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Hemophilia in the Neonate. April 19, 2002 Arturo A. Hernandez, M.D. TTUHSC - El Paso Dept. of Pediatrics. Hemophilia Overview. Hemophilia A & B are caused by deficiencies in clotting factors.

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Hemophilia in the neonate l.jpg

Hemophilia in the Neonate

April 19, 2002

Arturo A. Hernandez, M.D.

TTUHSC - El Paso

Dept. of Pediatrics


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Hemophilia Overview

  • Hemophilia A & B are caused by deficiencies in clotting factors.

  • Both are hereditary disorders which impair the clotting ability of blood and therefore prolong bleeding.

  • Small wounds & punctures are usu. not a problem, but uncontrolled internal bleeding is the issue.


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Hemophilia Overview (Cont.)

  • Mild cases demonstrate bleeding under severe stress, such as a major injury.

  • Moderate cases rarely bleed spontaneously but will bleed after surgery or trauma.

  • Severe cases exhibit spontaneous bleeding - w/o any recognizable trauma;

    - especially joints & muscles.


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Hemophilia Overview (Cont.)

  • Inheritance pattern is X-linked recessive.

  • Females are usu. trait-carriers.

  • Transmission of the gene accounts for 70% of cases while the other 30% occurs from spontaneous gene mutations.


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Hemophilia Overview (Cont.)

  • Family history of bleeding d/o aids in Dx;

    • Pronounced bruising at childbirth or w/ circumcision may suggest severe dz.

    • Moderate cases become apparent during toddler years when falls are common.

    • Mild cases may not become evident until adulthood when surgery is needed.

  • If index of suspicion exists may use labs;

    • Factor levels analysis & aPTT.


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    Hemophilia Overview (Cont.)

    • Signs and symptoms:

      - As toddlers, usu. bleed from simple falls

      - Hematuria

      - Tenderness and edema to bleeding sites such as muscles and joints

      - Bleeding into the CNS or upper airway can be life threatening


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    Hemophilia A

    • Definition:

      • A coagulation d/o characterized by a deficiency in Factor VIIIc (FVIII) resulting in a bleeding diathesis.

  • Epidemiology:

    • Incidence 1/10,000 live male births (80-85%)

    • About 17,000 Americans have Hemophilia A

    • Familial risk factors – X-linked recessive

      • Chromosome Xq28

      • Coagulation Factor VIIIc gene

    • One third of cases result from spontaneous gene mutation

    • Age of onset determined by severity


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    Hemophilia A (Cont.)

    • Pathogenesis:

      • Factor VIII is a complex of two components w/ different genetic control

        • Factor VIIIc - coagulation protein

        • FactorVIIIvW - platelet adhesion protein (carrier protein)

      • FVIIIc is final component of Intrinsic Pathway and along with activated Factor IX activates Factor X within the Common Pathway

      • Plasma levels of FVIIIvW are WNL

        • Female carriers and male fetuses in utero have FVIIIc/FVIIIvW ratio less than 1 (nl ratio is equal to 1)


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    Hemophilia A (Cont.)

    • Clinical severity related to FVIIIc level!

      • Severe

        • FVIIIc activity <1% of normal

        • Onset of bleeding in NBN period

        • FVIIIc does not cross placenta

        • Hematomas post injxn or circumcision

        • Hemarthrosis & deep tissue hemorrhages

        • Spontaneous bleeding

        • Clinical evidence of increased bleeding in 90% by 1yr


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    Hemophilia A (Cont.)

    • Moderate

      • FVIIIc activity 1-5% of normal

      • Onset of bleeding during infancy; excessive bruising w/increased ambulation and some arthrosis

      • Bleeding may be spontaneous but usu. follows mild to moderate trauma

    • Mild

      • FVIIIc activity is >6% of normal

      • Onset of bleeding during childhood

      • Bleeding is not spontaneous and follows moderate to severe trauma, dental work or surgery


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    Hemarthrosis

    Hallmark

    Elbows, knees & ankles

    Pain, edema & decr ROM

    Muscle Hematomas

    Pain, edema & atrophy

    Mucous Membranes

    Mouth, teeth, epistaxis, GI

    Hemorrhage Causing Peripheral Nerve Lesions

    Femoral, sciatic, tibial, perineal, median & ulnar

    Hematuria

    High Risk Hemorrhages

    Intracranial, intraspinal, retropharyngeal & retroperitoneal

    Hemophilia A Clinical Features:Common Sites of Hemorrhage


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    Hemophilia A (Cont.)

    • Serum Investigations:

      • Prolonged PTT, w/normalization after 1:1 mixing w/normal plasma

      • Decreased FVIIIc

      • Normal PT, BT, thrombin time, PLT count & FVIIIvW.


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    Hemophilia A Management

    • Supportive:

      • Avoid trauma and anticoagulants (ASA)

      • Pad crib and playpen

      • Apply pressure and cold compresses to bleeding sites

      • Hepatitis B vaccination

      • Immobilization of affected area & passive exercise w/in 48h to prevent stiffness & fibrosis


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    Hemophilia A Management Replacement Therapy

    • Principles:

      • To secure ordinary homeostasis;

        • Increase FVIIIc activity to 50% normal and maintain for 48-72h

        • May use e-aminocaproic acid (Amicar) and desmopressin (DDAVP) (0.3mcg/kg IV)

      • For high risk hemorrhages

        • Raise FVIIIc activity to 50% normal for 2wk


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    Hemophilia A Management Replacement Therapy

    • Cryoprecipitate

      • Inexpensive

      • Prepared from fresh plasma and therefore not recommended b/c carries risk of HIV & Hep C

      • 1bag/5kg BW incr. FVIIIc to 50% of normal

  • Factor VIIIc Concentrate

    • Expensive

    • Dispensed as lipophilized powder in 250-500U

    • 1U/kg raises FVIIIc activity by 2%

    • Dose is 20-50U/kg depending upon severity of hemorrhage

    • Contains anti-A and anti-B isohemagglutinins


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    Hemophilia A Managementwith FactorVIIIc Inhibitors

    • Results from developed antibodies to transfused FVIIIc

    • Use massive doses of FVIIIc concentrate

    • Plasmapheresis w/ FVIIIc replacement

    • Factor IX concentrates

    • Porcine FVIII

    • Use genetically engineered Recombinant FVIII

    • Steroids (immunosuppression)


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    National Hemophilia Foundation’s Medical and Scientific Advisory Council Recommendations (MASAC 1999)

    • Factor VIII products for young and newly diagnosed pts. who have not received any blood or plasma derivatives.

    • Immunoaffinity purified FVIII concentrate for pts. who are HIV seropositive.

    • Cryoprecipitate is not recommended b/c of high risk of HIV and hepatitis infection.

    • Mild hemophilia A should be treated with desmopressin, in a DDAVP injection or Stimate nasal spray.


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    Hemophilia A Management Advisory Council Recommendations (MASAC 1999)New Treatments

    • Gene therapy

    • Fetal tissue implantation techniques


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    Hemophilia B (Christmas Dz) Advisory Council Recommendations (MASAC 1999)

    • Definition:

      • A coagulation d/o characterized by a deficiency in Factor IX (FIX) resulting in a bleeding diathesis.

  • Epidemiology:

    • First described in Stephen Christmas, a British boy in He died in [email protected] age 46 from AIDS

    • Incidence 1/40,000 live male births (15-20%)

    • Familial risk factors – X-linked recessive

      • Chromosome Xq27.1-q27.2

      • Coagulation Factor IX gene

    • One fifth of cases result from spontaneous gene mutation

    • Age of onset determined by severity


  • Hemophilia b cont l.jpg
    Hemophilia B (Cont.) Advisory Council Recommendations (MASAC 1999)

    • Pathogenesis:

      • Factor IX is a component of the Intrinsic Pathway and in its activated form combines w/FVIII and a phospholipid to activate Factor X within the Common Pathway


    Hemophilia b cont21 l.jpg
    Hemophilia B (Cont.) Advisory Council Recommendations (MASAC 1999)

    • Clinical severity related to FIX level!

      • Severe

        • FIX activity <1% of normal

        • Onset of bleeding in NBN period

        • Hematomas post injxn or circumcision

        • Hemarthrosis & deep tissue hemorrhages

        • Spontaneous bleeding

        • Clinical evidence of increased bleeding in 90% by 1yr


    Hemophilia b cont22 l.jpg
    Hemophilia B (Cont.) Advisory Council Recommendations (MASAC 1999)

    • Moderate

      • FIX activity 1-5% of normal

      • Onset of bleeding during infancy; excessive bruising w/increased ambulation and some arthrosis

      • Bleeding may be spontaneous but usu. follows mild to moderate trauma

    • Mild

      • FIX activity is 5-20% of normal

      • Onset of bleeding during childhood

      • Bleeding is not spontaneous and follows moderate to severe trauma, dental work or surgery


    Hemophilia b clinical features common sites of hemorrhage l.jpg

    Hemarthrosis Advisory Council Recommendations (MASAC 1999)

    Hallmark

    Elbows, knees & ankles

    Pain, edema & decr ROM

    Muscle Hematomas

    Pain, edema & atrophy

    Mucous Membranes

    Mouth, teeth, epistaxis, GI

    Hemorrhage Causing Peripheral Nerve Lesions

    Femoral, sciatic, tibial, perineal, median & ulnar

    Hematuria

    High Risk Hemorrhages

    Intracranial, intraspinal, retropharyngeal & retroperitoneal

    Hemophilia B Clinical Features:Common Sites of Hemorrhage


    Hemophilia b cont24 l.jpg
    Hemophilia B (Cont.) Advisory Council Recommendations (MASAC 1999)

    • Serum Investigations:

      • Prolonged PTT

      • Decreased FIX

      • Normal PT, BT, thrombin time, & PLT count


    Hemophilia b management l.jpg
    Hemophilia B Management Advisory Council Recommendations (MASAC 1999)

    • Supportive:

      • Avoid trauma and anticoagulants (ASA)

      • Pad crib and playpen

      • Apply pressure and cold compresses to bleeding sites

      • Hepatitis B vaccination


    Hemophilia b management replacement therapy l.jpg
    Hemophilia B Management Replacement Therapy Advisory Council Recommendations (MASAC 1999)

    • Factor IX Concentrate

      • 1U/kg raises FIX activity by 1-1.2% of normal

      • 30-80U/kg depending upon severity of hemorrhage

      • Risk of Hepatitis B & C viruses

  • Fresh Frozen Plasma

    • 1 unit of FIX/cc


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    Hemophilia B Management Advisory Council Recommendations (MASAC 1999)with FactorIX Inhibitors

    • Results from developed antibodies to transfused FIX

    • Use massive doses of FIX concentrate

    • Plasmapheresis w/ FIX replacement

    • Porcine FVIII

    • Steroids (immunosuppression)

    • Genetically Recombinant FIX


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    National Hemophilia Foundation’s Medical and Scientific Advisory Council Recommendations (MASAC 1999)

    • Factor IX products for young and newly diagnosed pts. who have not received any blood or plasma derivatives.

    • Immunoaffinity purified FIX concentrate or Recombinant FIX for pts. who are HIV seropositive.

    • For pts. with inhibitors to factors VIII & IX, Recombinant FVIIa (NovoSeven) is available (produced by baby hamster kidney cells, no human albumin or other proteins used, reducing virus risk)


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    Hemophilia in the Newborn: Assessing a Bleeding NBN Advisory Council Recommendations (MASAC 1999)

    • Assess baby’s well being

    • Consider risk factors (esp. family history)

    • PE w/special attention to evidence of birth trauma, incl. bruises & petechiae, flank mass & HSM.


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    Hemophilia in the Newborn: Advisory Council Recommendations (MASAC 1999)Bleeding NBN Physical Exam

    • General signs of hemorrhage

      • Tachycardia, tachypnea & hypotension

    • Organ system-specific

      • CNS - abnl neuro exam & meningismus

      • GI - hepatic/splenic tenderness & pritoneal signs

      • GU - bladder spasm, distension, pain & CVAT

      • Musculoskeletal – joint tenderness, pain w/movement, decr ROM, effusion & calor


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    Hemophilia in the Newborn Advisory Council Recommendations (MASAC 1999)

    • Lab studies:

      • CBC (to assess H/H, plt count)

      • PT & aPTT

      • Factor VIII level

  • Imaging studies:

    • Head CT

    • Body CT as directed by clinical suspicion

    • MRI for further assessment

    • Angiography & nucleotide bleeding scan


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    Hemophilia in the Newborn Advisory Council Recommendations (MASAC 1999)

    • Medication:

      • Recombinant FVIII or FIX infusion to correct activity to 100% of normal

      • For CNS, GI & airway hemorrhage

        • 50U/kg FVIII, then cont. infusion of 2-3U/kg/hr to maintain FVIII>100 U/dL for 24hr, then for 5-7d to keep FVIII>50

        • 80U/kg FIX, then 20-30U/kg q12-24hr to maintain FIX>20U/dL for 5-7d then >30 for 5d


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    Hemophilia in the Newborn Advisory Council Recommendations (MASAC 1999)

    • Most commonly presents with prolonged oozing from heel puncture or bleeding from circumcision.

    • Prolongation of PTT

    • B/c FVIII reaches normal adult range by 20 weeks’ gestation, Dx is usu. not difficult to assign @ birth.

    • FIX develops more slowly and normal term infants may have FIX activities as low as 15%. Therefore only severe FIX deficiency Dx @ birth.


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    Hemophilia in the Newborn Advisory Council Recommendations (MASAC 1999)

    • Affected babies must receive factor infusions prior to surgery or invasive procedures.

    • Immunizations may be given IM & vitamin K may be delivered using careful technique to avoid muscle trauma.

    • Direct pressure for min of 10 min. in attempt to decrease hemorrhage.

    • IM administration of drugs (Abx) should be avoided.


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    Hemophilia in the Newborn: Advisory Council Recommendations (MASAC 1999)Current Issues

    • Intracranial Hemorrhage has been reported in 1-4% of hemophiliac NBNs.

      • May be the first indication of Dx

  • Surveys show that even in the face of documented ICH, few neonatalogists consider the Dx and/or order appropriate tests

  • Majority of hematologists disagree w/ administration of Clotting Factor Concentrates to Dx NBN to offset birth trauma


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    Hemophilia in the Newborn: Advisory Council Recommendations (MASAC 1999)Current Issues

    • Major concern is safe delivery w/ minimal trauma to minimize hemorrhage risks

      • No guidelines for mode of delivery (NVSD vs CS)

      • Avoid vacuum and forceps deliveries

  • Survey states only 47% OB routinely save cord blood for future clotting assays in NBN of known carrier


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    Thank you. Advisory Council Recommendations (MASAC 1999)

    • Dr. Carcamo

    • Dr. Quttromani

    • Questions?

    • Discussion


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