Ch.3 Hemodynamic Disorder Pt.2 Flashcards
Vasodialator, increases vascular permeability, modulator of pain
Bradykinin
Bradkykinin is degraded by what enzyme?
Angiotensen Converting Enzyme (ACE)
Vasoconstrictor! Opposite effect of bradykinn
Use of _____ raise the bodys level of bradykinin
ACE inhibitors. No enzymes secreted= no degredation of Bradykinin.
If levels of bradykinin in the body get to high, this can leave to a dangerous side effect; swelling of deep layers of skin
Angioedema
Bradykinin can also be degraded by ____ inhibitors from the complement system.
C1 Inhibitor
A deficiency in C1 inhibitor can cause what?
Hereditary Angioedema
What is the coagulation factor that activates coagulation cascade, and also activates the pathway that forms bradykinin?
Link between the coagulation & inflammation
Hagman factor XII
- Rare condition
- Markedly **prolonged PTT **(intrinsic pathway)
- **XII cannot **acitvate normally
- Coagulation deficiency
Prekallikrein deffinceny (PK deficiency)
Hagman factor XII requires what two things to generate bradykiin?
- Prekallikrein (PK)
- Hime molecular weight Kinogen (HMWK)
Prekallikrein deffinceny (PK deficiency) causes what to go up?
PTT
Thrombin does what ?
Fibrogen to cross linked fibrogen, amplifying generation of fibrin.
Activates Factor 5, 8, 11, stabalize clot activates 13
. Thrombin is a potent inducer of what?
Patlet activation
Features of what?
- Can mediate effects & contibute to tissue repair
- Anticoagulant effect; prevents clot from extending from site of injury
Thrombin
What factor that limits coagulation?
blood flowing past the site of injury washes out activated coagulation factors, which are rapidly removed by the liver
Simple Dilution
What factor that limits coagulation?
____ which are provided mainly by activated platelets, which are not present away from the site of injury.
negatively charged phospholipids
limits the size of the clot and contributes to itslater dissolution
fibrinolytic cascade
Fibrinolysis is accomplished largely through the enzymatic activity of _____ which breaks down fibrin and interferes with its polymerization.
plasmin,
Fibrin derived breakdown product of fibrogens,
good clinical marker for diffrent thrombotic states and to see if thrombosis was resolbed
D-Dimers
an inactive circulating precursor, by enzymatic cleavage that forms plasmin.
plasminogen
Where is tissue plasminogen activator t-PA? When is it most active?
t-PA is synthezised by endothelium and most active when bound to fibrin
Explain thromosis and antithrombotic properties of the endothelium.
There is a balance between anticoagulant and procoagulant activities of the endothelium
- Normal endothelial cells express factors that inhibit procoagulant activity of platelets and coagulation factors that augment firbinolysis= prevent thrombosis and limit vasucular damage
- If damaged, endothelial cells Lose their antithrombotic properties
WHat are the 3 effects of difrrent antithrombotic agents?
- Platlet inhibtion
- Anticoagulant effects
- Fibrinolytic effects
Release of:
* Prostacyclin (PGI2)
* Nitric Oxide (NO)
* Adenosin
* Binding of thrombin
By the endothelium all do what?
inhibit platlet aggregation
Adenosine degrades ADP and PGL2 & NO are vasodialators thus promoting
washout of coagulation factors. Thrombin bound inhibits ability to actiavtes platlets
What do
* Thrombomodulin
* Endotehlial C-Receptors
* Heprin Like molecules
on endothelium surface do?
bind
* thrombin
and
* protein C
respectively, in complexes on the endothelial cell surface.
Antitrhombosis
Anticoagulation effect
What occurs when thrombomoduline binds thrombin on the endothelial surface?
When thrombin is bound it loses the abilit to activate coagulation factors & platlets, instead it cleaves & activates protein C (with cofactor protien S)
protein C/S complex is a potent inhibitor of coagulation factors
Anticoagulant Effect
What do heprin like molecules on the surface of endothelum do?
Inactivate thrombin and other coagulationf actros by binding and activating Antithrombin III
What is the clincial utility of heprin and related durgs based on?
Their ability to stimulate antithrombin activity
Another anticoagulant effect, like protein C, requires protein S as a cofactor and, as the name implies, binds and inhibits tissue factor/factor VIIa complexes.
Tissure Factor Pathway Inhibitor
Normal endothelial cells synthesize t-PA, already discussed as a key component of the fibrinolytic pathway.
Fibronolytic effects, T-PA
Explain Virchow traid
3 Things leading to Thrombosis=
1. Endothelial Injury
2. Stasis or turbulant blood flow
3. Hypercoagulability of blood
Endothelial injury leading to platelet activation almost inevitably underlies thrombus formation ____ and ____ , where the high rates of blood flow otherwise impede clot formation.
These kinds of clots are rich in what?
- heart
- arterial circulation
rich in platlets
A shift in pattern of gene expression in the endothelium to one that is prothrombotic produced by physical injury, infectious agets, abnormal blod low, cytokienes, and metaboic abnormalities.
Endothelial Activation or dysfunction
what are 2 major prothrombic alterations in endothelial dysfunction?
- Procoagulant changes (downregulation of expression of coagulation inhiibitors)
- Antifibronolytic effects (increased secretion of plasminogen activator inhibitors which limit fibrynolysis by anatagonizig t-PA and urokinase)
____ contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis.
Turbulant blood flow
What 3 things does stasis and turbulant blood flow result in?
- Promote endothelial cell acitavted and enhanced pro-coagulant activity
- Stasis allows platlets and leukocytes to contact endothelium
- Stasis slows washout of activated clotting faactors, imbeating inflow of clotting factor inhibitors.
____ refers to an abnormally high tendency of the blood to clot and is usually caused by alterations in coagulation factors.
Hypercoagulability
Primary (inherited) hypercoagulability is most often caused by
Gentic
mutations in the factor V and prothrombin genes
Factor V, prothrombin mutation, increased levels Factor 8, 9, 11, fibrog
What form of hypercoaggubility is secondary?
Aquired; results in high or elevated risk of thrombosis
What specific hypercoaguable state?
Marked by the development of autoantibodies that bind complexes of heparin and platelet factor-4 (PF4)
- Occurs in 5% of pt treated with unfraction heprin
- Net result is prothrombotic state even with heprin administattion, clot still forms.
Heparin-induced thrombocytopenia (HIT) syndrome.
Where can arterial or cardiac thrombi arise? What about in veins?
- At sites of endotheliali injury or blood turbulance
- At sutes if stasis
How do venous vs arterial thrombi propogate and what can both result in?
Arterial thrombi= grows away from point of attachment
Venous thrombi= grow in direction of blood flow.
propogating portion is porly attached and prone to fragment & migrate to the heart as an embolus
Where are thrombi more common?
Veins because less blood flow!
most comonly embolized
veins off lower extremetuies most commonly affected
Thrombi occurring in heart chambers or in the aortic lumen
Mural Thrombi
Proimoted by Arrythmias, MI, myocarditis
What thrombus?
typically rich in platelets, as the processes underlying their development (e.g.,endothelial injury) lead to platelet activation
Arterial Thrombus
obstruct vessles and cause infarction locally
ruptured atherosclerotic plaque (e.g.,vasculitis, traum also trigger
What are the 4 events that come after a thrombolytic event?
- Propagation: thrombus enlages
- Embolization: Part of thrombus dislodge and travels elswhere
- Dissolution: (newer thrombus) fibronylitic factors lead to shrinkage and dissolution of thrombus. (older) harder to get rid of.
- Organization & Recanalization: older thronbi have ingrowht of cells
Where do superficial venous thrombi usually arise?
saphenous system (legs), particularly in the setting of varicosities; these rarely embolize but they may cause pain, local congestion, and swelling fro
Where do Deep venous thrombi usually arise?
DVTs
Larger leg veins at or above knee joint. more serious and more prone to emolize
Lower-extremity DVTs are associated with ____ and ____ states
Lower DVTs are assoociated with stasis and hypercoaguability states
Conjestive heart falure, bed rest, imobalization, pregnancy
widespread thrombosis within the microcirculation that may be of sudden or insidious onset.
Disseminated Intravascular Coagulation (DIC)
Excessive clotting, excessive bleeding.
A detached intravascular solid, liquid, or gaseous mass that is carried by the blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction
Embolisim
mostly derived from dislodged thromi; thromboembolism
Originate from deep venous thrombi and are responsible for the most common form of thromboembolic disease.
Pulmonary Thromboembolism
* Most are small
* Large embolus block major pulmonary arterys causing sudden death.
Mostly originating from deep leg vein thrombois
Most airse from intercardiac mural thrombi, usually arterial and can travel virtually anywhere , consequence depend on caliber of oluded vessles and presence or absence of colateral blood supply.
Systemic Thromboembolism
Soft tissue crush injury or rupture of marrow vascular sinusoids (e.g.,resulting from a long bone fracture) release microscopic fat globules and associated marrow elements into the circulation.
Fat Embolism
Attributed to platelet adhesion to fat globules and subsequent aggregation or splenic sequestration ; anemia may result from red cell aggregation and/or hemolysis.
Thrombocytopenia
an uncommon, grave complication of labor and the immediate postpartum period that is caused by the entry of amniotic fluid (and its contents) into the maternal circulation via tears in the placental membranes and/or uterine vein
Αmniotic embolism
Gas bubbles that enter the circulation can coalesce and obstruct vascular flow and cause distal ischemic injury
Air embolism
What form of air embolism occurs in divers?
decompression sickness is caused by sudden changes in atmospheric pressure. “the bends”
an area of ischemic necrosis caused by occlusion of the vascular supply of the affected tissue. In the Heart and the brain are common, important causes of illness.
Infarction
Can be red (venous occlsuons( or white (arterial occlusions)
What 3 things affect infaract development?
- **Anatomy of vascular supply **
- Rate of occlusion (how quick blood is being blocked, slow is less likley to become infarcted because allows time for collateral blood supply to kick in
- Tissue vaulnerability to hypoxia (how long can cell withstand lack of blood, ex. skeletal msucles cell vs neuron)
A state in which diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to cellular hypoxia
Shock
Prolonged shock leads to irreversible injury
results from low cardiac output as a result of myocardial pump failure. It may be caused by
* myocardial damage (infarction)
* ventricular arrhythmia
* extrinsic compression (cardiac tamponade)
* Ouflow obstruction
Cardiogenic Shock
Results from low cardiac output due to loss of blood or plasma volume resulting from
* hemorrhage
* fluid loss from severe burn
* Diarreah & vomiting
Hypovolemic shock
Triggered by microbial infections and is associated with severe systemic inflammatory response syndrome (SIRS). In addition to microbes, SIRS may be triggered by burns, trauma, and/or pancreatitis
**Mast cell degranulation, vasodialation, venous blood pooling,
Septic Shock
Mortalilty rate 20-30%, gram + bacterial infections
results from systemic vasodilation and increased vascular permeability and is triggered by IgE–mediated hypersensitivity reactions
Anaphylactic shock
The pathophysiology of Septic shock involves what?
- endothelial cell activation and injury
- vasodilation
- edema in many tissues
- disseminated intravascular coagulation
- Metabolic derangements.
