2013-10-28 Intro to Coagulation

Question 0

fibrinogen
—where made?
—fxn?
—stored?

Answer 0

made in liver
circulates in plasma
fxn is to aggregate platelets to one another by cross-linking GpIIb/IIIa

Question 1

vWF

• made where?
• synth?
• fxn?

Answer 1

• 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

Question 2

normal endothelial coags

Answer 2

PGI2 (prostacyclin), NO, Heparins

Question 3

Bernard-Soulier Dz

Answer 3

lack Gp1b
platelets can’t find to basement membrane
-big platelets (B.ig S.uckers) but thrombocytopenia

Question 4

Glanzmann’s Dz

Answer 4

GpIIb/IIIa deficieny —> no platelet aggregation

—similar to action of abciximab

Question 5

Steps of 1° Hemostasis

Answer 5

1. vasoconstriction (neurogenic + endothilin)
2. platelet adhesion (BM–vWF–Gp1b–Plt)
3. platelet activation/degranulation
   —ADP-causes expression on GpIIb/IIIa
   —TXA2-calls other platelets
   —Other agonists: 5-HT, thrombin, epi, collagen
4. platelet adhesion
   —PLT—GpIIb/IIIa-< fibrinogen>-GpIIb/IIIa—PLT
5. Support of coag with PF3 (platelet factor 3): phosphatidyl serine (PS) & phosphatidyl ethanolamine (PE)

Question 6

Scott’s Dz

Answer 6

missing PF3 (platelet factor 3) = phosphatidyl serine + p. ethanolamine

Question 7

Secondary Hemostasis

• -main point
• -where does it occur?
• -where are factors made?

Answer 7

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)

Question 8

Extrinsic pathway….GO!!!!

Answer 8

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

Question 9

Intrinsic pathway….GO!

Answer 9

1. 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
2. XIa causes THROMBIN BURST
3. This makes lots of IX—>IXa
4. X—->INTRINSIC TENASE: IXa + VIIIa (from platelets)—->Xa
5. II—->Xa + Va—->IIa
6. I—->IIa—->Ia (fibrin!!)

Question 10

Which steps need Ca2+?

Answer 10

intrinsic tenase (VIIa-TF + IXa)
extrinsic tenase (VIIIa + IXa)
prothrombinase (Xa + Va)

Question 11

Which factors require Vitamin K?

Answer 11

II, VII, IX, X

-proteins C&S

Question 12

Besides activating fibrinogen—>fibrin, what else does thrombin do?

Answer 12

—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

Question 13

How is clotting controlled?

Answer 13

1. blood flow removes factors
2. reticuloendothelial system (esp liver) removes activated factors
3. thrombin’s anth-thrombotic effects
4. anti-thromb proteins of endothel: Prots C&S, antithrombin, TFPI

Question 14

antithrombin

Answer 14

• made by liver and endothlium
• inhibits: thrombin, Xa and XIa
• potentiated by HEPARIN 1-4k fold!

Question 15

activated proteins C&S

Answer 15

• circulate in inactive form

- need vitamin K

Question 16

TFPI (tissue factor pathway inhibitor)

Answer 16

binds and inactivates Xa

Question 17

How does fibrinolysis go down?

Answer 17

Plasminogen—->tPA/uPA*—->plasmin**
*inhib by PAI1 (plasminogen activator inhibitor) **alpha2-antiplasmin
fibrin—->plasmin—->D-dimers, etc.

Question 18

quantitative platelet tests

qualitative platelet tests

Answer 18

QUANT: CBC, smear
QUAL: PFA-100, bleeding time, plt aggr studies, also smear

Question 19

Lab tests for 2° hemostasis/fibrin formation

Answer 19

• PT/INR
• aPTT (activated partial thromboplastin time)
• mixing studies
• individual factor assays
• thrombin time
• fibrinogen
• D-dimers

Question 20

What does thromboplastin (as in aPTT) mean?

Answer 20

*thromboplastin = TF + phospholipid

Question 21

aPTT

Answer 21

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

Question 22

PT/INR

Answer 22

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

Question 23

What top tube should you use when drawing blood for coag panel?

Answer 23

light blue top!
—contains citrate which binds Ca2+
—Ca2+ added back in the lab

Question 24

Top to use with CBC + additive

Answer 24

purple | —has EDTA as anti-coag which preserves cell morphology

Question 25

serum vs. plasma

Answer 25

``` serum = fluid left after clot is formed (i.e. does not have coag factors) plasma = fluid part of blood pre-clot ```

Question 26

Pseudo-thrombocytopenia

Answer 26

some folks' platelets clump when exposed to EDTA | —verify thrombocytopenia reading w/ smear to look for clumps

Question 27

ITP - cateogry - presentation - labs - tx

Answer 27

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

Question 28

TTP - category - cause - s/sx - labs

Answer 28

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

Question 29

TCT —what? -how —explanation for prolonged TCT?

Answer 29

``` Thrombin clotting time —detect fibrinogen deficiency or abnl —add bovine thrombin to pt plasma, measure clotting time in sec —hypofibrinogenemia —dysfibrogenemia —heparin, thrombin inhibs ```

Question 30

presentation of quantitative platelet d/o | —general causes

Answer 30

not clinically serious until <20k —bruising, petichiae, mucosal bleeding (nose, gums, GI) —menorrhagia —destruction, consumption, sequestration, decr prod

Question 31

destructive thrombocytopenia b/c of meds

Answer 31

QUANT THROMBOYTOPENIA: med-induced quinine: low plts and bleeding abx heparin **rarely causes a hypercoaguable state in some pts

Question 33

HELLP - category? - stands for

Answer 33

QUANT THROMBOYTOPENIA: HELLP Syndrome - Hemolysis, Elevated Liver enzymes, Low Platelets - similar to TTP

Question 34

thrombocytopenia 2° to splenomegaly - category - common causes of splenomegaly

Answer 34

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