Download - Common Inherited Coagulation Disorders - Amazon S3s3-us-west-2.amazonaws.com/capa-wp/wp-content/uploads/2017/06/... · Common Inherited Coagulation Disorders Bob Miller, PA 2017 Inherited

Common InheritedCoagulation Disorders

Bob Miller, PA

2017

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+VIII

vWF+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

P

P

P PPvWF+VIII

vWF+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

P

P

P PP

VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VIII

vWF+VIII

vWF vWF

ShearvWF

pP

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

vWF+VIII

P

PP

P

P

P

P PP

VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

VIII

vWF+VIII

vWF vFW vWFP PP

PP

P

Activated coagulation proteins form fibrin strands

vWF+VIII

P

PP

P

P

P

P PP

X

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF+VIII

vWF vWF vWFP

PP

PP

PIX XIIIVII V

IIIVIII

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 Glanzmann’s 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

Collagen

Ristocetin

Arachidonic 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)

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

Bernard Soulier Syndrome

vWD Glanzmann’s 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


• 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….diagnosis

Test 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” )


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:Ag

RCof

Type 1All three tests partially decreased

to similar levels

Typically 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)


Ristocetin (RCof.) 5 (50-150)(discordant)


Type 2 “Qualitative” defects

Type 2A

Lacks HMW multimers

Type 2B

“Gain of function”

Increased platelet binding = low platelet ct


Type 2 “Qualitative” defects

Type 2M

Decreased binding to GP1b

Type 2N (Normandy)

Normal amount of VWF (Ag & Rcof normal)

Decreased binding to FVIII = low FVIII

(? Misdiagnosed as hemophilia A)

VWF Multimers


Type 3

< 5% of VWD

VWF 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)


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


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)


Ristocetin (R cof.) 52 (50-150)

von Willebrand Disease Treatment

• DDAVP (desmopressin) intranasal (Stimate) or IV

Causes release of storage pool FVIII and VWF

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

Contraindicated 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 XII

XI

IX PTVIII VII

X

V

Prothrombin

Thrombin

Fibrin

Fibrinogen clot XIII

(not tested by PT/PTT)


XI

IX PTVIII VII

X

V

Prothrombin

Thrombin

Fibrin



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

Hemophilias

“Classic” hemophilia A

Factor VIII deficiency

Hemophilia B

Factor IX deficiency

“Christmas disease”

Hemophilia Severity

Factor 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


• Donor derived factor concentrates in the 70’s and 80’s led to viral complications

• HBV, HCV, HIV

MMWR

July 16, 1982Epidemiologic Notes and

Reports Pneumocystis carinii Pneumonia among

Persons with Hemophilia 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

A Recombinant Technology

MammalianCELLS

produce aprotein

Protein ispurified

Lyophilized

product

• 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]Targeted gene is removed (silenced) orreplaced (improved)

Federal Regional Hemostasis & Thrombosis Centers (HTCs)

(Hemophilia Treatment Centers)

Captain Morgan, The Rescue Dog


XI

IX PTVIII VII

X

V

Prothrombin

Thrombin

Fibrin



Normal PTT with abnormal PTisolates the problem to factor VII

Rare Coagulation Factor Deficiencies

Factor VII deficiency

• Autosomal

• Rare 1:500,000

• Bleeding variable

• Bleeding does not correlate 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)

Rare Coagulation 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 from umbilical stump


XI

IX PTVIII VII

X

V

Prothrombin

Thrombin

Fibrin

