disorders in children

prof. Mariusz Wysocki,

Katedra i Klinika Pediatrii, Hematologii i Onkologii

Collegium Medicum Bydgoszcz UMK Toruń

Hemostasis: definition

• the sum total of those specialized functions within the circulating blood and its vessels that are intended to stop hemorrhage Hemostasis: players and phases

• plasma factors • Vascular phase • inhibitors • phase • fibrinolisis • Plasma phase • • vessels

The system Bleeding disorders: clinical approach

• history • physical examination • laboratory tests

Bleeding diosrders:

Site Within normal May be abnormal Usually due to a limits and due to a bleeding disorder number of causes

Nose Finger – induced Unilateral Recurrent, requiring medical intervention or causing anemia

Oral Blood on brush Gum ooze < 30 min Gum ooze > 30 min

Gut Rectal fissure, blood Haematemesis, in nappy Melaena Bleeding diorders: signs and symptoms

Site Within normal May be abnormal Usually due to a limits and due to a bleeding disorder number of causes

Menstrual loss 4 – 7 days „same as Mum” Loss leading to anemia or transfusion

Skin Shins don’t count Bony prominences Spontaneous bruising over soft areas, laceration bleeding > 30 min

Joints and muscles Trauma induced Spontaneous

Intracranial Neonatal , trauma Spontaneous induced

History: neonates (Sharathkumar A, 2008, Bowman M, 2009)

• prolonged bleeding at the circumcision site, • cephalohematomas, • prolonged umbilical stump bleeding Warning signgs and symptoms: Epistaxis: (Sharathkumar A, 2008, SarnaikA, 2010) • positive family history • recurrent epistaxis: – bleeding disorder: 25 – 33% • both nostrils • requiring emergency department visit • physical examination: – in association with other bleeding signs • lasting for more than 15 minutes despite pressure application on the side of the nostril,

menorrhagia – definition (Sharathkumar A, 2008) • assessment of menstrual blood loss – quantitative: loss of > 80 ml of blood per cycle – semiquantitative: • frequent pad changes (<2 h frequency) • menses: • lasting: > 7 days • frequency: more than one menstrual period per month menorrhagia – reasons (Sharathkumar A, 2008)

• vWD (American College of and Gynecology (2000) - recommendation) • platelet function disorders • other

History: Surgical bleeding (Sharathkumar A, 2008, Bowman M, 2009) • outpatient : – circumcision, – tonsillectomy, – dental extractions (> 24 h lub transfusion) • inpatient surgery - bleeding: – surgical field – drains, vascular access – poor wound healing and infection • transfusion during or after surgery that normally does not cause significant blood loss When did the bleeding start? prenatal and neonatal • congenital infection - bleeding disorder • mucosal bleeding - haemorrhagic disease of the newborn • umbilical stump bleeding - factor XIII deficiency and dysfibrinogenaemias • intracranial haemorrhage - factor deficiencies and with neonatal alloimmune • prolonged bleeding following circumcision – , haemorrhagic disease of the newborn

When did the bleeding start? Early childhood

• often implies a congenital defect • bruising, muscle and joint bleeding is strongly suggestive of haemophilia • petechiae and mucosal bleeding suggests a platelet problem or von Willebrand disorder When did the bleeding start? Sudden onset • usually an acute problem such as immune thrombocytopenic • non-accidental injury may have a haemorrhagic presentation with inadequate explanations for each specific , which may have an unusual distribution • skeletal trauma and other stigmata of non-accidental injury often implies a congenital defect

Where is the bleeding ?

• joint bleeding: and B • nasal mucosa: local irritation; von Willebrand disorder and platelet dysfunction • gums, periosteum, skin: scurvy • gastrointestinal: babies - haemorrhagic disease of the newborn; older children - liver disease • retro-orbital: haematological malignancy or disseminated solid tumour Physical examination: the type of skin bleeding

• petechiae alone strongly suggest a platelet or vessel problem, • ecchymoses alone suggest a factor deficiency • combined petechiae and ecchymoses suggest a severe disorder, often of platelet origin

Physical examination: Splenomegaly

• hypersplenism occurs when a large spleen removes platelets from the circulation, which leads to bleeding • hepatomegaly, splenomegaly, lymphadenopathy and/or anaemia, in association with bleeding, strongly suggest leukaemia Lab tests

• initial screening tests ?

Bleeding disorders: initial screening tests

• full blood count and blood film • prothrombin time (PT) - measures the activity of factors II, V, VII and X • activated partial thromboplastin time (APTT) - measures the activity of factors II, V, VIII, IX, X, XI and XII • bleeding time (BT) ? • and • biochemical screen including renal and liver function tests Schematic representation of coagulation pathway

Schematic representation of coagulation pathway

A P P T T T

TT Differential diagnosis of abnormal PT/INR, and APTT

Abnormal PT/INR and/or aPTT

Mixing study (patient plasma:normal plasma – 1:1)

Correction No correction

Abnormal PT/INR with normal aPTT anticoagulant - Factor VII deficiency Specific factor inhibitors - Early - Oral vitamin K antagonist Abnormal PT/INR with normal aPTT - Factor XII deficiency - Factor XI deficiency - Factor IX deficiency - Factor VIII deficiency

Abnormal PT/INR with normal aPTT - deficiency - Factor V deficiency - Factor II deficiency - deficiency/dysfunction - Combined factor deficiencies - Vitamin K deficiency - Oral vitamin K antagonist excess

Lab skrining (Sarnaik A,2010) Disorders of bleeding due to vascular defects • Anaphylactoid purpura (Henoch-Schonlein purpura) • Infective states • Nutritional deficiencies

Anaphylactoid purpura (Henoch–Schonlein purpura) • rash over the buttocks, legs and backs of the elbows • abdominal pain, melaena, joint swellings, glomerulonephritis • Lab tests: the bleeding time, international normalized ratio (INR), activated partial thromboplastin time (aPTT),PTL - normal; • prognosis: excellent but …. • treatment European League against Rheumatism and Paediatric European Society

• palpable purpura (essential) + one of the following: – diffuse abdominal pain – any biopsy showing predominant IgA – acute arthritis/arthralgia – renal involvement (any haematuria or proteinuria ) large bowel demonstrating intussusception

Infective states

• meningococcaemia, • other septicaemias • dengue haemorrhagic fever Bleeding due to platelet disorders

• Inherited platelet disorders • Acquired platelet disorders

ITP: patophysiology - summary ITP. : nomenclature

Old: •ITP - “idiopathic” or “immune” New: •ITP - immune thrombocytopenia:

ITP.: definition

• in the past: PTL : – < 150 x 109/L (150,000/µL) • contemporary: PTL : – < 100 x 109/L (100,000/µL) – with no evidence of leukopenia and/or anemia ITP.: subclasses • primary • secondary: – infections: • HCV, HIV, Helicobacter pylori, CMV, Parvo B19 – autoimmune and lymphoproliferative disorders: • SLE • Wiskott-Aldrich Syndrome • Chronic lymphocytic leukemia • Antiphospholipid syndrome • common variable hypogammaglobulinemia – drugs: • quinine, trimethoprim-sulfamethoxazole

ITP.: clinical categories (Provan D, Blood 2010) ndITP 0 - 3 months from the diagnosis newly diagnosed ITP

pITP 3 - 12 month from the diagnosis persistent ITP cITP > 12 month from the diagnosis chronic ITP sITP is defined by bleeding at presentation severe ITP sufficient to mandate treatment, or new bleeding requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dosage of a current agent ITP.: clinical manifestation

skala 1 cm 2 cm 3 cm Purpura (reddish purple spots)— Petechiae leg ecchymoses

ITP.: clinical manifestation

Mucosal bleeding (wet MRI: intracranial purpura) hemorrhage ITP.: summary ITP children.: treatment – the aims (Kühne T 2017) • prevent life-threatening bleeding • stabilize and reduce bleeding, if clinically needed • increase HR-QoL • avoiding bleeding of patients with comorbidities • transiently increasing the platelet count before surgery • deferring splenectomy • preventing drug treatment side effects • reducing the need for rescue and concomitant treatment

ITP.: treatment options (Cooper N, 2017)

1. line 2. line

• steroids • Splenectomy • Immunosuppression • IVIG - MMF • Anti-D - Azathioprine immunoglobulins - Rituximab

• TPO-RA - Eltrombopag - Romiplostim

cITP – the aim: prevent life – threatening bleeding, improve, don’t look at the PTL count (!!!) ITP.: ASH Guidelines for the Management of nITP in Children (Neunert C, 2011) Children

We recommend:

• Children with no bleeding or mild bleeding (defined as skin manifestations, such as bruising and petechiae) be manager with observation alone regardless of platelet count (grade 1B); • In pediatric patients requiring treatment, a single dose of IVIg (0.8-1.0) or a short course of steroids be used as first-line treatment (grade 1B); • IVIg can be used if a more rapid increase in the platelet count is required (grade 1 B); • Anti-D immunoglobulin is not advised in children with a hemoglobin concentration that is decreased due to bleeding or with evidence of autoimmune hemolysis (grade 1C).

We suggest: • A single dose of anti-D immunoglobulin can be used as first-line treatment in Rh-positive, nonsplectomized children requiring treatment (grade 2 B).

ITP.: diagnostic and treatment algorithm (PasailaB BJH2008) Bleeding due to coagulation disorders

Haemophilia - prevalence

• Haemophilia A (factor VIII deficiency): 5-10 males per 100 000 • (Christmas disease, factor IX deficiency): 0.5-1 per 100 000. • Factor XI deficiency (): rare • other factor deficiencies: exceedingly rare Haemophilia: genetics

• haemophilia A and B are both X-linked • up to one-third of all new cases of haemophilia are due to new . • female carriers sometimes have low levels of factor VIII or IX and may have a bleeding disorder

Haemophilia A: severity

Factor VIII:C Severity Bleeding tendency

<1% Severe Spontaneous joint/muscle bleeds

1-5% Moderate Bleed after minor trauma

>5-40% Mild Bleed after surgery Haemophilia: clinical manifestation Neonatal period Early childhood •positive family history •1 year and up: skin and carrier status soft tissue bleeds •prolonged bleeding •Walking child - following circumcision Haemarthroses •intracranial haemorrhage •Young children – ankles •Older children - elbow and knee bleeding

Haemophilia: chronic illness

• synovial hypertrophy and arthritis • HIV/AIDS - 50% patients (1980-1985) • HBV/HCV infection • variant Creutzfeldt-Jakob disease (vCJD) is a prion disease • psychosocial problems due to: – chronic illness, – lifestyle restrictions – need for injections Haemophilia - complications

• inhibitors (anti-factor-VIII or anti-factor-IX antibodies) • central lines – infection – large vein

Haemophilia: management

• correct or prevent the bleeding tendency • choice of product • orthopaedic • haemophilia centers • inhibitors Correct and prevent the bleeding tendency • mild and moderate haemophilia A - desmopressin acetate • 1 unit of factor VIII/kg iv increases the factor VIII by approximately 2% • life-threatening bleeds require plasma factor levels of more than 80% • most other bleeds require plasma factor levels of 30-60% • prophylactic infusions of 25-40 U/kg three times a week 'converts' severe disease into moderate disease

Choice of product

• recombinant product to all haemophilia patients • plasma-derived factor products • screening for HIV and hepatitis B and C and then undergo two viral inactivation steps in the processing Orthopaedic

• R - Rest • I - Immobilization, Ice • C - Compression • E - Elevation

• splinting followed by exercises when pain has settled preserves function

Inhibitors

• occur in up to 30% of patients • at least half of these are low-titre inhibitors, which can be treated by high-dose factor VIII • high titre inhibitors require 'immune tolerance' therapy for eradication of inhibitor, and infusions of the factor VIII and IX bypass agent, recombinant factor VIIa, to treat bleeds Haemophilia centers

• focus of education and training for patient and family • multidisciplinary group with expertise in haemophilia management.

Haemophilia – haemarthrosis

• quantitative (types 1 and 3) or qualitative (type 2) deficiency of von Willebrand factor (vWF) • inheritance is usually autosomal dominant • common: 125 per million population • clinical picture: bruising, excessive, prolonged bleeding after surgery, mucosal bleeding such as epistaxis and menorrhagia • prolonged bleeding time but normal INR and aPTT, unless severe disease is present

Von Willebrand disease; treatment • type 1 vWD – treatment: DDAVP • DDAVP – repeat after 12-24 hours • severe types - plasma-derived FVIII concentrate • cryoprecipitate – no • i.m. injections, aspirin, non-steroidal anti-inflammatory drugs – no Bleeding diseases: diagnostic algorithm (Sharathkumar A, 2008)