Common Inherited Bleeding Disorders · Bleeding Disorders Bob Miller, PA October 8, 2015 VWF has two jobs Loosely bound to protect FVIII and tether to site of injury vWF+VIII P P

CAPA 2015 Annual Conference

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Common InheritedBleeding Disorders

Bob Miller, PA

October 8, 2015

VWF has two jobsLoosely bound to protect FVIII

and tether to site of injury

vWF+VIII

P

P

P

P

P

P

P

P PP

PvWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

All other coagulation factors also in circulation

Injury to the blood vessel

vWF+VIII

P

P

P

P

P

P

P

P PP

PvWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

Contact with tissue factor

and other subendothelial tissues


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Bleeding at site of injury with exposure tosubendothelium with platelet activation

vWF+VIII

P

P

P

P

P

P

P PP

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VIII

vWF+VIII

P P

P

VWF “tethers” to exposed endotheliumat site of injury

vWF+VIII

P

P

P

P

P

P

P PP

VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VIII

vWF+VIII

vWF vWF

Shear

vWF

pP

Platelets are activated and “adhere” to VWFand then “aggregate” to form “platelet plug”

vWF+VIII

P

P

P

P

P

P

P PP

VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VIII

vWF+VIII

vWF vFW vWFP P

P

P

PP


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Activated coagulation proteins formfibrin strands

vWF+VIII

P

P

P

P

P

P

P PP

X

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF vWF vWFP

PP

P

P

P

IXXIIIVII

V

III

VIII

Fibrin Strands

Fibrin Clot


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Reproduced with permission from:Rao AK. Am J Med Sci.1998;316:69–76.

A representationof normal plateletresponses and thecongenitaldisorders ofplatelet function

Bernard SoulierSyndrome

vWD Glanzmann’sThrombasthenia

Deficiency of PlateletCoagulant Activities

Fibrinogen

GPIIb/III

a

Afibrinogenemia


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Copyright © 2011 American Society of Hematology. Copyright restrictions may apply.

Peter Maslak, ASH Image Bank 2011; 2011-3689

Petechiae

Patterns of Bleeding

Platelet type …

• mucous membrane

• epistaxis

• petechiae

• menorrhagia

Coagulation type ...

• bruising

• soft tissue

• muscles

• joints

Platelet Function Evaluation

• IVY bleeding time

• Plt Aggregation to : ADP

Epinephrine

Collagen

Ristocetin

Arachidonic acid

• PFA - Platelet function analyzer


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Inherited Disorders AffectingPlatelets

• Low von Willebrand factor protein (common)

von Willebrands Disease (VWD)

• Function defects in the platelet (rare)

Glannsman’s thrombasthenia

Bernard-Soulier syndrome

• Vessel wall abnormalities (rare)

Connective tissue disorders

Reproduced with permission from:Rao AK. Am J Med Sci.1998;316:69–76.

A representationof normal plateletresponses and thecongenitaldisorders ofplatelet function

Bernard SoulierSyndrome

vWD Glanzmann’sThrombasthenia

Deficiency of PlateletCoagulant Activities

Fibrinogen

GPIIb/III

a

Afibrinogenemia

VWD….bleeding

VWD

• Mucous membranes

• Epistaxis

• Menorrhagia

• Superficial (petechiae)

Hemophilia

• Deep bruising

• Joints

• Muscles


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von Willebrand Disease

• Estimated 1% of population (autosomal)

• Type 1 mild / most common

• Type 2 mild to moderate

• Type 3 severe


Type 1

• Reduced quantity of VWF

• VWF normal, just reduced

• Mild and most common

• ~ 80% of all VWD

VWD….diagnosis

FVIII

VWF:Ag

RCof

Type 1

All three partiallydecreased tosimilar levels


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Basic Bleeding Work-up

CBC w/ platelet ct NL

PT 11.2 (10-12)

PTT 46 (31-43)

Extra coag tube

FVIII 38 (50-150)

VWF Antigen 42 (50-150)

Ristocetin (R cof.) 35 (50-150)



PT 10.9 (10-12)

PTT 46 (31-43)

Extra coag tube

FVIII 32 (50-150)




Type 2

Qualitative defects in function

• Type 2A

Lacks HMW multimers

• Type 2B

“Gain of function”

Increased platelet binding = low plt ct


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Type 2

Qualitative defects in function

• Type 2M

Decreased binding to GP1

• Type 2N (Normandy)

Normal amount of VWF

(Ag & Rcof normal)

Decreased binding to FVIII = low FVIII

? Misdiagnosed as hemophilia A

A Short Case # 1

• MR is a 10 y/o Caucasian male scheduledfor a tonsillectomy

• HX of excess bleeding beginning severalhours after recent tooth extraction. Epistaxishas been rare and of short duration. Someminor bruising in the past – usually aftersports. No recent medications.

Case #1 Initial Lab Values

Pre-op lab values revealed:

• Prolonged PTT = 45 sec (24-38)

• Normal PT = 11.5 sec (10-13)

• CBC normal except for a plt ct of 95,000


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Case #1 Lab Workup

• Prolonged PTT ?

Factor VIII level = 36% (50-150)

• Low platelet ct ? VWD type 2B ?

VWF Ag = 38% (50-150)

Rcof = 11% (50-150)

• Further confirming workup

RIPA increased

Multimers = loss of HMW

VWF Multimers


Type 3

• VWF very low or absent

• Severe clinical features


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PT 11.0 (10-12)

PTT, 1:1 mix 59 (31-43)

Extra coag tube

FVIII 3 (50-150)

VWF Antigen <12 (50-150)

Ristocetin R cof. <6 (50-150)

VWD ... lab tests

• VIII

• VWF:Ag

• RCof

• Bleeding time

• VWF multimers

• Blood group

• RIPA

• Platelet count


Diagnosis

• Repeated testing may be needed

• Bleeding history important

• Family history / inheritance

• Autosomal dominant / recessive


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PT 11.1 (10-12)

PTT 43 (31-43)

Extra coag tube

FVIII c 60 (50-150)




Treatment

• DDAVP (desmopressin) intranasal or IV

Most Type 1 respond, some Type 2, no Type 3

Contraindicated in Type 2B

• Factor VIII concentrates which include VWFmay be needed in some cases

Inherited Defects ofCoagulation Factors


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Coagulation Testing (oversimplified)aPTT XII

XI

IX PTVIII VII

X

V

Prothrombin

↓

Thrombin

↓

Fibrinogen Fibrin

Clot

XIII (not tested by PT/PTT)

Thromboelastograph (TEG)

PT & PTTmeasures clotinitiation

90% of clotdynamics occurafter clotinitiation

Coagulation Testing (oversimplified)

XII

XI

IX

VIII VII

X

V

Prothrombin

↓Thrombin

↓

Fibrinogen Fibrin

clot

PT

aPTT

Normal PT withabnormal PTTisolates the problemto these four factors


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Queen Victoria

Hemophilias

“Classic” hemophilia A

Factor VIII deficiency

Hemophilia B

Factor IX deficiency

“Christmas disease”


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Hemophilia Severity

Circulating FVIII or FIX level

Normal = 50 –150%

• Severe < 1 %

• Moderate 1 - 5 %

• Mild 6 - 50 %


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Hemophilia Treatment

• Prevent bleeding !

• Consider prophylactic FVIII or IX (2-3 x wk)

• Treat bleeding early - replace the missingfactor VIII or IX (given IV)

• Monitor for complications such as orthopedic,viral and inhibitors


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Hemophilia Prophylaxis

• IV Prophylaxisgiven 2 to 3 times aweek can preventmost bleedingepisodes

• Regimen basedmostly on half-life


• Donor derived factorconcentrates in the70’s and 80’s led toviral complications

• HBV, HCV, HIV

MMWR

July 16, 1982

Epidemiologic Notesand Reports

Pneumocystis cariniiPneumonia among

Persons withHemophilia A


• Safer plasma derived concentrates are now used

• Newer products using recombinant technology

• New products with a longer half-life

• DDAVP used in mild hemophilia A


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A Recombinant Technology

Mammalian

CELLSproduce aprotein

Protein ispurified

Lyophilized

product

• Mammalian cells are provided with geneticinformation to produce a target protein.

• Cell lines may include CHO, BHK, HEK …

Hemophilia Inhibitors

• Antibodies “inhibitors” develop in ~ 20%of persons with severe hemophilia A

• Antibodies neutralize the infusedcoagulation factor

• May require an “activated” concentrate tocontrol bleeding

Coagulation Testing (oversimplified)

XII

XI

IX

VIII VII

X

V

Prothrombin

↓Thrombin

↓

Fibrinogen Fibrin

clot

PT

aPTT

Normal PTT withabnormal PTisolates the problemto factor VII


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Coag Factor Deficiencies

Factor VII deficiency

• Autosomal

• Rare 1:500,000

• Bleeding variable

• Bleeding does notcorrelate with level

• Treat with rFVIIa

Factor XI deficiency

• Autosomal

• Rare > 1:100,000

• Ashkenazi Jews (8%)

• Bleeding variable

• Treat with FFP or rVIIa

(No FXI available)

Factor Deficiencies

Factor XII deficiency

• Autosomal

• Rare

• Prolongs the PTT

but does not result in

clinical bleeding

Surgery is OK

Factor XIII deficiency

• Autosomal

• Rare

• PT / PTT normal

• Excess bleeding fromumbilical stump

Federal Regional Hemostasis &Thrombosis Centers (HTCs)

(Hemophilia Treatment Centers)


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Captain Morgan, The Rescue Dog

Documents

Common Inherited Bleeding Disorders · Bleeding Disorders Bob Miller, PA October 8, 2015 VWF has two jobs Loosely bound to protect FVIII and tether to site of injury vWF+VIII P P