Emergency Care of a Patient with Hemophilia - PowerPoint Presentation

1. Emergency Care of a Patient with HemophiliaRobin Reid, MDClinical Director, Mary M Gooley Hemophilia CenterHematologist and Medical Oncologist, Rochester Regional HealthJuly 2021

2. OutlineHistory of the Mary M Gooley Hemophilia Treatment CenterBackground on Hemophilia Treatment of HemophiliaReal world cases Questions

3. Mary M Gooley Hemophilia CenterMary M. Gooley worked as a Medical Technician at Rochester General Hospital in the 1940s and was working in 1947 when a mother, Dorthea Golemb, brought in her 9 y/o son who had hemophilia.He had been stuck unsuccessfully many times that day. Mary Gooley and the nurse, Dorothy White, she was working directly with met the patient and family. Dorothy White was able to place the IV on the first attempt. They all became close friends.Together, the three of them joined forces to improve support and medical care for people with hemophilia. They created the first hemophilia support group in Rochester.This was on their own at RGH, no formal bleeding disorders program existed.

4. Mary M Gooley Hemophilia CenterThis grew to include other families and evolved into the Rochester Chapter of the National Hemophilia Foundation. One of the first NHF chapters outside of New York CityIn 1959, Mary M Gooley established a formal hemophilia treatment center (HTC) Mary kept plasma in her home freezer for patients, bringing it to the patients at their home on nights or weekends when needed. She trained volunteers to make cryoprecipitate She educated doctors, administrators, insurance companies, employers, schools, and families

5. Mary M Gooley Hemophilia CenterOur center, is one of the oldest treatment centers in the United States.Our center helped establish the other treatment centers in Buffalo, Syracuse, Southern Tier and AlbanyIt is a separate stand alone non-for-profit center. It is on Rochester Regional Health campus but is not part of RRH.It is a federally designated hemophilia treatment center (HTC), but also a chapter of the National Hemophilia Foundation (NHF)We have our own pharmacy that we run to provide factor directly to patients and hospitals

6. Mary M Gooley Hemophilia CenterIn addition to treating Hemophilia A (VIII) and B (IX), as well as VWD We also treat patients with rare bleeding disorders including:Factor VII deficiencyFactor X deficiencyFactor XI deficiencyFibrinogen (I) deficiency/defectDisorders in platelet function Acquired bleeding disorders: Acquired Hemophilia A (FVIII) and acquired VWD

7. Mary M Gooley Hemophilia CenterPhone: 585-922-5700Open M-F 8am-430 pmOur after hours info is on a message if calling after hours, after hours phone: 585-399-1717 There is a MD on call 24 hours a day, 7 days a weekWhen calling during the day; our administrative assistants and nurse coordinators are knowledgeable, easy to get a hold of, and know our patients wellhttp://www.hemocenter.org1415 Portland Ave MOB suite 500 Rochester, NY 14621

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9. What is hemophilia

10. How we form a clotFollowing injury to a blood vessel, the blood vessel will contract to limit flow to the areaThis exposes collagen and releases VWFPlatelets stick to the site of injury and release chemical signals More platelets stick and form a “platelet plug”Many clotting factors are on the surface of these activated platelets and together interact in the “coagulation cascade” to form a fibrin clotFibrin works like a mesh to stop the bleedingWFH inherited bleeding disorders

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12. Clotting cascadeHemophilia AHemophilia B

13. Hemophilia backgroundHemophilia A is a deficiency in factor VIII (8)Hemophilia B is a deficiency in factor IX (9)They are both congenital, x-linked disorders

14. Hemophilia backgroundAbout 22,000 people in the US have hemophilia and it affects approximately 1 in 5,000 new male births30% of cases are of new mutations without a family history (spontaneous mutation)It affects all races and ethnic groupsPrevalence in the United States is estimated to be 1: 10,000 for Hemophilia A (VIII) and 1:25,000 Hemophilia B (IX). With 50-60% of those cases being severe <1% factor levelsVon Willebrand Disease is more common. Equally affecting women and men and estimated to be 1% of the general population per CDC (1/100)

15. Hemophilia backgroundSeverity of the disease: “rule of thumb, normal factor levels are between 50%-150%”Severe hemophilia with Factor <1%Spontaneous bleeding, typically infancyModerate hemophilia Factor 1-5%Trauma related bleeding, toddler-childMild hemophilia Factor >5%Trauma related bleeding/surgery, teen or even adult at diagnosisSeverityFactor VIII (8) levelaPTTSevere<1%70-100secModerate1-5%50-70 secMild5-40%30-70 sec>50%Normal 22-36 sec

16. Clinical symptomsHemarthrothisis 75% of hemophilia bleeding is joint relatedKnees> elbows>ankles>shoulders>wrist>hipOften develop a “target joint” with cycle of inflammationIf not treated quickly, develop joint destructionOsteoporosis, cysts, joint space narrowingHematomas:Classic characteristic of hemophiliaCan bleed into muscles, develop compartment syndromePseudotumors Trauma/surgery

17. Hemophilia ManagementIdeally bleeds should be treated as soon as possible, but within 3 hours of the start of a bleedTreating a.s.a.p. will:Increase the successful outcome Decrease the overall amount of factor needed to treat the bleedDecrease the long-term damage to the patients (ex, target joint, risk for pseudotumor with muscle hematoma)Treat before imaging if emergency situation (MVA, trauma to head, etc)

18. Treatment of Hemophilia

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20. History of treatment products for hemophiliaFresh Frozen Plasma (FFP) introduced in 1960s. Contains all the coagulation factorsFFP has the lowest concentration of factors of all replacement products availableFactor concentration 1 IU/mL (FVIII and FIX)Concerns still exist over safety due to blood-born infections (roughly 1:1million risk HIV/Hepatitis per each blood transfusion/product)Cryoprecipitate introduced in 1960s: prepared from FFP, contains substantial amounts of FVIII, VWF, fibrinogen, and factor XIII (does not have FIX or FXI)Factor concentration of ~3-4 IU/mL FVIIIConcerns still exist over safety due to blood-born infections

21. History of treatment products for hemophiliaPlasma derived clotting factor concentrates (plasma derived factor) examples: alphanate, profilnine, mononine [Humate-P mostly VW but has VIII as well]Introduced 1969, processed from pooled plasma from multiple donorsContributed to HIV/Hepatitis outbreak in 1980sToday, virally inactivated and no further viral infection since the late 1990sFactor concentration ~2000 IU/mLRecombinant clotting factor concentrates examples: kogenate, advate, benefixIntroduced 1990sArtificially produced factor concentrates. No infectious complicationsFactor concentration ~2000 IU/mL

22. History of treatment products for hemophiliaExtended half-life clotting factor concentrates. Examples eloctate, alprolixArtificially manufactured clotting factor that is modified to extend half lifeIntroduced in 2014Non-factor replacement: emicizumab (hemlibra)Monoclonal antibody that functions like factor VIII (Hemophilia A pts only) to activate clotting cascadeApproved 2017

23. EmicizumabMeet factor VIII turns into FVIIIa when an injury happensFVIIIa brings IXa and X together to assist with forming a clotPeople with Hemophilia A have little to no FVIII depending on their severityhttps://www.hemlibra.com/patient/about-hemlibra/how-hemlibra-works.html

24. Emicizumabhttps://www.hemlibra.com/patient/about-hemlibra/how-hemlibra-works.htmlEmicizumab acts as a bridge to bring FIXa and FX together, it does what FVIII would normally do.Monoclonal antibody: much longer half life (20+days instead of 8 hours), Subcutaneous injection as opposed to IVCannot be measured (factor levels? Equivalent to around 15-30%, but maybe more like 7%)Interferes with clot based assays (normal coags in our labs) making aPTT very short, and unable to measure factor VIII levels at all.

25. Other treatment optionsDDAVP (desmopressin): releases stored FVIII and VWF from endothelium and temporarily increases levels in bloodCan be considered in mild hemophilia A patients. Not severe, does not work for hemophilia B patientsTachyphylaxis, hyponatremia, and seizures are concernsAntifibrinolytics including ɛ-aminocaproic acid (amicar) and tranexamic acid (lysteda)Best for mucosal bleeding, where the fibrinolytic system is most activeContraindicated in hematuria/genitourinary bleeding of unclear source due to risk of causing ureter obstruction/clot if bleeding from more proximal source (renal pelvis/kidney)

26. Other treatment optionsNovo7Recombinant factor VIIa, activatedUnable to measure lab effectsVery short half life and dosed roughly every 2 hoursFEIBA (Factor Eight Inhibitor Bypassing Agent)Inactivated factors II, IX, X and activated VII activated prothrombin complex concentrate (aPCC) Unable to measure lab effectsDosed roughly every 8 hoursWhat about KCENTRA?Inactivated PCC containing factors II, VII, IX and X (vitamin K dependent factors)Difference is that it is inactivated. Not studied in hemophilia with inhibitor. Approved for reversal of anticoagulation (warfarin)

27. Hemophilia ComplicationsInhibitors can develop in mostly those with Hemophilia A (VIII) and severe hemophilia (<1%)The immune system attacks the exogenous factor, making it degrade quickly or be ineffectiveDevelops within first 50 exposures to factor replacement (childhood)30% of those with Hemophilia A develop inhibitors, only 1-2% of those with Hemophilia BTreated with immune tolerance induction (ITI): high dose and frequent (daily or qod) infusion of factor replacement, at home, with goals of developing toleranceDuring active inhibitor presence, patient will not respond well to standard dosing factor VIII infusions, or at all, and will be typically treated by “bypassing agents”Novo7 or aPCC (FEIBA)

28. Emergency Room Cases

29. CASE 14 day old boy has circumcision just prior to discharge home. Following discharge, he starts to have bleeding soaking through 4 diapers and family brings him back to their local hospital. Attempt made to cauterize and silver nitrate applied and patient sent home1 hour later the bleeding restarted, they went back to their local ED. Reporting total 7 diapers soaked with blood.Labs obtained with Hgb/Hct 14/39, plt 186. no coagulation testing doneTransferred patient to Rochester, NYUpon ED arrival Hgb/Hct now 8.2/23. Five dissolvable stitches were placed Hgb/Hct 6.3/17Transfused 2 units of PRBCHematology consulted

30. Case 1The next day: coags obtained PT 12.1 sec/INR 1.1 [10-12.9 sec/ 0.9-1.1]aPTT 97.9 sec (H) [25.8-37.9 sec]VW antigen 190% [44-166%], VW activity 221% [37-174%]Factor VIII <5% [68-156%]Factor IX 69% [92-161%]Patient referred to our center following discharge and factor VIII level <1%No family history of hemophilia A, suspected spontaneous mutationPatient now on emicizumab (hemlibra) ppx

31. Case 1 pointsGet coags with unusual or persistent bleeding: PT, aPTT, FibrinogenThe prolonged aPTT was consistent with severe hemophiliaRecommend both FVIII and VW profile very rare type III VWD no VW and therefore low FVIII as wellWhy was the factor IX also low?Infant with vitamin K deficiency and immature liverThis baby could have bleed to deathSeverityFactor VIII (8) levelaPTTSevere<1%70-100secModerate1-5%50-70 secMild5-40%30-70 sec>50%Normal 22-36 sec

32. Case 218 week old male with known severe Hemophilia A (FVIII <1%) brought to his pediatrician for fever, decreased PO, and being “fussy.”Pediatrician noted swollen anterior fontanelle and sent emergently to EDStat CT head w/o contrast obtained

33. Case 2CT head w/o contrast:1. Left parieto-occipital intraparenchymal hemorrhage with perilesional edema. Region of hemorrhage measures up to approximately 4.6 x 3.9 cm in maximal axial dimensions. Secondary effacement of the posterior horn left lateral ventricle. 2. Several smaller regions of subdural hematoma overlying the right frontal lobe. 3. Minimal left to right midline shift measuring approximately 3 mm. 4. Bulging anterior fontanelle. 5. No CT findings to suggest acute osseous or superficial soft tissue head injury.

34. Case 2No known trauma but was in swing and has older siblings. Working hypothesis was that the siblings might have innocently pushed him on the swing and he develop coup and contrecoup traumatic head injuryHemophilia MD appropriately called by ED and recommended full replacement with goal of at least factor VIII 100% (typically 50-60u/kg). Frequent dosing recommended with monitoring/levelsPatient had PICC line placed, 2 week hospital stay, continued high dose factor prophylaxis upon dischargeHad full neurologic recovery. Multiple tunneled line infections until big enough for broviac/mediport placementNow on emicizumab (hemlibra) prophylaxis

35. Case 2 pointsHigh suspicion for intracranial bleed in severe hemophilia and bulging fontanelle Risk for ICH in newborn/child with severe hemophilia is estimated to be 2-4%Mostly birth-related or trauma relatedWhat could have been done better in this case?Give factor assuming head bleed before the CT scan is obtained!

36. Case 311 month old male with severe Hemophilia A, on demand therapy (no prophylaxis) presents to pediatrician with increase irritability, fever, with negative rapid flu test. Progressed over a few days and now not eating wellOn exam, the right trapezius muscle appears swollen and patient appears to leaning head forward

37. Case 3

38. Case 3Thought to be muscle bleed and infused factor to 100%. Patient sent home from clinic. No known traumaNo improvement the following morning so patient sent to ED for imaging and further evaluation. Mother infused another 100% replacement of factor prior to going to EDPatient assessed in ED and responded to morphine. Ultrasound obtained with “possible tiny lymph node adjacent to left occiput, appears benign but patient was agitated while scanning the occipital region”Differential diagnosis of torticollis or sternocleidomastoid spasmHemophilia MD on call recommended CT scan, non contrasted, head and neck

39. Case 3CT head: no evidence of bleedCT neck: “Increased attenuation along the posterior aspect of the spinal canal extending from the C1 level where the visualized thoracic spine with marked anterior displacement and compression of the thecal sac, concerning for epidural hematoma.”Sedation and MRI cervical/thoracic spine w/o contrast “Large heterogeneous epidural hematoma in the posterior spinal canal extending the entire length of the visualized spinal column from C1 through the lumbar spine. This hematoma causes multilevel severe spinal canal narrowing and anterior displacement and compression of the spinal cord.”

40. Case 3Admitted to PICU and given factor VIII replacement with goal 100% every 6 hoursHospital day 6 peak factor VIII was 12% on 51u/kg, trough <5% patient developed an inhibitor (24 total lifetime infusions at that point)Changed to Novo7 90 mcg/kg every 2 hours. Tapered during the stay and discharged home on Novo 7Started emicizumab (hemlibra) as outpatientCurrently, patient is undergoing immune tolerance induction (ITI) with factor replacement every other day

41. Case 3 pointsObtaining imaging in pediatric patients can be challenging. We want to limit radiation exposure and/or need for sedationHowever, in this situation, something “did not feel right” prompting the recommendation for CT scansPatient appropriately was infused factor prior to imaging due to suspicion/work-up for potential bleed

42. Case 42 y/o male with severe hemophilia A on advate prophylaxis M/W/F presents to ED with family with 5 days of abdominal pain, nausea, and non-bloody emesisAfebrile, WBC 11.7, Hgb 9.7, HCT 30 (Hgb 9.7, 6 months prior)Ultrasound abdomen “appendix is not clearly visualized. There is a complex area in the RLQ which may be bowel but concerning for abscess. Negative McBurney’s point. Recommend CT scan for further evaluation”CT A/P with contrast “free fluid in the RIGHT lower quadrant and pelvic cul-de-sac with a blind-ending tubular structure in the RLQ measuring 0.9cm with hyperemic wall and adjacent inflammatory changes”

43. Case 4Surgery/hematology consulted. Patient taken to OR for open appendectomy with adequate factor supportOp note: “Immediately upon entering, we noted that everything was extremely stuck down in the region and there was a lot of old clot and fibrous tissue. We were able to carefully mobilize the ileocecal region. Findings were this was an old retroperitoneal hematoma. We washed it out profusely and made sure there was nothing else that was bleeding at all. Then, we were able to find the appendix, which was slightly dilated, but not suppurative.”Pathology: appendix with reactive lymphoid hyperplasia and acute periappendicitisAppendiceal serosal inflammation without mucosal involvement: ie inflammation of the appendix from outside the appendix

44. Case 4 pointsHemophilia management is humbling. This is an example of appropriate evaluation for possible non-bleeding etiology of symptomsDon’t just say “abdominal pain due to hemophilia”That being said, fewer than 5% of patients with appendicitis are <5 years old

45. Case 524 y/o male severe Hemophilia A on kogenate prophylaxis M/W/F with history of nephrolithiasis presents to ED with hematuria. s/p infusion at home prior to admissionAdmitted due to the hematuria and CT renal colic w/ contrast “Minimal left-sided hydronephrosis and proximal hydroureter without evidence of obstructing calculi. The above findings may represent a recently passed calculus”On ROS, patient mentions 2 months of new cough s/p treatment of bronchitis, without resolution and gets CXRCXR “There is abnormal widening of the tracheal stripe and alteration of the right cardiac silhouette compared to the prior CTs. The upper mediastinum also appears widened” CT chest recommended

46. Case 5CT chest w/contrast “1. Abnormal density in the anterior mediastinum is most likely hemorrhage. Given the relative lack of mass effect this is likely subacute. 2. A neoplastic process cannot be entirely excluded therefore follow-up in 3 months recommended.”

47. Case 5

48. Case 5Treated for possible mediastinal hematoma while hospitalizedFollow-up post discharge with repeat CXR unchanged. Prompting PET/CT “Extensive supraclavicular, anterior mediastinal, posterior paraspinal, cervical, and bilateral axillary PET positive adenopathy concordant with clinical diagnosis of lymphoma. No PET positive disease is seen below the diaphragm.”Supraclavicular lymph node biopsy: Classical Hodgkin’s Lymphoma

49. Case 5 pointsAgain, don’t just think “bleeding due to hemophilia”Have to bleed from somewhere: there must be a holeHave a wide differential diagnosis for these patients

50. Case 629 y/o male severe hemophilia A (FVIII <1%) with Hepatitis C and cirrhosis, being worked up for liver transplant, presents to ED with fall and trauma to head. Patient on kogenate prophylaxis M/W/F Patient with alcohol dependence, recurrent paracentesis for ascitesLabs with Hgb/Hct 10.2/28, plt 88. PT/INR 20.0 sec/1.9aPTT 73.3Fibrinogen 114Factor VIII 5%CT head w/o contrast: no intracranial hemorrhage

51. Case 6Hematology fellow called to see patient by the ED. His factor VIII was low despite being on factor replacementThe fellow paged the Hemophilia attending on call after hours:“does he have an inhibitor? His level is much lower than I expected.”NOPE, he is just non-adherent to his prophylaxisPatient given Humate-P as that was given to him previously with prior admissions at that hospitalWRONG!! Humate-P is VWF containing plasma factor, which also contains VIII but not as much (less than half as much as he would have gotten with factor VIII product). This patient doesn’t need VWF. He just needed factor VIII and should have gotten Kogenate (which is what he was supposed to be taking at home anyhow)

52. Case 6 pointsThis patient unfortunately died from his cirrhosis, due to hepatitis C that he contracted from “bad blood” in the 1980sWe have another patient, born 10 days later also with severe hemophilia A who did not contract hepatitis C or HIV. That patient is now one of our oldest patients at the center with severe hemophilia, at the age of 37We lost generations of patients, and their brothers, uncles, and cousins, due to HIV and hepatitis C infectionsDocumentary on Amazon Prime “Bad Blood”

53. Case 6 pointsDue to his cirrhosis, he had other coagulopathyThrombocytopenia due to splenomegaly and sequestration as well as reduced platelet production (thrombopoietin)HypofibrinogenemiaProlonged PT/INR (factors II, V, VII, IX, X are liver dependent factors)Also hypercoagulable from cirrhosis with decreased protein C, protein STeaching point: replacing factor VIII does NOT make him hypercoagulable. We are just increasing his factor VIII to normal or even subnormal levels. And it is inactivated factor we are giving him

54. Take away

55. Highlights Call the Hemophilia MD on call 585-922-5700Hematology consults should also be called, we will work together with guidance on which factor to use, dosing, and what lab testing/frequency is indicated

56. HighlightsTreatment as soon as possibleBefore imaging!!!Have a wide differential diagnosis. Don’t just assume hemophilia relatedPatients with hemophilia, especially on prophylaxis, have to bleed FROM somewhere.

57. EMERGENCY ROOM CHECK-LISTType of Hemophilia? VIII IX Severity of hemophilia? severe(<1%) moderate (2-5%) mild (5-40%)Severity of bleed ?Severe (life-threatening-ICH,GIB, Compartment Syndrome)Infuse to 100%Moderate (joint bleeding)Infuse to 50-100%Mild (Soft tissue, epistaxis, oral)Infuse to 25-50%History of inhibitor?

58. Questions ?

59. Thank you!Phone: 585-922-5700