Hemophilia VWD

7/30/2019 Hemophilia VWD

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HEMOPHILIA

Inherited deficiency of factor VIII (hemophilia A) or

factor IX (hemophilia B)

Sex-linked inheritance; almost all patients male

Female carriers may have mild symptoms

Most bleeding into joints, muscles; mucosal andCNS bleeding uncommon

Severity inversely proportional to factor level

< 1%: severe, bleeding after minimal injury

1-5%: moderate, bleeding after mild injury> 5%: mild, bleeding after significant trauma or surgery


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GENETICS OF HEMOPHILIA

About half of cases of hemophilia A due toan inversion mutation in intron 1 or 22

Remainder genetically heterogeneous

Nonsense/stop mutations prevent factor

production Missense mutations may affect factor activity

rather than production

15-20% of cases due to new mutations


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IX

X

Fibrinogen Fibrin

PT

XIa

Xa

V

VIII

XIInjury

TF

VIIaIXaVIIIa

Xa

Va

ThrombinPropagation

Initiation

Deficiency of factor VIII or IX affects the propagation phase of

coagulation

Most likely to cause bleeding in situations where tissue factor

exposure is relatively low


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ACUTE COMPLICATIONS OF HEMOPHILIA

Muscle hematoma (pseudotumor)Hemarthrosis

(joint bleeding)


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LONG-TERM COMPLICATIONS OF

HEMOPHILIA

Joint destruction Nerve damage


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Hemophilic arthropathy

Target joint = irreversibly damaged

joint with vicious cycle of injury and

repeated bleeding


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Hemophilic arthropathy

J Throm b Hemost 2010;8:1895

H hili th th


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Hemophilic arthropathyVariable relationship between # of joint bleeds and severity

J Throm b Hemost 2010;8:1895

Green line: Evidence of early joint

damage with relatively few bleeds

Yellow line: Linear relationship

between # of bleeds and joint

damage

Red line: Joint damage occurs after

threshold # bleeds

Blue line: Little joint damage

despite many bleeds


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Management of hemophilic arthropathy

Physical therapy Weight control

COX-2 inhibitors safe and effective

Judicious use of opioids

Surgical or radionuclide synovectomy

Joint replacement


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OTHER COMPLICATIONS OF HEMOPHILIA

Pseudotumor: gradually enlarging cyst in

soft tissue or bone (requires surgery)

Retroperitoneal hemorrhage

Bowel wall hematoma

Hematuria renal colic (rule out structural

lesion)

Intracranial or intraspinal bleeding (rare but

deadly) usually after trauma

HEMOPHILIA


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HEMOPHILIATreatment of bleeding episodes

Unexplained pain in a hemophilia should be

considered due to bleeding unless proven

otherwise

External signs of bleeding may be absent

Treatment: factor replacement, pain control,rest or immobilize joint

Test for inhibitor if unexpectedly low

response to factor replacement


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Dosing clotting factor concentrate

1 U/kg of factor VIII should

increase plasma level by about2% (vs 1% for factor IX)

Half-life of factor VIII 8-12hours, factor IX 18-24 hours

Volume of distribution of factor

IX about twice as high as forfactor VIII

Steady state dosing about thesame for both factors initialdose of factor IX should be

higher

F t l t i h hili A


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Factor replacement in severe hemophilia A

Site of bleed Desired factor lev el Dose Other

Joint 40-50% 20-40 U/kg/day Rest, immobilization,

Muscle 40-50% 20-40 U/kg/day

Risk of compartment

syndrome or neurocompromise

Oral mucosa 50% initially 25 U/kg x 1Follow with

antifibrinolytic thera

EpistaxisIni tially 80-100%, then 30%

until h ealed40-50 U/kg then 30-40

U/kg dailyPressure, packing,

cautery

GIInitially 100%, then 30%

until h ealed

40-50 U/kg then 30-40

U/kg daily

Endoscopy to find

lesion

GUInitially100%, then 30%

until h ealed40-50 U/kg then 30-40

U/kg dailyR/O stones, UTI

CNSInitially100%, then 50%

until h ealed50 U/kg then 25 U/kg q

12h infusion

Trauma or surgeryInitially100%, then 50%

until h ealed50 U/kg then 25 U/kg q

12h infusionTest for inhibitor befo

surgery!

Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 daysTrough factor levels with q 12 h dosing after major surgery should be at least 50-75%

Most joint and muscle bleeds can be treated with minor (50%) doses for 1-3 days without

monitoring


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FACTOR VIII CONCENTRATE

Recombinant

Virus-free, most expensive replacement

Treatment of choice for younger/newly diagnosedhemophiliacs

Somewhat lower plasma recovery than with plasma-derived concentrate

Highly purified

Solvent/detergent treated, no reports of HIV or hepatitistransmission

Intermediate purity (Humate-P)

Contains both factor VIII and von Willebrand factor Solvent/detergent treated, no reports of HIV or hepatitis

transmission

Mainly used to treat von Willebrand disease


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FACTOR IX CONCENTRATE

Recombinant (slightly lower plasma recovery)

Highly purified (solvent/detergent treated, no

reports of virus transmission)

Prothrombin complex concentrate

Mixture of IX, X, II, VII Low risk of virus transmission

Some risk of thrombosis


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DDAVP

Releases vWF/fVIII from endothelial cells

Factor VIII levels typically rise 2-4 fold after 30-60

min (IV form) or 60-90 min (intranasal)

Enhanced platelet adhesion due to vWF

Useful for mild hemophilia (VIII activity > 5%) priorto dental work, minor surgery etc

Trial dose needed to ensure adequate response

Cardiovascular complications possible in older

patients


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Bethesda Assay for Inhibitors

Serial dilutions of patient plasma in normalplasma

Incubate 2 hours

Assay residual factor activity

1 Bethesda Unit neutralizes 50% of factor inan equivalent volume of normal plasma

Example: 1:100 dilution of patient plasma +normal plasma 50% residual factor

activity, so inhibitor titer is 100 BU


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Residualfactoractivity

dilution pt plasma

50%

1:1 1:10 1:100 1:1000

Bethesda Assay

100 BU

TREATMENT OF HEMOPHILIACS WITH


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TREATMENT OF HEMOPHILIACS WITH

INHIBITORS

Recombinant factor VIIa

FEIBA (Factor Eight Inhibitor Bypassing Activity)

Mixture of partially activated vitamin K-

dependent clotting proteases including VIIa

High dose factor VIII (if low titer inhibitor) Induction of tolerance with daily factor VIII

infusions

Optimal dose not established

Role for concomitant immunosuppression?


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Liver disease in hemophilia

Hepatitis C still a problem, though incidence

falling with safer factor concentrates

Treatment for hepatitis C with interferon

often causes thrombocytopenia

Liver transplantation done occasionally(cures hemophilia)

All newly diagnosed hemophiliacs should

be vaccinated against hepatitis A and B


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ACQUIRED FACTOR VIII DEFICIENCY


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ACQUIRED FACTOR VIII DEFICIENCY

Due to antibody to factor VIII (most common

autoimmune factor deficiency) Most patients elderly

Often presents with severe soft tissue or mucosalbleeding (different bleeding pattern than inherited

hemophilia) Laboratory: prolonged aPTT not corrected by

mixing, very low factor VIII activity

Normal INR, thrombin time and platelet count

Treatment: rVIIa, FEIBA, immunosuppression

VON WILLEBRAND DISEASE


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Common (most common?) inherited bleeding

disorder Partial lack of VWF causes mild or moderate

bleeding tendency Menorrhagia, bleeding after surgery, bruising

Typically autosomal dominant with variable

penetrance Laboratory:

Defective platelet adherence (PFA-100) or long bleedingtime

Subnormal levels of von Willebrand antigen and factor

VIII in plasma Low Ristocetin cofactor activity or VWF activity



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Type 1 decreased production of vWF

Levels 20-50%, antigen activity

Type 2 qualitative defect (missense mutation)

Several different types

Usually a disproportionate decrease in vWF activity vs

antigen

Type 3 severe deficiency

Antigen, activity and factor VIII levels < 10%

Hemophilia-like phenotype

Recessively inherited

T 2 WD


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Type 2 vWD

2A: Selective deficiency of large multimers

Defective assembly Increased susceptibility to proteolysis

2B: Increased affinity for platelet Gp Ib

Large multimers bind spontaneously to platelets and

cleared from blood Rarely, a mutation in Gp Ib may have the same effect

(platelet-type vWD)

2M: Decreased vWF function but no loss of largemultimers

2N: Decreased binding of factor VIII to vWF(recessive)


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Weibel-Palade bod y(arrows) in the cytoplasm of endothelial

cell. N - nucleus. Scale = 100 nm. (Human, skin.)

Desmopressin (DDAVP) in vWD


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Desmopressin (DDAVP) in vWD

DDAVP releases vWF from endothelial cells

Can be given IV or intranasally

0.3 mcg/kg IV, or 150 mcg per nostril

Typically causes 2-4 fold increase in blood

levels of vWF (in type 1 vWD), with half-lifeof 8+ hours

Response to DDAVP varies considerably

Administration of a trial dose necessary to

ensure a given patient responds adequately Peak response

Duration of response


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Indications for clotting factor concentrate


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administration in vWD

Type 2 or 3 vWD

Active bleeding

Surgery or other invasive procedure

Type 1 vWD with inadequate response to

DDAVP


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Acquired von Willebrand disease


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Acquired von Willebrand disease

Monoclonal gammopathy: vWF neutralized by

paraprotein (?) Autoimmune disorders: Autoantibody to vWF

Myeloproliferative disorder: large multimersabsorbed onto neoplastic cells (platelets?)

Cardiovascular diseases (AS, VSD, etc): High

shear stress causes unfolding/proteolysis of largemultimers

Hypothyroidism: Decreased release of vWF fromendothelial cells

Treatment varies depending on cause/mechanism

ACQUIRED VON WILLEBRAND DISEASE


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ACQUIRED VON WILLEBRAND DISEASE

NEJM 2009;361:1887

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Hemophilia VWD