Download Hemophilia in the Neonate

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.
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 threatening
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
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
Hemophilia A Clinical Features:
Common 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
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.
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 Management
with 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 Management
New 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
Hemophilia B Clinical Features:
Common 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
Hemophilia 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 Management
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
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