Hemophilia in the Neonate
Download
Report
Transcript 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