Transcript Coagulation

Coagulation
and
Hemostasis
• Hemostatic process
• Coagulation cascade
• Fibrinolysis
• Laboratory studies
• Medications
• Coagulation disorders
Hemostasis
Purpose

Ensure that coagulation mechanisms are
 activated when there is injury
 not unnecessarily activated

Restore tissue blood flow after repair of
injury (fibrinolysis)
Hemostatic Process
3 main steps

Primary hemostasis: local vasoconstriction &
platelet plug formation

Coagulation cascade

Fibrinolysis
Hemostatic Process
Platelet Plug Formation
• vascular injury
• release and binding of vWF to exposed
blood vessel collagen
• glycoprotein IB on platelet surface
membrane binds to vWF
• TxA2 → vasoconstriction & platelet adhesion
• platelet factor 3 (PF3) phospholipid layer
(procoagulant)
Platelet Activation & Aggregation
exposed endothelial surface
platelets exposed to collagen
“activated”
release contents of cytoplasmic granules
adenosine diphosphate (ADP)
accelerates platelet
aggregation/activation
thromboxane (Tx A2)
vasoconstriction
↑ ADP release from platelets
Hemostatic Process
Coagulation Cascade

to stabilize and reinforce the weak platelet plug

fibrinogen → fibrin

3 main steps:
1. formation of prothrombin activator
2. conversion of prothrombin into thrombin
3. conversion of fibrinogen to fibrin
Coagulation Cascade
TF =tissue factor
PK = prekallikrein
HK=high molecular
kininogen
a = activated
Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.
Coagulation Mechanism

activation of clotting factors

requires a phospholipid surface
 tissue factor (TF) extrinsic to the blood
 activated platelet (platelet factor 3 phospholipid)
intrinsic to blood

vitamin-K dependent factors (II, VII, IX, X)

formation of reaction complex
 labile factors : factors V and VIII
Factor VIII

extrahepatic origin

2 components (separate genetic control)
1. VIII R : Ag
VIII antigen + vWF
2. VIII : C
coagulant activity
*absence → hemophilia A

von Willebrand factor (vWF)
• mediates adhesion of platelets to surface collagen
• carrier of VIII:C
• vWD: appears to have defect in primary hemostasis
& hemophilia A
Factor VIII
F VIII:C
F VIII:vwF
hemophilia A
decrease
--------
vWD type 1
decrease
decrease
vWD type 2
normal
decrease
Coagulation Cascade
TF =tissue factor
PK = prekallikrein
HK=high molecular
kininogen
a = activated
Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.
Newer Concepts of Coagulation Reactions
2 main functions of tissue factor (TF)
1) to activate factor X to Xa
2) to activate factor IX to IXa
Control Mechanisms
1) TF pathway inhibitor
2) Protein C system
3) Antithrombin (e.g. AT III)
4) Glycoaminoglycans
APC: activated protein C
AT : antithrombin
GAG: glycoaminoglycans
T : thrombin
PC : protein C
S : protein S
TF : tissue factor
TM : thrombomodulin
Antithrombin III (AT III)

naturally-occuring anticoagulant

binds to factors IXa, Xa, XIa, XIIa (slow)

accelerated by heparin manyfold
Implication:
Heparin has almost NO anticoagulant
action without AT III
Coagulation Factors
FACTORS
PLASMA t ½
(hrs)
Fibrinogen (I)
72-120
Prothrombin (II)
60-70
V
12-16
VII
3-6
VIII
8-12
FACTORS
PLASMA t ½
(hrs)
XI
52
XII
60
Protein C
6
Protein S (total)
42
Tissue factor
--
IX
18-24
Thrombomodulin
--
X
30-40
antithrombin
72
Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.
Fibrinolysis

Plasminogen → plasmin

Release of tPA by the endothelium

Lysis of clot→ FDPs or FSPs

Reopening of blood vessel
Laboratory Monitoring
Prothrombin Time (PT)

test of extrinsic pathway activity

measures vitamin K - dependent factors activity
(factors II, VII, IX, X)

thromboplastin + Ca+2 to plasma = clotting time

normal values: 12-14 seconds

International Normalized Ratio (INR)
▪ standardizes PT reporting
 normal values: 0.8 -1.2 seconds
Laboratory Monitoring
Prothrombin Time (PT)

monitors coumadin therapy

most sensitive to alteration in F VII levels

prolonged: 55 % ↓ of normal F VII activity

antithrombotic activity: reduction of factor II
and factor X activity (after several days)
Laboratory Monitoring
Activated Partial Prothrombin Time (aPTT)

test for intrinsic and common pathways

dependent on activity of all coagulation factors,
except VII and XIII

normal values: 25 -35 seconds

monitors heparin tx & screen for hemophilia
Laboratory Monitoring
Activated Prothrombin Time (aPTT)

prolonged: heparin, thrombin inhibitors,
fibrin degradation products (FDP)

citrated plasma + surface activators +
phospholipid

prolonged only if coagulation factors reduced
to < 30 % of normal
Laboratory Monitoring
Activated Clotting Time (ACT)

monitors heparin anticoagulation in the OR
(cardiac and vascular surgeries)

normal values: 90 - 120 seconds
Laboratory Monitoring
Thrombin Clotting Time (TCT)

reflects abnormalities in fibrinogen → fibrin

plasma + excessive amount of thrombin

prolonged: heparin, thrombin inhibitors,
low fibrinogen, dysfibrinogenemia

monitors hirudin, bivalirudin, LMWH tx
 INR & PT may be normal or ↑
 TCT prolonged with adequate therapeutic levels
Laboratory Monitoring
Thromboelastography (TEG)

continuous profiles during all phases of
clot formation

provides more accurate picture of in vivo
coagulation process

to evaluate:
• hypo / hypercoagulable state
• hemophilia
• dilutional coagulopathy
• rare coagulation disorders anticoagulation tx
• coagulation problems with liver transplantation
Thromboelastogram
(TEG)
Bleeding time

monitors platelet function

not specific indicator of platelet function

not very reliable

very operator - dependent

variable from each institution
Bleeding time

other factors: degree of venostasis, depth
and direction of incision

no evidence as
• a predictor of risk of hemorrhage
• useful indicator of efficacy of antiplatelet therapy

insensitive to mild platelet defects
Laboratory Monitoring
Platelet Function Analyzer (PFA) - 100

relatively new global test of platelet adhesion
and aggregation

advantages
 noninvasive, simple, easy to perform
 very sensitive in detecting platelet defects
associated with vWD
 sensitive to dx of acquired platelet defects (ASA,
NSAID, dietary factors: excessive cocoa intake)

monitors pro-hemostatic treatment
 DDAVP & platelet transfusions
Laboratory Monitoring
PFA-100
Limitations
■ inflexibility
■ results should be interpreted in the context of
either a simultaneously or recently drawn full
blood count
■ platelet count < 80,000 or Hct < 30% will
prolonged CT even if no platelet abnormal
LABORATORY TEST
Bleeding time
COMPONENTS MEASURED
platelet function
NORMAL
VALUES
3 - 10 mins
vascular integrity
PT
I, II, V, VII, IX, X
12 - 14 secs
PTT
I, II, V, VIII, IX, X, XI, XII
24 - 35 secs
Thrombin time
I, II
12 - 20 secs
Implications for Therapy

Congenital & acquired factor deficiencies
 history
 medications
 congenital factors: vWD, hemophilia, platelet disorders
 acquired disorders: multifactor-renal, hepatic, DIC

Antiplatelet medications

Anticoagulants
Drugs affecting Coagulation
HEMOSTATIC
PROCESS
AFFECTED
CLASS OF
DRUGS
SPECIFIC
DRUGS
1º platelet plug
formation inhibition
antiplatelet drugs
reversible: NSAID
irreversible: ASA
coagulation cascade
IV anticoagulants
standard and LMW
heparins
warfarin
oral anticoagulants
fibrinolysis
fibrinolytic agents
Streptokinase
Urokinase
t-PA
Prostaglandin Synthesis
arachidonic acid
cyclooxygenase
prostaglandin G2
prostaglandin H2
prostacyclin
synthetase
peroxidase
thromboxane
synthetase
prostacyclin
thromboxane A2
PG F1a
thromboxane B2
Mechanism of Action
ASPIRIN
arachidonic acid
ASPIRIN
cyclooxygenase
prostaglandin G2
prostaglandin H2
prostacyclin
synthetase
peroxidase
thromboxane
synthetase
prostacyclin
thromboxane A2
PG F1a
thromboxane B2
Mechanism of Action
ASPIRIN and NSAIDS
arachidonic acid
ASPIRIN
cyclooxygenase
prostaglandin G2
prostaglandin H2
prostacyclin
synthetase
NSAIDS
peroxidase
thromboxane
synthetase
prostacyclin
thromboxane A2
PG F1a
thromboxane B2
Antiplatelet Medications
DRUG
SITE OF
ACTION
PLASMA METABOLISM
ROUTE t 1/2
Ø PRIOR
PROCEDURE
↑ PT /
PTT
ANTI –
DOTE
Aspirin
COX 1
and 2
oral
20 min
hepatic
7 days
No/No
none
Dipyridamole
adenosine
oral
40 min
hepatic
24 hrs
No/No
none
Clopidogrel
ADP
oral
7 hrs
hepatic
5 days
No/No
none
ADP
oral
4 days
hepatic
10 days
No/No
none
GPIIb-IIIa
IV
30 min
renal
72 hrs
No/No
none
Eptifibatide
GPIIb-IIIa
IV
2.5 hrs
renal
24 hrs
No/No
none
Tiroban
GPIIb-IIIa
IV
2 hrs
renal
24 hrs
No/No
hemodialysis
(Plavix)
Ticlodipine
(Ticlid)
Abciximab
(ReoPro)
Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.
Non-steroidal Anti-inflammatory Medications
DRUG
SITE OF
ACTION
PLASMA METABOLISM
ROUTE t 1/2
Ø PRIOR
PROCEDURE
↑ PT /
PTT
ANTI –
DOTE
Piroxicam
COX 1 & 2
oral
50 hrs
hepatic
10 days
No/No
none
Indome –
thacin
COX 1 & 2
oral/
supp
5 hrs
hepatic
48 hrs
No/No
none
Ketorolac
COX 1 & 2
oral /
IV
5-7 hrs
hepatic
48 hrs
No/No
none
Ibuprofen
COX 1 & 2
oral
2 hrs
hepatic
24 hrs
No/No
none
naproxen
COX 1 & 2
oral
13 hrs
hepatic
48 hrs
No/No
none
Diclofenac
COX 1 & 2
oral
2 hrs
hepatic
24 hrs
No/No
none
Celecoxib
COX 2
oral
10-17
hrs
hepatic
none
No/No
none
Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.
Anticoagulants & Thrombolytics
DRUG
SITE OF
ACTION
Unfractionated
heparin
IIa/Xa
LMWHs
Xa
IIIa
↑ PT / ANTI –
PTT DOTE
ROUTE
PLASMA
t 1/2
EXCRETION
Ø PRIOR
PROCEDURE
IV/SC
1.5 hrs
hepatic
6 hrs
No/
Yes
protamine
SC
4.5 hrs
renal
12-24 hrs
No/No
protamine
(partial)
Strepto kinase
plasmi –
nogen
IV
23 mins
hepatic
3 hrs
Yes/
Yes
antifibrinolytics
t-PA
plasmi –
nogen
IV
<5 min
hepatic
1 hr
Yes/
Yes
antifibrinolytics
vit-K dep.
factors
Oral
2-4days
hepatic
Oral
Anticoagulants
Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.
2-4 days
Yes/No Vit. K,
rFVIIa
Plasma,
Prothrom.
complex
conc.
Other Anticoagulants
DRUG
SITE
PLASMA METAOF
BOLISM
ROUTE t 1/2
ACTION
Ø PRIOR
PROCEDURE
↑ PT/
PTT
ANTI –
DOTE
Pentasaccharide
Xa
IV
14-17
hrs
renal
4 days
No/No
rFVIIa?
Bivalirudin
IIa
IV
25 min
hepatic
2-3 hrs
Yes/
Yes
None
Argatroban
IIa
IV
45 min
hepatic
4-6hrs*
Yes/
Yes
None
Hirudin
IIa
IV
1.5 hr
renal
8 hrs*
Yes/
Yes
PMMA
dialysis
Va/
VIIIa
IV
2 hrs
hepatic
12 hrs
No/Yes
none
IIa
IV
3 hrs
renal
24 hrs
Yes/
Yes
none
Activated
Protein C
(APC)
Ximelagatran
PMMA= polymethyl-methyl acrylate
*Argatroban &lepirudin may ↑ the normal PT 4-5 secs
Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.
Oral Anticoagulants
Warfarin

inhibits synthesis of vitamin - k dependent
factors II, VII, IX, X and protein C & S

reversal:
 stopping medication and waiting for ~4 days
for PT normalization
 vitamin K PO or IV (1-2mg)
 immediate: rFVIIa, FFP (1-2 units),
prothrombin complex concentrate

check PT prior to surgery
Oral Anticoagulants
Warfarin

biphasic effect on PT and INR
 initial ↑: ↓ F VII (shortest t ½) to 55 %
of normal
 subsequent ↑: ↓ F II and X – therapeutic
anticoagulant

discontinuation
 return to normal: F VII followed by F II & X
 caution: INR =/< 1.4 no assurance of
normal coagulation
Unfractionated Heparin

negatively charged, water - soluble
glycosaminoglycan

extracted from porcine gut or bovine lung

binds and ↑ anti - thrombin III (AT III) activity
to 1,000 fold →binds & inactivates factors IIa
and factor Xa

degree of inhibition: F Xa = IIa
*

LMWH inhibition of Xa > IIa
lesser inhibition on F XIa, XIa and F XIIa
Unfractionated Heparin
Low-dose or “minidose”

5,000 U SC q 12 hrs for thromboprophylaxis

peak action: 40 - 50 minutes

duration 4 - 6 hrs

low risk for hemorrhage during anesthesia
or surgery

4 reported cases of SEH with CNB
Unfractionated Heparin
Standard Dose

regular doses for therapeutic anticoagulation
 high risk of bleeding during & after surgery
 stop at least 6 hrs before surgery
 restarted ~ 12 hrs postop if needed with close
monitoring
 immediate reversal: protamine
Low Molecular Weight Heparin (LMWH)

4,000-6,500 daltons (vs. standard heparin 3,000
-30,000 daltons

retains anti-Xa activity

less anti -IIa than standard heparin

enhances AT-III interaction with F IIa & F Xa

degree of inhibition: F Xa > IIa
LMWH in the U.S.
LMWH
TRADE
NAME
MOLECULAR
WEIGHT
(daltons)
HALF - LIFE
(minutes)
Dalteparin
Fragmin
5,000
120
2:1
Enoxaparin
Lovenox
4,500
150
2.7:1
Danaparoid
Orgaran
6,500
1,100
20:1
Ardeparin
Normiflo
6,000
200
2:1
14,000
60-90
Standard
Heparin
Anti Xa:
Anti IIa
1:1
Standard Heparin vs. LMWH
PARAMETERS
STANDARD HEPARIN
LMWH
MOLECULAR WEIGHT
3, 000 - 30,000 daltons
4,000-6,500 daltons
BIOAVAILABILITY
variable due to binding to
predictable
plasma protein &
macrophages
MONITORING
PTT
dose adjusted based on PTT
HALF – LIFE
variable; dose-dependent
no need for monitoring
no dose adjustments
4-6 hrs
(30 min for 25 u/kg, 150
mins with 400 u/kg)
CLEARANCE
hepatic
renal
Standard Heparin vs. LMWH
PARAMETERS
EFFECT ON
PLATELETS
STANDARD HEPARIN
LMWH
Higher incidence of HIT
Lower incidence of HIT
Inhibition of platelet function
Less inhibition
Inhibits platelet-endothelium
No interaction
interaction
RISK OF BLEEDING
ANTI Xa: IIa
ACTIVITY
REVERSAL
higher
Lower
1:1
2:1
protamine
Only anti-IIa (90%) but
not anti-Xa (60%) activity
reversed by protamine (1
mg/100 anti-Xa units
LMWH
COST
inexpensive
expensive
Recombinant Factor VIIa
(NovoSeven)

FDA approved for use in hemophilia & patients
with inhibitors

enhances the TF pathway

binds loosely to platelets and directly activates F X
→ ↑ thrombin generation with F Va present

never completely normalizes thrombin generation
but enhances hemostasis

dose: 90-120 mcg/kg q 2 hrs x 1st 24 hrs
Recombinant Factor VIIa

variable individual thrombin- generating
capacity
 megadoses: 150-300 mcg/kg

“off label” use (non - FDA approved)
 liver disease
 liver transplant
 trauma
 ICH
 platelet disorders
Recombinant Factor VIIa

common denominator: defective thrombin generation
 thrombocytopenia
▪ hypothermia
 ↓ plasma coagulation proteins
▪ hyperfibrinolysis
 dilutional coagulopathy

prophylactic use reported for retropubic prostatectomy,
hepatectomy

potential use: Jehovah’s witness
Coagulation Disorders
Disorders of Hemostatic Mechanism

Classification: depends on involvement of
 platelets and/or clotting factors
 and/or presence of inhibitors (such as FDP)

Treatment
• transfusion of platelets and/or clotting factors
• pharmacologic agents affecting
 Platelets fx (DDAVP, antiplatelet drugs)
 Clotting factors (vit. K, coumadin, heparin)
 Inhibitors (antifibrinolytics, protamine, fibrinolytics)
Hereditary Platelet Disorder
von Willebrand Disease (vWD)

most common congenital bleeding disorder

quantitative or qualitative abn. of vWF

Type 1: most common form
 partial quantitative deficiency of vWF
 autosomal dominant
 mucocutaneous bleeding
 hematology consult prior to surgery
 prolonged bleeding time, normal platelet
Hereditary Platelet Disorders
von Willebrand Disease (vWD)
Type 2: qualitative alterations in the vWF structure
& function
Type 3: least common and most severe
 Complete absence of vWF in plasma or storage organelle
 Autosomal recessive

acquired vWD
 Lymphoproliferative disease
▪ cardiac/valvular disease
 Tumors
▪ medications (valproic acid)
 Autoimmune disease
▪ hypothyroidism
Hereditary Platelet Disorders
von Willebrand Disease

Treatment: Desmopressin (DDAVP)
 synthetic analog of vasopressin
 ↑ both F VIII and vWF 3 - 5x in 30 mins
 preop prophylactic dose: 0.3 mcg/kg IV in 50 100 ml NS infused 30-60 mins q 12-24 hrs PRN
 duration 8-10 hrs
 intranasal dose: 300 mcg – for home
treatment, not for preop prophylaxis
Hereditary Bleeding Disorders
von Willebrand Disease

DDAVP
 vasomotor effect: flushing, ↑HR, headache
 SE: hyponatremia, seizures
 not for children < 3 yrs old

unresponsive to DDAVP (15%)
 cryoprecipitate
 FFP
 factor VIII / vWF concentrate
Acquired Platelet Disorders

Thrombocytopenia : platelets <150,000/mm3
 inadequate production by bone marrow
 splenic sequestration
 consumption coagulopathy
 dilutional thrombocytopenia
 immunogenic destruction

Platelet dysfunction
 myeloproliferative and myelodysplastic syndromes
 renal failure, liver disease, DIC, CPB
 drugs: NSAIDS, ASA
*
DDAVP: tx platelet dysfunction due to uremia, liver disease, and
patients on ASA for CABG
Hereditary Factor Deficiencies
Hemophilia

x-linked recessive conditions (males only)

type A : F VIII:C deficiency (Classical Hemophilia)
B : F IX deficiency (Christmas disease)
C : F XI deficiency

unexplained bruising or bleeding in young males,
usually ~ 1 yr of age

joint & muscle bleeding → arthropathy
Hereditary Factor Deficiencies
Hemophilia
■ screening: prolonged PTT
■ hemophilia A
mild
moderate
severe : life-threatening (CNS bleed)

treatment
factor replacement
rFVIIa
Factor VIII Concentrate Necessary for Hemostasis
Factor VIII Concentrate
(% of normal)
Spontaneous hemorrhage
1-3 %
Moderate trauma
4-8 %
Hemarthrosis/deep skeletal
10-15 %
muscle hemorrhage
Major surgery
> 30%
Acquired Factor Deficiencies

Vitamin - K deficiency
malabsorption syndromes
pancreatic insufficiency
biliary obstruction
GI obstruction

treatment: vitamin K
Platelet Dysfunction, Factor Deficiencies &
Presence of Inhibitors

Liver disease
• synthesis of coagulation factors (except VIII),
anticoagulants, ATIII, protein C & S, plasminogen
• clearance of activated clotting factors, tPA, FDPs

DIC
Hypercoagulable States
Factor V Leiden Mutation

glutamine is substituted for arginine at
position 506→ resistant to inactivation by
protein C

dx: genetic screening

↑ risk for DVT in lower extremities & brain
homozygous (20x) >heterozygous (7x)

if asymptomatic: no anticoagulation
Hypercoagulable States
Factor V Leiden Mutation

Treatment
▪ warfarin x 6 mos or until thrombosis
free for 2 mos
▪ LMWH x 2 wks after warfarin
then retested
▪ long term anticoagulation if persist
or recurrent thrombotic event
Idiopathic Thrombocytopenic Purpura
(ITP)

more commonly found in children

diagnosis of exclusion

petechia <20,000x 109/l platelets

bleeding <10,000x 109/l

medical management
Blood Component Therapy
Platelet Transfusion

1 unit ↑ platelets count 10,000 mm3

adult dose: 1 unit/10 kg BW within 24 hrs

indications (NIH)
▪ thrombocytopenia with clinical coagulopathy
10, 000 in ITP
20, 000 in bone marrow suppression
40,000
during massive transfusion
▪ platelet dysfunction even with platelets>100,000
CPB
drugs (ASA, etc)
uremia
thrombasthenia
Blood Component Therapy
Transfusion of FFP
1) replacement of isolated factor deficiency
2) reversal of coumadin
3) antitrombin III deficiency
4) treatment of immunodeficiencies
5) treatment of TTP
6) massive blood transfusion
Blood Component Therapy
Cryoprecipitate

contains significant levels of factor VIIIC,
factor VIII: vwF, XIII, fibrinogen

indications:
1) hemophilia
2) von Willebrand disease
3) fibrinogen deficiencies
4) uremic platelet dysfunction
References






Roberts HR, Monroe DM, Escobar MA. Current Concepts of Hemostasis.
Anesthesiology 2004; 100:722-30.
De Souza GJ. Anticoagulation and Central Neuraxial Anesthesia. Progress in
Anesthesiology. 2000;vol XIV, Chap 9: 132-148.
Petrovich, CT. An approach to the patient who may have a bleeding
disorder. 2005 ASA nnual Meeting Refresher Course Lectures. Atlanta, GA.
2006;241:1-6.
Kelly RE, Yao FF. Hemophilia and Coagulation Disorders. Yao & Artusio’s
Problem Oriented Anesthesiology 4th Ed. Lippincott Williams & Wilkins.
1998. Chapter 40, pp 763-774.
Fleisher LA. Evidence-based Practice of Anesthesiology. Saunders. 2004.
Stoelting RK,Dierdorf, SF. Coagulation Disorders. Anesthesia and Coexisting diseases 3rd Ed. Churchill Livingston. 1993. Chapter 25, p 407-426.