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HEMOSTASIS
&
BLEEDING
Professor
Anwar Sheikha
MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP
Senior Consultant Clinical & Lab. Hematologist
Clinical Professor of Hematology
University of Mississippi Medical Center, Jackson, Mississippi
Professor of Hematology,
University of Salahaddin, Erbil, Kurdistan, IRAQ
HEMOSTASIS
ARREST OF BLEEDING
Hemostasis is a highly integrated process involving Blood Vessels,
Platelets and a number of plasma proteins that are collectively
responsible for Coagulation and Fibrinolysis
HEMOSTASIS
ARREST OF BLEEDING
Hemostasis is a highly integrated process involving Blood Vessels,
Platelets and a number of plasma proteins that are collectively
responsible for Coagulation and Fibrinolysis
DEFECT IN ANY OF
THESE COMPONENTS

BLEEDING
TRIGGERING OF ANY
OF THESE COMPONENTS

THROMBOSIS
HEMOSTASIS
ARREST OF BLEEDING
Hemostasis is a highly integrated process involving Blood Vessels,
Platelets and a number of plasma proteins that are collectively
responsible for Coagulation and Fibrinolysis
 
 
 
HEMOSTASIS
Hemostasis is a highly integrated process involving Blood Vessels,
Platelets and a number of plasma proteins that are collectively
responsible for Coagulation and Fibrinolysis
HEMOSTASIS
BRICKS
“Platelets”
CEMENT
“Clotting”
HEMOSTASIS
HEMOSTASIS
Blood Vessel
Platelet
‫ﮔﻪﺭﻩﻻﻮﮊﻩ‬
Clotting
BLOOD VESSEL
Collagen
Microfibrils
Nitric Oxide
von
Willebrand
Factor
BLEEDING
PURPURIC BLEEDING
‫ﻛﻪﭘﺮ‬
DEEP SEATED BLEEDING
‫ﻛﯚﺷﻚ‬
BLEEDING
PURPURIC BLEEDING
‫ﻛﻪﭘﺮ‬
DEEP SEATED BLEEDING
‫ﻛﯚﺷﻚ‬
How to do Bleeding Time?
Simplate
BLEEDING
DUE TO
VESSEL WALL
ABNORMALITIES
HEREDITARY
HEMORRHAGIC
TELENGIECTASIA
EHLERSDANLOS
SYNDROME
SENILE PURPURA
SCURVEY
MULTIPLE MYELOMA
HENOCH-SCHONLEIN PURPURA
ALLOPURINOL
INDUCED
PURPURA
SLE
SYSTEMIC LUPUS ERYTHEMATOSUS
WISKOTT-ALDRICH SYNDROME
PURPURA
PETICHAE
ECCHYMOSIS
BRUISES
HEMATOMA
The old practice of Bleeding Time & Clotting Time!
Do Platelet count  If Low  Do Bleeding Time  If Prolonged, give Platelets
Do Platelet count  If Low  Do Bleeding Time  If Prolonged, give Platelets
BLEEDING
DUE TO
PLATELET
ABNORMALITIES
Megakaryocytes




Largest hemopoietic
marrow cells (~100
um)
Multi-lobulated
nuclei; no mitosis
but nuclear
duplication
Abundant cytoplasm
with azurophilic
granules
Each Produces 3000
platelets
SHEIKHA
The committed platelet
progenitor cells
Megakaryocytes
do not undergo
classical mitosis;
instead they will develop
nuclear
duplications &
cytoplasmic expansion. The rapid
increase in cytoplasm is
accommodated by progressive
folding, or invaginations, of
megakaryocytic membrane. These
demarcation membranes will
eventually produce individual
platelet membranes.
MK pseudopodia penetrates marrow
sinusoids. Blood flow breaks off
large platelets that are finally
fragmented to individual
platelets in the pulmonary
microcirculation.
SHEIKHA
Megakaryocytes
In stressed
thrombopoiesis,
cytoplasm matures
quicker than
nucleus so that low
ploidy MK start to
produce platelets
that are larger,
denser and
metabolically more
active
EACH MK CAN
PRODUCE 3000
PALETLETS
SHEIKHA
THROMBOCYTOPENIA
↓ PRODUCTION
APLASTIC ANEMIA
LEUKEMIAS
CHEMOTHERAPY
MARROW INFILTRATION
THROMBOCYTOPENIA
↓ PRODUCTION
APLASTIC ANEMIA
LEUKEMIAS
CHEMOTHERAPY
MARROW INFILTRATION
↓ SURVIVAL
ITP
EVANS’
SLE
DIC
TTP/HUS
SEPSIS
THROMBOCYTOPENIA
↓ PRODUCTION
APLASTIC ANEMIA
LEUKEMIAS
CHEMOTHERAPY
MARROW INFILTRATION
↓ SURVIVAL
ITP
EVANS’
SLE
DIC
TTP/HUS
SEPSIS
LOSS FROM
CIRCULATION
SPLENOMEGALY
MASSIVE
TRANSFUSION
ITP
IMMUNE
THROMBOCYTOPENIC
PURPURA
Old View:
Increased Platelet Production
with High Platelet Turnover
New Concept:
Decreased Platelet Production!!
Spleen
in ITP
ITP
ACUTE
CHRONIC
“Childhood”
“Adult”
Preceding Infection
2–6
1:1
Acute
Common
20 – 40
1:3
Chronic
Unusual
Platelet Count
Often <20,000/uL
Often >20,000/uL
Spontaneous Remission
> 80%
2 – 4 weeks
< 20%
Peak Age “Years”
Sex “M/F”
Onset
Usual Duration
Months/ Years
EVANS’ SYNDROME
MANAGEMENT
OF
ITP
STEROID
IV IMMUNOGLOBULIN
Anti-D
SPLENECTOMY
?Platelet Transfusion
Rituximab “Anti CD20”
WAS
DRUG-INDUCED THROMBOCYTOPENIA
TTP/HUS
THROMBOTIC THROMBOCYTOPENIC PURPURA
HEMOLYTIC UREMIC SYNDROME
FEVER
ICU
TP
BROKEN RBCs
MAHA
A PHONE CALL
CNS
SAVE A LIFE
RENAL
Mortality Rate
85%
Mortality Rate
Recovery Rate
85%
85%
BERNARD-SOULIER SYNDROME
Advise your Bleeding
Patients to avoid
Aspirin, NSAID &
intramuscular
injections
BLEEDING
DUE TO
COAGULATION
DISORDERS
WORLD HEMOPHILIA DAY
HEMOPHILIA
Legg, in 1872, defined Hemophilia as
“A congenital and lifelong tendency
to hemorrhage into muscles and joints”.
This is still one of the best definitions for the disease
SEXLINKED
1/10,000
BIRTHS
1/5000
MALE
BIRHTS
A
QUARTER
OF
PATIENTS
HAVE FRESH
MUTATIONS
SEVERE
<1%
MODERATE
1-5%
MILD
5-20%
Upward of 1/3 of NEONATAL males with severe
Hemophilia will not bleed at circumcision
Black or White,
Royal or Beggar,
it does not matter,
as long as you are
A MAN!
Inhibitor
Novo7
CHRISTMAS DISEASE
HEMOPHILIA B
Factor IX Deficiency
Patients with
FIX Leyden
have severe hemophilia until Puberty,
when FIX levels spontaneously increase,
suggesting that
abnormal gene is androgen sensitive
HEMOPHILIA “A” or “B”
SEVERE
MODERATE
MILD
Neonatal
VIII,
IX
Level
%
all
Hph
A
% all
Hph.
B
<
1%
70
%
50
%
15%
15
%
>
5%
15
%
CNS
Bleed
Symptoms
Tooth
Extra
M.&J.
Bleed
Onset
AGE
<1
yr
PCB+++
ICH+ -
Spont.
High
Usual
30
%
Minor
Trauma
Mod.
Common
1-2 yr
PCB+++
ICH+/-
20
%
2adult
PCB ICH -+
Major
Trauma
Rare
Often
PCB: Post-circumcision Bleeding
ICH: Intra-cranial Hemorrhage
Upward of one third of hemophiliacs do not have excessive
post-circumcision bleeding.
MANAGEMENT OF HEMOPHILIAS
AND
ALL OTHER
BLEEDING DISORDERS IS BY
A NEW MAGIC UNIVERSAL HEMOSTATIC AGENT
CALLED
MANAGEMENT OF HEMOPHILIAS
AND
ALL OTHER
BLEEDING DISORDERS IS BY
A NEW MAGIC UNIVERSAL HEMOSTATIC AGENT
CALLED
NovoNordiscHawlerBayar
MANAGEMENT OF HEMOPHILIAS
AND
ALL OTHER
BLEEDING DISORDERS IS BY
A NEW UNIVERSAL HEMOSTATIC AGENT
CALLED
Novo7
“rVIIa”
FACTOR VIII:C
CONCENTRATE
DDAVP
TREATMENT
OF
HEMOPHILIA
A
ANTIFIBRINOLYTICS
Tranexamic Acid
EACA
Gene Therapy
Novo7 or FEIBA
“Inhibitors”
Factor
VIII
SA
(U/mg Protein)
LOW
PURITY
INTER.
PURITY
HIGH
PURITY
ULTRA
PURITY
<5
1-10
50-100
3000
(Specific
Activity)
Product
CRYOPRECIPITATE
Humate-P
Profilate
-OSD
FACTOR VIII
Alphanate
Koate-HP
*Plasma-derived,
MoAb-purified
*Recombinant F VIII
WE BLED, BUT THANK GOD NOW OUR HEMOSTASIS IS INTACT
LET US WISH THE SAME FOR THE REST OF OUR BELOVED IRAQ
THANK YOU
von Willebrand Disease
von Willebrand Disease
1%
10,000
PATIENTS
IN
HAWLER
of
the
POPULATION
10,000
PATIENTS
IN
SULY
If I were a surgeon I will be quite cautious, knowing that
most of these patients only bleed when challenged surgically
von Willebrand Disease
Von Willebrand Disease
Type 1
Partial Quantitative
↓ of VWF
Type 2
Qualitative ↓ of VWF
Type 3
Total ↓ of VWF
+
↓ ↓ VIII:C
Von Willebrand Disease
Type 1: Quantitative ↓ of VWF
Autosomal dominant
>70% of all vWD
~ 1% of Population
Von Willebrand Disease
Type 3
Total ↓ of VWF
&
↓ ↓ VIII:C
Autosomal recessive
CF: vWD + Hemophilia
↓VWF:Ag
↓VWF:RCo
↑APTT
Parents may be Type 1 with normal APTT
Von Willebrand Disease
Type 1: Quantitative ↓ of VWF
Type 2: Qualitative ↓ of VWF
Type 3: Total ↓ of VWF + ↓ ↓ VIII:C
Von Willebrand Disease
Type 2A
Von Willebrand Disease
Type 2B
↑ binding of VWF & Platelets 
Depletion of High Multimers & Platelets
LOVE
AFFAIR
‫ﺣﺐ‬
Von Willebrand Disease
Type 2M “Multimers”
↓ binding of VWF & Platelets
Normal Multimers
HATE
AFFAIR
‫ﻁﻼﻖ‬
Von Willebrand Disease
Von Willebrand Disease
Pseudo-vWD “Platelet type vWD”
↑ binding of Platelet GP Ib-IX-V & Large Multimer VWF
Indistinguishable from Type 2B
Treat with Platelet Transfusion
Von Willebrand Disease
Von Willebrand Disease
BLOOD GROUP “O” PEOPLE
HAS 25% LOWER THAN
OTHER BLOOD GROUPS
COULD THAT BE TRANSLATED
TO A LONGER SURVIVAL
WITH LESS ISCHEMIC EFFECTS?
TESTING
for
vWD
EVALUATION
APTT & FVIII Level
?BLEEDING TIME
VWF:Ag
VWF:RCo
VWF Multimers Analysis
RIPA
“Ristocetin-induced Platelet Aggregation”
FVIII binding assay
DNA sequencing of the Gene
Management of Von Willebrand Disease
DDAVP
Treatment of choice for Type 1 vWD
Favorable also for Type 2A & 2M but duration of response is shorter
In Type 2B it releases the abnormal VWF  Thrombocytopenia
Dose: 0.3 ug/kg (maximum 20 ug) over 20 minutes
Because of tachyphylaxis repeat dose only after 24 to 48 hours
Restrict fluids; monitor blood pressure and serum sodium
Management of Von Willebrand Disease
VWF-containing Factor VIII concentrate
Treatment of choice for most bleeds,
especially when severe
Purified VWF is available in Europe but not USA
No monoclonal or recombinant VWF
FVIII:C concentrate used for hemophilia is not effective
Management of Von Willebrand Disease
FFP & Cryoprecipitate should not be considered
for treatment of vWD because FFP cannot
contain enough VWF & Cryo cannot
be virally inactivated
Local therapy like antifibrinolytic mouth washes
for oropharyngeal bleeds
Tranexamic acid 1 gm q6h
EACA 2-3 gm q6h
Von Willebrand Disease
Q4.
Type 2B von Willebrand disease is due to:
A. Partial Quantitative deficiency of von Willebrand Factor “VWF”
B. Deficiency of the high molecular weight VWF multimers
C Increased binding of VWF to platelets causing depletion
of high molecular weight VWF and thrombocytopenia
D. Decreased binding of VWF to platelets, but with
normal VWF multimer distribution
E. Decreased binding of VWF to Factor VIII
causing low plasma Factor VIII:c
THANK YOU
ENJOY YOUR NOVO7 MEAL
Von Willebrand Disease
Von Willebrand Disease
Q1.
Type 2N “N = Normandy”
von Willebrand disease is due to:
A. Partial Quantitative deficiency of von Willebrand Factor “VWF”
B. Deficiency of the high molecular weight VWF multimers
C. Increased binding of VWF to platelets causing depletion
of high molecular weight VWF and thrombocytopenia
D. Decreased binding of VWF to platelets, but with normal
VWF multimer distribution
E Decreased binding of VWF to Factor VIII causing low
plasma Factor VIII:C
Von Willebrand Disease
Q2.
A
Type 1 von Willebrand disease is due to:
Partial Quantitative deficiency of von Willebrand Factor “VWF”
B. Deficiency of the high molecular weight VWF multimers
C. Increased binding of VWF to platelets causing depletion
of high molecular weight VWF and thrombocytopenia
D. Decreased binding of VWF to platelets, but with normal
VWF multimers
E. Decreased binding of VWF to Factor VIII causing low
plasma Factor VIII:c
Von Willebrand Disease
Q3.
Type 2M “M = Multimers”
von Willebrand disease is due to:
A. Partial Quantitative deficiency of von Willebrand Factor “VWF”
B. Deficiency of the high molecular weight VWF multimers
C. Increased binding of VWF to platelets causing depletion
of high molecular weight VWF and thrombocytopenia
D Decreased binding of VWF to platelets, but with normal
VWF multimers
E. Decreased binding of VWF to Factor VIII causing low
plasma Factor VIII:c
Von Willebrand Disease
Q4.
Type 2B von Willebrand disease is due to:
A. Partial Quantitative deficiency of von Willebrand Factor “VWF”
B. Deficiency of the high molecular weight VWF multimers
C Increased binding of VWF to platelets causing depletion
of high molecular weight VWF and thrombocytopenia
D. Decreased binding of VWF to platelets, but with
normal VWF multimer distribution
E. Decreased binding of VWF to Factor VIII
causing low plasma Factor VIII:c
Von Willebrand Disease
Q5.
One of the following types of
von Willebrand disease
is autosomal recessive:
A. Type 1 von Willebrand disease
B. Type 2A von Willebrand disease
C. Type 2B von Willebrand disease
D Type 2N von Willebrand disease
E. Type 2M von Willebrand disease
Von Willebrand Disease
Q6.
One of the following types of von Willebrand
disease is associated with thrombocytopenia:
A. Type 1 von Willebrand disease
B. Type 2A von Willebrand disease
C Type 2B von Willebrand disease
D. Type 2N von Willebrand disease
E. Type 2M von Willebrand disease
Von Willebrand Disease
Q7.
Type 2A von Willebrand disease is due to:
A. Partial Quantitative deficiency of von Willebrand Factor “VWF”
B Deficiency of the high molecular weight VWF multimers
C. Increased binding of VWF to platelets causing depletion
of high molecular weight VWF and thrombocytopenia
D. Decreased binding of VWF to platelets, but with
normal VWF multimers
E. Decreased binding of VWF to Factor VIII causing
low plasma Factor VIII:c
Von Willebrand Disease
Q8.
One of the following features does not
relate to Type 3 von Willebrand disease:
A
It is autosomal dominant
B.
There is virtual absence of von Willebrand Factor
C.
There is profound deficiency of Factor VIII:c with prolonged APTT
D.
Screening assays show absent VWF:RCo and VWF:Ag
E.
Parents of these patients may have Type 1 von Willebrand disease with bleeding
Von Willebrand Disease
Q9.
One of the following features is not true
about Type 2N “N = Normandy”
von Willebrand disease:
A
It is autosomal dominant
B.
Mutations selectively inactivate FVIII:C binding site on VWF
C.
The platelet-dependent functions of VWF is intact
D.
Factor VIII:C is usually <10% and APTT is prolonged
E.
Patients usually behave like hemophilia but with autosomal style of inheritance
Von Willebrand Disease
Q10.
Type 2N “N = Normandy” von Willebrand
disease should be suspected in:
A. Any patient with low FVIII:C in whom a Factor VIII inhibitor is ruled out
B. Any patient with low FVIII:C in whom X-linked inheritance is not clear
C. Any patient with low FVIII:C in whom therapy with recombinant or
monoclonal FVIII concentrate gives poor results
D All of the above
E. None of the above
Von Willebrand Disease
Von Willebrand Disease
Von Willebrand Disease
Von Willebrand Disease
Von Willebrand Disease
Von Willebrand Disease
von
Willebrand
Factor
DIC
DISSEMINATED
INTRAVASCULAR
COAGULATION
DIC
DIC Diagnostic Algorithm
1.
Risk Assessment: Does patient have underlying disorder
known to be ~ DIC?
If Yes proceed. If No, do not use algorithm.
2.
Order global coagulation tests?
Platelet; PT; Fibrinogen; SFM or FDP, etc
3.
Score Global Coagulation Test results:
Score
0
Platelet
1
>100 <100
No
↑Fibrin-related
2
3
Total
<50
Moder Strong
markers (SFM?FDP)
<3
sec
>1
g/L
↑ P.T.
Fibrinogen
>3 to <
6 sec
>1
g/L
>6
sec
Calculate Score;
If = or > 5 Compatible with overt DIC
Repeat scoring daily
If < 5
Suggestive (not affirmative)
for non-overt DIC;
Repeat next 1-2 days.
BLEEDING
IN
DENTAL SURGERY
PRACTICE
vWD
1%
HEMOSTASIS
ARREST OF BLEEDING
Hemostasis is a highly integrated process involving Blood Vessels,
Platelets and a number of plasma proteins that are collectively
responsible for Coagulation and Fibrinolysis
HEMOSTASIS
ARREST OF BLEEDING
Hemostasis is a highly integrated process involving Blood Vessels,
Platelets and a number of plasma proteins that are collectively
responsible for Coagulation and Fibrinolysis
DEFECT IN ANY OF
THESE COMPONENTS

BLEEDING
TRIGGERING OF ANY
OF THESE COMPONENTS

THROMBOSIS
DENTAL PROCEDURES
IN
HEMOPHILIA PATIENTS
*
Routine examination and cleaning generally
can be performed without raising F VIII level
DENTAL PROCEDURES
IN
HEMOPHILIA PATIENTS
*
Routine examination and cleaning generally
can be performed without raising F VIII level
*
Adequate coverage (FVIII +/- Antifibrinolytics)
SHOULD be given before & possibly after the
dental appointment in the following situations:
#
Deep cleaning or scaling because of heavy plaque &/or
calculus accumulation in which bleeding would be induced
Block local anesthesia or mandibular block
Dental extraction, especially multiple or other surgical
procedures
#
#
DENTAL PROCEDURES
IN
HEMOPHILIA PATIENTS
SUGGESTED THERAPY
Multiple dental extractions or other surgery:
Loading dose:Raise to 50%; Give 1 hr before surgery
Maintenance dose:? / repeat before bleeding
+
Tranexamic Acid / EACA for 7 days
DENTAL
SURGEON
INR
Hemophilia
&
vWD
HEMATOLOGIST
Dental
Hygiene
ITP
Leukemias
Conclusions:
Prior to any dental procedure, ask the following questions:
* Do you have any past problem with bleeding?
* Do you get bruised easily?
* Have you done any operation in the past and whether
you had any bleeding problem?
* Ask about circumcision in male patients
* Any family history of bleeding.
* Any drug history, especially Warfarin.
On the slightest suspicion, referral to a hematologist is justified.