Haemostasis
part3
DIC
Lab: - fibrinogen
- platelet
- PT
- aPTT
- fibrin degradation product
acute DIC:
- prolongation of aPTT, PT and TT
- reduction of platelets, AT III and protein C
- decreased fibrinogen
- elevated fibrin degradation products
chronic DIC:
- aPTT and PT may be within normal ranges
- slightly decreased platelets
- elevated fibrin degradation products and D-dimer
Platelet Functional Abnormalities
congenital
1
1. Bernard-Soulier syndrome
•
•
•
defect in platelet adhesion
autosomal recessive
defect in platelet membrane glycoprotein (GP Ib)
2
2. thrombasthenia
•
•
•
•
•
defect in platelet aggregation
autosomal recessive
defect in platelet membrane glycoprotein (GP IIb & IIIa)
no fibrinogen linking of platelets
easy bleeding and no clot retraction
Platelet Functional Abnormalities
acquired
1. aspirin
•
•
inhibits cyclooxygenase
suppression of TXA2 synthesis
effect lasts for 72 hours
2. thrombocythemia
•
•
•
platelet : >3,000,000/ml
functionally abnormal platelets
occasionally seen in myeloproliferative disorders
Approach to the diagnosis of bleeding
disorder
Clinical Evaluation
History
Physical Examination
Family history
Laboratory Evaluation
Screening test
Specific test
Clinical Features of Bleeding Disorders
Platelet disorders Coagulation
disorders
Site of bleeding
tissues
Skin
Deep in soft
(epistaxis, gum,
vaginal, GI tract)
Mucous
membranes,
joints, muscles)
Petechiae
Yes
No
Ecchymoses (“bruises”)
Small, superficial
Large, deep
Hemarthrosis / muscle bleeding
Extremely rare
Common
Bleeding after cuts & scratches
Yes
No
Bleeding after surgery or trauma
Immediate,
Delayed (1-2
days),
usually mild
often severe
Platelet
Petechiae, Purpura
Coagulation
Hematoma, Joint bl.
Tests for Primary Hemostasis
• Bleeding time
platelet & vascular phases
• PFA – 100 system
Platelet function
• Platelet count
Quantification of platelets
• Blood smear
Quantitative & morphological
abnormalities of platelets ,
Detection of underlying
haemotological disorder
PLATELET COUNT
 NORMAL
150,000 - 400,000 CELLS/MM3
< 100,000
Thrombocytopenia
50,000 - 100,000
Mild Thrombocytopenia
< 50,000
Sev Thrombocytopenia
BLEEDING TIME
PROVIDES ASSESSMENT OF
PLATELET COUNT AND FUNCTION
NORMAL VALUE
2-8 MINUTES
Laboratory diagnosis of the coagulopathies
Contact activation
INTRINSIC
Tissue thromboplastin (TF)
EXTRINSIC
XII
VII
XI
IX
Blood
coagulation
time
VIII
X
APTI
COMMON
V
II
I
Fibrin
Prothrombin
INR
INR: International normalized ratio
-was established by the WHO and the International Committee on Thrombosis and
Hemostasis for reporting the results of prothrombin tests
-All PT results are standardized by this calculation:
INR= ( Patient PT / Control PT)
ISI
ISI= International sensitivity index
- Given by the manufacturer for each particular thromboplastin reagent and instrument
combination
ACTIVATED
THROMBOPLASTIN TIME
 Measures Effectiveness of the Intrinsic
Pathway & common pathway
NORMAL VALUE
25-40 SECS
APTT prolongs..
1.
Intrinsic pathway factor deficiencies (FXII, XI,VIII, IX, HMWK, prekallikrein )
- Inherited or acquired
- Consumption (DIC)
- PIVKA factors in cumarin therapy
2. Specific inhibitors against FXII, XI, VIII, IX, HMWK, prekallikrein
3. Lupus anticoagulant
4. Non-fractionated heparin therapy
THROMBIN TIME
 Time for Thrombin To Convert
Fibrinogen
Fibrin
 A Measure of Fibrinolytic Pathway
NORMAL VALUE
9-13 SECS
TT Prolongs..
1. Hypo- afibrinogenaemia
2. Dysfibrinogenaemia
3. Non fractionated heparin
4. Fibrinogen/ fibrin degradation product s
5. Chronic liver disease
Diagnosis of bleeding disorders by the screening tests
Platelet
count
Bleeding APTI
time
Prothrom- Presumptive
bin
diagnosis
Decreased
Prolonged
Norm.
Norm.
Thrombocytopenia
Norm.
Prolonged
Prolonged
Norm.
von Willebrand’s disease
Norm./
increased
Prolonged
Norm.
Norm.
Thrombocytopathia
Norm.
Norm.
Prolonged
Norm.
„intrinsic” pathway
abnormality
(FVIII. IX. XI. XII)
Norm.
Norm.
Norm.
Prolonged
„extrinsic”pathway
abnormality (FVII)
Norm.
Norm.
Prolonged
Prolonged
„common” pathway
abnorm. (FI. II. V. X.)
Norm.
Norm.
Norm.
Norm.
- /FXIII deficiency/ milde
bleeding disorder
ANTICOAGULATION & FIBRINOLYSIS
Vascular Wall
Anti-Coagulation Factors
Fibrinolytic Factors
ANTICOAGULATION & FIBRINOLYSIS
Vascular Wall
• Endothelial Cell
•
•
•
•
prostacyclin (PGl2)
heparan sulfate
thrombomodulin
tissue plasminogen activator (tPA)
• Muscle
• muscular dilation
Protein C
• vit K dependent zymogen
• produced in liver
• inactivates Va and VIIIa
XII
XI
IX
VIII
VII
X
V
Protein S
• vit K dependent binding protein
• co-factor for protein C
• binds C4b-binding protein
II
I
XIII
Stable clot
Anticoagulation
Heparin
• Heparin activates Antithrombin III (AT III)
• AT III inactivates Thrombin and Factor Xa
• rapid onset of action
XII
XI
IX
VIII
Laboratory monitoring:
• aPTT : ~1.5X – 2.5X normal mean
• heparin level :
0.2 – 0.4 U/mL by protamine
titration
0.35 – 0.70 by Factor Xa
inactivation assay
VII
X
V
II
I
XIII
Stable clot
Anticoagulation
Heparin
AT
AT
I
I
AT
I
I
AT
I
I
AT
I
I
AT
I
I
AT
I
I
Coumadin (Warfarin) Anticoagulants
•inhibits hepatic synthesis of
vit K-dependent clotting
factors (II, VII, IX, X)
•competitive inhibition of gcarboxylation
inactivate
“acarboxy” forms
synthesized
•onset delayed 3 to 5 days
•also inhibits synthesis of
protein C & S
XII
XI
IX
VIII
VII
X
V
II
I
XIII
Stable clot
Coagulation Tests
1. Bleeding Time : in vivo test
measures adequacy of plt function
normal : <6 min.
2. Platelet Count
normal : >200,000/mL
3. aPTT : intrinsic pathway (XII, XI, IX, VIII, X, V)
used to guide heparin therapy
4. 50/50 mixing study
pt’s plasma + nl. plasma
if mixing correct aPTT = Pt is deficient in intrinsic
factor(s)
no correction = circulating anticoagulants or inhibitors
5. Prothrombin Time (PT) : extrinsic pathway (II, VII, V, X)
monitoring warfarin/coumadin effects
Coagulation Tests
6. Fibrinogen Level
normal : 200 – 500
mg/dL
7. ADP platelet aggregation
8. Ristocetin aggregation test
• test for presence or activity of vWF
9. Thrombin Time (TT)
normal : 20 – 30 sec
• measures 3rd stage of coagulation
• prolonged if
• def or abnormality of fibrinogen
• presence of fibrin split products
• presence of heparin
History & Physical Exam
are
most important
most sensitive
most specific
Tests of Hemostasis
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 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
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
peroxidase
prostaglandin H2
prostacyclin
synthetase
prostacyclin
PG F1a
thromboxane
synthetase
thromboxane A2
thromboxane B2
Mechanism of Action
ASPIRIN
arachidonic acid
ASPIRIN
cyclooxygenase
prostaglandin G2
peroxidase
prostaglandin H2
prostacyclin
synthetase
prostacyclin
PG F1a
thromboxane
synthetase
thromboxane A2
thromboxane B2
Mechanism of Action
ASPIRIN and NSAIDS
arachidonic acid
ASPIRIN
cyclooxygenase
prostaglandin G2
NSAIDS
peroxidase
prostaglandin H2
prostacyclin
synthetase
prostacyclin
PG F1a
thromboxane
synthetase
thromboxane A2
thromboxane B2
Diagnosis of bleeding disorders by the screening tests
Platelet
count
Bleeding APTI
time
Prothrom- Presumptive
bin
diagnosis
Decreased
Prolonged
Norm.
Norm.
Thrombocytopenia
Norm.
Prolonged
Prolonged
Norm.
von Willebrand’s disease
Norm./
increased
Prolonged
Norm.
Norm.
Thrombocytopathia
Norm.
Norm.
Prolonged
Norm.
„intrinsic” pathway
abnormality
(FVIII. IX. XI. XII)
Norm.
Norm.
Norm.
Prolonged
„extrinsic”pathway
abnormality (FVII)
Norm.
Norm.
Prolonged
Prolonged
„common” pathway
abnorm. (FI. II. V. X.)
Norm.
Norm.
Norm.
Norm.
- /FXIII deficiency/ milde
bleeding disorder
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.
Bleeding time
• Measure of efficiency of vascular or platelet
phases.
• Do not discriminate between vascular defects
, thrombocytopenia or platelets dysfunction.
• Not reproducible.
• Not a screening test .
• normal bleeding time do not exclude a
bleeding disorder- american society of clinical
pathologists.
Platelets function assays
• Platelets aggregation using platelets rich plasma.standard method.
• Nephelometric or photometric measurements.
• ADP- produce platelets aggregation directly
irrespective of release of ADP from platelets.
• RISTOCETIN- antibiotic that induce platelets
aggregation in presence of von Willebrand factor.
• Collagen, epinephrin, thrombin- cause platelet
aggregation by release reaction.
D-DIMERS and FDP:
• FDP results from proteolytic cleavage of fibrin by
plasmin.
• Increased in DIC and fibrinolysis.
• RA factor or residual fibringen may yield false
positive results.
• D-DIMER- specific fibrin degradation product.
• DDE- TRIMER.
• UN POLYMERISED FIBRIN MONOMER.
• UREA CLOT LYSIS ASSAY:
•
•
•
•
FACTOR XIII assay.
XIII Stabilises fibrin.
Deficiency leads to premature clot lysis.
Screening test. Abnormal results should be
confirmed by quantitative measurements of
XIII.
FIVE DRUGS
THAT INTERFERE WITH HEMOSTASIS
l ASPIRIN
l ANTICOAGULANTS
l ANTIBIOTICS
l ALCOHOL
l ANTICANCER
Laboratory Evaluation of the Coagulation
Pathways
Prothrombin time
(PT)
Partial Thromboplastin Time
(PTT)
Thromboplastin
Tissue factor
Phospholipid
Calcium
Surface activating agent
(Ellagic acid, kaolin)
Phospholipid
Calcium
Extrinsic pathway
Intrinsic pathway
Thrombin time
Common pathway
Thrombin
Fibrin clot
Clot
Fibrin
Initial Evaluation of a Bleeding
Patient - 1
Normal PT
Normal PTT
Abnormal
Urea
solubility
Factor XIII
deficiency
Normal
Consider evaluating for:
Mild factor deficiency
Abnormal fibrinolysis
(a2 anti-plasmin def)
Elevated FDPs
Monoclonal gammopathy
Platelet disorder
Vascular disorder
Initial Evaluation of a Bleeding
Patient - 2
Normal PT
Abnormal
PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific factors: VIII,IX, XI
Non-specific (anti-phospholipid
Ab)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency in intrinsic pathway (factors VIII,
IX, XI)
Multiple factor deficiencies (rare)
Initial Evaluation of a Bleeding
Patient - 3
Abnormal PT
Normal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific: Factor VII (rare)
Non-specific: Anti-phospholipid
(rare)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency of factor VII (rare)
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin,
DIC)
Initial Evaluation of a Bleeding
Patient - 4
Abnormal PT
Abnormal
PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific : Factors V, X, Prothrombin,
fibrinogen (rare)
Non-specific: anti-phospholipid
(common)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency in common pathway: Factors V, X,
Prothrombin, Fibrinogen
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin,
Laboratory Evaluation of Bleeding
Overview
CBC and smear
Platelet count
RBC and platelet morphology
Thrombocytopenia
TTP, DIC, etc.
Coagulation
Prothrombin time
Partial thromboplastin time
Coagulation factor assays
50:50 mix
Fibrinogen assay
Thrombin time
Extrinsic/common pathways
Intrinsic/common pathways
Specific factor deficiencies
Inhibitors (e.g., antibodies)
Decreased fibrinogen
Qualitative/quantitative
fibrinogen defects
Fibrinolysis (DIC)
FDPs or D-dimer
Platelet function
von Willebrand factor
Bleeding time
Platelet function analyzer (PFA)
Platelet function tests
vWD
In vivo test (non-specific)
Qualitative platelet disorders
and vWD
Qualitative platelet disorders
Liver Disease
Decreased synthesis of II, VII, IX, X, XI, and fibrinogen
Prolongation of PT, aPTT and Thrombin Time
Often complicated by
Gastritis, esophageal varices, DIC
Lab Results in Hemophilia, VWD and Vit K Def
Haemophilia
V W Disease
Vit K Deficiency
Bleeding Time
Normal
Increased
Normal
PT
Normal
Normal
Increased
APTT
Increased +
Increased ±
Increased
V111 levels
Decreased ++
Decreased
Normal
vWF levels
Normal
Decreased
Normal
Hemophilia A
Hemophilia B Von Willebrand
Disease
Inheritance
X linked
X linked
Autosomal
dominant
Factor deficiency
VIII
IV
VWF
Bleeding site(s)
Muscle,joint
Surgical
Muscle ,joint
Mucous
Skin
Prothrombin time
Normal
Normal
Normal
Activated PTT
Prolonged
Prolonged
Prolonged
Bleeding time
Normal
Normal
Prolonged or
normal
Factor VIII
Low
Normal
Normal
VWF
Normal
Normal
Low
Factor IX
Normal
Low
Normal
Normal
Normal
Platelet aggregation Normal
Summary
Symptom
Petechiae
Sites
Time
Ecchymoses
/Hematomas
Platelet
Yes
Coagulation
No
Skin &
Mucosa
Immediate
Deep Tissue
Yes
Yes
Delayed
Summary Hemostatic Disorders
BT
-
Vascular Dis
Plt
PT
PTT
-
-
-
-
-
-
PLT Disorder
-
Factor 8/9
*Congenital
-
-
-

Vit K / Liver
*Acquired
-
-

-

-

Combined (DIC)

Case scenario-1
2 year old boy had a fall from chair. He developed
swelling of right shoulder and upper arm.
On examination at a hospital the boy had a
hematoma of the right shoulder.
There was no previous h/o surgeries, trauma or
medication.
Following aspiration of hematoma the patient
developed profuse bleeding.
His mother said that the boy’s cousin had a similar
bleeding problem.
Investigations :
• Hb- 8 gms
• Hematocrit- 26%
• Platelets- 2 lakhs.
• Bleeding time- normal
• Coagulation profile:
• PT- 12 sec
• aPTT- 60 sec
• Thrombin time- normal
questions
1.Does the lab data support a diagnosis of
bleeding disorder?
2.The tests done shows what type of disorder?
3.What confirmatory test should be done ?
Case scenario-1
Answers:
1. it’s a coagulation defect.
2. normal platelets, bleeding time.
APTT prolonged, with normal PT, THROMBIN
TIME. indicate a intrinsic pathway defect with
normal common pathway.
There is a defect in factor VIII, IX, XI, XII.
3.Specific factor assay, factor substitution testing.If
factor 8 activity < 1%
Diagnosis- hemophilia A
CASE SCENARIO-2
21 yr man was admitted for hernia surgery. No h/o of any
medical illness, bleeding , or drug intake. Family history ?
Investigations:
 Hb-15 gms
 Hematocrit-44%
 platelet count –normal
 bleeding time-10 mins
 PT- NORMAL
 APTT- 55 seconds
 Repeat APTT was also prolonged.
 Surgery was postponed for him.
Questions:
• 1.What coagulation disorder likely to be
present?
• 2.what are the other investigations required?
• 3.what is the diagnosis if the patient has low
normal factor 8 levels and defective ristosetin
induced platelet aggregation?
Answers-2
1.Normal PT, prolonged APTT suggest a deficiency of
VIII, IX, XI, XII deficiency.
Since deficiency of XI, XII are rare, this can be due to def
of VIII, or XI.
2. factor substitution study.
Specific factor assay.
3. in this factor VIII assay showed 30% activity (n- 50150%). This finding and lack of bleeding history show
he may not have classic factor viii deficiency.
Further tests showed
Answer-2
•
•
•
•
Bleeding time prolonged.
Platelets aggregation decreased.
Factor VIII/ VWF decreased.
the lab findings support a diagnosis of
von willebrand disease
Case scenario-3
 62 year old with abnormal bleeding was
admitted for dental surgery. His brother had died
of traumatic bleeding following a car accident.
 I- AT 7 YEARS following a lymph node resection.
 II- at 30 years the pt had 3 weeks of bleeding
following dental extraction.
 At 31 years the pt received blood transfusion
before appendicectomy.
 At 59 years the pt developed gi bleeding
following surgery for hiatus hernia. He received
blood transfusions -4 units.
Lab data:
 Hb-7 gms
 Hematocrit-23%
 Platelet count- 4.98 lakhs
 Bleeding time-2mins
 Clotting time-188 mins.
 APTT- 53 sec( control- 35 sec)
 PT- 13.8 SEC( control-13 sec).
 Specific assay for factor VIII, IX Showed factor IX
level less than 5%
questions
• 1.what is the diagnosis?
• 2. can the patient safely undergo surgery?
Answers-3
1. hemophilia –B
2.yes.
He should receive factor IX concentrate rather
than whole blood/.
Case scenario-4
• 22 year female was being evaluated for
menorrhagia. Her menses lasted for 8-12 days.
The patient also had several nose bleeds
which needed cautery. She also reported that
her mother and 2 sisters also had long
menstrual periods, and her brother needed
transfusion following an appendicectomy.
• On examination the patient was pale and had
large bruises in the extremities.
Lab data:
• Hb-10 gms
• Hematocrit-27%
• platelet count – 2.5 lakh/cumm.
• Bleeding time-7 mins( n- 1to 3 mins)
• PT- 11 SEC (control-12 sec)
• APTT- 29 sec( control-34 sec)
questions
1.What is the likely abnormality?
2.What are the further tests required?
3. what is the most likely diagnosis if the patient
has defective platelet aggregation?
Answers-4
1.Thrombasthenia
2. Platelet function studies
3. the patient had deficient platelet aggregation.
A diagnosis of Glanzmann’s thrombasthenia
was made.
Autosmal recessive disorder.
Platelet concentrate is needed during
surgeries.
Case-5
• A woman was admitted in labour in an
obstetric ward. Pt had no significant history
and examination was normal. The patient had
irregular contractions.
• In the delivery room she developed profuse
bleeding.
Lab data:
•
•
•
•
•
•
•
•
•
Hb-10 gms
Hematocrit-27%
Platelet count -75000
Bleeding time-10 mins
PT-19 SECONDS- ( control-13 sec).
APTT- 65 sec( control-35 sec)
Thrombin time-30 sec( n- 18-22 sec)
Fibrinogen- 90 mg/dl (200-400 mg/dl)
Fibrin split product- positive
1. what is the probable diagnosis?
2. what is the probable etiology?
3. will whole blood transfusion repress the
bleeding?
Answers-5
1. the diagnosis is DIC.
2. may be due to release of placental tissue in to
maternal circulation triggering the coagulation
mechanism. There is evidence of fibrinolysis.
3. transfusions may temporarily help. Heparin
may be useful
Condition
Partial
Prothrombi
thromboplastin
n time
time
Bleeding
time
Platelet
count
Von Willebrand disease
unaffected
prolonged
prolonged
unaffected
Vitamin K deficiency or
Warfarin
prolonged
prolonged
unaffected unaffected
Uremia
unaffected
unaffected
prolonged
Haemophilia
unaffected
prolonged
unaffected unaffected
Factor V deficiency
prolonged
prolonged
unaffected unaffected
Aspirin
unaffected
unaffected
prolonged
unaffected
Thrombocytopenia
unaffected
unaffected
prolonged
decreased
End-stage Liver failure
prolonged
prolonged
prolonged
decreased
Disseminated intravascular
coagulation
prolonged
prolonged
prolonged
decreased
Bernard-Soulier syndrome
unaffected
unaffected
prolonged
decreased
unaffected
Functions of the Liver
Most clotting Factors are produced in the liver
Microsoft clipart
Factor Name
Roman Numeral
Source
Fibrinogen
I
Liver
Prothrombin
II
Liver *
Tissue Factor
III
Damages cells
Calcium
IV
Gut and bone
Preaccelerin
V
Liver and platelet
Proconvertin
VII
Liver * *
Antihemophilic Factor
VIII
Platelets and endothelium
Christmas Factor
IX
Liver * *
Stuart-Prower Factor
X
Liver * *
Plasma thromboplastin antecedent
XI
Liver
Hageman Factor
XII
Liver
Fibrin-stabilizing Factor
XIII
Liver
* * Dependent on vitamin K for synthesis in liver
Nowak, T.J., Handford, G. A. (2004). Pathophysiology:
Concepts and Applications for Health Care Professionals. (3rd Ed). McGraw-Hill. NY
*
What happens if the Liver is Damaged?
Which of these Factors is not synthesized in the liver?
Click on the correct response:
a) Prothrombin (Factor II)
b) Antihemophilic Factor (Factor VIII)
X Incorrect
Correct
Source: Platelets and endothelium
c) Hageman Factor (Factor XII)
X No
d) Stuart-Prower Factor (Factor X)
X Try Again
So the well equipped guy comes
PLATELETS
• They have receptors
• They provide a phospholipid surface…
• They contain granules
 Dense - serotonin , ADP , Ca++
 Alpha - coagulation factors , vWF , PDGF
Endothelial damage:
Platelet plug formation
• Endothelial damage  exposure to collagen:
– Promotes platelet adherence and activation
– Activated platelets secrete ADP and TxA2
• ADP  promotes platelet recruitment
• TxA2  promotes platelet aggregation
– Result: formation of platelet plug (white clot)
No one can hide the insults from
them……
• ADHESION – [vWF]
• S EC R E T I O N - [ Tx A 2 , A D P ]
• A G G R E G AT I O N
L e a d s t o P R I M A R Y H E M O S TA S I S
Leads to….
PRIMARY HEMOSTASIS
• Occurs within SECONDS
The balancing act
• PG E2
• PG I2
• NO ……..
all these oppose TxA2 & ADP
In need of…. FIBRIN
• The linking of platelets in the primary
plug, by fibrin, converts it into a
definitive clot. This requires the
participation of the Coagulation Cascade.
This process is known as SECONDARY
HEMOSTASIS
In need of…. FIBRIN
• The linking of platelets in the primary
plug, by fibrin, converts it into a
definitive clot. This requires the
participation of the Coagulation Cascade.
This process is known as SECONDARY
HEMOSTASIS
Thrombin generation to fibrinplatelet clot formation
• Thrombin generation:
the pivotal point of the
coagulation process
• Thrombin actions:
– Activates FXI, amplifying
thrombin generation
– Converts fibrinogen to
fibrin
– Activates FXIII
– Activates platelets
• Result: RED CLOT
Cascade vs. cell-based model
Cell-based model
•
Tissue factor
bearing cells
Hemostasis represented as:
1. Initiation
• Occurring on two cell surfaces
• Tissue factor bearing cells
• Platelets
• Three overlapping phases:
IIa
• Initiation (TF bearing cells)
• Amplification (platelets)
• Propagation (platelets)
•
•
The coagulation cascades are still
important, but are cell-based
• The extrinsic pathway works on the
surface of the tissue factor bearing
cells
• The intrinsic pathway works on the
surface of platelets
Routine coagulation tests do not represent
the cell-based model of hemostasis.
2. Amplification
Platelets
3. Propagation
Activated platelets
IIa
Clot:
The end product of hemostasis