HEMOSTASIS & BLEEDING
Jan 06, 2016
HEMOSTASIS&
BLEEDING
ProfessorAnwar SheikhaAnwar Sheikha
MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP
Senior Consultant Clinical & Lab. Hematologist
Clinical Professor of HematologyUniversity 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
CEMENT
“Clotting”
BRICKS
“Platelets”
HEMOSTASIS
HEMOSTASIS
گهرهالوژه
Blood Vessel
PlateletClotting
Collagen
Microfibrils
Nitric Oxide
BLOOD VESSEL
von Willebrand
Factor
BLEEDING
PURPURIC BLEEDING DEEP SEATED BLEEDING
كهپر كۆشك
BLEEDING
PURPURIC BLEEDING DEEP SEATED BLEEDING
كهپر كۆشك
BLEEDING TIME CLOTTING SCREEN
How to do Bleeding Time?
Simplate
BLEEDING DUE TO
VESSEL WALL ABNORMALITIES
HEREDITARYHEMORRHAGICTELENGIECTASIA
EHLERS-DANLOSSYNDROME
SENILE PURPURA
SCURVEY
MULTIPLE MYELOMA
HENOCH-SCHONLEIN PURPURA
ALLOPURINOLINDUCEDPURPURA
SLESYSTEMIC LUPUS ERYTHEMATOSUS
WISKOTT-ALDRICH SYNDROME
PETICHAE
PURPURA
BRUISES
ECCHYMOSIS HEMATOMA
EPISTAXIS
GI BLEEDING
MENORRHAGIA
METRORRHAGIA
Do Platelet count If Low Do Bleeding Time If Prolonged, give Platelets
The old practice of Bleeding Time & Clotting Time!
Do Platelet count If Low Do Bleeding Time If Prolonged, give Platelets
BLEEDING DUE TO
PLATELETABNORMALITIES
Largest hemopoietic Largest hemopoietic marrow cells (~100 marrow cells (~100 um)um)
Multi-lobulated Multi-lobulated nuclei; no mitosis nuclei; no mitosis but nuclear but nuclear duplicationduplication
Abundant cytoplasm Abundant cytoplasm with azurophilic with azurophilic granulesgranules
Each Produces 3000 Each Produces 3000 plateletsplatelets
Megakaryocytes
SHEIKHA
Megakaryocytes
SHEIKHA
The committed platelet The committed platelet progenitor cells progenitor cells do not undergo do not undergo classical mitosis;classical mitosis;
instead they will develop instead they will develop nuclear nuclear duplications & duplications & cytoplasmic expansion. The rapid cytoplasmic expansion. The rapid increase in cytoplasm is increase in cytoplasm is accommodated by progressive accommodated by progressive folding, or invaginations, of folding, or invaginations, of megakaryocytic membrane. These megakaryocytic membrane. These demarcation membranes will demarcation membranes will eventually produce individual eventually produce individual platelet membranes.platelet membranes.
MK pseudopodia penetrates marrow MK pseudopodia penetrates marrow sinusoids. Blood flow breaks off sinusoids. Blood flow breaks off large platelets that are finally large platelets that are finally fragmented to individual fragmented to individual platelets in the pulmonary platelets in the pulmonary microcirculationmicrocirculation..
Megakaryocytes
SHEIKHA
In stressed In stressed thrombopoiesis, thrombopoiesis, cytoplasm matures cytoplasm matures quicker than quicker than nucleus so that low nucleus so that low ploidy MK start to ploidy MK start to produce platelets produce platelets that are larger, that are larger, denser and denser and metabolically more metabolically more activeactive
EACH MK CAN PRODUCE 3000 PALETLETS
THROMBOCYTOPENIA
↓ PRODUCTION
APLASTIC ANEMIALEUKEMIAS
CHEMOTHERAPYMARROW INFILTRATION
THROMBOCYTOPENIA
↓ PRODUCTION
APLASTIC ANEMIALEUKEMIAS
CHEMOTHERAPYMARROW INFILTRATION
↓ SURVIVAL
ITPEVANS’
SLEDIC
TTP/HUSSEPSIS
THROMBOCYTOPENIA
↓ PRODUCTION
APLASTIC ANEMIALEUKEMIAS
CHEMOTHERAPYMARROW INFILTRATION
↓ SURVIVAL
ITPEVANS’
SLEDIC
TTP/HUSSEPSIS
LOSS FROMCIRCULATION
SPLENOMEGALY
MASSIVETRANSFUSION
ITPIMMUNE
THROMBOCYTOPENICPURPURA
Old View:Increased Platelet Productionwith High Platelet Turnover
New Concept:Decreased Platelet Production!!
Spleenin ITP
ACUTEACUTE““Childhood”Childhood”
CHRONICCHRONIC““Adult”Adult”
Peak Age Peak Age “Years”“Years” 2 – 6 2 – 6 20 – 4020 – 40
Sex “M/F”Sex “M/F” 1:11:1 1:31:3
OnsetOnset AcuteAcute ChronicChronicPreceding InfectionPreceding Infection CommonCommon UnusualUnusual
Platelet CountPlatelet Count Often <20,000/uLOften <20,000/uL Often Often >20,000/uL>20,000/uL
Spontaneous RemissionSpontaneous Remission > 80%> 80% < 20%< 20%
Usual DurationUsual Duration 2 – 4 weeks2 – 4 weeks Months/ YearsMonths/ Years
ITP
EVANS’ SYNDROME
MANAGEMENTOF 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 TP MAHA CNS RENAL
ICU BROKEN RBCs A PHONE CALL SAVE A LIFE
Mortality Rate
85%
Mortality Rate
85%
Recovery Rate
85%
BERNARD-SOULIER SYNDROME
Advise your BleedingPatients to avoidAspirin, NSAID &intramuscular injections
BLEEDING DUE TO
COAGULATIONDISORDERS
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
1/10,000 BIRTHS
1/5000MALE
BIRHTS
SEX-LINKED
AQUARTER
OFPATIENTS
HAVE FRESHMUTATIONS
SEVERE<1%
MODERATE1-5%
MILD5-20%
Upward of 1/3 of NEONATAL males with severeHemophilia will not bleed at circumcision
Black or White,
Royal or Beggar,
it does not matter,
as long as you are
A MAN!
Novo7Inhibitor
Factor IX Deficiency
Patients with
FIX Leyden have severe hemophilia until Puberty,
when FIX levels spontaneously increase, suggesting that
abnormal gene is androgen sensitive
CHRISTMAS DISEASE
HEMOPHILIA B
HEMOPHILIA “A” or “B”
VIII, IX
Level
% all Hph A
% all
Hph. B
Onset
AGE
NeonatalSymptom
s M.&J.Bleed
CNSBleed Tooth
Extra
SEVERE
< 1%
70%
50%
<1 yr
PCB+++ ICH+ -
Spont. High Usual
MODERATE
1-5%
15%
30% 1-2
yr
PCB+++ ICH+/-
Minor Traum
a
Mod. Common
MILD > 5%
15%
20%
2-adult
PCB - ICH -+
Major Traum
a
Rare OftenPCB: Post-circumcision Bleeding ICH: Intra-cranial
Hemorrhage
Upward of one third of hemophiliacs do not have excessive post-circumcision bleeding.
MANAGEMENT OF HEMOPHILIASAND
ALL OTHER BLEEDING DISORDERS IS BY
A NEW MAGIC UNIVERSAL HEMOSTATIC AGENT CALLED
MANAGEMENT OF HEMOPHILIASAND
ALL OTHER BLEEDING DISORDERS IS BY
A NEW MAGIC UNIVERSAL HEMOSTATIC AGENT CALLED
NovoNordiscHawlerBayar
MANAGEMENT OF HEMOPHILIASAND
ALL OTHER BLEEDING DISORDERS IS BY
A NEW UNIVERSAL HEMOSTATIC AGENT CALLED
Novo7“rVIIa”
TREATMENTOF
HEMOPHILIAA
ANTIFIBRINOLYTICS
Tranexamic Acid EACA
Gene Therapy
Novo7 or FEIBA “Inhibitors”
FACTOR VIII:CCONCENTRATEDDAVP
Factor VIII
LOWPURITY
INTER.PURITY
HIGHPURITY
ULTRAPURITY
SA (U/mg Protein)
(Specific Activity)
<5 1-10 50-100 3000
Product
CRYO-PRECI-PITATE
Humate-PProfilat
e -
OSD
Alphanate
Koate-HP
*Plasma-derived, MoAb-
purified*Recombinant F
VIIIFACTOR VIII
WE BLED, BUT THANK GOD NOW OUR HEMOSTASIS IS INTACT
LET US WISH THE SAME FOR THE REST OF OUR BELOVED IRAQ
HIGH HEM DIPLOMA
THANK YOU
von Willebrand Disease
von Willebrand Disease
1%of the
POPULATION10,000
PATIENTSIN
SULY
10,000PATIENTS
IN HAWLER
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 2Qualitative ↓ 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
طالق
Von Willebrand Disease
Typ
e 2
N“N
orm
andy
”
↓ bi
ndin
g of
VW
F &
VIII
:C
L
ow V
III:C
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
Pseudo-vWD “Platelet type vWD”
Manage with Platelet transfusion
Type 2B vWD
Treat with VWF-containing
FVIII concentrate
Von Willebrand Disease
BLOOD GROUP “O” PEOPLE HAS 25% LOWER THANOTHER BLOOD GROUPS
COULD THAT BE TRANSLATED TO A LONGER SURVIVAL
WITH LESS ISCHEMIC EFFECTS?
TESTINGfor
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
DDAVPTreatment of choice for Type 1 vWD Favorable also for Type 2A & 2M but duration of response is shorterIn 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 consideredfor treatment of vWD because FFP cannot contain enough VWF & Cryo cannot be virally inactivated
Local therapy like antifibrinolytic mouth washesfor oropharyngeal bleeds
Tranexamic acid 1 gm q6hEACA 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
HIGH HEM DIPLOMA
HIGH HEM
DIPLOMA
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. Type 1 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
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 depletionof 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 causinglow 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 Willebranddisease 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
DICDISSEMINATED
INTRAVASCULARCOAGULATION
DIC
DIC Diagnostic Algorithm
1. Risk Assessment: Does patient have underlying disorderknown 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:
ScoreScore 0 1 2 3 Total
PlateletPlatelet >100
<100 <50
↑↑Fibrin-related Fibrin-related markers markers (SFM?FDP(SFM?FDP))
No Moder
Strong
↑ ↑ P.T.P.T. <3 sec
>3 to < 6 sec
>6 sec
FibrinogenFibrinogen >1 >1 g/Lg/L
>1 >1
g/Lg/LCalculate 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
DENTAL EXTRACTIONHEMOPHILIACHRISTMAS DISEASEANTICOAGULATION
PATIENT
VON WILLEBRAND DISEASEITPLEUKEMIA
vWD 1%
DENTAL SOCKET
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 &/orcalculus 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
HEMATOLOGISTDENTALSURGEON
INR Hemophilia&
vWD I T P Leukemias
DentalHygiene
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.