j. martin johnston, md pediatric project echo 7 december 2018€¦ · pediatric project echo. 7...

J. Martin Johnston, MD

Pediatric Project ECHO7 December 2018

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

The chief complaint

“Easy” bruising Nosebleeds Petechiae Menorrhagia Bleeding after

Circumcision Tonsillectomy/adenoidectomy, tooth extraction Mild (head) trauma

• Everyone bleeds.

• All bleeding eventually stops.

The problem….

The bleeding history Birth/neonatal Tooth eruption/shedding Bruising Nosebleeds Surgeries? (don’t forget circumcision!) Orthopedic hx (traumas, joints) Menstruation Family history

How much bleeding is too much? Neonatal

ICH, needle/heel sticks, post-circumcision


ICH, needle/heel sticks, post-circumcision Infant

Petechiae, chest/back/buttock bruising Consider

NAT



Petechiae, chest/back/buttock bruising Toddler

Soft tissue or joint bleeds, large/palpable bruises

Consider

NAT



Petechiae, chest/back/buttock bruising Toddler

Soft tissue or joint bleeds, large/palpable bruises Older child

Recurrent prolonged nosebleeds (bilateral), joint bleeds, hematomas, menorrhagia

“Easy” bruising Without associated trauma (painless) Unusual locations Palpable (hematomas) “Bigger than a quarter”?

Petechiae Considerations:

Low platelets Dysfunctional platelets Vasculitis○ Viral? HSP?

“Trauma”○ Cough, vomiting, venous stasis (“choking”)

Collagen disorder: ↓ vascular integrity

Menorrhagia Definition:

Excessive but regular menstrual bleeding○ > 80 mL blood loss / cycle


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



Passing clots Saturating pad/tampon q 2 hours○ Double barrier○ Replacing overnight

Not just number of pads/tampons

Pad

Tampon

Clots?

Overflow?

1x25¢

“Bleeding Score” (history) to identify von Willebrand Disease

Rodeghiero F et al. J Thromb Haemost 2005; 3:2619-26

90%

25%90%90%

Putting it all together….

• Everyone bleeds.

The problem….

Family history Known diagnoses?

“Free bleeders” Unexplained death in childhood

Recurrent (prolonged) nosebleeds Menorrhagia Patterns of inheritance:

Dominant: vWD X-linked: hemophilia Recessive: rare factor deficiencies

Platelet disorders

Physical exam Conjunctival/mucosal hemorrhages Petechiae

Distribution Bruises

Age/color Number/size Palpable? Tender? Distribution

Physical exam (cont)

Joints Warm/tender/tense Boggy Range of motion:○ Chronic arthropathy?○ Hyperextensible?

2

2

2

2

1

May suggest an underlying

collagen disorder

Initial lab evaluation of suspected coagulopathy

CBC/smear PT/INR aPTT Platelet function analysis?

Thrombocytopenia If isolated and mild (>100k), often not

significant (MPV?) If isolated and severe, think ITP


significant (MPV?) If isolated and severe, think ITP Associated anemia?

Blood loss; hypersplenism, Evans syndrome, TTP



Blood loss, hypersplenism, Evans syndrome, TTP Neutropenia?

Viral illness, autoimmune, acute leukemia



Blood loss, hypersplenism, Evans syndrome, TTP Neutropenia?

Viral illness, autoimmune, acute leukemia Pancytopenia?

Acute leukemias, aplastic anemia, neuroblastoma

Platelet morphology

Larger platelets often suggest a destructive process, e.g., ITP

Platelet morphology

Large platelets often suggest a destructive process

Dysfunctional platelets may look abnormal Gray platelet syndrome Bernard-Soulier syndrome Bloodjournal.com

Platelet morphology

Large platelets often suggest a destructive process

Dysfunctional platelets may look abnormal Gray platelet syndrome Bernard-Soulier syndrome

But most dysfunctional platelets looknormal

Platelet function PFA-100

in vitro “substitute” for template bleeding time Theoretical screen for platelet function defects

and vWD Issues with sensitivity/specificity, reproducibility

Platelet function Platelet function analysis Platelet aggregometry

Not available in Reno Patient must be sent (fresh specimen required)

Electron microscopy, gene profiles

F X F Xa

Prothrombin (F II)

Thrombin (F IIa)

Fibrinogen Fibrin monomer

Cellular injury:

Tissue Factor

F VIIa F VII

F V F Va

Fibrin multimerCrosslinked fibrin

TFPI

F XIIIF XIIIa

Contact system:

HMWK, PK, F XII Kallikrein, F XIIa

F XI F XIa

F IX F IXa

F VIII F VIIIa

Protein C + thrombomodulin

Protein S

Activated Protein Ca

Antithrombin

Heparin cofactor II

PT/INR

Contact system:

HMWK, PK, F XII Kallikrein, F XIIa

F XI F XIa

F IX F IXa

F X F Xa

Prothrombin (F II)

Thrombin (F IIa)

Fibrinogen Fibrin monomer

F VIII F VIIIa

F V F Va

Fibrin multimerCrosslinked fibrin

F XIIIF XIIIa

Cellular injury:

Tissue Factor

F VIIa F VII

Protein C + thrombomodulin

Protein S

Activated Protein Ca

Antithrombin

TFPI

Heparin cofactor II

aPTT

Prolonged aPTT with normal PT/INR Deficiency versus inhibitor

Mixing studies help distinguish○ Correction implies something is “missing”○ Lack of correction implies “active” inhibition


Mixing studies help distinguish Inhibitor: possible “Lupus anticoagulant”

In young children, usually benign/transient If persistent, risk of clotting, not bleeding!


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!

2nd-tier coag testing

Mixing studies Specific factor levels von Willebrand panel Fibrinogen Thrombin time factor XIII

775-982-5427775-982-KIDS912-658-5223

High Uintas Wilderness Area, Utah

Questions?

“Common” pediatric bleeding disorders

ITP von Willebrand disease Hemophilia

ITP (idiopathic thrombocytopenic purpura)

ITP (immune thrombocytopenic purpura)

ITP (immune thrombocytopenia)

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

von Willebrand disease

Hereditary Pseudohaemophilia (1926)


Dominantly inherited (types 1 and 2) Relatively common Rarely life-threatening


Dominantly inherited (types 1 and 2) Relatively common Rarely life-threatening Mucocutaneous bleeds

Menorrhagia Dental/oral bleeds Post-tonsillectomy/adenoidectomy


Deficiency or dysfunction of von Willebrand factor (vWF)

(Type 1) (Type 2)


Deficiency or dysfunction of von Willebrand factor (vWF), which: Mediates initial platelet adhesion at sites of

vascular injury

(Type 1) (Type 2)


Deficiency or dysfunction of von Willebrand factor (vWF) Mediates initial platelet adhesion at sites of

vascular injury

Self-polymerizes to form multimers Binds and stabilizes factor VIII

“von Willebrand panel” assays all of these


Work-up: aPTT may be normal or mildly prolonged PFA-100 “should” be abnormal


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


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


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)

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

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

von Willebrand panel/profile (multimeric)

Type 1 vWD (most common) Quantitative deficiency: ↓ antigen/activity +/- VIII


Type 1 vWD Quantitative deficiency: ↓ antigen/activity +/- VIII

Type 3 vWD (very rare) Homozygous Type 1: absent 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

+/- abnormalmultimers




Type 2 vWD Qualitative defect:○ 2A: ↓ ↓ ↓ activity with ↓ antigen○ 2B: ↓ activity/antigen + ↓ platelets○ 2N: ↓ activity/antigen + ↓ ↓ fVIII○ 2M: ↓ ↓ ↓ activity with ↓ antigen w normal multimers




Type 2 vWD Qualitative defect:○ 2A: ↓ ↓ ↓ activity with ↓ antigen OR○ 2B: ↓ activity/antigen + ↓ platelets OR○ 2N: ↓ activity/antigen + ↓ ↓ fVIII

Hemophilia A?

vWD treatment

DDAVP (desmopressin, Stimate® spray) Effective for type 1 “Releases” vWF from platelets and endothelium 2- to 3-fold “boost” with T1/2 ~12 hours

vWD treatment

DDAVP (desmopressin, Stimate® spray) Effective for type 1 “Releases” vWF from platelets and endothelium 2- to 3-fold “boost” with T1/2 ~12 hours

vWF concentrates (I.V.) Effective for all types Plasma-derived (Humate-P ®, Wilate ®, etc.) New recombinant (VONVENDI)

“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™)

Hemophilia:

Congenital deficiency of clotting factor

VIII or IX.

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)

Fully manifest in males onlyAll daughters of affected males are carriersOffspring of carrier females at 50% risk:

Hemophilia if maleCarrier if female

BUT: 25-30% of cases result from newmutation

AND: Many female carriers are symptomatic:

menorrhagiabruising arthritis

BUT: Factor levels are not always predictive; consider genetic testing

*

Hemophilia A

Congenital factor VIII deficiency ~1 in 6000 live male births ~400 new US cases per year ~30% are de novo mutations

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

Bleeding in hemophiliacs

Post-circumcision; ↑ aPTT Mucous membranes Soft tissue Hemarthroses (“target” joints) Intracranial Menorrhagia (in carrier females)

Hemophilia work-up Prompted by family history (maternal carrier

or affected male sibling) or by bleeding symptoms

aPTT prolonged with factor < ~40%

Hemophilia work-up aPTT prolonged with factor < ~40% Is it fVIII or fIX? (or fXI or fXII….)

Specific activity

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

Hemophilia severity

Normal range for VIII or IX is ~50 to ~150% Levels below 40% = hemophilia

5-39% = “mild” 1-5% = “moderate” <1% = “severe”

Correlates with bleeding tendency, especially spontaneous bleeds (but significant variability within groups)

Some female carriers have <40% fVIII activity;

often symptomatic

Managing bleeds Remember the basics:

RICE for joint / soft tissue bleeds


RICE for joint / soft tissue bleeds For nosebleeds, pressure, ice


RICE for joint / soft tissue bleeds For nosebleeds, pressure, ice, Afrin


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


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™)

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)

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

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; T1/2 ~12 hours

For factor 9, activity increases ~1% for each unit/kg; T1/2 ~20 hours

Factors for managing hemophilia Factor VIII

Recombinant○ 1st generation

Recombinate – Baxter ○ 2nd generation

Helixate FS – CSL-Behring Kogenate FS – Bayer

○ 3rd 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

Factors for managing hemophilia Factor IX

Recombinant○ 3rd generation

Benefix – Pfizer Rixubis – Baxter Alprolix (Fc fusion) – Biogen Idelvion (PEGylated) – CSL Behring

Plasma-derived Bebulin – Baxter Mononine – CSL-Behring

Different approaches to hemophilia prophylaxis

(…in hemophilia)

• Emicizumab (“ACE 910,” Hemlibra®)– Bi-specific antibody– Binds factors IX and X– Similar to what fVIII does:

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

Novel approaches

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

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

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

775-982-5427775-982-KIDS912-658-5223

QUESTIONS?

j. martin johnston, md pediatric project echo 7 december 2018€¦ · pediatric project echo. 7...

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