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Neonatal Screening for HemoglobinopathyPain Management (2 phase approach)Epistaxis: The Hematological AngleThrombophilia Investigation: When and How Hadi.

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Presentation on theme: "Neonatal Screening for HemoglobinopathyPain Management (2 phase approach)Epistaxis: The Hematological AngleThrombophilia Investigation: When and How Hadi."— Presentation transcript:

1 Neonatal Screening for HemoglobinopathyPain Management (2 phase approach)Epistaxis: The Hematological AngleThrombophilia Investigation: When and How Hadi Sawaf MD

2 Pain Management and the Codeine Story

3 Health care professionals should prescribe an alternate analgesic for post-operative pain control in children who are undergoing tonsillectomy and/or adenoidectomy. Codeine should not be used for pain in children following these procedures A new BOXED WARNING, FDA’s strongest warning, will be added to the drug label

4 Codeine effect is dependent upon its conversion to morphine by the hepatic cytochrome P450 2D6 (CYP2D6). Some people have DNA variations that make this enzyme more active, causing codeine to be converted to morphine faster and more completely than in other people High levels of morphine can result in breathing difficulty, which may be fatal. Taking codeine after tonsillectomy and/or adenoidectomy may increase the risk for breathing problems and death in children who are “ultra-rapid metabolizers.” For other types of pain in children, codeine should be used if the benefits are anticipated to outweigh the risk Codeine

5

6 +/- adjuvant Non-opioid Weak opioid Strong opioid Pain persists or increases By the Clock W.H.O. ANALGESIC LADDER +/- adjuvant 1 2 3

7 Non-opioid opioid Pain persists or increases By the Clock ANALGESIC LADDER +/- adjuvant 1 2

8 MedicineNeonate: 0 to 29 days Infants: 30 d to 3 mos Infant 3-12 mos or child 1-12 yrs Maximum Daily dose Acetaminophen5–10 mg/kg every 6–8 hr 10 mg/kg every 4–6 hr 10–15 mg/kg every 4–6 hrs 4 doses/day Ibuprofen5–10 mg/kg every 6–8 hrs Child: 40 mg/kg/day Oral Dose

9 Intravenous Acetaminophen Approved by FDA for the use in children 2 years of age and older Maximum serum concentration after IV acetaminophen was 70% higher than the same dose given orally Does not appear to increase the risk for hepatotoxicity Dose: 12.5 mg/kg IV every 4 hours or 15 mg/kg IV every 6 hours, with a maximum dose of 75 mg/kg every 24 hours.

10 Opioid Brand Names Generic NameBrand Name fentanylDuragesic hydrocodoneNorco, Vicodin hydromorphoneDilaudid, Exalgo morphineAstramorph, Avinza oxycodoneOxyContin, Percocet

11 Starting dosages for opioid * MedicineRoute of administration Starting dose MorphineOral (immediate release)1–2 years: 200–400 mcg/kg Q 4 hrs 2–12 years: 200–500 mcg/kg Q 4 hrs (max 5 mg) IV injection1–2 years: 100 mcg/kg Q 4 hrs 2–12 years: 100–200 mcg/kg Q 4 hrs HydromorphoneOral (immediate release)30–80 mcg/kg Q 3–4 hrs (max 2 mg/dose) Oral (prolonged release)15 mcg/kg Q 3–6 hrs *opioid-naive children

12 OPIOID ANALGESIA + Break Through Q 4 hrs (10%) Convert to a new opioid (50%) Escalate dose by 25% until pain relieved or adverse effects unacceptable PRN PO morphine Q 4 hrs PO morphine Q 12 hrs PO Slow Release (50%) IV Morphine (1:3 ratio)

13 OPIOID CONVERSION Least Potent ASA Acetamenophen Naproxen Ibuprophen 1:130 1:50 1:40 Morphine 1:1 Oxycodone Hydrocodone Hydromorphone Methadone 1.3:1 1.2:1 5:1 10:1 Fentanyl 100:1 Most Potent Opioid NSAIDS

14 Neonatal Screening for Hemoglobinopathy

15 Amino Acid Disorders: X 14 Fatty Acid Oxidation Disorders: X 12 Organic Acid Disorders: X13 Hemoglobinopathies: S/Beta thalassemia S/C disease Sickle cell anemia Variant hemoglobinopathies Hemoglobin H disease Endocrine Disorders: X 2 Other Disorders: X 7 - August 1865-Phenyketonia - June 1977-CH - Spring 1985-Galactosemia - October 1987-Niotinidase Deficiency, - MSUD and Hemoglobinopathy - July 1993-CAH - April 2003-MCAD - October 2007 CF and Hearing - October 2004-HCY, CIT, ASA - April 2014-CCHD - October-2011 SCIDCCHD - April MS/MS Disorders

16

17 Sickle Cell Disease in Michigan

18 SCD Subtype, Confirmed Cases, 2011 SubtypeN% Hemoglobin SS (HbSS)3354 Hemoglobin SC (HbSC)2033 Sickle Beta Thal Plus813

19 Neonatal Screening for Hemoglobinopathy

20  Other hemoglobins are reported as “V”. They invariably have no or minimal clinical or genetic significance and are not report to parents  Hemoglobins are generally reported in decreasing order of concentration (F>A>S)  Newborn hemoglobinopathy screening will not identify beta thalassemia trait Neonatal Screening for Hemoglobinopathy

21 Initial Test Result of FS DIAGNOSIS CONFIRMATORYFAMILY STUDIES Sickle Cell Anemia (SS)FSBoth parents AS Sickle Beta Thalassemia Zero (Sβ°) FSOne parent AS One parent AA with elevated HB A2 Sickle Cell with HPFH FFSOne Parent AS One parent AF with Hb F approx. 20 ‐ 30%

22 Education Session Completion Sep Oct % 20% 30% 40% 50% 0 2 sessions completed 1 session completed Previously educated Refuse or unable Unknown Session 2 Transmission of SCD Types of SCD Late health problems Session 1 SCD overview Early health problems Sickle cell trait vs disease

23 20% 40% 60% 80% 100% Percent of Children with SCD Receiving Antibiotic Prophylaxis 5% 10% 15% 20% 25% Percent of Children with SCD with TCD Screen by Year and Gender Female Male Within 120 days Before 5 mos Birth Year Sickle Cell Disease in Michigan

24 ACTION REQUIRED  Confirm diagnosis  Penicillin prophylaxis  Disease Education  Referral to Pediatric Hematology/Oncology Sickle Cell Disease

25 S,C,D,E Trait Reporting Table RESULTDIAGNOSISACTION REQUIRED FASSickle cell trait Clinically benign but genetically significant No confirmatory testing Genetic counseling FACHemoglobin C trait Clinically benign but genetically significant No confirmatory testing Genetic counseling FADHemoglobin D trait Clinically benign but genetically significant No confirmatory testing Genetic counseling FAEHemoglobin E trait Clinically benign but genetically significant No confirmatory testing Genetic counseling

26 FAV/FABart’s Reporting RESULTDIAGNOSISACTION REQUIRED FAV Fetal hemoglobin, normal adult and an unidentified hemoglobin variant Most likely clinically insignificant hemoglobin variant Physician of record responsible for reassuring the parent that this is clinically insignificant. No confirmatory testing required. FA-Bart’s Fetal Hemoglobin, Hemoglobin A and Bart’s Hemoglobin Hemoglobin H disease Alpha Thalassemia Trait MDCH will send specimen to reference lab for further analysis. SCDAA will provide information to parents and physician of record for clinically significant findings

27 Thrombophilia Testing Who and How

28 Definition: Thrombophilia an inherited or acquired abnormality of hemostasis predisposing to thrombosis

29  Some form of Thrombophilia can be identified in approximately half of patients presenting with VTE  Thrombophilia factors may enhance the risk of recurrent thrombosis.  Therapeutic and prophylactic measures are not necessarily different for children with or without thrombophilic risk factors  Individualized approach is warranted

30  Incidence: 5 cases per 10,000 children per year  Mortality rate for major vessel thrombosis is 1% - 4%  Thrombus recurrence: 6.5% to 21% of children with VTE  Many cases of DVT and pulmonary embolism (PE) go unrecognized in part due to a low index of suspicion for young patients

31 Number of Children Age (years) Venous Thrombosis in Children From Canadian Registry

32 Venous Thromboembolism in Children Site Presentation Dx

33 XII XI IX VIII VIIX V II I Fibrin clot AT PC/PS t-PA TFPI D-Dimer FDP Plasminogen PAI

34 Procoagulant Anticoagulant Other High levels of factor VIIIAntithrombin deficiencyFactor V Leiden (FVL) High levels of factor IXProtein C deficiencyAntiphospholipid syndrome High levels of factor XIProtein S deficiencyHyperhomocysteinemia High levels of fibrinogenDysfibrinogenemia Prothrombin 20210A Risk factors for venous thrombosis

35 Hypercoagulable State General Population % InheritanceRisk for 1 st VTE % Patient with single VTE % Thrombophilic Families Factor V Leiden3-7AD Prothrombin G20210A 1-3AD Anti-thrombin deficiency 0.02AD Protein C deficiency AD Protein S deficiency AD Homocysteinemia5-10AR N/A Antiphospholipid antibodies 0-7Acquired N/A Prevalence of Major Hypercoagulable States

36 Some numbers for U.S. population; approximation)

37 Number of Children

38  Spontaneous  Recurrent  Unusual site  Positive family history Who should be tested? Testing is probably not helpful VTE at a young age with  Catheter related thrombosis  Before initiation of contraceptive  Asypmtomatic child with positive family history

39  Multitrait thrombophilia  Spontaneous VTE  Homozygous factor V Leiden  Prothrombin gene mutation  Antiphospholipid Abs  Elevated D-dimer at the end of anticoagulant therapy Incidence: % *The recurrence risk did not decrease with increased duration of anticoagulation

40 ThrombophiliaLaboratory Tests Level (I )TestingFactor V LeidenPCR or clotting assay (APC res.) Prothrombine G20210APCR Level (II) TestingAntithrombin deficiencyChromogenic or clotting assay Protein C deficiencyChromogenic or clotting assay Protein S deficiencyClotting assay or immunologic HomocysteinemiaFasting homocysteine Antiphospholipid antibodiesClotting or chromogenic assay Elevated factor VIIIClotting assay Level (III)TestingDysfibrinogenemiaClotting or immunologic assay Elevated factor IX, XIClotting assay Thrombophilia Diagnostic Laboratory Studies

41 Nose Bleed ? Bleeding disorder

42 A 5- year-old boy presents to clinic with his parents who are concerned about his 3-month history or recurrent nosebleeds On 2 occasions he was send home from school because of the nose bleed His physical examination was entirely normal with no petechia or bruises noted. When in your office he developed epistaxis that lasts about 15 minutes. His platelet count is 178,00,000. His complete blood count and smear review were normal Case History:

43 ▸ Inflammation – URI – Allergic rhinitis – Foreign body – Vasculitis ▸ Trauma – Nose picking – External trauma ▸ Anatomic – Septal deviation ▸ Medications – Topical steroid spray – Nasal decongestants – Anticoagulants ▸ Hematologic – Idiopathic thrombocytopenic purpura – Von Willebrand disease – Hemophilia ▸ Neoplasms – Benign ∘ Nasopharyngeal angiofibroma ∘ Pyogenic granuloma ∘ Inverted papilloma – Malignant ∘ Rhabdomyosarcoma ∘ Lymphoma ▸ Vascular abnormalities – Hereditary hemorrhagic telangiectasia – Hemangioma ▸ Idiopathic

44  Epistaxis unrelieved by 10 minutes  Epistaxis requiring ER visit, or blood transfusion  History other bleeding manifestations  Bleeding from trivial wounds >15 mints  Bleeding from dental procedures > 1 day or requiring a blood transfusion  Heavy, prolonged or recurrent bleed after surgical procedure  Heavy menses  Family history of a bleeding disorder

45 ComponentScore Frequency 5-15/yr 16-25/yr >25/yr Duration < 5 min 5-10 min >10 min Amount < 15 ml ml >30 ml Epistaxis history/age < 33% 33-67% >67% Site Unilateral Bilateral 0202 Epistaxis Scoring system Mild: 0-6 Severe: 7-10

46 Likelihood ratio for VWD based on Vicenza bleeding assessment tool Elsevier 2007 Bleeding Score Likelihood Ratio for VWD

47 CBC, PT, PTT. Fibrinogen or TT (optional) If bleeding history is strong consider performing initial VWD assays Initial VWD assay VWF:Ag VWF:Rco FVIII Referral for appropriate evaluation Possible referral for appropriate evaluation Referral for specialized VWD studies Repeat VWD panel VWF:Rco/VWF:Ag Multimer analysis Collagen binding RIPA binding Plat VWF studies DNA sequencing Prolonged PTT 1:1 mixing Other cause identified. eg. thrombocytopenia, Prolonged PT or TT Not corrected FVIIF, IX and FXI Corrected Antiphospholipid antibody

48 Case Discussion Coagulation testing: PTT 42 sec ( sec). Normal PT, and platelet count. Mixing studies: - PTT corrected with 1:1 mixing with Plasma TestResultNormal F XI 59%50-150% F IX:C 78%60-150% F VIII:C 32%50-150% vWF R:Co 35%45-200% vWF:Ag 30%36-157%

49 von Willebrand Disease ä Most common hereditary coagulation abnormality in human ä Estimated to occur in 1% to 0.1% of the population ä Female /Male ratio is 2:1 ä Borderline or modestly low VWF levels are unlikely to run in families, and usually symptomatic ä VWD subtype I and II are dominant. Type III is recessive ä Type II and III can be diagnosed by molecular genetic testing ä rVWF (BAX 111) has recently been introduced

50 Adherence of platelet to damaged endothelium is vWF dependent platelet plugfibrin clot vWF platelet endothelial cell F-VIII

51 Personal history of excessive bleedingLow VWF levels Known mutation consistent with VWD (type II) In absence of all three criteria, modestly low VWF levels should be treated as a risk factor for bleeding rather than a bleeding disorder

52 GP IbGP IIb& IIIa GP Ia Aggregation site Collagen binding site Adhesion site Reduced production VWD type 1 Reduced production VWD type 1 Impaired binding of VWF to collagen VWD type 1C Impaired binding of VWF to collagen VWD type 1C Decreased binding of vWF to factor VIII VWD type 2N Decreased binding of vWF to factor VIII VWD type 2N Decreased binding to platelet VWD type 2A VWD type 2M Decreased binding to platelet VWD type 2A VWD type 2M Increased binding to platelet VWD type 2B Increased binding to platelet VWD type 2B Complete deficiency of VWF VWD type 3 Complete deficiency of VWF VWD type 3

53 D1D2D3A1A2A3D4C1C2C3 NC F VIII GPIb Collagen GPIIb/IIIa Type 1>100 different mutations throughout the gene, missense predominate 2M 2B 2N2N Mutations 2A Type 2AMutation in proteolysis site at A2 region (most common) Type 2ALoss of propeptide, required for multimer formation from dimers Type 2AMutation in C-terminus, required for dimer formation from monomers Type 2BMutation in GPIb binding site, causing increased binding of vWF to GPIb Type 2MMutation in GPIb binding site, causing decreased binding of vWF to GPIb Type 2NMutation in N-terminis (FVIII binding) with decreased binding of vWF to factor VIII Type 3Large null mutations

54 Analysis of von Willebrand factor (VWF) multimers: The distribution of VWF multimers is analysed using sodium dodecyl sulphate (SDS)–agarose electrophoresis followed by immunostaining

55 Management  Local measure, pinching  Topical antiseptic cream  Nasal cauterization  Topical hemostatic agents such as tranexamic acid  Correcting underlying clotting problems (i.e. DDAVP)


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