Bleeding 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 • Platelet phase • fibrinolisis • Plasma phase • platelets • vessels The coagulation system Bleeding disorders: clinical approach • history • physical examination • laboratory tests Bleeding diosrders: signs and symptoms 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 Obstetrics and Gynecology (2000) - recommendation) • platelet function disorders • other coagulopathies History: Surgical bleeding (Sharathkumar A, 2008, Bowman M, 2009) • outpatient surgery: – 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 thrombocytopenia • prolonged bleeding following circumcision – haemophilia, 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 purpura • non-accidental injury may have a haemorrhagic presentation with inadequate explanations for each specific bruise, 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: haemophilia A 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 Lupus anticoagulant Heparin - Factor VII deficiency Specific factor inhibitors - Early vitamin K deficiency - 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 - Factor X deficiency - Factor V deficiency - Factor II deficiency - Fibrinogen 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 Rheumatology 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” thrombocytopenic purpura 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 therapy 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