MOD: Hemostatis I and II Flashcards
Platelet components
Alpha granules (protein storage eg thromboglobulin etc) and Dense granules (ATP, serotonin, calcium etc), and PF3 (platelet factor 3 surface marker) hidden in inner memb that becomes exposed when platelet activated
What are two platelet receptors
GP1B: VWF receptor (von willebrand factor), adhesion
GP2B: (mostly fibrinogen receptor), step 2 aggregation
What prevents blood from clotting in vessels?
House collagen in endoth, so when broken can come out, neg charge of both endoth and plasma prots keeps them away from ea other, thrombomodulin etc
Clotting mech:
primary hemostasis platelet adhesion
Endoth cell dmg rel collagen which binds to VWF, which concentrates platelets in dmg region
What events happen in primary hemostasis?
Platelets, adhesion & aggregation
Platelet structure
discoid if inactiv, purple on smear, pseudopodia if active
How does platelet adhesion of damaged endoth occur
subendoth collagen exposed, binds vWF, platelets also bind VWF via GP1b, platelets activated and secr granules, serotonin and ADP cause vasoconstr to slow flow,
-GP2b changes shape and binds fibrinogen, causing platelets to aggregate, forming plug
What catabolizeds von willebrand multimers?
ADAMTS13 (missing in TPP)
Von Willebrand Factor?
Multimer prot in megakaryoctyes and endoth cells, and stored in endoth cell Weibal-Palade bodies (which also hold P selectin)
- its also the primary transport protein for factor VIII in the serum (so VWF allows factor 8 to circul8)
- binds GP1b on one side and subendoth collagen on the other
What does <150k platelets mean?
>450k?
Thrombocytopoenia <150k
Thrombocytosis >450k
What are the labs to test platelets?
CBC bn 150k-450k, MPV
Periph blood smear
Bleeding time, replaced by:
Platelet fxn analyzer-100 (PFA-100), cartridge in collagen coated with ADP or epi, measure time it takes for platelets to occlude cartridge, req VWF
Sx of platelet issues?
longer clotting time on test,
mucosal bleeding, purpura, post-ob bleeding
Immune Thromobocytopenic purpura aka ITP
Autoimmune clearance of platelets via autoantibodies to them
drugs that can cause clotting issues
Aspirin COX inhibition decr TXA and inhibs platelets,
Plavix inhibs ADP receptor
Bernard-Soulier Syndrome
lack gp1b VWF receptor on plaletets, probs with adhesion so incr bleeding time on PFA-100 etc
- v v large platelets!
- usu young pt with bleeding disorder and assoc anemia
Glanzman Thrombesthenia
Def in GP2 fibrinogen receptor so plalets cant aggregte/bind
Gray Platelet syndrome
alpha storage granule deficiency, look gray, incr bleeding time, purpura and some bleeding
Von Willebrand Disease sx
-usual platelet disorder sx
Acquuired platelet issues
CPB cardiopulm bypass, myeloma ab’s on platelts, MPN incr platelet count , etc etc
Inherited VWD genetics?
Types?
all types AD except type 3 is AR
type 1 decr conc of normal VWF, most common
type 2 normal conc but abnormal VWF
type 3 complete VWF absence so low factor 8 (hemophilia A phenotype)
autoimm issues can also remove VW factor
Abnormal Ristocetin cofactor test means?
VWD!!!
Can also use VWF multimer test, large are more hemostatic
When would you not evaluate VWF?
stren exercise/stress
2nd3rd trim of pregnancy
VWD Tx
- best for type 1; desmopressin (stim VWF release into bloodstream), dont give for type2b bc causes thrombocytopenia (already have normal quantity)
- for other types: factor 8 first
What is TPP (Thrombotic Thrombocytic Purpura)
Loss of ADAM gene causes failture to make large multimers of VWF into smaller, causes too muc platelet activation and thrombosis
- causes the pentad: fever, thrombocytopen, microangiopathic hemolytic anem w schistiocytes, mental status changes, renal failure
- PRIMARY aggregation problem (secondary hemostasis coag is normal)
- fatal if untreated, so give plasma to replace ADAM
How to distinguish TTP from DIC?
In DIC, PTT etc tests will be abnormal, but will be NORMAL IN TTP!
HUS (Hemolytic Uremic Syndrome)
pediatric disease similar to TTP, but with renal failure instead of mental status change, caused by Shiga toxin in E coli O157:h7, no VWF involved, plasma exchange wont work (supportive tx only)
Antiphospholipid Syndrome (Lupus anticoagulant) HIT (Heparin Induced thrombocytopenia)
Anti-phospholipid syndrome: ab’s to platelet phospholipids, causes platelet activation thus thrombosis
- elevated aPTT (but this disorder isnt a bleeding disorder), dx with russel venom viper test (dRVVT)
- HIT: ab to PlateletFactor 4 (PF4) and heparin causes platelet activation thus thrombosis
What IS desmopressin
exogenous vasopressin to stim rel of preformed VWF in endoth/megakaryocytes to boost conc in periphery
How do you distinguished acquired VWD (assoc with some other diseases) vs inherited?
In inherited, pts have family history of bleeding (so fam history, duh), wont have easy bruising but may have DVT
If you see the PENTAD of fever
thrombocytopenia, microangiopathic hemolytic anemia (schistocytes), mental status changes,
renal failure, what might this suggest?
TTP!!!
What does secondary hemostasis form?
fibrin clot
cascade involves intrinsic and extrinsic paths converrging to common (prothrombin (II) and fibrinogen (I)
where are the non-VWF other clotting factors made?
liver!
what ARE the clotting factors?
serine proteases
what happens in hemo 2 cascade
endoth dmg exposes Tissue factor (TF), which complexes with VII (7) which turns into VIIa, starts off secondary hemostasis in vivo, turns IX to IXa (crossover path where extrinsic crosses over to activate intrinsic path), IXa combines with VIII to convert X to Xa
But in vitro, 7a converts 10 to 10a, complexes to 5 to convert 2 to 2a, which then converts fibrinogen to fibrin
what does fibrin do w platelets
what vitamin do u need
stabilizes platelet plug
-need presence of vitamin K to carboxylate (add negative charge) to some of the factors)
What does thrombin do?
converts fibrinogen to fibrin, activates 5 and 8, converts 11 to 11a, converts 13 to 13a to make more stable fibrin clot (starts tertiary hemostasis)
TFPI (tissue factor pathway inhibitor)
rel by damaged tissue and shuts off extrinsic path, so need factor 11a to keep activating factor 9 (since extrinsic pathway wont do it), so we need thrombin which converts 11 to 11a
What does tertiary hemostasis start with
formation of cross linked fibrin, factor 13a forms to stabilize clot (looks like net)
What does tPA (tissue plasminogen activator) do?
What is it inhibited by?
recruits plasminogen into plasmin at site of clot (lyses fibrin into fibrin split products, such as D-DIMER!!!)
-Inhib by Plasminogen activator inhibitor (PAI) and alpha-2 antiplasmin, which inhibs breakdown of fibrin
What are some natural anticoagulants
protein c-activated by binding to thrombomodulin, then activated protein binds to protein S, which activates 8a and 5a
What does antithrombin do?
inhibits serine proteases, esp 2a thrombin and 10a
What are 5 basic tests of clotting factors?
PT PTT TT Fibrinogen test Mixing studies
PT
Prothrombin time!
functional test of extrinsic and common paths so all must be present to have normal PT, if prolonged could be liver disease, malabs of vit k (or warfarin, a vit k antagonist), could be fibrin/fibrinogen degrad prods
-INR calculated from PT to montior warfarin
PTT
Partial thromboplastin time!
fxnl test of intrinsic and common path
heparin etc etc
Diffs in PT vs PTT
diff activators
PT uses TF, PTT uses clay coating
TT
Thrombin time!
fxnl test of fibrin generation
add exoenous thrombin and Ca to plasma and measure conversion of fibrinogen to fibrin (increased in fibrinogen disorders, which can also be in liver dis)
Fibrinogen test
fxnl assay that adds LARGE amoutn of thrombin and measures conversion of fibrinogen to fibrin, low if low conc of dysfuxn of fibrinogen
-can use mass assay like ELISA immunoassay
When are Mixing studies used?
procedure?
When theres a prolonged PT/PTT to determine if its due to deficiency of a factor or inhibition of a factor
-mix pt plasma with normal plasma: factor deficiency would show >50% activity, if inhibitor of factor then will show clotting time that doesnt correct, must mean an ab (or drug like heparin) is present
What are disorders of secondary hemostasis?
A type of hemorrhagic disroder, show hemarthrosis (bleeding into joints), echymoses (large bruises), delayed post-op or trauma bleeds, examples are Hemophila A and B
Hemophilia A
Missing factor, genetics, test results, and tx?
FACTOR 8 DEFICIENCY!
X linked recessive, severe for most
INCREASED PTT!
Tx by replacing missing factor!
Hemophilia B
Deficient factor, genetics, test results?
deficiency in factor 9
same genetics and clinical stuff as HEMOPHILIA A
DIC (disseminated intravascular coagulation) histo
Schistiocytes (fragments) and thrombocytopenia (v few platelets in smear), microangiopathic hemolytic anemia on smear (unlike TTP)
DIC sx and tests?
excessive clotting AND fibrinolysis, bleeding and/or thrombosis
increases on ALL THREE TESTS! PT/PTT/TT
decreased fibrinogen
increased FSP like D-DIMERS
DIC assocs?
assoc with blood cancers like APL, sepsis etc etc etc
Other thrombotic disorders
Antithrombin deficiency
APCR (acctivatd protein c resistance) usu due to factor 5 Leiden mutation
Protein C def (need to inactiv8 factor 5 and 8)
Protein S def (cofactor for protein C)
Hyperhomocystinemia (mutation in MTFH receptor)
