Congenital BleedingDisorders

Ma. Ysabel Lesaca-Medina, MDPediatric Hematology-Oncology

Prince Leopold

Born

1853

Princess beatrice,9th child

Princess louise

Prince leopold, 8th child

Married to Princess Helene: 1882

Princess Alice Hemophilia carrier

London news:Death of the

duke of albany

March 27, 1884

Villa Nevada

Morphine side effects

Prince charles

Princess alice

Outline What is and how does hemostasis occur?

How does one evaluate a patient presenting with bleeding?

What are the features of the Congenital Bleeding Disorders?

Hemophilia A, Hemophilia B Von Willebrand Disease Platelet function disorders Rare Coagulation Factor Deficiencies

What is Hemostasis ?

Maintenance of fluid blood flow

Prevention of bleeding

Hemostasis – 3 stages

1. Vascular

– vasoconstriction

2. Platelet (PRIMARY HEMOSTASIS)

– Platelet plug formation

3. Coagulation (SECONDARY HEMOSTASIS)

– Fibrin thrombus formation

– Clotting factors

Intact vessel

Platelet Phase

platelet phase

Resting activated platelets

Coagulation phase

Fibrin Clot

PTT

APTT

PT

TT

Factor XIII cross links fibrin

Clinical Evaluation of Bleeding patient

Clinical History

Detailed History Symptoms:

Epistaxis

gum bleeding, easy bruising, menorrhagia, hematuria, GI bleeding

(platelet problem)

hemarthrosis, intramuscular bleed

(coagulation problem)

Delayed onset bleeding

(factor XIII problem)

Detailed History Response to hemostatic challenge:

circumcision, surgery, phlebotomy, immunization, suture placement/removal

Underlying medical conditions : liver disease, renal failure, vitamin K

deficiency

Medications: antiplatelet drugs, anticoagulants,

antimetabolites, antibiotics

Detailed History

Family history:

similar symptoms response to hemostatic challenge, consanguinity Menorrhagia

> 3 soaked pads /day Flooding Hb < 10g/L

Physical Examination

Physical Examination

Petechiae < 2mm Purpura 2mm – 1 cm

Hematoma

Ecchymoses > 1 cm

Physical Examination

HEMARTHROSIS

Physical Examination

INTRAMUSCULAR BLEED, PSOAS

Laboratory evaluation

Laboratory Evaluation Initial lab tests

CBC with platelet PT (extrinsic)- VII, X, V, II, I PTT (intrinsic)- XII, XI, IX, VIII, X, V,II, I

Further work up:

Thrombin time PFA, platelet aggregation Mixing Studies, clotting factor assays, VW

antigen tests, urea clot lysis assay

DDX, based on initial screen

↑ PTNormal

plt, Normal

PTT

↑ PTTNormal plt, Normal PT

↑ PT,PTTNormal plt

•Early Liver Disease

•Early Vit K Def

•F VII Def

•F VIII def(hemophilia or VWD)

•F IX, XI, XII def

•Inhibitors

•Late Liver Disease

•Late Vit K deficiency

•Massive Transfusion

↑ PTT, TTNormal PT, Normal plt

All normal Platelet dec

Heparin - activates AT III AT III inactivates thrombin

- PTT more sensitive to heparin

VWDPlatelet fxn d/oMild factor def (VIII, IX, XI, XIII )

Collagen DisorderVitamin C def

CAMT, TAR,BSSWAS, GPS

ITPInfection

CAMT = Congenital Amegakaryocytic Thrombocytopenia BSS = Bernard Soulier Syndrome

TAR = Thrombocytopenia with Absent Radius

GPS = Gray Platelet Syndrome WAS = Wiskott Aldrich Syndrome

Out Patient Clinic Time

6 year/ M

Needs dental extraction; sent for hematologic clearance

History of easy bruisability

Mother and aunts report easy bruisability and strong menses

2 cousins died during delivery of unknown cause

Labs

CBC Normal

PT Normal

PTT 39.3 (23 – 33 secs)

DDX, Normal plt, Normal PT prolonged PTT,

Dec Factor VIII due to

Hemophilia A VWD

Dec Factor IX, XI, XII

Lupus anticoagulant or other coagulation factor inhibitors

Factor VIII : 0.29 u/ml (0.5 – 1.5 u/ml)

VWF : 1.2 u/ml (0.5 – 1.5 u/ml)

Hemophilia A, mild

Diagnosis

HEMOPHILIA Essentials

Factor VIII (or IX ) deficiency X-linked (2/3) or

spontaneous mutation (1/3) Sxs: Bruising, soft tissue

bleeding, hemarthrosis Labs: Prolonged PTT + dec

factor VIII (or IX) levels

HEMOPHILIA Most common severe congenital

bleeding disorder

Prevalence

Hemophilia A (Factor VIII) 1 / 10,000 males

Hemophilia B (Factor IX) 1 / 50,000 males

HEMOPHILIA – severity classification

Factor VIII – reported in units / ml ( 1 unit/ml = 100%

factor activity)

- Normal range: 0.5 – 1.5 IU/ml (50 – 150%)

Classification

- Severe (60% of cases) : < 1% factor VIII (spontaneous bleeding)

- Moderate : 1 to < 5%

- Mild : 5 – 50 % ( only with trauma and surgery)

HEMOPHILIA- Lab findings

PTT (normal plt; normal PT)

Dx is confirmed by Factor Assay

F VIII ( with normal VWF ) = Hemophilia A

Dec F IX = Hemophilia B

HEMOPHILIA- S/Sx Severe Hemophiliacs

Usually initial presentation in 1st 2 years of life ( severe bruising and joint bleeds)

40 – 50% present in the 1st month of life

1- 4% present in the neonatal period (birth trauma)

HEMOPHILIA Mild or Moderate

Boys Trauma related bruising or bleeding

Excessive bleeding following surgery or dental extraction

Girls ( carriers )

~ Often with Factor VIII < normal

Mild bruising or bleeding

Heavy menstrual periods

HEMOPHILIA-Cxs Hemarthroses

If recurrent joint destruction Intracranial hemorrhage

Leading cause of death among hemophilliacs

Intramuscular hematomas

Compartment syndrome muscle and nerve death ( anterior forearm, anterior tibial compartment)

HEMOPHILIA-Cxs• Infection

• HIV, Hep B, Hep C• Not at risk, With current donor screening and

viral inactivation of factor concentrates,

• But still at risk for:

• Hepatitis A• Creutzfeld-Jakob Disease• Parvovirus B-19

• Recommend Hep A and Hep B vaccines for all pxs

HEMOPHILIA-Cxs

• Acquired antibody to Factor VIII

• Antibody that inactivates F VIII function

• Develops in

• 30% of pxs with severe hemophilia

• < 5% of Hemophilia B

Antibody to factor VIII

• Quantified by Bethesda units• 1 Bethesda unit – inactivates 50% of F VIII

function

• TREATMENT:

• < 5 B.U.

• Increase dose of F VIII

• > 5 BU

• Bypass agents: prothrombin complex conc ; FVII

• ITI (immune tolerance induction)

HEMOPHILIA-Tx

General aim of Mx:

correct factor VIII to w/in normal limits prevent or stop bleeding

Mild

May respond to desmopressin (ADH)

- Releases endothelial stores of VWF

Most still need exogenous F VIII after

HEMOPHILIA-Tx• Factor VIII dose

• Non-life/limb threatening bleed• 20 to 30 u/kg 40 – 60% F VIII activity

• Large hemarthrosis and life/limb threatening bleed• 50 u/KG 100% F VIII activity

• Cryoprecipitate • 100 u F VIII / unit• e.g. 10 kg child –> 20 u/kg =

• 200 u F VIII -> 2 u cryoppt)

• (FFP (contains factor IX) – used for Hemophilia B)

HEMOPHILIA-Tx Prophylaxis

Preventive F VIII infusions 2 to 3x, weekly To achieve F VIII level >1% Expensive Initiate after 1st joint bleed Do not start before 6 months of

age – increases risk of inhibitor devlpt

HEMOPHILIA TREATMENT

in the pipe line

GENE THERAPY

NEXT PATIENT please…

13 / female

Cc: menometrorhagia

Easy bruising and occasional epistaxis since childhood

Gum bleeding on toothbrushing

No previous BT

Iron supplement in the past

Family History

Maternal grandmother and mother with epistaxis and heavy menses

3 brothers and 2 sisters normal

Hb 114

Platelet 300 (150 – 450)

PT : normal; 12.9 sec INR 1.1

PTT : normal; 32.5 (23.5 – 33.5)

↑ PTT, TT

Normal PT, platelet

All normal Platelet dec

Heparin VWDPlatelet fxn d/o

Mild factor def (VIII, IX, XI, XIII )

Collagen Disorder

Vitamin C def

CAMT, TAR,BSS

WAS, GPS

ITP

2 Infection

VIII

0.48 u /ml (0.5 – 1.5 u/ml)

VWF Ag

0.20 u /ml (0.5 – 1.5 u/ml)

VonWillebrand Disease,

type 1DIAGNOSIS

Von Willebrand Disease

Most common inherited bleeding disorder (Prevalence: 1% - by lab def’n; only 10% symptomatic)

Quantitative or Qualitative deficiency of vWF

Easy bruising / epistaxis from childhood / menorrhagia

Dr. Erik Von Willebrand, 1926

Diagnosis

Criteria VWF Ag < 30% Or VWF Ag 30-50% , in

patient with clinical symptoms supportive of VWF

The Von Willebrand Factor

Protein in plasma

Function

1. Tethers platelets to damaged endothelium

2. Binds and protects Factor VIII

Endothelial cells w/stored VWF

vWD

vWD- Classification Type 1

Classic ; 80% of patients Partial quantitative deficiency

Type 2

Dysfunctional VWF- qualitative

Type 3

Nearly COMPLETE deficiency

vWD-Inheritance Mostly AD ; can be AR

Theoretically, equal males and females But more females dxd (menorrhagia)

Can be acquired

rare Hypothyroidism, Wilms tumor,

Cardiac disease, Renal disease or SLE / Valproic acid

Most often caused by Ab to VWF

vWD- S/Sx Increased bruising and excessive epistaxis

Prolonged bleeding with trauma or surgery

Menorrhagia

Significant menorrhagia from menarche

prompt investigation for congenital bleeding d/o

vWD-Labs Initial screen:

- PT normal

- PTT sometimes prolonged

> in type 3 (factor VIII dec)

- Platelet sometimes dec

> in types 2 and 3

Most of the time: PT, PTT, platelet --- NORMAL

Blood type ‘O ’ – normally lower vWF

VWD Bleeding time

- prolonged

Platelet function analyzer – prolonged

closure time

vWF assay

- Definitive test

vWD -Treatment VWD types 1 and 2

Desmopressin Releases vWF from endothelial stores IV or intranasal ( high concentration spray ) Variable response measure VIII and vWF

60 minutes after May cause fluid shifts (hyponatremia

seizures ) Tachyphylaxis occurs (stored VWF limited)

Further therapy with VWF concentrate or cryoprecipitate

VWD -treatment Intermediate purity F VIII

concentrates

Cryoprecipitate

AdjunctiveTreatment Antifibrinolytic agents

(Tranexamic acid / E-aminocaproic acid ) Prevents plasminogen plasmin For mucosal bleeding

Topical thrombin and fibrin glue Estrogen containing contraceptive tx

For menorrhagia

Rare Coagulation Disorders

Rare coagulation disorders

Other congenital coagulation factor deficiencies Afibrinogenemia /hypofibrinogenemia Deficiencies of factor V, VII, X, XI, XIII

Combined, occur in 1-500,000 to 1:2,000,000 Autosomal recessive

Most common : Factor VII def Causes most bleeding sxs: Factor X and

Factor XIII def

Rare coagulation disorders

S/Sx

Umbilical stump bleeding

Delayed cord separation

Intracranial or intestinal hemorrhage

Muscle hematomas

Easy bruising

Prolonged bleeding ff heelprick

Inherited platelet Disorders

Inherited platelet disorders

Decreased number and abn function

Bernard Soulier Syndrome (BSS) Wiskott Aldrich Syndrome (WAS) Gray Platelet Syndrome (GPS)

Normal number but abn function

Glanzman Thrombasthenia (GT) Storage Pool Disorder (SPD)

Dec # and abn platelet fxnDefect S/Sx Labs

BSS No GPIb/IX plt receptor -> defective binding to VWF

ARecessive

Bruising/ bleeding from infancy

Moderate thrombocytopenia

Large platelets

GPS Alpha granule deficiency

Severe bruising bleeding from early age

Mild thrombocytopenia

Large gray/Agranular platelets

GLANZMANN THROMBASTHENIA

Defect S/Sx Labs

Normal number

Normal morph

Platelet GP IIb/IIIA

(fibrinogen receptor) – FAILS TO AGGREGATE

ARecessive

Severe spont’ mucosal bleeding

Presents in infancy

BT

Flow cytometry

Plt aggregation

SUMMARY

Summary Hemostasis

3 stages Vasoconstriction

Platelet phase

Coagulation phase

Congenital bleeding disorders

Hemophilia A, B VWD Rarer coagulation disorders Inherited platelet disorders

Summary Suspect a congenital bleeding disorder

Symptoms presenting in early infancy/childhood

Similar symptoms in family members Consanguinity

Most common disorders

Hemophilia VWD

Summary Do coagulation screen

Deranged PTT only Think…

Hemophilia – hemarthrosis/intramuscular bleed

VWD – bruising / petechiae, epistaxis

Platelet, PT, PTT all normal Think…

VWD Platelet function disorder Mild coagulation disorders

Hemophilia A or B

(factor VIII /IX def)

VWD

(VWF def or abn)

Inheritance X linked

De novo (1/3)

AD

(few AR)

S/Sx Easy bruisability

Hemarthrosis

Soft tissue bleed

Menorrhagia

Easy bruisability

Epistaxis

Menorrhagia

Labs Prolonged PTT Normal plt, PT, PTT

< Prolonged PTT (few) >

Confirmatory test

Factor VIII /IX assay VWF assay

Treatment Desmopressin (for mild Hemophilia A)

Recomb Factor VIII /IX

Cryoprecipitate /FFP

Desmopressin

Intermediate purity FVIII

Cryoprecipitate