Hemophilia in the Neonate

1
Hemophilia in the Neonate

• April 19, 2002
• Arturo A. Hernandez, M.D.
• TTUHSC - El Paso
• Dept. of Pediatrics

2
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.

3
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.

4
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.

5
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.

6
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

7
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

8
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)

9
Hemophilia A (Cont.)

• Clinical severity related to FVIIIc level!
• Severe
• FVIIIc activity
• 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

10
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

11
Hemophilia A Clinical FeaturesCommon Sites of
Hemorrhage

• 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

12
Hemophilia A (Cont.)

• Serum Investigations
• Prolonged PTT, w/normalization after 11 mixing
  w/normal plasma
• Decreased FVIIIc
• Normal PT, BT, thrombin time, PLT count FVIIIvW.

13
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

14
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

15
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

16
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)

17
National Hemophilia Foundations 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.

18
Hemophilia A ManagementNew Treatments

• Gene therapy
• Fetal tissue implantation techniques

19
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_at_ 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

20
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

21
Hemophilia B (Cont.)

• Clinical severity related to FIX level!
• Severe
• FIX activity
• 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

22
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

23
Hemophilia B Clinical FeaturesCommon Sites of
Hemorrhage

• 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

24
Hemophilia B (Cont.)

• Serum Investigations
• Prolonged PTT
• Decreased FIX
• Normal PT, BT, thrombin time, PLT count

25
Hemophilia B Management

• Supportive
• Avoid trauma and anticoagulants (ASA)
• Pad crib and playpen
• Apply pressure and cold compresses to bleeding
  sites
• Hepatitis B vaccination

26
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

27
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

28
National Hemophilia Foundations 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)

29
Hemophilia in the Newborn Assessing a Bleeding
NBN

• Assess babys well being
• Consider risk factors (esp. family history)
• PE w/special attention to evidence of birth
  trauma, incl. bruises petechiae, flank mass
  HSM.

30
Hemophilia in the NewbornBleeding 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

31
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

32
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 FVIII100 U/dL for 24hr, then for
  5-7d to keep FVIII50
• 80U/kg FIX, then 20-30U/kg q12-24hr to maintain
  FIX20U/dL for 5-7d then 30 for 5d

33
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 _at_
  birth.
• FIX develops more slowly and normal term infants
  may have FIX activities as low as 15. Therefore
  only severe FIX deficiency Dx _at_ birth.

34
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.

35
Hemophilia in the NewbornCurrent 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

36
Hemophilia in the NewbornCurrent 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

37
Thank you.

• Dr. Carcamo
• Dr. Quttromani
• Questions?
• Discussion