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Common InheritedCoagulation Disorders

Bob Miller, PA2017

Inherited Coagulation Disorders Brief review of coagulation Disorders related to platelet dysfunction

(not the acquired thrombocytopenias) Disorders related to coagulation factor deficiencies

Focus: Presenting features and initial lab tests Basics of treatment approaches

All coagulation factors and platelets in circulation(unactivated)

vWF+VIII

P

PP

P

P

PP

P PP

PvWF+VIII

vWF+VIIIvWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VWF has two jobs ...Binds and protects FVIII & tethers to site of injury

Site of injury with exposure to subendothelium with platelet activation

vWF+VIII

P

PP

P

PP

P PPvWF+VIIIvWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VIII

vWF+VIII

P PP

Contact with tissue factor other subendothelial tissues

VWF tethers to exposed endothelium at site of injury

vWF+VIII

P

PP

P

PP

P PP

VIII

vWF+VIIIvWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VIII

vWF+VIII

vWF vWFShear

vWF

pP

Platelets are activated and adhere to VWF and then aggregate to form platelet plug

vWF+VIII

P

PP

P

PP

P PP

VIII

vWF+VIIIvWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VIII

vWF+VIII

vWF vFW vWFP PP

PPP

Activated coagulation proteins form fibrin strands

vWF+VIII

P

PP

P

PP

P PP

X

vWF+VIIIvWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF vWF vWFP

PP PP

PIX XIIIVII

VIII

VIII

Fibrin Strands

Fibrin Clot

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

A representation of normal platelet responses and the congenital disorders of

Bernard Soulier Syndrome

vWD Glanzmanns Thrombasthenia

Deficiency of Platelet Coagulant Activities

Fibrinogen

GP IIb/III

a

Afibrinogenemia

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 / gums petechiae menorrhagia

Coagulation type ...

bruising soft tissue muscles joints

If there is platelet pattern bleeding ... CBC gives you the platelet count And also the H&H may reflect the amount of

bleeding possibly leading to anemia

If the count is normal, look at platelet function

Platelet Function Evaluation IVY bleeding time Plt Aggregation to : ADP

Epinephrine CollagenRistocetinArachidonic acid

PFA - Platelet function analyzer Consider VWD as cause of platelet pattern bleeding

Inherited Disorders Affecting Platelets Low von Willebrand factor protein (very common)

von Willebrand Disease (VWD)

Functional defects of the platelet (rare)Glannsmans thrombastheniaBernard-Soulier syndrome

Vessel wall abnormalities (rare)Connective tissue disorders

Reproduced with permission from: Rao AK. Am J Med Sci. 1998;316:6976.

A representation of normal platelet responses and the congenital disorders of platelet function

Bernard Soulier Syndrome

vWD Glanzmanns Thrombasthenia

Deficiency of Platelet Coagulant Activities

Fibrinogen

GP IIb/III

a

Afibrinogenemia

VWD.patterns of bleeding

VWD Mucous membranes Epistaxis Gum bleeding Menorrhagia Superficial (petechiae)

Hemophilia Deep bruising Hematomas Joints Muscles

von Willebrand Disease

Estimated 1% of population (autosomal)

Type 1 mild / most common

Type 2 mild to moderate

Type 3 severe

von Willebrand Disease Platelet count is normal (except in rare VWD 2B)

The platelets are normal but have reduced adhesion to site of injury if inadequate VWF (the glue)

The FVIII is normal but reduced amount because lack of VWF to carry and protect FVIII

VWD.diagnosisTest for these assays (levels)

FVIII (FVIII function) VWF:Ag (presence of Ag)Ristocetin cof (VWF function)

These are the basic initial lab tests to order to look for VWD

( some would add VWF multimers )

von Willebrand Disease

Type 1

Reduced quantity of VWF (quantitative) VWF normal, amount is reduced Mild and most common type ~ 80% of all VWD

VWD.diagnosis

FVIII VWF:AgRCof

Type 1All three tests partially decreased

to similar levelsTypically 20 to 50% (50-150)

Basic Bleeding Work-upCBC w/ platelet ct WNL

PT 11.2 (10-12)

PTT 46 (31-43)Extra coag tube

FVIII 38 (50-150)VWF Antigen 42 (50-150)Ristocetin (RCof.) 35 (50-150)

Basic Bleeding Work-upCBC w/ platelet ct WNL

PT 10.9 (10-12)

PTT 46 (31-43)Extra coag tube

FVIII 38 (50-150)VWF Antigen 12 (50-150)Ristocetin (RCof.) 5 (50-150)

(discordant)

von Willebrand DiseaseType 2 Qualitative defects

Type 2ALacks HMW multimers

Type 2BGain of functionIncreased platelet binding = low platelet ct

von Willebrand Disease

Type 2 Qualitative defectsType 2M

Decreased binding to GP1bType 2N (Normandy)

Normal amount of VWF (Ag & Rcof normal)Decreased binding to FVIII = low FVIII

(? Misdiagnosed as hemophilia A)

VWF Multimers

von Willebrand Disease

Type 3

< 5% of VWDVWF very low or absent (quantitative)Severe clinical features

Basic Bleeding Work-upCBC w/ platelet ct NL

PT 11.0 (10-12)

PTT, 1:1 mix 79 (31-43)Extra coag tube

FVIII 6 (50-150)VWF Antigen 3 (50-150)Ristocetin RCof. 0 (50-150)

All 3 low

VWD ... lab tests to fine tune DX

VIII VWF:Ag RCof

Bleeding time VWF multimers Blood group RIPA Platelet count Genetic

von Willebrand Disease

Diagnosis Repeated testing may be needed if borderline values Bleeding history important Family history / inheritance Autosomal dominant / recessive

Basic Bleeding Work-upCBC w/ platelet ct NL

PT 11.1 (10-12)

PTT, 1:1 mix 43 (31-43)Extra coag tube

FVIII c 60 (50-150)VWF Antigen 41 (50-150)Ristocetin (R cof.) 52 (50-150)

von Willebrand Disease Treatment DDAVP (desmopressin) intranasal (Stimate) or IV

Causes release of storage pool FVIII and VWFMost Type 1 respond, some Type 2, no Type 3Contraindicated in Type 2B

Factor VIII concentrates containing VWF needed for cases unresponsive to DDAVP. (new rVWF available)

Inherited Defects of Coagulation Factors

Coagulation Testing (oversimplified) PTT XIIXI

IX PTVIII VII

XV

Prothrombin

Thrombin

Fibrin Fibrinogen clot XIII

(not tested by PT/PTT)

Coagulation Testing (oversimplified) PTT XIIXI

IX PTVIII VII

XV

Prothrombin

Thrombin

Fibrin Fibrinogen clot XIII

(not tested by PT/PTT)

Normal PT with abnormal PTTisolates the problem to these four factors

Thromboelastograph (TEG)PT & PTT measures clot initiation

90% of clot dynamics occur after clot initiation

Queen Victoria

HemophiliasClassic hemophilia AFactor VIII deficiency

Hemophilia BFactor IX deficiencyChristmas disease

Hemophilia SeverityFactor VIII or IX level

Normal = 50 150%

Severe < 1 %

Moderate 1 - 5 %

Mild 6 - 50 %

Hemophilia Treatment Prevent bleeding ! Consider prophylactic FVIII or IX (2-3 x wk) Treat bleeding early - replace the missing factor VIII

or IX with concentrates given IV

Monitor for complications such as orthopedic, viral and inhibitors

Hemophilia Inhibitors Antibodies inhibitors develop in ~ 20% of persons

with severe hemophilia A Antibodies neutralize the infused coagulation factor

May require an activated concentrate to control bleeding

Hemophilia Treatment Donor derived

factor concentrates in the 70s and 80s led to viral complications

HBV, HCV, HIV

MMWRJuly 16, 1982

Epidemiologic Notes and Reports Pneumocystis

carinii Pneumonia among Persons with Hemophilia A

Hemophilia Treatment

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

A Recombinant Technology

MammalianCELLS

produce aprotein

Protein ispurified

Lyophilizedproduct

Mammalian cells are provided with genetic information to produce a target protein.

Cell lines may include CHO, BHK, HEK

CRISPR Gene EditingClustered Regularly Interspaced Short Palindromic Repeats

(CRISPR)

Genome can be cut to remove or add genes Palindrome is set of characters reading the same forward

& backwards (madam / racecar) helps to localize and identify gene sequences

? Hemophilia, Thalassemia, SSA, CF, Others

CRISPR (Cut ... or Cut & Paste)

[ ]DNA target sequence

[ ] RNA guide

[ ]Cas9 Enzyme cuts both DNA strands

[x]Targete