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 <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

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. 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 Clinical Features:Common Sites of Hemorrhage

12. 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.

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 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.

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@ 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 <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

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. 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 Clinical Features:Common Sites of Hemorrhage

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 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)

29. 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.

30. 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

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 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

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

36. 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

37. Thank you. • Dr. Carcamo • Dr. Quttromani • Questions? • Discussion