Pathophysiology Exam #3 Flashcards
The precursor to fibrin is?
fibrinogen
Hemocytoblast Stem Cell become Myeloid Stem Cells which become Megakaryoblast which form Megakaryocytes……each Megakaryocytes can fragment into how many platelets?
2000 - 5000
The precursor cell for platelets is?
Megakarycote—>platelets are formed from the fragments of them
Platelets are anuclear…what does this mean?
- they cannot multiply and divide(they have no nucleus)
- Bone marrow (BM) has to be constantly producing and moving those platelets from the BM into the circulation to maintain an adequate circulating level of platelets
What is the normal circulating concentration and the lifespan of platelets?
• Normal circulating concentration:
150,000 – 450,000/μL (could also use mm3)
• Half-life: 8 – 12 days
What are six things that are found in the cytoplasm of platelets?
- Contractile proteins
- ER and Golgi apparatus
- Mitochondria
- PGs and TXA2 synthesis
- Fibrin-stabilizing factor synthesis
- Growth factors
What are three contractile proteins found in the cytoplasm of platelets?
- actin
- myosin
- thrombosthenin
What is the function of the ER and Golgi apparatus that is found in the cytoplasm of platelets?
-Ca++ storage and enzyme synthesis
§ Ca is very important in the coagulation cascade (both intrinsic and extrinsic pathways of the coag cascade)
§ ER ribosomes will produce enzymes that are needed for coag
§ Golgi apparatus will further process the enzymes needed
What is the function of the mitochondria found in the cytoplasm of platelets?
ADP and ATP synthesis
§ ADP itself actually aids in the aggregation of platelets, as well as recruitment of other platelets
What is the function of the Fibrin-stabilizing factor?
§ Once you get to the final clot, the final fibrin fibers, the fibrin−stabilizing factor enhance the bonds between the fibrin fibers and create a stronger clot
What is the function of the Growth factors found in the cytoplasm of platelets?
cause vascular endothelial cells, vascular smooth muscle cells, and fibroblasts to grow and divide for repair of damaged blood vessels.
§ When you have an injury and platelets respond, those growth factors are released from the platelets which helps aid in the healing of that damaged tissue
What makes up the cell membrane of platelets?
- Glycoprotein coating
- Phospholipids
- Receptors
What is the characteristics of the Glycoprotein coating of the platelet cell membrane?
o Glycoprotein coating that prevents adherence to normal vascular endothelium, but causes adherence to
injured endothelium.
§ Very important because this prevents the platelets from adhering to normal vascular endothelium; platelets will not adhere to NORMAL vasc endothelial cells.
§ Anything that’s causes injury to the vasc endothelium, will activate the platelets and they will respond to the damaged vasc endothelium
What is the role of the phospholipids found in the platelet cell membrane?
Plays important role in the clotting cascade
What is important about the receptors found in the platelet cell membrane?
o Numerous receptors involved in platelet plug formation and coagulation
o When individuals have clotting disorders, that are r/t platelets; it’s the receptors themselves that are dysfunctional or deficient which leads to the coagulopathy
What is the definition of hemostasis?
prevention of blood loss
How is hemostasis achieved and in what order does it occur(5)?
- Vascular constriction
- Platelet plug formation
- Blood coagulation/blood clot
- Fibrin formation and repair of injured vessel
- Clot lysis
What are four ways in which Vascular Constriction achieves hemostasis?
• TRAUMA CAUSES VASCULAR CONSTRICTION, WHICH DECREASES BLOOD LOSS
• VASCULAR SMOOTH MUSCLE SPASM
o The greater the trauma to the blood vessel (BV), the greater the spasm
o EX: Nick yourself shaving in the bathroom; you think your going to bleed to death while a crushing injury or severed limb: because of the greater degree of injury, the greater degree of vasospasm
• PAIN AND SNS REFLEXES: VASOCONSTRICTION
o NE is released from the postganglionic symp fibers
o EPI/NE released from the adrenal medulla
o causing activation of alpha1 receptors of the vasc smooth muscle; causing vasoconstriction
• PLATELETS → TXA2 → VASOCONSTRICTION
§ When platelets become activated they release thromboxane A2 (TxA2)
§ TxA2 is also a very very potent vasoconstrictor
Platelet plug is the second way in which Hemostasis occurs…what are the characteristics of Platelet plug?
• PLATELETS CONTACT DAMAGED VASCULAR ENDOTHELIUM AND COLLAGEN IN BLOOD VESSEL WALL
o Swell, exude pseudopods
§ pseudo = false; pod = foot
o Actin, myosin, thrombosthenin contract: release active clotting factors
o Platelets then become sticky and aggregate; adhere to collagen and von Willebrand factor (vWF) in blood vessel wall
§ vWF has to be present for the platelets to stick to the collagen in the BV wall
§ vWF is a protein secreted by the BV endothelial cells; it mediates platelet adhesion to the BVs by
forming a bridge between the collagen and the platelets
§ von Willebrand factor binds to both platelet membrane receptors and collagen in the vascular wall to
form the bridges
o ADP and TxA2 secretion: activation of other platelets
v ADP and TxA2 actually combine with receptors on other platelets and recruit them to come play along
o More and more platelets aggregate and are activated and form the platelet plug in the vasc wall
o Eventually the platelets will Express fibrinogen receptors; and the fibrinogen receptors will bind with
the fibrinogen
v the fibrinogen forms bridges between the fibrinogen receptors of the platelets to form platelet plug
o Fibrin threads form in platelet plug
o Platelet plug may seal small blood vessels injury
o However, Large injury also requires blood
coagulation/blood clot
Some people are born with a deficit or a complete absence of vWF; and they will need surgery.
Q: What will you do to correct that problem?
Administer vWF; they have vWF concentrate that you can admin; can also admin cryo
The third stage of hemostasis is Blood coagulation/Blood clot….what are its characteristics?
• BEGINS: 1-2 MIN. FOR MINOR TRAUMA AND 15 – 20 SEC. FOR MAJOR TRAUMA
• 3 – 6 MIN. TEAR IN VESSEL FILLED WITH CLOT
• CLOT RETRACTS IN 20 – 60 MIN.: CLOSES TEAR(APPROXIMATES) MORE AND AIDS IN HEALING
• NORMALLY THERE’S A BALANCE BETWEEN PROCOAGULANTS AND ANTICOAGULANTS
o Normal conditions: anticoagulants predominate
o After injury: procoagulants predominate
o However, procoagulants predominance should be
localized to the area of the injury; you do not
want systemic procoagulant predominance
There are three steps of coagulation in relation to hemostasis…what is the the first step?
- Activation of blood coagulation factors and formation of PROTHROMBINASE (PROTHROMBIN ACTIVATOR)
There are three steps of coagulation in relation to hemostasis…what is the the second step?
- Prothrombinase converts PROTHROMBIN TO THROMBIN
There are three steps of coagulation in relation to hemostasis…what is the the third step?
- Thrombin converts FIBRINOGEN TO FIBRIN FIBERS = Enmesh platelets, blood cells, and plasma to form the clot
What is the final outcome of step 1 of coagulation?
Prothrombinase is the final outcome of step 1 of coagulation
There are two pathways for prothrombinase formation in step one…what are they?
- Extrinsic (tissue factor) pathway
- Intrinsic (contact activation) pathway
What are the characteristics of the Extrinsic pathway
v Its called extrinsic because the damage is EXTERNAL to the BV
v Once tissue is damaged, that causes the release of thromboplastin; released from the traumatized tissue
v Thromboplastin along with Factor VII and Ca ions activate Factor X
v Activated Factor X, Factor V, platelet phospholipids, and Ca ions activate prothrombinase (the final outcome of step 1 of the coagulation pathway.
In step one of coagulation, what initiates the action of the extrinsic clotting pathway, and what is the final outcome of it?
- tissue damage(trauma)
- Prothrombinase
In step one of coagulation, what initiates the action of the intrinsic clotting pathway, and what is the final outcome of it?
- contact w/ collagen of damage bv activates factor xii
- Prothrombinase
Do both the intrinsic and the extrinsic pathways lead to the same result?
yes; Note that beginning with activation of Factor X, both become a common pathway
What ion plays an important role in both the intrinsic as well as the extrinsic pathway?
§ You can see here that Ca plays an important role in both the intrinsic and extrinsic coag pathways
v If you have low levels of extracellular Ca, that is going to affect your ability to clot
§ The extrinsic pathway actually feeds into the intrinsic pathway
§ Extrinsic pathway can become out of control—EXPLOSIVE; intrinsic pathway has a much more
controlled and slower response
§ If blood vessel ruptures, both pathways are activated simultaneously
In step two of coagulation, what initiates the action of the clotting pathway and what is the final outcome?
• Prothrombinase converts prothrombin to thrombin
-The final outcome of step 2 is THROMBIN
o Requires sufficient Ca++
o Prothrombin
§ An alpha-2 globulin (plasma protein) an unstable
protein that can split easily.
§ Synthesized in liver
§ Vit K dependent coagulation factor
§ Vitamin K required for normal activation of
prothrombin (also required for liver synthesis of
Factors VII, IX, X)
v Sources of vitamin K: diet and synthesis by E. coli
in colon
Q: SO, consider your pt is on an antibiotic that is
decreasing the amount of E. coli within their GI tract or they have a colon cleansing (GoLYTELY) before the procedure; what kind of implications will that have?
A: Decreased synthesis of prothrombin of the liver.
v Vitamin K is a fat soluble vitamin, so adequate bile in the GI tract is necessary for vitamin K absorption
In step three of coagulation, what initiates the action of the clotting pathway and what is the final outcome?
• THROMBIN, ALONG WITH CALCIUM IONS, converts FIBRINOGEN into FIBRIN FIBERS, which, in
combination with platelets, blood cells, and plasma, FORM A CLOT.
o Requires Ca++
• NOW WE HAVE THE FINAL CLOT: meshwork of fibrin fibers entrapping platelets, blood cells, plasma
Clot retraction is a part of step three of hemostasis ….what are its characteristics?
• The clot retracts and Expresses most fluid (serum) from clot within about 20−60 minutes
o Actin, myosin, thrombosthenin, and Ca++ in platelets
o What happens is actually the actin, myosin and thrombosthenin, those contractile proteins actually
causes the platelets to contract which causes total clot retraction
• Pulls edges of blood vessel closer together: aids in hemostasis and healing
What is the name of the fluid expressed from the clot that has all of the clotting factors removed from it?
serum
The fourth step of hemostasis is fibrin/ fibroblasts formation and repair of injured blood vessel…what is the characteristics of this step?
• Following formation of fibrin fibers (see above), clot becomes invaded by fibroblasts, which form connective tissue throughout clot
• If the entire Clot is changed to fibrous tissue and repair is complete in about 1 to 2 weeks
o Now depending on the extent of injury, this depends on if this new tissue is similar to function and form to the original tissue
o Think about a myocardial infarction, tissue becomes damaged, it gets repaired; does it function the same
as it did before
o EX: burn victim’s skin forming contractures, etc
o So depending on the extent of the injury, if the injury is small that tissue can be similar in function and form; if it is large, the new tissue will be scar tissue and will not heal or function like it used to
• Platelet growth factors enhance repair
Describe the 5th step of hemostasis…clot lysis.
• When blood has leaked into tissues and clot is formed, it must be dissolved.
• Very essential step; do not want clot hanging around in your body
• Plasminogen (inactive plasma protein) trapped in clot
o Plasminogen is usually in the inactive state
• Injured tissue and vascular endothelial cells release tissue plasminogen activator (t-PA)
• In 1−2 days after clot has stopped the bleeding, t-PA will convert plasminogen to plasmin
• Plasmin
o Proteolytic enzyme
§ Breaks down proteins, digest the fibrin fibers and the clot is lysed
o Digests fibrin fibers and procoagulants
How does the vascular endothelium help prevent coagulation in normal blood vessels?
• VASCULAR ENDOTHELIUM
o Smooth (under normal conditions) prevents activation of intrinsic pathway
§ when it is smooth that is a good thing; that does not activate the coag cascade
o There’s also a Mucopolysaccharide glycocalyx on the vasc endothelium that repels platelets and clotting
factors
o Thrombomodulin is a protein that is bound with the vasc endothelium; it binds thrombin and removes it
from the blood
o When Endothelial tissue/ cells is damaged: that activates the INtrinsic pathways, with the activation of
Factor XII and platelets
How do fibrin fibers help prevent coagulation in normal BV?
• Fibrin fibers (after a clot has been formed) will absorb thrombin and remove it from blood to prevent spread
of clot.
o Remember that thrombin feed back into the INtrinsic pathway; if that kept happening, then the clot would just continue to grow and spread
o So the fibrin fibers will absorb the excess thrombin to prevent the spread of the clot and keep it localized
just to the damaged tissue
How does Antithrombin III help prevent coagulation in normal BV?
• Antithrombin III: an endogenous substance that combines with and inactivates thrombin
o It also removes Factors VII, IX, X, XI, XII (with the endogenous heparin)
How does endogenous heparin help prevent coagulation in normal BV?
• Endogenous heparin
o Synthesized and secreted by mast cells and basophils
§ Mast cells are responsible for secreting heparin in the tissue spaces
§ Basophils secrete the heparin into the blood; basophils are located within BVs
o Neg. charged polysaccharide, which combines with Antithrombin III and increases effect by
100 – 1000 X to inactivate thrombin
o Removes Factors VII, IX, X, XI, XII
Endogenous heparin is synthesized and secreted by what kind of cells?
mast cells and basophils
Q: If I give to much heparin or I want to reverse the heparin at the end of a case; what do I use to reverse
heparin?
A: PROTAMINE:
§ It neutralizes it; heparin is a strong acid, protamine a base
§ Must give protamine on a weight−by−weight basis according to how much heparin you gave;
protamine alone is an anticoagulant
Q: What if someone has a warfarin overdose; what do you give to reverse?
A: Vitamin K; there is a formula that will tell you how much Vit K to give based on the warfarin levels
When we think of HEPARIN we want to associate it with the _____ pathway; and warfarin with the
_____ pathway.
- Intrinsic
- Extrinsic
What clotting factors are inhibited by Heparin?
ACTIVATED FACTOR VII ACTIVATED FACTOR IX ACTIVATED FACTOR X (ALSO INHIBITED BY LOVENOX) FACTOR XI FACTOR XII THROMBIN
• As you can see, heparin acts on the ACTIVATED factors whereas warfarin acts on the factors BEFORE
they become activated
• Heparin also works on Factors XI and XII
What clotting factors are inhibited by Warfarin?
FACTOR VII
FACTOR IX
FACTOR X
PROTHROMBIN
• As you can see, heparin acts on the ACTIVATED factors whereas warfarin acts on the factors BEFORE
they become activated
• Heparin also works on Factors XI and XII
Platelet count?
-measures platelet concentration in blood
-150,000 – 450,000/μL
o Just because someone has an adequate number of platelets doesn’t mean that person has adequate
platelet function
o there are many people who have adequate platelets but they have a deficiency of a certain receptor or a
dysfunction of a certain receptor on the platelets which causes those platelets to be dysfunctional
o Even though they have an adequate number, they are not going to work properly
o EX: When I patient’s lab values are WNL and the competent surgeon says, “this patient is oozing”.
Prothrombin time?
o Assesses the extrinsic and the common pathway
-11 – 16 sec. (compared with International Normalized Ratio [INR])
What drug did I say affects the EXtrinsic pathway?
WARFARIN
o WARFARIN = PT
INR?
§ If a patient’s INR is 1; that patient’s PT is equal to the INR for NORMAL
§ 2 = 2x the standard for normal; and so on
§ Used to standardize PT levels from one lab to another
§ Different goals for INR levels based on patient’s reason for being on warfarin; a−fib, prosthetic
valve, etc
• Activated partial thromboplastin time?
o Used to assess heparin
o Measures the INtrinsic and common pathway
D-dimer test
o Measure of fibrin breakdown; degradation products
o After a clot has been formed, it then gets lysed; this measure those degradation products
What does a positive D-dimer test mean?
o If the D−dimer is POSITIVE, that is suggestive of an increase or excessive fibrinolysis and/ or
coagulopathy
Q: What do we use a D−dimer test to look for?
A: PEs; DIC
ACTIVATED PARTIAL THROMBOPLASTIN TIME (APTT)?
- measures intrinsic and common pathway
- 26 – 42 sec
PLASMA FIBRINOGEN?
-assesses plasma level of the precursor of fibrin.
adequate level needed for normal clot formation.
-200 – 400 mg/dl
What is DISSEMINATED INTRAVASCULAR COAGULATION(DIC)?
o Initially, procoagulants predominate until they are consumed faster than they are synthesized, then
anticoagulants predominate
§ Hence, the paradox of widespread, extensive blood clotting and then widespread, extensive bleeding
o An acquired clinical syndrome with manifestations the result of increased protease activity in the blood
caused by unregulated release of thrombin with subsequent fibrin formation and accelerated fibrinolysis
o May be localized to one organ or may be generalized
There are many predisposing conditions that may cause DIC…what is the most common one?
o Infection (most common cause, especially
gram-negative septicemia, but also grampositive
septicemia, fungal infections, protozoal infections, and viral infections)
§ Gram neg bacteria septicemia causes DIC from the endotoxins
§ When the bacteria is lysed, the endotoxins is released into the body fluid
§ Those endotoxins increase all the inflammatory immune response
o Cardiopulmonary arrest
§ The longer the arrest is, the greater the chance the pt will develop DIC
How is DIC managed in the OR setting?
o Remove/treat underlying causes
o Talk to the surgeon and discuss importance of the surgery
o Restore balance between coagulation and fibrinolysis
§ Heparin (use in DIC is very controversial, and currently not usually done)
v If you prevent the initial clotting you can prevent the using up of clotting factors that lead to the
sequence of events that lead to DIC
§ Platelet transfusions
§ Fresh frozen plasma, cryoprecipitate, packed RBCs to replace clotting factors
§ Antithrombin III
v Same as heparin above…
o Maintain organ viability
LABORATORY RESULTS TYPICAL OF DIC
• Bleeding time?
-increased
o All of their coagulation factors have been used up
LABORATORY RESULTS TYPICAL OF DIC
• Platelet count?
-decreased
o All the platelets are being used up
LABORATORY RESULTS TYPICAL OF DIC
• Plasma fibrinogen?
-decreased
LABORATORY RESULTS TYPICAL OF DIC
• Fibrin degradation products?
-increased
o Because of widespread clotting and widespread lysis of those clots
LABORATORY RESULTS TYPICAL OF DIC
• D-dimer test?
-increased
