hemostasis & bleeding. professor anwar sheikha md, frcp, frcpath., fcap, frcpa, frcpi, facp...

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.