2013-10-28 Intro to Coagulation Flashcards
fibrinogen
—where made?
—fxn?
—stored?
made in liver
circulates in plasma
fxn is to aggregate platelets to one another by cross-linking GpIIb/IIIa
vWF
- made where?
- synth?
- fxn?
- MADE: most from endothelium (multimers stored in Weibel-Palade bodies) megakaryoccytes (multimers stored in alpha granules);
- SYNTH: multimers —-ADAMSTS13—-> monomers
- FXNS: [1] tether platelets to basement membrane, [2] chaperone Factor VIII
normal endothelial coags
PGI2 (prostacyclin), NO, Heparins
Bernard-Soulier Dz
lack Gp1b
platelets can’t find to basement membrane
-big platelets (B.ig S.uckers) but thrombocytopenia
Glanzmann’s Dz
GpIIb/IIIa deficieny —> no platelet aggregation
—similar to action of abciximab
Steps of 1° Hemostasis
- vasoconstriction (neurogenic + endothilin)
- platelet adhesion (BM–vWF–Gp1b–Plt)
- platelet activation/degranulation
—ADP-causes expression on GpIIb/IIIa
—TXA2-calls other platelets
—Other agonists: 5-HT, thrombin, epi, collagen - platelet adhesion
—PLT—GpIIb/IIIa-< fibrinogen>-GpIIb/IIIa—PLT - Support of coag with PF3 (platelet factor 3): phosphatidyl serine (PS) & phosphatidyl ethanolamine (PE)
Scott’s Dz
missing PF3 (platelet factor 3) = phosphatidyl serine + p. ethanolamine
Secondary Hemostasis
- -main point
- -where does it occur?
- -where are factors made?
POINT: ∆ cross-linking fibrinogen into FIBRIN using enzyme THROMBIN which comes from prothrombin
OCCURS: within the membrane of the platelet
–all the factors are made in the liver, except VIII (platelets)
Extrinsic pathway….GO!!!!
HERE WE GO
1. TF is released by damaged tissue
2. VII—-TF—->VIIa
3. FT-VIIa forms “extrinsic tenase” by activating:
—X to Xa directly
—IX to IXa which forms extrinsic tenase (IXa-VIIa-TF)
4. X—-IXa-VIIa-TF-Ca++—->Xa
5. prothrombin (II)—-Xa-Ca++—->thrombin (IIa) s…l…o…w…l…y
Intrinsic pathway….GO!
- The small amts of thrombin made thru extrinsic path activating XII* and XI
—*XII (Haegman factor) not necess. in vivo, but it:
——activates HMW kininogen —> binds PK + XI
——activates PK—>kallikrein
——activates XI—>XIa - XIa causes THROMBIN BURST
- This makes lots of IX—>IXa
- X—->INTRINSIC TENASE: IXa + VIIIa (from platelets)—->Xa
- II—->Xa + Va—->IIa
- I—->IIa—->Ia (fibrin!!)
Which steps need Ca2+?
intrinsic tenase (VIIa-TF + IXa) extrinsic tenase (VIIIa + IXa) prothrombinase (Xa + Va)
Which factors require Vitamin K?
II, VII, IX, X
-proteins C&S
Besides activating fibrinogen—>fibrin, what else does thrombin do?
—amps up its own prod via V, VIII, IX
—activates VIII which stabilizes thrombin
—agonist of plts
—stimulates PAI-1 to inhibit fibrinolysis
—also INHIBITS coag: binds thrombomodulin to activate Prot C & S
How is clotting controlled?
- blood flow removes factors
- reticuloendothelial system (esp liver) removes activated factors
- thrombin’s anth-thrombotic effects
- anti-thromb proteins of endothel: Prots C&S, antithrombin, TFPI
antithrombin
- made by liver and endothlium
- inhibits: thrombin, Xa and XIa
- potentiated by HEPARIN 1-4k fold!
activated proteins C&S
- circulate in inactive form
- need vitamin K
TFPI (tissue factor pathway inhibitor)
binds and inactivates Xa
How does fibrinolysis go down?
Plasminogen—->tPA/uPA*—->plasmin**
*inhib by PAI1 (plasminogen activator inhibitor) **alpha2-antiplasmin
fibrin—->plasmin—->D-dimers, etc.
quantitative platelet tests
qualitative platelet tests
QUANT: CBC, smear
QUAL: PFA-100, bleeding time, plt aggr studies, also smear
Lab tests for 2° hemostasis/fibrin formation
- PT/INR
- aPTT (activated partial thromboplastin time)
- mixing studies
- individual factor assays
- thrombin time
- fibrinogen
- D-dimers
What does thromboplastin (as in aPTT) mean?
*thromboplastin = TF + phospholipid
aPTT
activated partial thromboplastin time —INTRINSIC path (T-T couple still together mnemonic) —measure in vitro things: XII, PK, HK —VIII, IX, XI —common path, too: X, V, II*, I** *II = prothrombin *I = fibrinogen
PT/INR
Prothrombin Time
—EXTRINSIC (T-T couple broke up/”ex” mnemonic)
—measures VII + common path (X, V, II, I)
—nl INR = 1
—tests warfarin but not heparin b/c it is degraded
What top tube should you use when drawing blood for coag panel?
light blue top!
—contains citrate which binds Ca2+
—Ca2+ added back in the lab
Top to use with CBC + additive
purple
—has EDTA as anti-coag which preserves cell morphology
serum vs. plasma
serum = fluid left after clot is formed (i.e. does not have coag factors) plasma = fluid part of blood pre-clot
Pseudo-thrombocytopenia
some folks’ platelets clump when exposed to EDTA
—verify thrombocytopenia reading w/ smear to look for clumps
ITP
- cateogry
- presentation
- labs
- tx
QUANT THROMBOYTOPENIA: Immune thrombocytic purpura
—most common cause of thrombocytopenia in kids & adults
—ACUTE: kids, ~wks s/p viral infx or vaccin; self-limited w/in wks
—CHRONIC: adults, usu women of child-bearing age; 1° or 2° (e.g. due to SLE. [may cause short-lived thrombocytopenia in infants b/c IgG cross the placenta]
—Common in HIV
—anti-platelet abs made in spleen—>plts eaten in spleen
—labs: plts roids; adults: IVIG, splenectomy
TTP
- category
- cause
- s/sx
- labs
QUANT THROMBOYTOPENIA: Thrombotic Thrombocytopenic Purpura
—decr ADAMSTS13: vWF multimers pile up —> abnl plt adhesion
—s/sx: pentad:1)MAHA, 2)thrombocytopenia, 3) fever, 4) neuro ∆s, 5) renal failure [neuro > renal vs HUS]
—labs: thrombocytopenia, incr bleeding time, anemia w/ schistocytes shorn off by that platelet plug), incr megakaryocytes **nl PT/aPTT
TCT
—what?
-how
—explanation for prolonged TCT?
Thrombin clotting time —detect fibrinogen deficiency or abnl —add bovine thrombin to pt plasma, measure clotting time in sec —hypofibrinogenemia —dysfibrogenemia —heparin, thrombin inhibs
presentation of quantitative platelet d/o
—general causes
not clinically serious until <20k
—bruising, petichiae, mucosal bleeding (nose, gums, GI)
—menorrhagia
—destruction, consumption, sequestration, decr prod
destructive thrombocytopenia b/c of meds
QUANT THROMBOYTOPENIA: med-induced
quinine: low plts and bleeding
abx
heparin **rarely causes a hypercoaguable state in some pts
HELLP
- category?
- stands for
QUANT THROMBOYTOPENIA: HELLP Syndrome
- Hemolysis, Elevated Liver enzymes, Low Platelets
- similar to TTP
thrombocytopenia 2° to splenomegaly
- category
- common causes of splenomegaly
SEQUESTRATION
-nl holds 30% of circ plts at any given time
-enlarged can hold >90%!
Causes: portal HTN (cirrhosis, portal or hepatic vein thrombosis), myeloproliferative d/o
