Hemophilia in the Neonate

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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 NeonateApril 19, 2002Arturo A. Hernandez, M.D.TTUHSC - El PasoDept. of PediatricsHemophilia 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.
  • 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.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.
  • 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.
  • 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 threateningHemophilia 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
  • 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)
  • 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
  • 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
  • HemarthrosisHallmarkElbows, knees & anklesPain, edema & decr ROMMuscle HematomasPain, edema & atrophyMucous MembranesMouth, teeth, epistaxis, GI Hemorrhage Causing Peripheral Nerve LesionsFemoral, sciatic, tibial, perineal, median & ulnarHematuriaHigh Risk HemorrhagesIntracranial, intraspinal, retropharyngeal & retroperitonealHemophilia A Clinical Features:Common Sites of HemorrhageHemophilia 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.
  • 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
  • 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
  • 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
  • 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)
  • 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.
  • Hemophilia A ManagementNew Treatments
  • Gene therapy
  • Fetal tissue implantation techniques
  • Hemophilia B (Christmas Dz)
  • 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 1993@ 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.)
  • 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 (Cont.)
  • 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 (Cont.)
  • 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
  • HemarthrosisHallmarkElbows, knees & anklesPain, edema & decr ROMMuscle HematomasPain, edema & atrophyMucous MembranesMouth, teeth, epistaxis, GI Hemorrhage Causing Peripheral Nerve LesionsFemoral, sciatic, tibial, perineal, median & ulnarHematuriaHigh Risk HemorrhagesIntracranial, intraspinal, retropharyngeal & retroperitonealHemophilia B Clinical Features:Common Sites of HemorrhageHemophilia B (Cont.)
  • Serum Investigations:
  • Prolonged PTT
  • Decreased FIX
  • Normal PT, BT, thrombin time, & PLT count
  • Hemophilia B Management
  • 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
  • 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
  • Hemophilia B Managementwith 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
  • 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)
  • Hemophilia in the Newborn: Assessing a Bleeding NBN
  • 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.
  • Hemophilia in the Newborn: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
  • Hemophilia in the Newborn
  • 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
  • Hemophilia in the Newborn
  • 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
  • Hemophilia in the Newborn
  • 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.
  • Hemophilia in the Newborn
  • 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.
  • Hemophilia in the Newborn: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
  • Hemophilia in the Newborn: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
  • Thank you.
  • Dr. Carcamo
  • Dr. Quttromani
  • Questions?
  • Discussion
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