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. 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

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 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)

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 Management New 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. 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

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 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

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