Common Inherited Coagulation Disorders - Amazon...

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Common Inherited Coagulation 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 P P P P P P P P P P vWF+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

Transcript of Common Inherited Coagulation Disorders - Amazon...

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

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….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” )

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: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)

VWF Antigen 12 (50-150)

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

von Willebrand Disease

Type 2 “Qualitative” defects

Type 2A

Lacks HMW multimers

Type 2B

“Gain of function”

Increased platelet binding = low platelet ct

von Willebrand Disease

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

von Willebrand Disease

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)

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 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)

Coagulation Testing (oversimplified) PTT XII

XI

IX PTVIII VII

X

V

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

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

Hemophilia Treatment

• 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

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

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

Coagulation Testing (oversimplified) PTT XII

XI

IX PTVIII VII

X

V

Prothrombin

Thrombin

Fibrin

Fibrinogen clot XIII

(not tested by PT/PTT)

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

Coagulation Testing (oversimplified) PTT XII

XI

IX PTVIII VII

X

V

Prothrombin

Thrombin

Fibrin

Fibrinogen clot XIII

(not tested by PT/PTT)