Common Bleeding Disorders :

Diagnosis and Treatment

Michael Laposata, M.D., PhDEdward and Nancy Fody Professor of Pathology

Vanderbilt University School of MedicinePathologist in Chief, Vanderbilt University Hospital

Common Bleeding Disorders :

Diagnosis and Treatment

Michael Laposata, M.D., PhDEdward and Nancy Fody Professor of Pathology

Vanderbilt University School of MedicinePathologist in Chief, Vanderbilt University Hospital

Common Bleeding Disorders :

Diagnosis and Treatment

Michael Laposata, M.D., PhD

I have no disclosures to make that are relevant to thispresentation and will make no reference to any specific

product or company with which I am connected.

Common Bleeding Disorders :

Diagnosis and Treatment

Michael Laposata, M.D., PhD

I have no disclosures to make that are relevant to thispresentation and will make no reference to any specific

product or company with which I am connected.

Common Bleeding Disorders :Diagnosis and Treatment

•To learn the basic cellular and molecular events associated with blood coagulation.  •To understand the evaluation of a patient with a hemorrhagic disorder.•To learn the pathogenesis of disseminated intravascular coagulation and bleeding associated with liver disease.•To understand the indications and use of the anticoagulants warfarin and heparin.

Common Bleeding Disorders :Diagnosis and Treatment

•To learn the basic cellular and molecular events associated with blood coagulation.  •To understand the evaluation of a patient with a hemorrhagic disorder.•To learn the pathogenesis of disseminated intravascular coagulation and bleeding associated with liver disease.•To understand the indications and use of the anticoagulants warfarin and heparin.

Common Bleeding Disorders :Diagnosis and Treatment

This patient has a platelet count of 250,000/mL and a normal PT and PTT. The platelet aggregation studies are abnormal. Which of the following is true?a) the patient has a qualitative platelet disorder but not a quantitative platelet disorder.b) the patient has a quantitative platelet disorder but not a qualitative platelet disorder.c) the patient has both a quantitative and a qualitative platelet disorder.d) the patient has no platelet disorder.

Common Bleeding Disorders :Diagnosis and Treatment

This patient has a platelet count of 250,000/mL and a normal PT and PTT. The platelet aggregation studies are abnormal. Which of the following is true?a) the patient has a qualitative platelet disorder but not a quantitative platelet disorder.b) the patient has a quantitative platelet disorder but not a qualitative platelet disorder.c) the patient has both a quantitative and a qualitative platelet disorder.d) the patient has no platelet disorder.

OUTLINE OF PRESENTATIONOUTLINE OF PRESENTATION

1. Clot Formation and Overview of the Diagnosis of Bleeding Disorders

2. Bleeding History

3. Bleeding Disorders and Severity of Thrombocytopenia

4. Bleeding Disorders and Decreased Platelet Function— Including von Willebrand’s Disease

5. Common Bleeding Disorders Associated with Prolongations of the PT, PTT or both & HIT

Clot Formation and Overview of the

Diagnosis of Bleeding Disorders

Clot Formation and Overview of the

Diagnosis of Bleeding Disorders

Vessel Wall Injury

CLOT FORMATIONCLOT FORMATION

Platelet Adhesion

Fibrin Formation

Vessel Wall Contraction

Platelet Aggregation

- --- --- - - -

- --- --- - - -

Platelets

THE ELEMENTS OF HEMOSTASISTHE ELEMENTS OF HEMOSTASIS

Coagulation Factors

FibrinogenFactor II

Tissue FactorFactor V

Factor VIIFactor VIII

Von Willebrand FactorFactor IXFactor XFactor XIFactor XIIFactor XIII

Blood Vessels

ThrombosisBleeding

Balance

The Appropriate Level of HemostasisThe Appropriate Level of Hemostasis

Too Much Anticoagulation in a Thrombotic patient

ThrombosisBleeding Balance

12

A Bleeding Patient with a HighRisk for Thrombosis

ThrombosisBleeding

Balance

Bleeding HistoryBleeding History

FIRST POINT IN DIFFERENTIAL DIAGNOSIS:COAGULATION FACTORS VS. PLATELETS

FIRST POINT IN DIFFERENTIAL DIAGNOSIS:COAGULATION FACTORS VS. PLATELETS

Bleeding History

PREOPERATIVE HEMOSTASIS EVALUATIONPREOPERATIVE HEMOSTASIS EVALUATION

Negative

Preoperative evaluationdictated by

surgical procedure

Establish diagnosis ofcoagulopathy and if

possible the successfulmeasures for hemostasis

Positive

Platelets CoagulationFactors

Number: platelet count

Function: not the bleeding time

PT PTT

Treatment, if any, of abnormal lab values depends on cause of abnormality, degree of abnormality and severity of hemostatic challenge

Bleeding History

OPERATIVE & POSTOPERATIVE HEMOSTASIS EVALUATION

OPERATIVE & POSTOPERATIVE HEMOSTASIS EVALUATION

Coagulopathy Surgical BleedFrom Procedure?

Platelets CoagulationFactors

Number: platelet count

Function: not the bleeding time

PT PTT

BLEEDING HISTORYBLEEDING HISTORY

Epistaxis: Infrequent, brief, self-limited episodesEasy bruising with traumaProlonged bleeding after brushing teethDental extraction: prolonged bleeding*HemoptysisHematemesisMelenaObstetrical/Gynecological Bleeding (menorrhagia, post-partumPost-Operative Bleeding (prolonged* or delayed)Intracranial HemorrhageUmbilical HemorrhagePositive Family History

111222223344

For each of the following positive findings, addup the indicated number of points:

BLEEDING HISTORYBLEEDING HISTORY

Excessive bleeding following injury to mouth or loss of deciduous teethProlonged bleeding from minor injuries*Epistaxis: Frequent prolonged, or requiring treatmentHematuriaHemarthrosis in absence of major traumaTelanglectasiaPetechiae Likelihood for a coagulopathy: > 10 Highly suspicious 5 - 9 Suspicious < 5 Not suspicious

5555888

Each of the above should have no surgical or anatomic lesion to account for the bleeding.*prolonged bleeding = more than one hour

YES

PREOPERATIVE COAGULATION TESTINGPREOPERATIVE COAGULATION TESTING

Screening history for bleedingis negative & minor surgery

Screening history for bleeding is negative & prior surgerywithout problems

Screening history suspiciousfor bleeding or surgical procedurewhich may impair hemostasis orsurgical procedure in which asmall bleed is hazardous

No screening tests butPT/PTT/Platelet countnot unreasonable

No screening tests butPT/PTT/Platelet countnot unreasonable

PT / PTT / Platelet count-bleeding time is not likelyto be useful - von Willebrandtesting and platelet aggregationstudies reasonable

YES

YES

NO

NO

Bleeding Disordersand Severity of

Thrombocytopenia

Bleeding Disordersand Severity of

Thrombocytopenia

PLATELET NUMBER VS. BLEEDING RISKPLATELET NUMBER VS. BLEEDING RISK

400,000

Bleeding manifestation

300,000

Severe spontaneous bleeding

Spontaneous bleeding

Abnormal bleeding with trauma

200,000 100,000

150,000 40,000

10,000

Normal Range

Adequate for Hemostasis

Platelet count / µL

Hemostasis & Thrombosis: A Conceptual Approach, 1979

QUANTITATIVE PLATELET DISORDERSQUANTITATIVE PLATELET DISORDERS

Thrombocytopenia

Very Common

Thrombocytosis

Not Common

THROMBOCYTOPENIATHROMBOCYTOPENIA

Decreased plateletproduction:

Platelet transfusion increases the platelet count

Increased plateletdestruction:

Platelet transfusionsusually do not

increase the platelet count and, if they do, it is

for only short periods

CAUSES OF THROMBOCYTOPENIACAUSES OF THROMBOCYTOPENIA

Immune

Immune thrombocytopenicpurpura-acute & chronic

Post-transfusion purpura

Neonatal alloimmunethrombocytopenic purpura

Drug-induced purpura

Non-immune

Disseminatedintravascular

coagulation

Thromboticthrombocytopenic

purpura

Selected drugs

Bleeding DisordersAnd Decreased

Platelet Function-Including Information onvon Willebrand’s Disease

Bleeding DisordersAnd Decreased

Platelet Function-Including Information onvon Willebrand’s Disease

DIAGNOSIS OF COAGULOPATHIES INVOLVING COAGULATION FACTORS

DIAGNOSIS OF COAGULOPATHIES INVOLVING COAGULATION FACTORS

Screening Tests:

Further Evaluation:

Result:

PT & PTT

Mixing StudiesFactor AssaysInhibitor Assays

> 90% success ratein determining etiologyof abnormal PT / PTT

DIAGNOSIS OF COAGULOPATHIES INVOLVING PLATELET FUNCTION

DIAGNOSIS OF COAGULOPATHIES INVOLVING PLATELET FUNCTION

Screening Tests &

Further Evaluation:

Further Evaluation:

Several tests available – results may not agree

Complex Assays for Wide Variety of Molecules

Result: When a bleeding patient has a normal PT, PTT and platelet count, it is usually very difficult to determine if there is a platelet function defect which may explain the bleeding.

DIAGNOSTIC OVERVIEWDIAGNOSTIC OVERVIEW

PT / PTT Normal - Coagulation Factors AdequatePlatelet Count Normal - Platelet Number Adequate

If Yes, Presume Platelet Function Defect, butWhich Qualitative Platelet Disorder and WillPlatelet Transfusion Promote Hemostasis?

BLEEDING?

PLATELET AGGREGATION STUDIES:THE AGONISTS

PLATELET AGGREGATION STUDIES:THE AGONISTS

AGONIST

Collagen

Arachidonate

ADP

Epinephrine

Ristocetin

RELATIVE POTENCY

Strong

Strong

Moderate - Weak

Weak

Strong - Weak

VerifyNow™ AspirinRapid, easy, and accurate

• RAPID– Result available in 5 minutes

• EASY – Whole blood - no sample

preparation– Automatic sampling from closed

tube– Factory calibrated reagents– Internal quality controls

• ACCURATE– A quantitative reference point

measured in ARUs that correlate to the gold standard of optical aggregometry

• COST-EFFECTIVE– Reimbursement/ CPT code– CLIA-waived

Insert assay device

Add blood sample

Result in one to five minutes

VERIFYNOWTM ASPIRIN MIMICS OPTICAL AGGREGOMETRY

VERIFYNOWTM ASPIRIN MIMICS OPTICAL AGGREGOMETRY

From VerifyNowFrom VerifyNow

DIAGNOSIS OF COAGULOPATHIES INVOLVING PLATELET FUNCTION

DIAGNOSIS OF COAGULOPATHIES INVOLVING PLATELET FUNCTION

Causes ofAcquired Disorders

Drugs (Hundreds)UremiaParaproteinsMany Others

Causes ofCongenital Disorders

IIb - IIIa DeficiencyIb - IX - V DeficiencyAlpha, Delta or Alpha/Delta Granule DeficiencyVon Willebrand Factor AbnormalityCyclooxygenase DeficiencyThromboxane Synthetase DeficiencyThromboxane Receptor Deficiency

If platelet aggregation studies are abnormal,what tests should be performed subsequently

to identify the specific platelet function defect?

von Willebrand’s Disease –

Diagnosis and Treatment

von Willebrand’s Disease –

Diagnosis and Treatment

VON WILLEBRANDS DISEASE:PATTERN OF BLEEDING

VON WILLEBRANDS DISEASE:PATTERN OF BLEEDING

95% of Bleeding Episodes of von Willebrand’s Disease

Patients are Mild to Moderate

Common Bleeding Episodes:Mucosal Bleeding

Bleeding After Surgeryand Dental Extractions

THE TWO DIFFERENT ACTIVITIES OF THEFACTOR VIII-VON WILLEBRAND FACTOR COMPLEX

THE TWO DIFFERENT ACTIVITIES OF THEFACTOR VIII-VON WILLEBRAND FACTOR COMPLEX

Fibrinogen Fibrin

XII

XI

IX VII

VIII vW

VIII

Blood Vessel Wall

vWvWPLT

vWvWPLT

X Xa

III

II IIa

V

TYPE 1 VON WILLEBRAND’S DISEASE

TYPE 1 VON WILLEBRAND’S DISEASE

Quantitative disorder with normal multimer distribution - von Willebrand

factor and ristocetin cofactor decreased approximately equally

Factor VIII may be normal or low

VIII

DDAVP can completely correct

entire defect if it is mild,

by stimulating vW Factor

release from endothelium

TYPE 1 VON WILLEBRAND’S DISEASE

TYPE 1 VON WILLEBRAND’S DISEASE

Decrease in high molecular weight multimers in plasma and sometimes in platelets

Synthesis of large multimers defective or increased proteolysis of large multimers

Ristocetin cofactor and von Willebrand factor antigen both very low

TYPE 2A VON WILLEBRAND’S DISEASE

TYPE 2A VON WILLEBRAND’S DISEASE

Decrease in high molecular weight multimers in plasma only

High molecular weight multimers of vW factor removed from plasma by binding to normal platelets

Plasma ristocetin cofactor and von Willebrand factor antigen both very low

Platelet Membrane Plasma

TYPE 2B VON WILLEBRAND’S DISEASE

TYPE 2B VON WILLEBRAND’S DISEASE

TYPE 3TYPE 3

Quantitative disorder with nearly undetectable levels of von Willebrand

antigen and ristocetin cofactor

Either markedly reduced synthesis of normal von Willebrand factor or synthesis of a highly

dysfunctional von Willebrand factor

Multimer Analysis for Types and Subtypes of von Willebrand’s Disease

Multimer Analysis for Types and Subtypes of von Willebrand’s Disease

INFLUENCE OF ABO BLOOD GROUPON vW FACTOR ANTIGEN VALUES IN

VOLUNTEER BLOOD DONORS

INFLUENCE OF ABO BLOOD GROUPON vW FACTOR ANTIGEN VALUES IN

VOLUNTEER BLOOD DONORS

ABO Type

O

A

B

AB

von Willebrand Factor Mean Value

74.8

105.9

116.9

123.3

n

456

340

196

109

Blood 69, 1691-1695, 1987

TEST FOR DDAVP RESPONSETEST FOR DDAVP RESPONSE

Normal responseof a normal subject

Lack of response

N. Engl. J. Med., 318-881-887, 1988

vWF

300275250225200175150125100 75

-15 0 15 30 45 60 75 90 105 120 135 150 165

Time (Minutes)

vWF

300275250225200175150125100 75

-15 0 15 30 45 60 75 90 105 120 135 150 165

Time (Minutes)

DDAVPInfusion

Common Bleeding DisordersAssociated with

Prolongations of the PT, PTT or both

&Heparin-Induced

Thrombocytopenia

Common Bleeding DisordersAssociated with

Prolongations of the PT, PTT or both

&Heparin-Induced

Thrombocytopenia

MOST CASES WITH COAGULATION FACTORDEFICIENCES ARE MULTIPLE AND ACQUIRED

MOST CASES WITH COAGULATION FACTORDEFICIENCES ARE MULTIPLE AND ACQUIRED

In liver disease, all the factors except VIII are low

In DIC, there is consumption of factors V, VIII fibrinogen and others

With Warfarin and low vitamin K - There are decreased amounts of factors II, VII, IX, and X

In proteinuria, there may be decreases in both factors XI and XII

DISSEMINATED INTRAVASCULARCOAGULATION (DIC)

DISSEMINATED INTRAVASCULARCOAGULATION (DIC)

1) DIC is always a response to an underlying process

2) It results in a generalized activation of hemostatic mechanism

3) The mortality in DIC is related to the underlying disease

DISSEMINATED INTRAVASCULARCOAGULATION (DIC)

DISSEMINATED INTRAVASCULARCOAGULATION (DIC)

Infection

Complications of Pregnancy

Malignancy

Massive Tissue Trauma

FibrinFormation

Thrombin

PlateletActivation

FibrinDegradation

Products

CONDITIONS ASSOCIATED WITH THEDEVELOPMENT OF DIC

CONDITIONS ASSOCIATED WITH THEDEVELOPMENT OF DIC

• Severe infections• Complications of pregnancy - Amniotic fluid embolism - Premature separation of the placenta - Septic abortion - Retained dead fetus - Retained fetal products after delivery• Malignancies• Massive tissue trauma• Hemorrhagic shock• Severe liver disease• Burns

Platelets

Fibrinogen

FDP or D-Dimer

PT

PRACTICAL LABORATORY EVALUATION FOR DIC

PRACTICAL LABORATORY EVALUATION FOR DIC

Changes in DIC

Low or decreasing

Low or decreasing

Increased

Increased

DIAGNOSTIC AND THERAPEUTIC APPROACH TO DIC

DIAGNOSTIC AND THERAPEUTIC APPROACH TO DIC

Bleeding controlled?

DIC risk factor present

Watch forbleeding

Yes

Yes

Yes

No

No

NoLaboratory tests results consistent with DIC?

DIC is present

Is the patient bleeding?

Plasma and platelets, possibly cryoprecipitate for hemostasis, and packed red blood cells

Factor asunmodified

protein

Warfarin Interrupts the Action of Vitamin K - Reducing the Amount of Functional Factors II, VII, IX, and X

Warfarin Interrupts the Action of Vitamin K - Reducing the Amount of Functional Factors II, VII, IX, and X

Factor withgamma

carboxy-glutamic

acids

Warfarin

Vitamin Kepoxide

reductaseactivity

Vitamin K

Vitamin KEpoxide

CH2

CH2

COOH

CH2

HC - COOH

COOH

ALGORITHM FOR WARFARIN USEALGORITHM FOR WARFARIN USE

Maintain As Necessary

Overdose?

Desire to regain theanticoagulated stateas soon as possible?

Significantbleeding?

Stop warfarin& administer

vitamin K

Discontinuewarfarin - give

plasma and Vit K to stop

bleeding

Decrease dose from before

Yes

Yes

Yes

Yes

No

No

NoMaintain

INR at 2.0 - 3.0 or2.5-3.5

Discontinue warfarin & allow

INR to decline

1) Thrombosis/embolism - primary or recurrent

2) Anticipated thrombosis from atrial fibrillation

3) Anticipated thrombosis from presence of prosthetic heart valves

COMMON INDICATIONS FOR WARFARIN THERAPYCOMMON INDICATIONS FOR WARFARIN THERAPY

Rapid Onset Anticoagulant

Clot Warfarin

• In most circumstances, do not administer with anti-platelet drugs (aspirin) to avoid bleeding complications

• With appropriate reagents, adequate anti- coagulation when PTT is > 2.0 X mean of normal PTT range; cannot give orally or instramuscularly- given IV or subcutaneously

• Half life of unfractionated heparin usually 60-90 minutes-effect quickly reversible with discontinuation of heparin

OVERVIEW OF HEPARIN THERAPY WITHSTANDARD UNFRACTIONATED HEPARIN

OVERVIEW OF HEPARIN THERAPY WITHSTANDARD UNFRACTIONATED HEPARIN

ALGORITHM FOR HEPARIN USEALGORITHM FOR HEPARIN USE

No Monitoring

Maintainas Necessary

Full-doseunfractionated

heparin

PTT to > 2.0 X mean of

normal range

Overdose?

Prophylaxis

Low molecular weightheparin prophylaxis or

therapy in non-obese adultswith normal renal function?

Significantbleeding?

Stop heparin-Neutralize with

protamine sulfate

Moreprotamine

sulfate

Persistentbleeding?

Discontinueheparin - & watch

carefully for at least 2 hours

Bleeding?Decrease heparin dose

YesYes

Yes

Yes

Yes

Yes

No

No

No

No

No

NAMEI (Fibrinogen)II (Prothrombin)III (Tissue Factor)VVIIVIIIVon Willebrand FactorIXXXIXIIXIII

COAGULATION FACTORS: SITE OF SYNTHESIS

COAGULATION FACTORS: SITE OF SYNTHESIS

SITE OF SYNTHESISLiver/MegakaryocyteLiver, Vitamin K DependentMultiple Body TissuesLiver/MegakaryocyteLiver, Vitamin K DependentLiver & Other Site(s)Endothelial Cells/ MegakaryocytesLiver, Vitamin K DependentLiver, Vitamin K DependentLiverLiverLiver/Megakaryocyte

Congenital factorDeficiencies –

Some are rare, othersare uncommon and

some are high incidence

Congenital factorDeficiencies –

Some are rare, othersare uncommon and

some are high incidence

FACTOR

IIIVVIIVIIIIXXXIXIIXIII

INCIDENCE OF CONGENITALDEFICIENCY

RARERARERARE

NOT UNCOMMONNOT UNCOMMONNOT UNCOMMON

RARECOMMONCOMMON

RARE

An Example of Not Uncommon Coagulation

Factor Deficiencieswith Serious Bleeding –

Hemophilia A and Hemophilia B

An Example of Not Uncommon Coagulation

Factor Deficiencieswith Serious Bleeding –

Hemophilia A and Hemophilia B

HEMOPHILIA A

HEMOPHILIA A & BHEMOPHILIA A & B

DEFICIENCY OF FACTOR VIII

IN THE COAGULATION CASCADE

HEMOPHILIA B

DEFICIENCY OF FACTOR IX

IN THE COAGULATION CASCADE

DISEASE PATTERN:HEMOPHILIA A & HEMOPHILIA B

DISEASE PATTERN:HEMOPHILIA A & HEMOPHILIA B

Severe

Moderate

Mild

InhibitorsPresent

< 1% Activity

1-5 % Activity

5-50 % Activity

Patients (%)

0 10 20 30 40 50 60

HEMOPHILIA A & HEMOPHILIA BHEMOPHILIA A & HEMOPHILIA B

Genetics of Inheritance: X - Linked Transmission

MotherCarrier

FatherNormal

MotherNormal

FatherHemophiliac

ORX X X Y X X X Y

X X X X X XX XX Y X Y X YX YCarrierNormal Normal Hemophiliac Carrier Carrier Normal Normal

The Use of Recombinant Factor VIIaThe Use of Recombinant Factor VIIa

• Patients with hemophilia A or hemophilia B complicated by inhibitors: Not controversial

• Factor VII Deficiency: Not controversial

• Intracerebral Hemorrhage: Controversial

• Uncontrolled hemorrhage following surgery or trauma: Controversial – limited number of controlled trials but large number of anecdotal reports of hemostatic advantage over conventional therapy

Bleeding History

OPERATIVE & POSTOPERATIVE HEMOSTASIS EVALUATION

OPERATIVE & POSTOPERATIVE HEMOSTASIS EVALUATION

Coagulopathy Surgical BleedFrom Procedure?

Platelets CoagulationFactors

Number: platelet count

Function: not the bleeding time

PT PTT

SUMMARY OF PRESENTATIONSUMMARY OF PRESENTATION

1. Clot Formation and Overview of the Diagnosis of Bleeding Disorders

2. Bleeding History

3. Bleeding Disorders and Severity of Thrombocytopenia

4. Bleeding Disorders and Decreased Platelet Function— Including von Willebrand’s Disease

5. Common Bleeding Disorders Associated with Prolongations of the PT, PTT or both & HIT