Coagulation Disorders I & II Flashcards
outline the events of primary hemostasis
triggered by vessel injury:
-
adhesion phase:
- vessel injury exposes 1. subendothelial collagen & 2. Von-Willebrand factor (vWF)
- vWF binds collagen
- vWF then binds GP-1b receptor on platelets, linking them to injury site.
-
activation phase. :
-
platelets change shape, which causes:
- conformation change of GP-IIb & GP-IIIa to so that they → fibrinogen
- binding of neg charged phospholipids to platelets to serve as a site for factors
-
platelets release granules
- TXA-2: promotes aggregation
- ADP: promotes aggregation, recruits more factors
- activation of platelets by PAR, released by thrombin
-
platelets change shape, which causes:
- aggregation phase - fibrinogen forms bridges between activated platelets
what is “irreversible” platelet contraction & what causes it?
- = irreversible platelet aggregation
- caused by stabilization of clot by thrombin, which cleaves fibrinogen to fibrin, which cross links the clot
what are the roles of the GP receptors on platelets?
- GP-Ib: binds vWF on the exposed subendothelial collagen, linking the platelet to the injury site (adhesion phase)
- GP-IIb & GPIIIa: bind fibrinogen (during activation phase) which is necessary for aggregation phase
what are protease activated receptors & their role in clotting?
- released by thrombin
- “activate” platelets to that they can aggregate
outline the events of secondary hemostasis
-
extrinsic pathway - initiated by tissue factor (TF)
- TF cleaves VII → VIIa
- VIIa cleaves IX → IXa
- IXa cleaves X → Xa (common pathway starter)
-
intrinsic pathway - initiated by XII autoactivation or lab stimulus
- XIIa cleaves XI → XIa
- XIa cleaves IX → IXa
- IXa, with the help of VIIIa, cleaves X → Xa (common path starter)
-
common pathway
- Xa, with the help of Va, cleaves II (prothrombin) → IIa (thrombin), which
- cleaves Ia (fibrinogen) to I (fibrin), which forms “stable” (irreversible) clot
- Xa, with the help of Va, cleaves II (prothrombin) → IIa (thrombin), which
outline the intrinsic pathway
part of secondary hemostasis
- XIIa cleaves XI → XIa
- XIa cleaves IX → IXa
- IXa, with the help of VIIIa, cleaves X → Xa (common path starter)
outline the extrinsic pathway
-
extrinsic pathway - initiated by tissue factor (TF)
- TF cleaves VII → VIIa
- VIIa cleaves IX → IXa
- IXa cleaves X → Xa (common pathway starter)
summarize the key roles of thrombin
pro-coagulation effects (at injury site):
- primary hemostasis: produce PAR → activates platelets
- secondary hemostasis:
- fibrinogen → fibrin, making insoluble/stable clot
- V, VII, XI & XIII activation (take 5 at 7-11 on friday the `3th)
anticoagulant effects (beyond injury site):
- upon contacting normal endothelium, thrombin becomes prevent clotting from extending byeond injury site
what clotting factors does thrombin activate?
- Ia (fibrin), and
- Va, VIIa, XIa, XIIIa (take 5 at 7-II)
PAR
- is produced by?
- does what?
- release is mediated by thombin
- activates platelets in the activation phase of _primary hemostasi_s so that they can then aggregate
what clotting factors does thrombin activate?
- Ia (fibrin), and
- Va, VIIa, XIa, XIIIa (take 5 at 7-II on Friday the 13th)
summarize the counter-regulatory mechanisms are in place to limit the hemostatic process
- induction of fibrinolysis by (t-PA)
- factor dilution of blood flow past injury
-
restriction of clotting to injury site:
- requirement of - charged phospholipids on platelets for factor activation
-
platelet inhibitors: they release
- PGI2
- NO
- adenosine diphosphatase (degrades ATP)
-
anti-coagulant affects:
- thrombomodulin & protein C: when thrombin binds healthy tissue
- anti-thrombin: bound by heparin & heparin like molecules
- tissue factor pathway inhibitor (TFPI)
outline fibrinolysis. what factors regulate fibrinolysis?
- activated largely by tissue plasminogen activator (t-PA), which
- converts plasminogen → plasmin, which:
- breaks down fibrin & fibrinogen
- is inhibited by a1-antiplasmin inhibitor
- converts plasminogen → plasmin, which:
what is the role of plasmin in the coagulation?
serves as an counter-regulatory mechanism that limits the hemostatic process (anti-coagulant)
- breaks down fibrin / fibrinogen
- activated by tPA
- inhibited by a2-antiplasmin inhibitor
what is the role of a2-antiplasmin inhibitor in coagulation?
inhibits free plasmin to limit excessive fibrinolysis
what pro-coagulant and anti-coagulant factors do platelets release?
- pro-coagulant (activation phase of primary hematopoiesis)
- ADP
- TXA-2
- anti-coagulant:
- PGI2
- NO
- adenosine diphosphatase
discuss the role of thrombomodulin the coagulation?
counter regulatory mechanism (anti-coagulant)
-
thrombomuodlin + protein C is found on healthy endothelium
- thrombin binds complex &
- cleaves protein C into → into active protein C, which
- binds protein S
- deactivates factors V & VII
- cleaves protein C into → into active protein C, which
- thrombin binds complex &
what is the role of antithrombin in coagulation?
counter regulatory mechanism (anti-coagulant)
- is activated by
- heparin (medication), or
- heparin like agents (endogenous)
- binds & inactivates several clotting factors, importantly, thrombin
what is the role of TFPI in coagulation?
- counter regulatory mechanism (anti-coagulant)
- inhibits factor (VIIa)-tissue factor (beginning of intrinsic pathway)
what is the major differencing in clotting in the lab (in-vitro) vs in vivo (in the body)
the intrinsic pathway (initiated by autoactivating XIIa or lab ingredients) is not as important in-vivo. tissue factor most important for in-vivo.
to run hemostasis tests, what proper set up must occur?
- blood needs to be in blue tubes: 2.3% citrate, and must have a ratio of:
- 9:1 whole blood: anti-coagulant
what factors does warfarin inhibit?
- VII (initiates common pathway)
- IX (initiates common pathway)
- X (starts common pathway)
- II (thrombin)
(the factors that require vitamin K)
pro-thrombin time (PT)
- requires what ingredients?
- screens for what factors?
- is particularly useful clinically for…?
- requires: thromboplastin (phospholipid + TF), Ca++
- assesses extrinsic + common pathways: i.e, factors:
- VIIa (extrinsic)
- Xa, Va, IIa, Ia (common)
- esp clinically useful to:
- monitoring warfarin
- screening for Vitamin K
prolonged PT can be caused by?
-
deficiency/inhibition of:
- extinsic path factors (VII)
- common path factors (X, V, II, I))
- warfarin - inhibits extrinsic & common
- heparin - though less usefull than APTT/TT
- FDP/D-dimer
deficiency / inhibition of what factors will NOT significantly prolong the PT?
- intrinsic path factors:
- XII
- XI
- IX
- VIII
- HMWK
- pre-kallikrein
what is the purpose of INR? how is INR calculated?
- use to standardize warfarin therapy.
- INF = patient’s PT / mean reference interval
APTT (activated partial thromboplastin time)
- requires what ingredients?
- screens for what factors?
- is particularly useful clinically for…?
- requires: an activator + partial thromboplastin (phospholipid) + Ca++
- assesses intrinsic + common pathways: i.e, factors:
- XII, XI, IX, VIII (intrinsic)
- X, V, II, I (common)
- is esp useful for:
- monitoring heparin therapy
- pre-kalkreinin & HMWK
- lupus anticoagulant
- direct thrombin inhibitors
what can cause prolonged APTT?
-
deficiency/inhibition of:
- intrinsic path factors (XII, XI, IX, VIII)
- common path factors (X, V, II, I))
- heparin - most common cause
- lupus anti-coagulant
- thrombin inhibitors
- improper storage
- FDP/D-dimer (like PT)
what is APTT not affected by?
- extrinsic pathway factors: i.e., factor VII only!!
when getting getting an PT or an APTT, what could cause a shortened time (rather than a normal or a prolonged time)
-
a traumatic blood draw while obtaining sample that activates the coagulation cascade of blood being tested
- if no evidence of traumatic blood draw: person might have an increased thrombosis risk
thrombin time (TT)
- requires what ingredients?
- screens for what factors?
- is particularly useful clinically for…?
- requires: no ingredients
- assesses: thrombin - measures time it takes to convert fibrinogen → to fibrin
- clinical uses:
- heparin detection: most sensitive test!! too sensitive to used to monitor therapy
-
to dx decreased fibrin: esp good to dx
- afibrinogenemia
- hypofibrinogenemia
- dysfibrinogenemia
what can cause a prolonged TT
- thrombin inhibition:
- heparin: activates antithrombin, which inhibits thrombin (IIa) & many other factors
- direct thrombin inhibitors
- FDPs
- decreased fibrinogen synthesis:
- afibrinogenemia
- hypofibrinogenemia
- dysfibrinogenemia
what are FDPs?
- how are they formed?
- in what situations are they elevated?
- what role do they play in coagulation?
- how do they effect the hemostasis tests?
fibrin degradation products
- formed from degradation of fibrin by plasmin (activated by tPA)
- are elevated in:
- hyper-clotting states (lots of clots broken down)
- DIC
- thrombosis
- decreased clearance by liver:
- cirrhosis
- some mucous secreting adenocarcinomas
- hyper-clotting states (lots of clots broken down)
- compete with thrombin to convert fibrinogen to fibrin & are prolong the:
- PT
- aPPT
- TT
what is d-dimer? what is its clinical significance?
- is a type of FDP - tends to break down cross-linked fibrin
- like all FDPs
- elevated in
- DIC, thrombosis (inc clot breakdown)
- cirrhosis (dec clearance)
- mucin secreting adeocarcinomas
- prolongs PT, aPTT, TT
- elevated in
mixing studies
- what is their role?
- how are they conducted?
- how are they interpreted?
- distinguishes a factor deficiency from factor inhibition (in either PT or aPPT)
- pt plasma mixed with donor plasma at 1:1 ratio
- interpretation:
- correction of time = deficiency
- no correction of time = inhibition
which clotting factor is seen in highest concentration in the plasma?
fibrinogen
what is the most commonly inherited bleeding disorder?
von willibrand disease
von-willebrand disease
- definition
- pathogenesis
- presentation
- common
