venous thrombosis due to endothelial damage (a rareity)?
Phlebitis- inflammation of the veins
What are five disease states associated with stasis?
1. CHF and atrial fibrillation - venous backup
3. Pregnancy- uterus compresses pelvic veins (decreased flow back to heart)
4. Obesity- compression of veins
5. Soft tissue/bone injury
What are 3 examples of acquired hypercoagulability?
1. systemic malignancies- neoplasms like adenocarcinomas
2. antiphospholipid antibody syndrome
3. smoking and oral contraceptives
What are 5 examples of hereditary hypercoagulability?
1. Factor V Leiden mutation
2. Thrombin mutation
3. Protein C deficiency
4. Protein S deficiency
5. Antithrombin III deficiency
A patient that has what disease would have hyperviscous blood contributing to disrupted laminar flow?
What are the three steps in the formation of a venous thrombi?
1. Disruption of laminar flow (stasis) brings platelets in contact with endothelial cells, activating them
2. Local platelet adhesion, activation and aggregation
3. accumulation of leukocytes
What events are associated with the activation of platelets?
1. Release of calcium, ADP, TXA2 which promotes further activation of platelets and aggregation
2. activation of intrinsic coagulation factors
What is platelet aggregation?
the formation of linkage between fibrinogen of the ECM and platelets via GpIIb/GIIIa glycoprotein receptors on the surface of platelets
When a platelet aggregate forms, what things are released, expressed, and generated?
1. release of ADP and TXA2
2. expression of platelet membrane phosoholipid complexes (irreversible)
3. generation of thrombin
What are the four most important consequences of local activation of the coagulation cascade?
1. thrombin promotes further platelet activation and leukocyte adhesion leading to the formation of an irreversibly fused, contracted platelet mass
2. Fibrin forms from fibrinogen (catalyzed by thrombin) and with activated factor 13 forms a cross-linked fibrin meshwork
3. Fibrin meshwork traps erythrocytes, platelets, and leukocytes contributing to mass of thrombus
4. As thrombus enlarges, it causes further stasis which increased local concentration of coagulation factors and reduces delivery of anticoagulants
What allows you to grossly differentiate a thrombi from a clot?
Lines of Zahn- the aggregates of platelet, leukocytes and fibrin appear as grey-tan lines
Where do lines of Zahn become less obvious?
In areas distal to the origination point of the propogating thrombus
The clinical diagnosis of venous thrombosis is difficult. Superficial venous thrombi may cause ______________ and _______. Deeper thrombi may cause _______________ distal to the site of obstruction.
Superficial - local swelling and pain (heat and tender)
Deeper- edema of the extremity distal to the site of obstruction
Most venous thrombi are ______ and the first clue to their presence may be a ____________.
clinically silent until a pulmonary embolism occurs
Since embolisms compromise the lumen of the vessel, they can cause what?
local ischemic injury (particularly with arterial thrombi) and infarct if the ischemia is sufficient to cause cell death
What are the three fates of a thrombi?
2. Organization and recanalization
How can a thrombi be dissolved?
Fibrinolytic (TPA) dissolves the fibrin matrix that holds the thrombus together and the patency of the vessel is restored
What would cause organization of the thrombus?
If the thrombus persists long enough for fibroblasts, smooth muscle cells, and endothelial cells to migrate into the fibrin-rich thrombus
What are the three potential outcomes of organization of a thrombus?
1. a small, collagen rich scar incorporates into the vessel wall
2. calcification of the thrombus (visible in x-rays as phleboliths)
3. recanalization where new vessels are developed within the substance of the thrombus
What is a phlebolith?
a calcified thrombus that is visible on Xray
After recanalization, what happens to the diameter of the vessel?
The vessel diameter decreased that those of the lumen of the vessel prior to the thrombus, but blood flow is partially restored
What causes an embolism?
If the thrombus or part of thrombus detaches from the vessel wall and is swept in the bloodstream to a distal site.
In addition to thromboemboli, what else can form an embolus?
An embolus is any free-floating intravascular mass that is carried in the bloodstream to a distal location.
1. tissue fragments
2. fat droplets
4. foreign material
What is one of the major consequences of an arterial emboli causing vascular obstruction?
ischemic injury to the tissue distal to the site of occlusion
Emboli in the arteries of the brain can cause what?
What is a pulmonary embolism?
An embolic obstruction of the pulmonary arterial tree
How many deaths annually are caused by pulmonary embolism?
(20-25 in every 100,000 patients)
What causes the overwhelming majority of pulmonary embolisms?
If you have had a pulmonary embolism in the past, what percent chance are you to have another?
Where do the majority of pulmonary emboli originate? (3 main locations)
What two locations are less common, but still happen?
the large deep veins of the proximal lower extremities (leg above knee), pelvis, inferior vena cava
Less commonly- right cardiac chambers, veins
What is a massive pulmonary embolism?
embolic occlusion of more than 50-60% of the pulmonary arterial tree (from one large clot or multiple little ones)
Extensive occlusion of the arterial pulmonary circuit causes an acute _________________________.
elevation in pulmonary arterial pressure
What does increased pulmonary arterial pressure cause?
abnormal hemodynamic burden on the thin walls of the RV
Burden on the walls of the RV (increased tension due to the raised arterial pulmonary pressure) causes what?
increased oxygen demand of the RV myocardium which leads to RV dysfunction and RV decreased output
Because pulmonary occlusion causes RV to decrease output, the LV ________ and LV ___________ decrease.
filling and output
What are the three major consequences of decreased LV output?
1. systemic hypotension
2. Decreased coronary artery perfusion (myocardial ischemia)
3. Decreased cerebral perfusion (ischemic brain injury)
What is a minor pulmonary embolism?
Less than 30% of the pulmonary arterial circulation is blocked
What allows patients with previously healthy hearts and lungs to be rather unaffected by minor pulmonary embolisms?
1. low resistance of pulmonary circulation
2. high capacitance
Pulmonary embolisms that occlude between 30 and 50% of pulmonary arterial circulation can cause ____________.
RV dysfunction but the patients are often able to maintain normal systemic pressure so you dont get:
1. decreased coronary artery perfusion/myocardial ischemia
2. decreased cerebral perfusion
If a minor pulmonary thromboemboli is allowed to organize, what can occur?
permanent occulision of the arterial branches resulting in eventual RV failure due to chronic pulmonary hypertension
What are some of the symptoms of pulmonary embolism?
Why is it hard to diagnose clinically?
tachycardia, syncope, dyspnea, substernal chest pain, fluctuating BP
It is difficult to diagnose because it has the same symptoms of coronary artery disease, pneumonia, asthma and aortic dissection
Diagnosis of PE should be consider in patients that display risk factors for __________.
DVT (deep vein thrombosis)
What are the three criteria for PE diagnosis?
1. high level of suspicion- predisposing factors
2. pulmonary angiogram (gold standard)
3. lab test- elevated D-dimers
What are examples of tissue fragments that can cause PE?
1. fragments of placental tissue entrapped in pulmonary vessels
2. amniotic fluid that enters venous circulation
3. Neoplastic cells - from carcinomas (epithelial neoplasms)
When are fat emboli common?
Following traumatic long bone fracture and blunt trauma
If someone fractures a long bone traumatically, what type of embolism should be considered?
What two things will the patient present with?
Consider a fat emboli.
The patient will have:
1. respiratory distress from the fat emboli
2. confusion bcasue of fact in cerebral microcirculation
What are examples of foreign bodies that can cause embolism?
catheter tips, foreign matter from IV drug injection
What is the most common form of a gas embolism?
Air embolism- introduced into circulation via traumatic injury to a large vessel or through an intravascular catheter
What is decompression sickness? How does it typically occur?
It is when there is a rapid pressure reduction following increased body pressure (rising too fast when coming up from scuba diving)
It can cause a gas emboli
Gas emboli are better tolerated in the _________ than the __________ system.
Better tolerated venous than arterial
Infarcts occur in what percent of pulmonary emboli? Why?
They occur in less than ten percent of pulmonary emboli because the lung has dual circulation so some blood flow still gets in via collateral circulation
What are the two potential causes for local decrease in blood flow to the lung?
What is the major cause of pulmonary infarct?
1. global decrease in perfusion pressure
2. local vessel obstruction (emboli)
The major cause of pulmonary infarct is PE
What are the three situations where bronchial circulation may not be enough to deliver blood to areas compromised by PE?
1. Pre-existing lung disease (pneumonia, previousPE)
2. Congestive heart failure
3. Systemic hypotension
What area of the lung is susceptible to infarct?
near the pleural surface specifically at the costophrenic angle
What causes the "sharp, pleuritic pain" in pulmonary infarct?
Necrosis of lung parenchyma provokes inflammatory reaction with fibrin deposition. The inflammatory response causes pleuritic pain
What type of infarct (red, white, septic) are most pulmonary infarcts? why?
Red because of the loose parenchyma and collateral circulation
What is shock?
hemodynamic and metabolic disturbance that causes generalized decrease in perfusion of the microcirculation resulting in inadequate O2 and nutrient delivery to tissue
Shock decreases ____________ and increases________________.
Decreases O2 and nutrient delivery to tissue
Increases metabolic waste products in the tissue
What are the three most common types of shock?
1. cardiogenic- pump failure
2. hypovolemic- blood loss/extreme dehydration
3. septic- infection
(the other two are neurogenic and anaphylactic)
What is cardiogenic shock?
What are common causes?
IT is when the heart cannot pump sufficient amounts of blood to maintain tissue perfusion
1. myocardial infarct
2. ventricular rupture
4. cardiac tamponade
What is hypovolemic shock? What are common causes?
When blood volume loss is so severe tissues cannot be perfused.
1. massive hemorrhage
2. burn injury
What is septic shock?
overwhelming microbial infection initiates a cascade of events resulting in peripheral vasodilation and high-output myocardial dysfunction
Tissue changes common to all forms of shock are _________ injury.
Depending on the severity and duration of the shock, changes in the brain can range from __________ to ________________.
Occasional necrotic neurons to generalized brain parenchymal necrosis
What type of necrosis develops in the heart as a result of shock?
Subendocardial myocyte necrosis because this area is last to be perfused by coronary arteries
Where does the liver get acute necrosis following shock?
What gross appearance does this have?
Acute hemorrhagic centrilobar necrosis because the central vein is the last area to be perfused.
Grossly this is called nutmeg liver
What change occurs in the kidneys as a result of shock?
Acute tubular necrosis with the development of oliguria.
What gross changes are observed on a kidney following shock?
What microscopic changes?
Gross- swelling and pale renal cortex with medullary swelling
Micro- patchy loss of tubular epithelial cells with necrotic cells in the distal convoluted tubule
What cells repopulate the areas of epithelial necrosis in the kidneys?
Basophilic flattened, regenerating epithelial cells
Lungs are acutely congested in cases of __________shock but are pale in cases of _________ shock.
Acute congestion- cardiogenic shock
Pale- hypovolemic shock
In what kind of shock would you see diffuse alveolar damage reflecting injury to the alveolar capillaries and endothelial cells?
What is the leading cause of septic shock?
Gram positive bacteria
In most cases, septic shock is caused by _____________ infections, although occassionally they can be triggered by more _________ infection.
Usually they are widely disseminated infections although sometimes it can be a local infeciton
What is a PAMP?
Pathogen associated molecular pattern (like LPS on G- bacteria) that is recognized by receptors on macrophages and other cells in the innate immune system
Generalized endothelial activation/dysfunction and coagulation abnormalities result in the development of ______________________.
Disseminated intravascular coagulation