Exam IV: Hemodynamic Disorders and Thromboembolic Diseases II Flashcards
Coagulation Cascade
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
Proteolytic Cascade
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)
Clinical Assessments of Coagulation Dysfunction
Assess the function of the two arms of the coagulation pathway
Two standard assays:
1. Prothrombin time (PT)
2. Partial thromboplastin time (PTT)
PT Assay
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
PTT Assay
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
Thrombin
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
Anticoagulation Restriction
Coagulation cascade must be restricted to the site of vascular injury to prevent runaway clotting of the entire vascular tree
Three Categories of Endogenous Anticoagulants
- 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 - Proteins C and S: vitamin K-dependent proteins that act in a complex that proteolytically inactivates factors Va and VIIIa
- Tissue Factor Protein Inhibitor (TFPI) is a protein produced by endothelium that inactivates tissue factor-factor VIIa complexes
Endothelial Cells
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
Fibrinolytic System: Fibrin Degradation Products
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
Virchow’s Triad
Three primary abnormalities that lead to thrombus formation (called Virchow’s triad):
- Endothelial injury
- Stasis or turbulent blood flow
- 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
Endothelial Injury
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)
Endothelial Dysfunction
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
Turbulence
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
Normal Blood Flow
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
Stasis and Turbulence
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
Hypercoagulability
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
Inherited Hypercoagulation Diseases
Inherited causes (most common): Point mutations in the factor V gene Prothrombin gene
Homocysteine and Thrombosis
Elevated levels of homocysteine contribute to arterial and venous thrombosis
Prothrombotic effects of homocysteine due to thioester linkages
Rare Inherited Causes of Primary Hypercoagulability
Deficiencies of anticoagulants: antithrombin III, protein C, or protein S
Clinical presentation:
Begins in adolescence or early adulthood
Venous thrombosis
Recurrent thromboembolism
HIT Syndrome
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
Anti-Phospholipid Antibody Syndrome
AKA lupus anticoagulant syndrome
Autoantibodies induce a hypercoagulable state causing endothelial injury
Directly activates platelets and complement
Clinical manifestations:
- Recurrent thrombosis, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia
- Pulmonary embolism, pulmonary hypertension, stroke, bowel infarction, or renovascular hypertension
- Fetal loss
Typical of younger patient that has lots of clots
Young adult who has had several miscarriages
Secondary Antiphospholipid Syndrome
Individuals with a well-defined autoimmune disease
Systemic lupus erythematosus
Primary Antiphospholipid Syndrome
Exhibit only the manifestations of a hypercoagulable state
Lack evidence of other autoimmune disorders
Association with certain drugs or infections
Morphology of Thrombi
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
Arterial vs. Venous Thrombi
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
Lines of Zahn
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
Post-Mortem Clots
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
Mural Thrombi
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
Arterial Thrombi
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
Venous Thrombosis (Phlebothrombosis)
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)
Post-Mortem vs. Venous Thrombi
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
Vegetations
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)
Fate of Thrombus
Survival of the initial thrombosis ensues days to weeks Thrombi undergo some combination of the following four events:
- Propagation: thrombi accumulate additional platelets and fibrin
- Embolization: thrombi dislodge and travel to other sites in the vasculature
- Dissolution: result of fibrinolysis and leads to shrinkage and total disappearance of recent thrombi
- Organization and recanalization: older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts
DVT
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
Disseminated Intravascular Coagulation
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
Embolus
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
Embolic Occlusions
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
Large vs. Small Emboli
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
Causes of Emboli
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
Pathophysiologic Response and Clinical Significance of Pulmonary Embolism
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
Emboli Result in Two Main Pathophysiologic Consequences
- Respiratory Compromise due to the nonperfused, though ventilated, segment
- Hemodynamic Compromise due to increased resistance to pulmonary blood flow engendered by the embolic obstruction.
Compensation for Pulmonary Emboli
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
Cardiopulmonary Resuscitation Aftermath
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
Pulmonary Embolism Dx
Spiral CT= best imaging
Other diagnostic methods:
Ventilation perfusion scanning
Pulmonary angiography
Duplex ultrasonography for DVT
Pulmonary Embolism Prevention and Treatment
Prevention:
Major clinical problem that does not constitute an easy solution
Prophylactic therapy: early ambulation, stockings, anticoagulation, filter
Treatment: thrombolysis and anticoagulation
Pulmonary Embolism: Gross Examination
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
Pulmonary Embolism: Microscopic Examination
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
Fat and Marrow Embolism
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
Air Embolism
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
Air Embolism: Decompression Sickness
Sudden decreases in atmospheric pressure
At risk: scuba and deep sea divers, underwater construction workers, and individuals in unpressurized aircraft in rapid ascent
Air Embolism: The Bends
Rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints
Air Embolism: The Chokes
Gas bubbles in the vasculature
Causes edema, hemorrhage, and focal atelectasis or emphysema, leading to a form of respiratory distress
Caisson Disease
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
Amniotic Fluid Embolism
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
Amniotic Fluid Embolism: Underlying Cause and Classic Findings
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
Shock
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
Shock Categories
Three general categories:
- Cardiogenic shock
- Hypovolemic shock
- Septic shock
Consequences of Hypovolemic, Cardiogenic, and Septic Shock
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
