Flashcards in Coagulation/anticoagulants Deck (65):
Inappropriate deviation from haemeostasis. Activation of blood clot formation (thrombus) that blocks blood flow.
The process by which a clot is dislodged from its site of origin and travels through the bloodstream to a capillary bed.
The maintenance of blood's fluidity, viscosity, and vessels. The regulation of clots.
A platelet driven clot within an artery. Can travel to any organ. Clot can cause ischemia (restriction of blood supply to a tissue). Embolism can cause stroke, MI.
A coagulation cascade driven clot within a vein. Named for system blocked; deep vein (femoral), renal, and portal vein thrombosis.
What is the driving force behind venous vs arterial thrombosis?
Venous: coagulaiton cascade
Arterial: platelet driven
A floating clot the has dislodged from the position where it came from.
4 steps to clot formation:
2. primary hemostasis
3. secondary hemostasis
4. Antithrombotic counter regulation
Primary hemostasis occurs within seconds of tissue injury. Platelets are activated.
Secondary hemostasis occurs simultaneously: Additional coagulation factors or clotting factors respond in a cascade to form fibrin strands, which strengthen the platelet plug.
Thrombosis is caused by one of the following:
-Irregularity in the composition of the blood.
-Blood vessel irregularity.
-`Nature of the blood flow (stasis/turbulent)
What type of proteins are most coagulation factors?
Protease enzymes (II - XII)
What is factor I?
What is the end product of the coagulation cascade?
What is factor II?
What is factor III?
Tissue factor, aka Thromboblastin
What triggers the extrinsic coagulation cascade?
Factor 3 (tissue factor, TF) is released or exposed at the site of injury by damaged endothelial cells. TF initiates the cascade by activating Factor VII.
Factor I in the common pathway. Catalyzed from fibrinogen with the help of thrombin. Fibrin. Coagulation is the crosslinking of active fibrin.
Factor IIa in the common pathway. Catalyzed from prothrombin with the help of Xa and Va. Thrombin also activates factors 5, 8, 11, 13., as well as platelet activation.
What is the final step in the coagulation cascade?
Thrombin (Factor IIa) activates Fibrinogen to fibrin (Factor Ia), which spontaneously polymerizes.
Negatively charged phospholipids on activated platelets initiate:
XII -> XIIa
XIIa + XI -> XIa
XIa + IX -> IXa
IX + VIIIa (cofactor) + X -> Xa
Note: Ca+ is an important cofactor in these reactions.
Trauma + VII -> VIIa
VIIa + X + Tissue Factor-> Xa
Tissue factor and Ca+ are important mediators in this reaction.
Xa + Va (cofactor) initiate prothrombin (II) to become Thrombin (IIa), which initiates Fibrinogen (I) to become Fibrin (Ia) monomers, which with the help of XIIIa spontaneously polymerizes, forms a clot
Tissue Factor pathway inhibitor.
TFPI is a naturally occurring anticoagulant that inactivates Factor Xa and produces feedback inhibition to Tissue Factor/Factor VIIa.
The balance between TF and TFPI regulate coagulation.
Where is Fibrinogen synthesized?
What is its structure?
Fibrinogen is a large complex of 6 polypeptide chain produced in the liver. 2x alpha, beta, gamma. It has alternating negative and positive charges due to aspartate and glutamate amino acids.
Fibrin monomers are hydrolyzed by thrombin.
Intrinsic pathway. Complex formed by VIIIa and IXa, which activates Xa.
Where are coagulation factors synthesized?
Coagulation cascade cofactor?
How is the intrinsic pathway activated?
Activated platelets present a negatively charger phospholipid on their surface. this activates prekallikrein to kallikrein, a protease that activates Factor VIIa.
What is the role of Ca+ in coagulation?
Ca mediates the binding between the negatively charged phospholipids on the surface of activated platelets and Factors Xa and IXa.
Ca+ is also in vitamin K dependent coagulation factors.
Role of Vitamin K?
Vitamin K is a fat-soluble vitamin found in leafy greens. It is an essential catalyst in the synthesis of coagulation factors II (prothrombin), VII (extrinsic), IX (intrinsic) and X (common), as well as protein C/S.
What favors coagulation (general)?
What inhibits coagulation (general)?
Intact endothelium expresses:
1. Heparin proteoglycans, to which Antithrombin III (AT3) binds. This activates AT3, which goes on to inhibit thrombin.
2. Thrombomudulin activates protein C and S, which go on to degrade factor Va and VIIIa.
3. TFPI is present in plasma, which inhibits extrinsic pathway.
Anti-thrombin III is a plasma protein that is a weak inhibitor for thrombin and Factor Xa. When ATIII is bound to Heparin, however, its potency increases 1000 fold.
Like Heparin, thrombomodulin is also expressed on the surface on intact endothelial cells. It binds to and inhibits thrombin forming a complex that acquires new functions:
The complex activates protein C, which along with protein S, inhibits factor Va and VIIIa (activated protein C pathway [APC])
Factor V Leiden
Factor V Leiden is a genetic disorder of blood clotting from a mutation of Factor V. The mutation makes Factor V resistant to the activated protein C regulator pathway, causing hypercoagulability.
Heparin sulfate is a naturally occurring proteoglycan produced on the surface of intact endothelial cells. It forms a complex with ATIII that is an effective inhibitor of Thrombin and Factor Xa.
Too little coagulation-causes
A: Factor VIII
B: Factor IX
Too little Vitamin K
Excessive demand of coagulation system
Too much coagulation-causes
Defiiciciency of regulatory mechanisms
Factor V Leiden
After MI, stroke, Angina
Peripheral arterial disease
The prothrombin time (PT) is an assay that evaluates the extrinsic pathway of coagulation. PT measures factors I (fibrinogen), II (prothrombin), V, VII, and X.
Activated partial thromboplastin time (aPTT) is a medical test that characterizes blood clotting and to monitor the treatment effects with heparin. It measures the intrinsic pathway and common coagulation pathways. It assess factors: I, II, V, VIII, IX, X, XI, XII.
International normalized ration (INR) is a ratio of PTtest over PTnormal.
What test is used to asses the intrinsic pathway?
Factors VIII, IX, XI, XII
What test is used to asses the extrinsic pathway?
PT/INR (INR is better)
Factors II, V, VII, X
What test is used to assess the common pathway?
TT - thrombin thrombin time.
Hemmorhagic disease of the newborn.
What is it, how is it diagnosed and treated?
Newborns present with bleeding from GIT, umbilicus. Due to vitamin K deficiency.
Diagnosed by prolonged PT/INR.
Treat with vitamin K supplementation.
Alcoholic Liver Disease
What is it, how is it diagnosed and treated?
Patients present with bleeding disorders due to poor diet and decreased liver function.
Prolonges INR and aTTP, with decreased platelet count.
Treat with vitamin K supplementation or frozen plasma.
How are venous hypercoagulation issues treated?
How are arterial hypercoagulation treated?
Anti-platelets and thrombolytics
Haemophilia; types and causes
Haemophilia is a mostly inherited genetic disorder (X chromosome) that impairs the body's ability to make blood clots. Results in people bleeding longer after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain.
There are two main types of haemophilia: haemophilia A, which occurs due to not enough clotting factor VIII, and haemophilia B, which occurs due to not enough clotting factor IX. (Intrinsic).
What is the purpose of anti-coagulants?
Anti-coagulants (warfarin and heparin) prevent coagulation of blood. It does NOT break up existing clots. The drugs are used by people who are at risk of thrombosis, DVT, PE, coronary heart disease.
Vitamin K antagonist. Thereby prevents the liver's synthesis of factors II, VII, IX, X by gamma-glutamyl-carboxylase.
Warfarin; administration and use.
Orally administered. Takes 1-3 days to begin working, since it stops the synthesis of coagulation factors. Therefore, it also takes 2-5 days for effects to be reversed. It is used for longterm use for people at risk for clots.
Low therapeutic index. Must be monitored closely by PT.
Warfarin; contraindications and interactions.
Drug is metabolized by CYT P450 in liver, so any alteration in liver function (via drugs, disease, or alcohol) changes efficacy.
99% of drug is plasma protein bound, leaving 1% to act freely. Therefore, it may provoke complications with other plasma bound drugs.
Disturbs embryo development (teratogenic) so should not be used during conception or pregnancy.
Low therapeutic index. Must be monitored by PT/INR.
Modifies Factors II, VII, IX, X, by adding a carboxyl group to glutamic acid residues. Vitamin K is an essential catalyst.
Warfarin blocks the recycling of Vitamin K via VKOR (vitamin K reductase oxidase).
Because warfarin takes several days to take effect, patients must be monitored 4-5 times per week until PT/INR stability is achieved (initiation phase).
Once the dose and PT/IRS are stable, patient must be monitored every 4 weeks (stable phase).
Transitions phases occur when there are changes to medications, medical condition, or diet.
Heparin is naturally expressed on the surface of healthy endothelial cells. It is a cofactor that enhances the inhibitory effects of Antithrombin III, thereby blocking the common pathway. Inhibits Factor II and Xa.
Unfractionated Heparin; pros and cons
-1-2 hour half life with immediate onset.
-Requires aPTT monitoring.
-IV or subcutaneous only
-Can cause HIT
-Easily inactivated with Protamine sulfate
Low-Molecular-Weight Heparin; pros and cons
LMWH has a 4-5 hour half life with slower onset (20-30 minutes)
-Does not require monitoring.
-Anticoagulant of choice during pregnancy.
-Lower risk of HIT.
-Less easily inactivated with Protamine sulfate
It is used to treat DVT, PE, to prevent VTE (venous thromboembolism) after surgery, and for treatment of myocardial infraction (MI).
Heparin administration and reversal
It is administered by subcutaneous injection or intravenously. It has a short half life but acts quickly and can be quickly terminated.
Must be monitored by aPTT.
Protamine sulfate can immediately reverse the effects.
Heparin adverse effects
Heparin-induced thrombocytopenia (HIT syndrome).
Heparin-induced thrombocytopenia is an immunological response to Heparin that causes platelet aggregation as well as the using up of coagulation factors. This can result in thrombosis or excessive bleeding.
In HIT, the platelet count in the blood falls below the normal range, a condition called thrombocytopenia.
How can heparin be reversed?