Week 4 Flashcards
3 qualities that you would find vital to hemostasis
- Localized and precise
- Rapidly responsive
- Self-limited
Goal of hemostatsis
maintain blood flow
Types of hemostasis
- Primary: platelet adhesion and aggregation, forming platelet plug
- Secondary: cascade, clotting factors; Happens at same time as primary
- Tertiary: clot resorption
Inactive Coagulation system
- vWF: in collagen, platelet, or free floating in plasma
- GPIa: active in resting state
- GPIIb/IIIa: inactive in resting state
Steps of hemostasis
- Injury to site- collagen is exposed and tissue factor is released
- Endothelial and subendothelial cells release vFW which will unwind and go to collagen and tissue factor begins forming thrombin
a. Thrombin: will activate platelets
b. vFW: will activate platelets - Activated platelets bind to vFW via GPIb
- Bound platelets expose GPIIb/IIIa
- Fibrinogen in blood will bind to GPIIb/IIIa of two platelets to cross link them and begin forming platelet plug
Activating platelet
- what induces?
- what is down stream effect?
- by tissue factor and binding to vWF
- induces exposure of GPIIb/IIIA
- Undergo conformation change
- Degranulate- will recruit more platelet to site of injury
- Arachodonic acid is taken from phospholipid membrane and converted to thromboxane A2
Importance of conformational change in platelets
-from disc shape to spiny shape; important because it allows for increased surface area, because stuff happening in secondary hemostasis happens in membrane of platelet
Granules in platelets
-electron dense and specific granule
Electron dense granule
-secretions
- ADP: activates more platelets
- Serotonin: localized vasoconstriction
Specific granule
-secretions
- Fibrinogen: links two platelets together to form platelet plug
- vWF: glue between platelets and collagen, draws platelet to site of injury
- PDGF: will start repair
Secondary Hemostasis
- Forms fibrin meshwork around platelet plug
- contributors: blood coagulation factors, platelets, calcium
Fibrin meshwork
- Gives platelet plug stability
- Will permanently seal the site of injury
Blood coagulation factors
- produced by:
- types:
- liver; already produced and present in blood, but inactive
- Serine proteases (II, VII, IX, X, XI); break down proteins with serines
- Cofactors: assist process by attaching to endothelium and collagen to help other enzymes bind
Coagulation factors I, II, III
-descriptive name, function/active form
I: fibrinogen, fibrin
II: prothrombin, serine protease
III: Tissue factor; cofactor
Extrinsic cascade
- function
- activation
- pathway
- produce small amount of Xa, to make small clot
- Exogenous Tissue Factor (Factor III)- thromboplastin
- Vascular injury–III (thromboplastin) + Ca–VII to VIIa (serine protease)–X to Xa (serine protease)
Intrinsic in-vitro
- function
- activated by
- pathway
- co-agulates blood outside of body
- activated by contacting negatively charged surface; ex. Glas (Kininogen and kallirein)
- produces large amount of Xa
- XII to XiI a–XI to XIa–IX to IXa–IXa and Factor VIIIa converts X to Xa
Intrinsic in-vivo
- function
- activation
- pathway
- co-agulates blood in body by producing large amount of Xa
- response to injury
- Tissue Factor activates VII to VIIa, VIIa then binds to Tissue Factor; Thrombin activates XI to XIa; XIa and VIIa/TF combine to change IX to IXa; Thrombin activates VIII to VIIIa; IXa and VIIIa combine to make tenase; tenase then changes X to Xa
Common pathway
- Xa + Va + Ca will activate prothrombin to thrombin; thrombin then activates fibrinogen to fibrin monomer and XIII to XIIIa; XIIIa then cross links fibrin monomers to make cross linked fibrin polymers (hard clot)
Thrombocytopenia
- definition
- based on
- below in hospital patients
- below in healthy patients
- decreased number of platelets in blood
- Defined based on reference range
- Below 50,000 would be worried about spontaneous bleeding
- In healthy patients 20,000 should be enough to stop spontaneous bleeding
Causes of thrombocytopenia
- Destruction
- Consumption: Decreased due to be used to make clot
- Decreased production in the bone marrow
Chronic ITP thrombocytopenic purpura
-cause
- Idiopathic (unknown cause) but it autoimmune mediated; Antibodies directed at platelets, Platelets destroyed in the spleen
- Purpura: easy superficial bruising
Treatment for Chronic ITP thrombocytopenic purpura
- Corticosteroid: Suppress immune response and decrease production of antibodies
- Retuximab: Mono-clonoal antibody that targets b-cells making antibodies
- Splenectomy: When nothing else works
Importance of history in bleeding disorders
-trying to figure out whether sxs are from genetic or acquired problem
What are we looking out for in PE for bleeding disorder
-collateral veins, bruising, redness, edema
Purpura
-superficial bleeding larger than 3 mm
Petichie
-superficial bleeding smaller than 3 mm, usually occurs in multiples
Labs ordered in patients with bleeding
CBC, PT, PTT
Labs for ITP
platelet: low
PT: normal
PTT: normal
peripheral blood smear: reduced amnt platelets and shows immature platelets
Von Willebrand Disease labs
platelet: normal
PT: normal
PTT: elevated
Platelet function assays
Clues that can distinguish between factor VIII/IX disorder and von Willebrand disorder
-von willebrand is included in primary and secondary clotting, so it will be seen in deep tissue and superficial bleeding
How is von Willebrand involved in secondary hemostasis?
It combines factor VIII and IX together to make tenays complex which will then activate factor X
Treatment for von Willebrand
- Concentrated von Willebrand
- DDADP: vasopressin that causes endothelial cells to release all the von Willebrand factor that they have
Factor VIII deficiency labs
- platelets normal
- PT normal
- PTT elevated
PTT mixing study
- to detemine whether it is fator VII/IX deficiency or von Willebrand
- will mix patients plasma with control plasma and repeat PTT, if PTT still elevated means that it is Factor deficiency
How to determine between factor VIII and factor IX deficiency
- mix patients serum with serum of patient who has confirmed deficiency of one of the factors, then repeat PTT
- If PTT is normal, then that patient has the opposite factor deficiency, if PTT remains elevated then that patient has that factor deficiency
Levles of Hemophilia A
Severe: only 1-2% of Factor VIII works
Moderate: 2-4% of factor VIII works
Mild: 4-30% of factor VIII works
Inheritance pattern of hemophilia A
-x-linked recessive
Treatment of Factor VIII deficiency
-treat with concentrated Factor XIII pooled from plasma donations
Vit K deficiency
-acquired form of bleeding problem, NOT hereditary
Vit K deficiency labs
- PT: elevated
- PTT: elevated
- Factor panels: II, VII, IX, X all low
What does elevated PT and PTT mean?
-defect in common pathway OR in multiple factors
Treatment for Vit K deficiency
- Increase vitamin K in diet, dark/leafy greens
Role of Vit K in hemostasis
- helps to activate factors II, VII, IX, X (serine proteases)
- Gammacarboxlyatin of glutamine residues: Helps with binding of Ca, which then helps to bind with negatively bound phosphomembrane and allows for factors to bind
Types of vit K
- Filoquinone (K1): green leafy veggies
- Melaquinone (K2): from animals
- Meladinone (K3): Has a lot of issues, not used often
Filoquinone conversion
- Filoqinone is converted to melaquinone through gut microbiota
- Melaquinone is more active and stable form
Causes of Vit K deficiency
- antibiotics: would kill gut micro co plant vit K cannot be turned into stable more active form
- Fat malabsorption: because kitamin k is fat soluble vitamin
- New born babies: need vitamin k shots
Tertiary hemostasis
will occur a few days after clot formation because it breaks down the clot
Clot retraction
- clot shrinks: will help to close wound by pulling ends together
- Fibrinolysis: will degrade fibrin polymers
Plasminogen
created in liver and in plasma, it’s the inactive form–activated to plasmin
tPA and U-PA
- activates plasminogen to plasmin
Streptokinase
- tPA produced by bacteria that can bind to plasminogen and create plasmin
Plasmin
- breaks down fibrin
- is in free and bound form
a2- antiplasmin
-turns off free form of plasmin so that it will not degrade clot
How is hemostatic cascade turned off?
- Protein C-Protein S
- Serpins and anti-thrombin
Protein C
- Production: by the liver, inactive form in present in the blood and is activated by thrombomodulin
- will destroy factor V and VIII so that pro-thrombulin complex cannot be made and prothrombin will not be activated into thrombin
thrombomodulin
-receptor on endothelial membrane, will activate protein C once thrombin binds to receptor
difference between bound thrombin and free thrombin
- Free: would activate factor V - pro hemostasis
- Bound: would inactivate factor V through protein C-anti hemostasis
Serpins
serine protease inhibitors; needed to deactivate proteases so they do not start breaking down random proteins in the body
Anti-thrombin III
- specific serpin
- Binds to free thrombin and inactivates it
- Will also inhibit thrombin production by inhibiting factor 12, 11, 10, 9
Heparin
-Produced by mast cells; will bind to anti-thrombin to make it fit thrombin more tightly to inactivate thrombin better
Thrombosis
- Pathological formation of a clot; no injury occurs
- different from hemostasis because hemostasis clot formation is to help with injury
Virchows triad
-endothelial injury, hypercoagilability and abnormal blood flow cause thrombosis
Endothelial injury
-endothelium maintains balance b/w pro-thrombosis (clotting factors) and anti-thrombosis (turns off mechanism)
Extrinsic thrombotic factors
Tissue factor (factor III)
Intrinsic thrombotic factors
- vWF (present in sub-endothelium as well)
- Factor VIII
- Endothelin
Anti-thrombotic factors
- tPA
- Thrombomodulin
Causes of endothelial changes
- Trauma, inflammation, plaques, free radicals (oxidative stress), toxins, infections
- all of these will make epithelium hyperactive or dysfunctional; these change gene expression from anti-thrombotic to pro-thrombotic to prod. A diff. set of proteins that might be contributory towards the process
Procoagulant changes
- Prod. TPA inhibitor which won’t degrade the fibrin
- Won’t express thrombomodulin so you have lots of free floating thrombin which is prothrombin
- Might dec. internal heparin meaning anti-thrombin 3 won’t be activated
stasis
slowing of blood flow
causes of turbulence and stasis
- Plaques or aneurysms
- Ppl wit sickle cell anemia have abnormal blood cells that can get stuck in smaller blood vessels causing stasis leading to thrombosis
- Polycythemia - Change in laminar blood flow damaging endothelium causing thrombotic effects
Plaques
caused by cholesterol, calcium, and macrophages settling in blood vessel and being trapped in endothelial and being oxidized by free radicals
Hypercoagulability
-Forming more blood clots that can be due to genetics (primary hypercoagulability) and acquired (secondary hypercoagulability)
Factor V Leiden
• Point mutation in factor 5 gene
• Isn’t inhibited by protein C
• Another example of hypercoagulability: pro-thrombin (point mutation in regulatory region that leads to prod. Of a lot of clots)
-Anti-thrombin III deficiency
Methionine
- First a.a present in eukaryotic proteins
- It has a thiol group so has sulfur
- produces homocysteine through methylation by using SAM and B9
- B12 helps B9 grab methyl group
Homocysteine
-precursor to cysteine (transulfuration through vit B6) or can be reconverted to methionine
Risk factors for CAD
- Hypertension - endothelial damage that dep. On other secondary affects patient has from hypertension; basically having high pressure damaging endothelium
- Elevated cholesterol - plaque formation which can cause turbulent blood flow and endothelial dysfunction
- Smoking - causes endothelial damage
- Inc. age: less elasticity in vessels
Arterial thrombus
-caused by Atherosclerosis
-Composed of platelet aggregates
- high flow
endothelial damage both activate platelets to make a firm clot to withstand high blood flow
-use anti-platelet medications (aspirin)
Venous thrombus
○ Has platelets but more rich in fibrin
○ Don’t have as much platelet involvement
○ more related to low blood flow conditions
loss of laminar flow b/c cells are just sitting there not flowing so can initiate contact and adhesion
-use anti-coagulant medications
Aspirin
- Irreversible cox 1 inhibitor so inhibits aracondonic acid
- Has more of a platelet affect than other meds
- If having outpatient elective surgery then patient should stop aspirin for a 7-10 days b/c that’s about how long platelets live for; should at least stop 5 days before b/c then would have at least a good amount of functional platelets; there are several tests that can test the functions of platelets w/ drug use
How does myocardial infraction place the patient at an increased risk of cardiac thrombus formation?
- fibrosis of wall: decreased motility
- potential focal thinning of wall: aneurysm formation
Abciximab
- Monoclonal antibody
- 2b3a receptor blocker
- 2b3a binds to fibrinogen and that allows for platelet aggregation
- Given intravenously (IV form)
- Limited to patients going in for percutaneous
- Prevents additional thrombotic
Clopidogrel
• Blocks ADP receptor which are in granules in platelets and when they become activated the platelets degranulate
• Used in combination w/ aspiring
-Delivered orally
Lab test for DVT
D-dimer; ultrasound
Treatment for DVT
- Initial: Lovonox - low molecular weight only inhibits factor VIII (been cut up and only keeps parts that are active), subcutaneously; don’t give for kidney problems; Heparin - unfractioned molecular weight; given intravenously or subcutatenously; would give if need to act quickly and don’t know patient history
- Long term: Warfarin - would give while still on heparin b/c protein C; vit. C has to be in the reduced form and it serves as a co-factor; has to be converted back into its reduced form but warfarin blocks it (2, 7, 9, 10); protein C and factor 7 have a very short half life
Heparin MOA
- unfactionate heparin: binds to anti-throbin III to inactivate thrombin and Xa
- lower molecular (enoxaprin) and fondaparinux: inhibits prod. Of Xa from X; lower bleeding risk profile
Rivaroxaban
- Factor Xa inhibitor
- oral
Dabigatran
- Thrombin inhibitor
- oral
Strokes
- diagnosis
- time importance
- CT; check if hemorrhagic or ischemic stroke b/c if they’re bleeding you don’t want them to bleed more
- tissue plasminogen needs to be given w/I 2 hrs
Fibrinolytics
-More and more fibrin so starts to get more dense and has cross-linking
TPA
- breaks down fibrin
- not as effective after 3-4 hours because of fibrinolytics
