Chapter 4 Flashcards
What is cor pulmonale and what causes it
Right side heart failure, and occurs when an emboli obstructs 60% or more of the pulmonary circulation
What is the result of the parasite filariasis
Induces fibrosis of lymphatic channels and nodes leading to lymphatic obstruction
What is the general steps that decreased oncotic pressure leads to edema
1) Reduced intravascular volume
2) Renal hypoperfustion
3) Increased aldosterone secretion (secondary hyperaldosteronism)
4) Water and salt retention leads to further edema
What are the three main factors that limit blood clotting
1) Dilution of blood taking factors away
2) Requirement of negative charge phospholipids only seen on activated platelets
3) Factors expressed by healthy epithelium to restrict activation
What are the factors that are expressed by endothelial cells to prevent coagulation
1) Thrombomodulin
2) Endothelial protein C receptor
3) Heparin like molecules
4) tissue factor pathway inhibitor
What occurs following a loss of blood >20% of blood volume
Hemorrhagic (hypovolemic) shock
Which condition is the usual cause of pulmonary edema
Most commonly with left ventricular failure, but can also be with renal failure, or acute respiratory distress syndrome
What occurs immediately following injury to a blood vessel
Vasoconstriction in order to reduce blood flow to injured area
Septic shock is most commonly triggered by which pathogen
Gram positive bacteria
What will acute pulmonary congestion present with morphologically
Enlarged alveolar capillaries, alveolar septal edema, and focal intraalveolar hemorrhage
What are the most common inherited causes of hypercoagulability
1) Point mutations in factor 5 gene
2) Point mutations in Prothrombin gene
Where is the process of clotting occurring
On the negatively charged phospholipid surface of platelets
What is the role of endothelial protein C receptor
Hold protein C, so bound thrombin to thrombomodulin, can inactivated factors 5a and 8a
Of people with DVTs, what percent are associated with factor 5 Leiden mutation
60%
During platelet aggragation, what is the significance in the changes to complex 2B/3a
Allows the binding of fibrinogen, and subsequent bridging of adjacent platelets
How is the level of plasmin regulated
Alpha2-plasmin inhibitor (PAI) which bind to and inactivate free plasmin
What are the conditions that can lead to impaired venous return and subsequent increases in hydrostatic pressure
CHF, constrictive pericarditis, ascites (liver failure), venous obstruction or compression, arterial dilation
What condition with patients regularly receive a false positive for during antiphospholipid antibody Syndrome
Syphilis, due to binding to cardiolipin
What is the main enzyme responsible of for fibrinolysis
Plasmin
What is the most important activator of factor 10
9a/8a
For the PTT test, what are the materials added
Negative charged particles (beads)
Phospholipids
Calcium
What is the cause of congestion
Reduction in the outflow of blood from a tissue as in cardiac failure or venous obstruction
How will cardiac and hypovolemic shock present in clinic
Hypotension, weak but rapid pulse, tachypnea, cool but clammy skin
What is the general order of events in primary hemostasis
1) von Willebrand factor and collagen are exposed
2) Platelets adhere and activate, become spiky balls
3) Platelets degranulate and release factors
4) Platelets aggregate
What are the three general mechanisms that disruption in laminar flow can lead to thrombin activation
1) Promotes endothelial activation and adhesion of proinflamatory factors
2) Brings platelets in contact with the epithelium
3) prevents washout and dilution of Activated Factors
Rapid loss up to which percent of blood volume can normally occur without effects
20%
What are the characteristics of subcutaneous edema
Accumulate in the areas with high hydrostatic pressure, which is usually determined by areas influenced by gravity (legs when standing) aka dependent edema
What is trousseau syndrome, aka migratory thrombophlebitis
Increased risk of thromboembolism due to tumor associated inflammation and coagulation factors released from tumors
What is the result of increased salt retention
1) increased hydrostatic pressure due to increased intravascular fluid volume
2) Decreased vascular oncotic pressure due to dilution
What is the condition of thrombophilia
Hypercoagulability and predisposes patient to thrombi
What do the antibodies in antiphospholipid antibody Syndrome bind to
Bind to proteins that are somehow induced by phospholipids (Beta2 glycoprotein 1
What are the conditions leading to lymphatic obstructions
1) Inflammation
2) Neoplasticism
3) Postsurgical
4) Postirradiation
What are usual defects in secondary hemostasis
Coagulation defects
What two conditions stem from increased blood volumes within tissues
Hyperemia and congestion
What are the conditions associated with antiphospholipid antibody Syndrome
Recurrent thrombosis, repeated miscarriages, cardiac valve vegetations, thrombocytopenia
How does an MI lead to increased risk of thrombi
Results in areas of noncontractile myocardium, which create areas of stasis and mural thrombi
What are the two factors that lead to increase movement of fluid out of vessels and into tissues
1) Increased hydrostatic pressure
2) Decreased colloid osmotic pressure
During platelet activation, what are the two factors that are released to cause coagulation
Thrombin and ADP
Following platelet activation, what complex undergoes a change
Gp2b/3a
How does administration of aspirin affect platelet activation
Prevents TxA2 production by COX1, which is a platelet aggregation induced
What are the symptoms of fat embolism syndrome
Pulmonary insufficiency, neuro symptoms, anemia, and thrombocypenia, tachycardia, dyspnea, tachypnea, and diffuse
The prothrombin time (PT) assays asses which proteins of which pathway
Extrinsic pathways
Factors 2,5,7,10, and fibrinogen
What is the risk of developing thrombi with a mutation in the prothrombin gene
3x more likely
Where is stasis commonly found and what are the conditions that can increase it
Generally found in venous system and is triggered by atrial fibrillation and bed rest
What are the ways that plasmin is activated
1) Factor 12 pathway
2) plasminogen activators (tPA) and urokinase
How does polycythemia Vera (hyper-viscosity) lead to thrombi
Increased resistance to flow causes small vessel, leading to stasis
What are the factors that posses a gamma-carboxylase glutamic acid
Factor 2,7,9,10
Protein C & S
Defects in primary hemostasis usually result in which symptoms
1) Epistaxis (nose bleeds)
2) GI bleeding
3) Excessive menstruation (menorrhagia)
What are the most common sites of edema
Subcutaneous tissues, lungs and brain
What are petechiae
Small bleed 1-2 mm
What is the difference between primary and secondary antiphospholipid antibody syndrome
Primary- no association with any autoimmune diseases
Secondary- Associated with autoimmune diseases, especially Lupus
What is the effect of aneurysms in disruption of blood flow
A result of aortic and arterial dilation that result in local stasis
What will chronic passive hepatic congestion present with morphologically
Nutmeg liver, which are depressed and red areas
Bloodborne bacteria can affect valves of the heart how?
Adhereing to damaged valves, or by causing damage to heart valves known as infective endocarditis
What is the source of the majority of systemic emboli
80% arise from intracranial mural thrombi (2/3 are from LV0
What is the affect of administering Coumadin
Antagonizes the use of vitamin K as a cofactor in the reactions producing gamma-glutamic acid
Epithelial injury most often occurs in what location and what is the rate of blood flow
High rate of blood flow, usually in the heart and arterial circulation
What is factor 11 deficiency associated with
Mild bleeding
What are purpura
Small bleeds >3mm
What are the procoagulant changes seen in Activated epithelial cells
Down regulation of thrombomodulin, protein C and tissue factor inhibitors
Following platelet activation, what does the change in the complex cause
Increased affinity for fibrinogen
What is the most important activator of factor 9
Factor 7a/Tissue factor
What is the cause of heparin-Induced thrombocytopenia (HIT) syndrome
Administration of fractionated heparin, which leads to antibodies against heparin and platelet factor 4 on platelets, causing aggregation
What is the function of tissue factor pathway inhibitor (TFPI)
Binds and inhibits tissue factor/factor 7a complexes
What are vegetations
Thrombi on heart valves
How does antiphospholipid antibody Syndrome lead to repeated miscarriages
Antibody mediated interference with the growth and differenation of trophoblasts, leading to failure of placentation
What is the general order of secondary hemostasis
1) Tissue Factor is deposited at the site of injury
2) Activation of factor 7
3) Thrombin activation occurs
4) Thrombin causes the activation of fibrin
5) Fibrin polymerization occurs and the more permanent plug is formed
What is the diseases associated with a defect in vWF
Von Willebrand Disease (a bleeding disorder)
What is the condition of caisson disease
Chronic decompression sickness, with necrosis generally at the heads to the femur, tibia, and humeri
What will acute hepatic congestion present with morphologically
Central vein and sinusoids are distended. Centrilobular (distal end of blood Supply) undergo necrosis while the periportal hepatocytes undergo fatty changes
Antiphospholipid antibody syndrome is present in what percent of the population without any symptoms
5-15%
What is the result of factor 5 Leiden mutation
Resistant to cleavage and inactivation via protein C
How will septic shock present in clinic
Warm and flushed due to peripheral vasodilation
Enzyme reactions that produce gamma-glutamic acid require which vitamin
Vitamin K
Immediate vasoconstriction at the site of injury is due to which factor and where is it derived from
Local secretion of endothelin, which is derived from endothelium
What is the difference between primary and secondary hypercoagulabilty disorders
Primary is genetic while secondary is acquired
What is the mutation in the factor 5 Leiden
Glutamine residue is substituted with arginine at position 506
What are the conditions leading to reduced plasma oncotic pressure aka hypoproteinemia
1) Protein losing glomerularphathies (nephrotic syndrome)
2) Liver failure (cirrhosis or ascities)
3) Malnutrition
4) Protein losing gastroenteropathy
How does rheumatic mitral valve stenosis lead to thrombi
Results in left atrial dilation, and in conjunction with atrial fibrillation leads to stasis
What will acute hepatic congestion present with morphologically
Septa are thickened and fibrotic, with macrophages (aka heart failure cells) full of hemosiderin. Usually caused by heart failure
What is the result of renal failure on platelet count and coagulation
1) Renal failure leads to increase in uric acid (uremia)
2) Uremia inhibits platelet formation
3) Leads to defects in primary hemostasis
What is the condition of nonbacertial thrombotic endocarditis
Sterile vegetation’s on heart valves in patients in a hypercoagulability state
What are the four general steps in coagulation
1) Arterial constriction
2) Primary Hemostasis plug
3) Secondary hemostasis plug
4) Clot stabilization and resorption
What are the conditions that lead to fluid retention
Compromised renal function, and cardiovascular disorders (such as congestive heart failure)
What is the respiratory distress known as the chokes associated with
The bends
What are the associated symptoms with amniotic fluid embolism
Dyspnea, cyanosis, and shock, diffuse alveolar damage, pulmonary edema due to DIC
What are the some of the factors that can lead to acquired thrombophilia
1) Oral contraceptives
2) hyperestrogenic state
3) Coagulants from cancer tumors
4) Heparin induced
5) antiphopspholipid antibody syndromes
What is the phospholipid composition change on activated platelets and what is the significance
Negatively charged phospholipids (phosphotidylserine) moves to surface, which allows the binding of Calcium, serving as assembly sites for factor complexes
What is the role of thrombomodulin
Binds thrombin, which removes it ability to activate platelets, and instead causes it to cleave and activate protein C, which is anti coagulative
Where is turbulent flow commonly found and what are the conditions that can cause it
Usually found in arterial and cardiac thrombosis. Commonly due to narrowing of vessels secondary to atherosclerosis
What is a feared complication of thrombocytopenia
Intracerebral hemorrhage
What is the result of mutations in the prothrombin gene that lead to coagulation
Increased levels of thrombin in circulation
Subcutaneous edema is usually a sign of what conditions
Renal or cardiac disease
What is the mutation in the prothrombin gene that is common
Single nucleotide change (G20210A) in the 3 prime untranslated region
What is the mechanism that thrombin activates platelets
GPCR known as protease-activated receptor (PAR), which is activated by the cleavage of thrombin
What is periorbital edema usually indicative of
Renal dysfunction
What are the general causes of increased hydrostatic pressure
Disorders that impair venous return
What are Thrombin’s most important functions
1) Conversion to fibrinogen to crosslinked fibrin
2) Platelet Activation (via PARs, and TxA2)
3) Proinflammatory effects (neutrophil adhesion and monocyte activation)
4) Anticoagulant effects (yes this is right)
What is the fucntion of heparin like molecules
Bind and activate antithrombin 3, which then inhibits:
Thrombin, 9a,10a,11a,12a
What conditions are generally associated with secondary hemostasis defects
1) Bleeds into soft tissue
2) Bleeding into joints (hemarthrosis)
Commonly occur after minor trauma that wouldn’t be an issue
What is endothelial activation or dynfunction caused by
Physical injury, infection, Ab normal blood flow, metabolic conditions, hypercholesterolemia, homocystinuria, toxins (smoke)
When is t-PA most active
When it is bound to fibrin, so the presence of a clot will lead to the increase activation of plasmin (only at the site of the recent thrombus)
What is the mechanism of amniotic fluid embolism
Biochemical activation of coagulation factors and innate immune factors by substances in the amniotic fluid
What are the contents of dense granules
ADP, ATP, ionized calcium, serotonin and epinephrine
What are the anticoagulant receptors that require Protein S
1) Protein C
2) Tissue Factor Pathway inhibitor (TFPI)
What is the disease associated with a defect in Gp1b
Bernard-Soulier syndrome (bleeding disorder)
Is prothrombin defects compatible with life
Nopers
How are leukocytes usually entrapped in a secondary plug
Due to adherence to P selectins located on the activated platelets
What diseases is associated with a defect in the Gp2b/3a Complex
Glanzmann thrombasthenia (a bleeding disorder)
What is the mechanism of elevated levels of homocysteine leading to thrombi
Thioester linkages formed between homocysteine metabolites and proteins, including fibrinogen.
What is the epidemiology of the mutation in the prothrombin gene
1-2% of the population
How are the complex components held together in the clotting cascade
Via calcium ions, which are required for the reaction to work
What are the vast majority of emboli from
Dislodged thrombi, aka thromboembolism
What are the conditions leading to sodium retention
1) Excesive sodium intake without renal compensation
2) Increased tubular reabsorption (renal hypofusion or increased RAA secretion
What is the result of HIT syndrome when there is heparin present and low levels of platelets
Will still cause aggregation and a prothrombin state
What is the clinical significance of D-Dimers
Byproduct of the breakdown of fibrinogen, so can be measured to get a relative thrombotic state estimate
What are the general results seen from lymphatic obstruction
Edema in the external genitalia and lower limbs. Can also become so pronounced that it will cause elephantiasis. May require irrational on axillary lymph and breasts if in the upper limb
What is the mechanism of thrombin creating fibrin
1) Cleaves fibrinogen (soluble) into fibrin (insoluble)
2) Amplifies pathways (via activation of cofactor 5, 8,11)
3) Stabilizes plug with activation of factor 13, which covalently crosslinks fibrin
What are the three primary abnormalities that lead to thrombosis
1) Epithelial injury
2) Stasis or turbulent flow
3) Hypercoagability
What is the common cause for the decrease in plasma oncotic pressure
Inadequate synthesis of albumin, or increased los of albumin from circulation
What is added to the prothrombin time (PT) assay
Tissue factor, phospholipids, and calcium
What are peritoneal effusions aka ascites generally associated with
Portal hypertension, and are prone to bacteria leading to fatal infection
What percentage of PEs come from leg DVT
95%
What are the three main substances that are released by endothelial cells to prevent coagulation
1) Prostacyclin (PGI2)
2) Nitric oxide (NO)
3) ADPase (breaks down ADP)
What is the cause of hyperemia and what is the color
Active process in which arterial dilation leads to increase in bloodflow. Tissue will be red due to the increase in blood flow
What is the epidemiology of factor 5 Leiden
2-15% of Caucasians carry the mutation
What factors are associated with moderate to severe bleeding disorders
5,7,8,9,10
Arterial thrombi are usually result in what
Obstruction of:
1) Coronary artery
2) Cerebral artery
3) Femoral artery
In the platelet reaction complexes, what ion is required and what does it bind to
Calcium is required to bind to gamma-carboxylase glutamic acid
What is the mechanism that will lead to damage via a fat embolism
Biochemically, due to the release of free fatty acids from the fat globules, leading to inflammation and platelet activation
What is the Hageman factor and which pathway is it in
Factor 12, and associated with the intrinsic pathway
What is factor 12 defects associated with
Inability to bleed and increased risk of thrombosis
What is the rate of risk for venous thrombi in homozygotes and heterozygotes for mutation in factor 5 Leiden
Hetero- 5x more likely
Homo-50x more likely
Where do phlebothrombosis commonly occur
Aka venous thrmobosis, which occurs in the deep and superficial veins of the legs
For the partial thromboplastin time (PTT) assay, which factors of which pathway are being tested
Intrinsic pathway
Factors 2,5,8,9,10,11,12, and fibrinogen
What is required for the activation of protein C to begin cleaving
1) Binding to thrombin to thrombomodulin
2) Cleavage by thrombin bound to thrombomodulin
3) Vitamin K
4) Protein S
When does Libman-sacks endocarditis occur
Sterile endocarditis in which occurring secondary to Lupus
What are the factors that are mediating platelet adhesion
1) vWF, which bridges 2) Gp1b (on platelet) and exposed 3)collagen
What are the content so the alpha granules
1) P selectin
2) Coagulative Factors (fibrinogen, Factor 5, vWF, fibronectin, platelet factor 4, PDGF, and TGF-beta)
How does sickle cell anemia lead to thrombi
Impedes blood flow through small vessels and result in stasis
When should hypercoagulability be considered in young patients
In patients less than 50 who present with thrombosis, even if acquired risks are present
What is chronic passive congestion associated with
Chronic hypoxia may lead to injury and scarring. Capillary rupture is also very common, leading to small hemorrhages and hemosiderin laden macrophages
Non inflammatory edema is assocaited with which conditions
Heart failure, liver failure, renal disease, and nutritional disorders
What is the results if elevated levels of homocysteine
Increased risk of arterial and venous thrombi
What are the antifibrinolytic effects seen in Activated epithelial cells
Secrete plasminogen activator inhibitors (PAIs), down regulate t-PA
