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.


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.


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.


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)


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


• 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


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 concentratePlasmapheresis w/ FVIIIc replacementFactor IX concentratesPorcine FVIIIUse genetically engineered Recombinant FVIIISteroids (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 therapyFetal 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


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


• 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


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 concentratePlasmapheresis w/ FIX replacementPorcine FVIIISteroids (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 beingConsider 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


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


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

Prolongation of PTTB/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.


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. CarcamoDr. QuttromaniQuestions?Discussion

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Hemophilia in the Neonate