Hemophilia royal disease
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Hemophilia (Royal Disease). KJFKLSDJKL. Royal Family Pedigree. Review 1. All coagulation pathways lead to activation of prothrombin and formation of fibrin clot! The activity = enzyme action Enzyme action depends on amount of protein present and the structure of protein.

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Hemophilia (Royal Disease)

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Hemophilia royal disease

Hemophilia (Royal Disease)

KJFKLSDJKL


Hemophilia royal disease

Royal Family Pedigree


Review 1

Review 1

  • All coagulation pathways lead to activation of prothrombin and formation of fibrin clot!

  • The activity = enzyme action

  • Enzyme action depends on amount of protein present and the structure of protein

Graphic accessed http://www.ganfyd.org/images/3/32/CoagulationAndFibrolyticPathways.png, 2009.


Introduction genetics and inheritance x linked recessive

Introduction :Genetics and InheritanceX-linked Recessive

  • X-linked genes are never passed from father to son

  • An affected female must have an affected father

  • Males are always hemizygous for X linked traits, that is, they can never be heterozygoses or homozygotes

  • Males are never carriers

    • In a male a single dose of a mutant gene will produce a mutant phenotype in the male

    • In a female will be either homozygous for the normal gene, heterozygous (carrier), or homozygous (have trait) for the mutant gene.

Information and graphic accessed http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=glossary&rendertype=box&id=further_illus-226, 2009.


Hemophilias introduction

Hemophilias Introduction

  • Hemophilia

    • Inherited

    • X-linked (recessive)

      • A & B

    • Autosomal

      • C

    • Single factor deficiencies

    • Anatomic soft tissue bleeding

Graphic accessed URL http://www.daviddarling.info/images/hemophilia_inheritance_1.gif, 2008.


Hemophilias introduction genetics

Hemophilias Introduction: Genetics

A & B

genes for both FVIII and FIX are located on the long arm of chromosome X

The gene for FVIII (F8C) is unusually large

FVIII contains 2332 amino acids

Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of hemophilia A defects

The FIX gene (F9) is small

FIX contains 415 amino acids

Point mutations and deletions in the FIX gene are the most common causes of hemophilia B

C

gene for factor XI is on the distal arm of chromosome 4

Mutations described so far are associated with mainly failed or reduced production of the active protein, and only a few are related to the production of a dysfunctional molecule.

Graphic accessed http://www.biochem.arizona.edu/classes/bioc471/pages/Lecture25/TktR-2.jpeg, 2009.


Hemophilias introduction1

Hemophilias Introduction

  • Prevalence

    • North America & Europe

      • A - 1 in 5000 male births

        • US 21 cases per 100,000 male individuals w/ 60% severe disease

      • B – 1 in 25,000 male births

        • US 5.3 cases per 100,000 male individuals w/ 44% severe disease

      • C – 1 in 100,000 population

        • High prevalence in Ashkenzai and Iraqi Jews

        • Israel – 8% rate

        • United Kingdom 383 in 58 million population

  • Severity Classification

    • Clinical bleeding symptoms

      Or

    • Plasma procoagulant levels

      • < 1% normal factor activity

        • Severe

      • 1 – 5% normal factor activity

        • Moderately severe

      • 5 – 40% normal factor activity

        • Mild hemophilia


Classic hemophilia viii deficiency

Classic Hemophilia – VIII Deficiency

  • FVIII 2-chain glycoprotein produced by liver and endothelium

  • Cleaved by thrombin producing a calcium dependent heterodimer that complexes with IXa

  • VIIIa-IXa (Tenase) cleaves X

  • Deficiency of VIII slows production of thrombin

    • hemorrhage

Graphic accessed http://kuwaitmd.hsc.edu.kw/main/files/images/Coagulation_cascade.png, 2009.


Hemophilia a clinical manifestations

Hemophilia A: Clinical Manifestations

  • Anatomic Bleeds

    • Deep muscle

    • Joint

    • Wound oozing

    • CNS bleeds – can be the fatal event in those younger than 18 years of age

    • Body cavity hemorrhage

  • Loss of mobility

  • Neurological symptoms

http://www.kelleycom.com/blog/uploaded_images/synovitis-784213.jpg

Graphic accessed URL http://library.thinkquest.org/05aug/00112/Images/knee.jpg, 2008.


Hemophilia a diagnosis

Hemophilia A Diagnosis

  • Clinical Presentation

    • Family history

    • Abnormal neonatal bleeding

      • Umbilicus

      • Circumcision

      • Intracranial

  • Laboratory

    • Prolonged PTT

      • PT prolonged in newborns

    • Factor assay

      • VIII, IX, XI

  • Rule out:

    • vWD

    • PLT disorders

    • Other factor deficiencies

    • Hypo/dysfibrinogenenia

Graphic accessed URL http://labtestsonline.org/understanding/analytes/coag_cascade/Coag%20Testing%20Cascade.pdf, 2008.


Treatment

Products available

Recombinant FVIII

Factor VIII concentrate

Recombinant VIIa

DDAVP – increase vWF

Aminocaproic acid – anti-fibrinolytic

FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours.

Treatment regimen examples

Severe epistaxis

Factor concentrate until 50% level achieved

Also consider aminocaproic acid 1-2 days

Surgery

Factor VII concentrate until 80% level achieved

10-14 days

Treatment

  • Goal – reduce morbidity, prevent complications


Hemophilia b a k a christmas disease

Hemophilia B a.k.a Christmas Disease

  • X-linked, recessive disorder

  • Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors

    • spontaneous hemorrhage

    • excessive hemorrhage in response to trauma

  • Occurrence

    • 1 in 25,000 males in US

    • 1 in 60,000 males worldwide

Graphic accessed URL http://coursewareobjects.elsevier.com/objects/elr/Rodak3e/IC/jpg/Chapter41/041005.jpg, 2008.


Hemophilia b differential diagnosis

Lab Studies

CBC

PLT count – NL

PT - NL

PTT - prolonged

Factor XI - severe disease less than 1%; moderate disease 1-5%; mild disease greater than 5%.

Hemophilia B – Differential Diagnosis

  • Hemophilia A

  • VWDVitamin K and other factor deficiencies

  • Afibrinogenemia

  • Fibrinolytic diseases

  • Platelet disorders


Treatment1

Treatment

Recombinant factor IX - level should be corrected to 100% of normal for potentially serious hemorrhage

Goal to keep trough level > 50% activity

Coagulation factor IX concentrates - used to correct the patient's native deficiency

Goals: 1) achieve a normal hematologic response to hemorrhage; 2) prevent hemorrhage

Factor IX complex concentrates (II, X, VII)

Circumvent inhibitor issue

FFP

Coagulation Factor VIIa (Recombinant) - activate coagulation factor X to factor Xa as well as coagulation factor IX to IXa

Epsilon aminocaproic acid (Amicar)


Hemophilia c

Hemophilia C

  • Factor XI deficiency (variable bleeding usually following trauma/surgical interventions)

  • Autosomal inheritance

    • 1 per 100,000 persons

    • Even heterozygotes can have bleeds

  • Mild to moderate bleeding

    • bleeding risk in hemophilia C is not always influenced by the severity of the deficiency

  • Prevalence in Ashkenzai Jews

  • Severity of bleeding episode not correlated with factor levels

    • PT, TT – normal

    • PTT – prolonged

  • Rule out

    • PLT dysfunction

    • Other factor deficiencies


Hemophilia c treatment

Hemophilia C Treatment

  • “Factor XI concentrates

    • FFP 

    • Fibrin glue (e.g., Tisseel VH)

    • Aminocaproic acid

Matthew Prasad, MB, BS, DCH - Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico.


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