J. Martin Johnston, MD. Pediatric Project ECHO 7 December 2018
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1 J. Martin Johnston, MD Pediatric Project ECHO 7 December 2018
2 Objectives Review history and physical exam as they relate to a potential bleeding disorder Discuss step-wise laboratory evaluation: screening labs and follow-ups Review some common congenital and acquired bleeding disorders, and their management
3 Objectives Review history and physical exam as they relate to a potential bleeding disorder Discuss step-wise laboratory evaluation: screening labs and follow-ups Review some common congenital and acquired bleeding disorders, and their management
4 Objectives Review history and physical exam as they relate to a potential bleeding disorder Discuss step-wise laboratory evaluation: screening labs and follow-ups Review some common congenital and acquired bleeding disorders, and their management
5 The chief complaint Easy bruising Nosebleeds Petechiae Menorrhagia Bleeding after Circumcision Tonsillectomy/adenoidectomy, tooth extraction Mild (head) trauma
6 The problem. Everyone bleeds. All bleeding eventually stops.
7 The bleeding history Birth/neonatal Tooth eruption/shedding Bruising Nosebleeds Surgeries? (don t forget circumcision!) Orthopedic hx (traumas, joints) Menstruation Family history
8 How much bleeding is too much? Neonatal ICH, needle/heel sticks, post-circumcision
9 How much bleeding is too much? Neonatal ICH, needle/heel sticks, post-circumcision Infant Petechiae, chest/back/buttock bruising Consider NAT
10 How much bleeding is too much? Neonatal ICH, needle/heel sticks, post-circumcision Infant Petechiae, chest/back/buttock bruising Toddler Consider NAT Soft tissue or joint bleeds, large/palpable bruises
11 How much bleeding is too much? Neonatal ICH, needle/heel sticks, post-circumcision Infant Petechiae, chest/back/buttock bruising Toddler Soft tissue or joint bleeds, large/palpable bruises Older child Recurrent prolonged nosebleeds (bilateral), joint bleeds, hematomas, menorrhagia
12 Easy bruising Without associated trauma (painless) Unusual locations Palpable (hematomas) Bigger than a quarter?
13 Petechiae Considerations: Low platelets Dysfunctional platelets Vasculitis Viral? HSP? Trauma Cough, vomiting, venous stasis ( choking ) Collagen disorder: vascular integrity
14 Menorrhagia Definition: Excessive but regular menstrual bleeding > 80 ml blood loss / cycle
15 Menorrhagia Definition: Excessive but regular menstrual bleeding > 80 ml blood loss / cycle > 7 days of menstruation
16 Menorrhagia Definition: Excessive but regular menstrual bleeding > 80 ml blood loss / cycle > 7 days of menstruation Passing clots Saturating pad/tampon q 2 hours Double barrier Replacing overnight
17 Menorrhagia Definition: Excessive but regular menstrual bleeding > 80 ml blood loss / cycle > 7 days of menstruation Passing clots Saturating pad/tampon q 2 hours Double barrier Replacing overnight Not just number of pads/tampons Pad Tampon 1x25 Clots? Overflow?
18 Bleeding Score (history) to identify von Willebrand Disease Putting it all together. 90% 25% 90% 90% Rodeghiero F et al. J Thromb Haemost 2005; 3:
19 The problem. Everyone bleeds.
20 Family history Known diagnoses? Free bleeders Unexplained death in childhood Recurrent (prolonged) nosebleeds Menorrhagia Patterns of inheritance: Dominant: vwd X-linked: hemophilia Platelet disorders Recessive: rare factor deficiencies
21 Physical exam Conjunctival/mucosal hemorrhages Petechiae Distribution Bruises Age/color Number/size Palpable? Tender? Distribution
22 Physical exam (cont) Joints Warm/tender/tense Boggy Range of motion: Chronic arthropathy? Hyperextensible? May suggest an underlying collagen disorder
23 Initial lab evaluation of suspected coagulopathy CBC/smear PT/INR aptt Platelet function analysis?
24 Thrombocytopenia If isolated and mild (>100k), often not significant (MPV?) If isolated and severe, think ITP
25 Thrombocytopenia If isolated and mild (>100k), often not significant (MPV?) If isolated and severe, think ITP Associated anemia? Blood loss; hypersplenism, Evans syndrome, TTP
26 Thrombocytopenia If isolated and mild (>100k), often not significant (MPV?) If isolated and severe, think ITP Associated anemia? Blood loss, hypersplenism, Evans syndrome, TTP Neutropenia? Viral illness, autoimmune, acute leukemia
27 Thrombocytopenia If isolated and mild (>100k), often not significant (MPV?) If isolated and severe, think ITP Associated anemia? Blood loss, hypersplenism, Evans syndrome, TTP Neutropenia? Viral illness, autoimmune, acute leukemia Pancytopenia? Acute leukemias, aplastic anemia, neuroblastoma
28 Platelet morphology Larger platelets often suggest a destructive process, e.g., ITP
29 Platelet morphology Large platelets often suggest a destructive process Dysfunctional platelets may look abnormal Gray platelet syndrome Bernard-Soulier syndrome Bloodjournal.com
30 Platelet morphology Large platelets often suggest a destructive process Dysfunctional platelets may look abnormal Gray platelet syndrome Bernard-Soulier syndrome But most dysfunctional platelets look normal
31 Platelet function PFA-100 in vitro substitute for template bleeding time Theoretical screen for platelet function defects and vwd Issues with sensitivity/specificity, reproducibility
32 Platelet function Platelet function analysis Platelet aggregometry Not available in Reno Patient must be sent (fresh specimen required) Electron microscopy, gene profiles
33 Contact system: HMWK, PK, F XII Kallikrein, F XIIa Cellular injury: Tissue Factor PT/INR F XI F XIa F VIIa F VII F IX F IXa TFPI F VIII F VIIIa F X F Xa Antithrombin F V Prothrombin (F II) F Va Thrombin (F IIa) Heparin cofactor II Activated Protein Ca Protein S Protein C + thrombomodulin Fibrinogen Crosslinked fibrin Fibrin monomer Fibrin multimer F XIIIa F XIII
34 Contact system: HMWK, PK, F XII Kallikrein, F XIIa Cellular injury: Tissue Factor aptt F XI F XIa F VIIa F VII F IX F IXa TFPI F VIII F VIIIa F X F Xa Antithrombin F V Prothrombin (F II) F Va Thrombin (F IIa) Heparin cofactor II Activated Protein Ca Protein S Protein C + thrombomodulin Fibrinogen Crosslinked fibrin Fibrin monomer Fibrin multimer F XIIIa F XIII
35 Prolonged aptt with normal PT/INR Deficiency versus inhibitor Mixing studies help distinguish Correction implies something is missing Lack of correction implies active inhibition
36 Prolonged aptt with normal PT/INR Deficiency versus inhibitor Mixing studies help distinguish Inhibitor: possible Lupus anticoagulant In young children, usually benign/transient If persistent, risk of clotting, not bleeding!
37 Prolonged aptt with normal PT/INR Deficiency versus inhibitor Mixing studies help distinguish Inhibitor: possible Lupus anticoagulant In young children, usually benign/transient Risk of clotting, not bleeding! Deficiency: fviii, fix: hemophilia vwf: carrier for fviii fxi: Ashkenazi? ( hemophilia C ) fxii: relatively common; does not cause bleeding!
38 2 nd -tier coag testing Mixing studies Specific factor levels von Willebrand panel Fibrinogen Thrombin time factor XIII KIDS
39 Questions? High Uintas Wilderness Area, Utah
40 Common pediatric bleeding disorders ITP von Willebrand disease Hemophilia
41 ITP (idiopathic thrombocytopenic purpura)
42 ITP (immune thrombocytopenic purpura)
43 ITP (immune thrombocytopenia)
44 ITP (immune thrombocytopenia) Antibody-mediated platelet destruction Acute (resolves within 6-12 months) most common in toddlers Abrupt onset of bruising/petechiae; otherwise well Isolated, profound thrombocytopenia Debate re best management: observation is often appropriate More likely to persist ( chronic ITP) in older/female patients Immune suppression Splenectomy Thrombopoietin analogues
45 von Willebrand disease Hereditary Pseudohaemophilia (1926)
46 von Willebrand disease Dominantly inherited (types 1 and 2) Relatively common Rarely life-threatening
47 von Willebrand disease Dominantly inherited (types 1 and 2) Relatively common Rarely life-threatening Mucocutaneous bleeds Menorrhagia Dental/oral bleeds Post-tonsillectomy/adenoidectomy
48 von Willebrand disease (Type 1) (Type 2) Deficiency or dysfunction of von Willebrand factor (vwf)
49 von Willebrand disease (Type 1) (Type 2) Deficiency or dysfunction of von Willebrand factor (vwf), which: Mediates initial platelet adhesion at sites of vascular injury
50 von Willebrand disease Deficiency or dysfunction of von Willebrand factor (vwf) Mediates initial platelet adhesion at sites of vascular injury von Willebrand panel assays all of these Self-polymerizes to form multimers Binds and stabilizes factor VIII
51 von Willebrand disease Work-up: aptt may be normal or mildly prolonged PFA-100 should be abnormal
52 von Willebrand disease Work-up: aptt may be normal or mildly prolonged PFA-100 should be abnormal von Willebrand panel Notoriously variable Lower limits of normal are debated
53 von Willebrand disease Work-up: aptt may be normal or mildly prolonged PFA-100 should be abnormal von Willebrand panel Notoriously variable Lower limits of normal are debated <50% suggestive <40% suspicious <30% definitive
54 von Willebrand disease Work-up: aptt may be normal or mildly prolonged PFA-100 should be abnormal von Willebrand panel Notoriously variable Lower limits of normal are debated <50% suggestive <40% suspicious <30% definitive (maybe)
55 von Willebrand panel/profile vwf antigen How much protein? vwf (a.k.a. ristocetin cofactor) activity How well does it function? fviii activity Because vwf carries factor VIII
56 von Willebrand panel/profile (multimeric) vwf antigen How much protein? vwf (a.k.a. ristocetin cofactor) activity How well does it function? fviii activity Because vwf carries factor VIII Multimer pattern Gel electrophoresis to assess stacking of vwf
57 von Willebrand panel/profile (multimeric) Type 1 vwd (most common) Quantitative deficiency: antigen/activity +/- VIII
58 von Willebrand panel/profile (multimeric) Type 1 vwd Quantitative deficiency: antigen/activity +/- VIII Type 3 vwd (very rare) Homozygous Type 1: absent antigen/activity/viii
59 von Willebrand panel/profile (multimeric) Type 1 vwd Quantitative deficiency: antigen/activity +/- VIII Type 3 vwd Homozygous Type 1: absent antigen/activity/viii Type 2 vwd Qualitative defect: 2A: activity with antigen 2B: activity/antigen + platelets 2N: activity/antigen + fviii +/- abnormal multimers
60 von Willebrand panel/profile (multimeric) Type 1 vwd Quantitative deficiency: antigen/activity +/- VIII Type 3 vwd Homozygous Type 1: absent antigen/activity/viii Type 2 vwd Qualitative defect: 2A: activity with antigen 2B: activity/antigen + platelets 2N: activity/antigen + fviii 2M: activity with antigen w normal multimers
61 von Willebrand panel/profile (multimeric) Type 1 vwd Quantitative deficiency: antigen/activity +/- VIII Type 3 vwd Homozygous Type 1: absent antigen/activity/viii Type 2 vwd Qualitative defect: 2A: activity with antigen OR 2B: activity/antigen + platelets OR 2N: activity/antigen + fviii Hemophilia A?
62 vwd treatment DDAVP (desmopressin, Stimate spray) Effective for type 1 Releases vwf from platelets and endothelium 2- to 3-fold boost with T 1/2 ~12 hours
63 vwd treatment DDAVP (desmopressin, Stimate spray) Effective for type 1 Releases vwf from platelets and endothelium 2- to 3-fold boost with T 1/2 ~12 hours vwf concentrates (I.V.) Effective for all types Plasma-derived (Humate-P, Wilate, etc.) New recombinant (VONVENDI)
64 Non-specific tx for bleeding (e.g., vwd) Avoid blood thinners (ASA, NSAIDs) For menorrhagia, hormonal therapies are often most effective even in the setting of a coag disorder Anti-fibrinolytics: Oral or topical Tranexamic acid (Lysteda ) Aminocaproic acid (Amicar )
65 Hemophilia: Congenital deficiency of clotting factor VIII or IX.
66 Factors VIII and IX Factor IX is vitamin K-dependent serine protease Factor VIII is cofactor for IXa; circulates bound (noncovalently) to vwf IXa + VIIIa = factor Xase Both involved in intrinsic pathway; deficiencies cause prolonged aptt Both genes on X chromosome; affected males, carrier females (+/- symptomatic)
67 BUT: 25-30% of cases result from new mutation Fully manifest in males only * All daughters of affected males are carriers Offspring of carrier females at 50% risk: Hemophilia if male Carrier if female AND: Many female carriers are symptomatic: menorrhagia bruising arthritis BUT: Factor levels are not always predictive; consider genetic testing
68 Hemophilia A Congenital factor VIII deficiency ~1 in 6000 live male births ~400 new US cases per year ~30% are de novo mutations
69 Hemophilia B Congenital factor IX deficiency ~1 in 20,000 live male births ~100 new US cases per year 25-30% are de novo mutations
70 Bleeding in hemophiliacs Post-circumcision; aptt Mucous membranes Soft tissue Hemarthroses ( target joints) Intracranial Menorrhagia (in carrier females)
71 Hemophilia work-up Prompted by family history (maternal carrier or affected male sibling) or by bleeding symptoms aptt prolonged with factor < ~40%
72 Hemophilia work-up aptt prolonged with factor < ~40% Is it fviii or fix? (or fxi or fxii.) Specific activity
73 Hemophilia work-up aptt prolonged with factor < ~40% Is it fviii or fix? (or fxi or fxii.) Specific activity Genetic testing can I.D. F8 or F9 mutation/deletion in >95% of cases Knowing mutation can help predict, e.g., risk of developing an inhibitor Once mutation is known, screening female family members is easier/cheaper
74 Hemophilia severity Normal range for VIII or IX is ~50 to ~150% Levels below 40% = hemophilia 5-39% = mild 1-5% = moderate <1% = severe Some female carriers have <40% fviii activity; often symptomatic Correlates with bleeding tendency, especially spontaneous bleeds (but significant variability within groups)
75 Managing bleeds Remember the basics: RICE for joint / soft tissue bleeds
76 Managing bleeds Remember the basics: RICE for joint / soft tissue bleeds For nosebleeds, pressure, ice
77 Managing bleeds Remember the basics: RICE for joint / soft tissue bleeds For nosebleeds, pressure, ice, Afrin
78 Managing bleeds Remember the basics: RICE for joint / soft tissue bleeds For nosebleeds, pressure, ice, Afrin Bacon fat (source of thrombin) For mouth bleeds: tea bags Various OTC proprietary clotting agents
79 Managing bleeds Remember the basics: RICE for joint / soft tissue bleeds For nosebleeds, pressure, ice, Afrin Bacon fat (source of thrombin) For mouth bleeds: tea bags Various OTC proprietary clotting agents Antifibrinolytics (Rx) Aminocaproic acid (Amicar ) Tranexamic acid (Lysteda )
80 Managing bleeds (cont.) DDAVP (for mild-moderate hemophilia A or symptomatic carriers) Stimate nasal spray (Desmopressin1.5 mg/ml) Causes release of stored vwf/fviii Typically, 2- to 3-fold increase in VIII activity So not useful in severe hemophilia Tachyphylaxis Fluid retention (may cause hyponatremia)
81 Dosing factor 8 or 9 (I.V.) For management of bleeding, goal is to attain level commensurate with risk: 20-40% for soft tissue bleeds 50-70% for joint bleeds >100% for life-threatening bleed/injury
82 Dosing factor 8 or 9 (I.V.) For management of bleeding, goal is to attain level commensurate with risk: 20-40% for soft tissue bleeds 50-70% for joint bleeds >100% for life-threatening bleed/injury For factor 8, activity increases ~2% for each unit/kg; T 1/2 ~12 hours For factor 9, activity increases ~1% for each unit/kg; T 1/2 ~20 hours
83 Factors for managing hemophilia Factor VIII Recombinant 1 st generation Recombinate Baxter 2 nd generation Helixate FS CSL-Behring Kogenate FS Bayer 3 rd generation Advate Baxter Kovaltry Bayer NovoEight Novo-Nordisk Xyntha (B-domain-deleted) Wyeth Eloctate (Fc fusion) Biogen Adynovate (PEGylated) Baxter Jivi (PEGylated) Bayer Afstyla (single chain) CSL Behring Nuwiq (human cell line) OctaPharma Plasma-derived Hemofil-M Baxter Koate-DVI Kedrion Monoclate CSL Behring No albumin in final product No albumin in cell culture or final product Engineered products
84 Factors for managing hemophilia Factor IX Recombinant 3 rd generation Benefix Pfizer Rixubis Baxter Alprolix (Fc fusion) Biogen Idelvion (PEGylated) CSL Behring Plasma-derived Bebulin Baxter Mononine CSL-Behring
85 Different approaches to hemophilia prophylaxis
86 ( in hemophilia)
87 Novel approaches Emicizumab ( ACE 910, Hemlibra ) Bi-specific antibody Binds factors IX and X Similar to what fviii does:
88 Novel approaches Emicizumab ( ACE 910, Hemlibra ) Bi-specific antibody Binds factors IX and X Similar to what fviii does: Initial trials in inhibitor patients Significant benefit given SQ q 2-4 wks Recently FDA approved for non-inhibitor pts
89 Novel approaches Fitusiran (Alnylam pharmaceuticals) sirna against antithrombin III Phase 3 trials coming soon Phase 1-2 trials suggest safety and efficacy given SQ q 4 weeks Effective in hemophilia A or B and potentially in other rare bleeding disorders
90 Gene therapy Hemophilia as a model disease for GT Protein circulates in blood Small amounts have clinical benefit No need for complex regulation Hemophilia B first (smaller gene) Two types of vector under development AAV primarily extrachromosomal Lentivirus - integrates Trials underway
91 Objectives Review history and physical exam as they relate to a potential bleeding disorder Discuss step-wise laboratory evaluation: screening labs and follow-ups Review some common congenital and acquired bleeding disorders, and their management KIDS
92 QUESTIONS?
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