EVIDENCE BASED MANAGEMENT OF PEDIATRIC THROMBOPHILIA Professor Azza Abdel Gawad Tantawy, MD Professor of Pediatrics Pediatric Hematology/Oncology Unit Ain Shams University, Cairo , Egypt • TO DEFINE THROMBOPHILIA • TO IDENTIFY CAUSES OF THROMBOPHILIA • TO PRESENT EVIDENCE BASED UPDATES IN PEDIATRIC THROMBOPHILIA: WHO TO TEST , WHY TO TEST AND CLINICAL IMPACT OF THROMBOPHILIA TESTING Thrombophilia Thrombophilia is defined as both an acquired or congenital abnormality of hemostasis predisposing to venous and/or arterial thrombosis Acquired Inherited Mixed/unknown Immobilization Antithrombin deficiency High levels of factor VIII Plaster cast Protein C deficiency High levels of factor IX Trauma Protein S deficiency High levels of factor XI Major surgery Factor V Leiden (FVL) High levels of fibrinogen Orthopedic surgery Prothrombin 20210A High levels of TAFI Malignancy Dysfibrinogenemia Low levels of TFPI Factor XIII 34val APC-resistance in the absence of FVL Fibrinogen (G) 10034T Antiphospholipid syndrome Non-O blood group Hyperhomocysteinemia Myeloproliferative disorders High levels of PCI (PAI-3) Polycythemia vera Central venous catheters Age Obesity F. R. ROSENDAAL and P. H. REITSMA ; JHT 2009 TAFI, thrombin-activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; PCI, protein C inhibitor; PAI-3, plasminogen-activator inhibitor-3. Age-distribution at the first thrombotic onset in pediatric patients with spontaneous venous thrombosis [not associated with secondary causes of thrombosis] Ulrike Nowak-Göttl et al ; Blood 2001 Genetic risk factors for venous thrombosis Strong risk factors deficiencies of antithrombin, protein C and protein S Moderately strong factor V Leiden, prothrombin 20210A, non-O blood group & fibrinogen 10034T Many weak genetic risk factors including variants of fibrinogen, factor XIII and factor XI F. R. ROSENDAAL and P. H. REITSMA ; JTH 2009 Strong risk factors Deficiencies of natural coagulation inhibitors ● Deficiencies of antithrombin, protein C, and its cofactor protein S found in less than 1% of the population (antithrombin deficiency in only 1 per 5000) ● Hundreds of mutations responsible for defective genes ● Deficiencies can lead to a highly penetrant phenotype with over tenfold increased risks for heterozygous carriers ● Prevalence in Caucasians 0.2–0.5% ● Less common than factor V Leiden or prothrombin G20210A mutation ● Associated with familial venous thrombosis ● Autosomal dominant ; gene on chromosome 2 (2q13–14) Homozygotes can develop severe thrombotic tendency in infancy characterized as purpura fulminans Heterozygotes for protein C deficiency have an increased risk of developing warfarin-induced skin necrosis Protein C deficiency has been implicated in adverse pregnancy outcomes such as DVT, preeclampsia, intrauterine growth restriction and recurrent pregnancy loss Classical clinical presentation of homozygous PC /PS deficiency : ● Cerebral or ophthalmic damage (or both) that occur in utero ● Purpura fulminans within hours or days of birth ● Rarely large-vessel thrombosis ● Purpura fulminans : acute, lethal syndrome of DIC characterized by rapidly progressive hemorrhagic necrosis of skin due to dermal vascular thrombosis ● Skin lesions start as small, ecchymotic sites , increase in radial fashion, become purplish black with bullae, then turn necrotic and gangrenous ● Lesions occur mainly on extremities but can occur on buttocks, abdomen, scrotum, and scalp, at pressure points, at sites of previous punctures, and at previously affected sites Purpura Fulminans Diagnosis Diagnosis : •Protein C/protein S level usually undetectable The presence of very low levels of •Heterozygous state in parents protein C/protein S in the • Identification of the molecular defect absence of clinical manifestations and of a family history cannot be considered diagnostic because physiologic plasma levels can be as low as 0.12 U/mL in neonate Antithrombotic Therapy in Neonates and Children : American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition) ● For neonates with homozygous protein C Replacement therapy should be continued deficiency, we recommend administration of until all of the clinical lesions resolve, either 10 to 20 mL/kg of FFP q12h or protein C which is usually at 6 to 8 weeks concentrate, when available, at 20 to 60 U/kg until the clinical lesions resolve (Grade 1B) ● We suggest long-term treatment with VKAs (Grade 2C), LMWH (Grade 2C), protein C In addition to the clinical course, replacement (Grade 1B), or liver transplantation plasma d-dimer concentrations (Grade 2C) may be useful for monitoring the effectiveness of therapy Monagle P, e tal . Chest. 2012 Feb;141(2 Suppl):e737S-e801S. doi: 10.1378/chest.11-2308. 2018 ASH GUIDELINES IN HOMOZYGOUS PROTEIN C DEFICIENCY AND PURPURA FULMINANS IN ACUTE SETTING Anticoagulation plus protein C replacement, rather than anticoagulation alone AFTER ACUTE ATTACK ▪ ASH suggests protein C replacement, rather than anticoagulation ▪ But if cannot supply full dose of protein C , ASH suggests combined anticoagulation and protein C The ASH guideline panel suggests using either liver transplantation or no liver transplantation (anticoagulation or protein C replacement) in pediatric patients with congenital purpura fulminans due to homozygous protein C deficiency Monagle P et al , Blood Adv. 2018 Nov 27; 2(22): 3292– 3316 Genetic risk factors for venous thrombosis Strong risk factors deficiencies of antithrombin, protein C and protein S Moderately strong factor V Leiden, prothrombin 20210A, non-O blood group & fibrinogen 10034T Many weak genetic risk factors including C>T variant at position 677 in MTHFR , variants of fibrinogen, factor XIII and factor XI F. R. ROSENDAAL and P. H. REITSMA ; JTH 2009 Moderately Strong genetic risk factors Factor V Leiden 1st described in in 1994 by Bertina et al A transition (guanine to adenine) at nucleotide 1691 results in replacement of arginine by glutamine. This gene product: factor V Leiden (after Netherlands city it was first identified) , also called factor V Q506 F.V Leiden is not susceptible to cleavage by APC →hypercoagulable state as more factor Va is available increasing generation of thrombin FV Leiden decreases the anticoagulant activity of activated protein C ● Found in 20% of patients with venous thrombosis ● Found in 50% of patients with familial thrombophilia ● Thrombosis risk is 5-fold increased in heterozygotes, & 50 fold in homozygotes Moderately Strong genetic risk factors Prothrombin 20210A Described in 1996 by Poort et al A mutation in the 3'-untranslated part of the prothrombin gene (prothrombin 20210A) leads to increased prothrombin levels, which are associated with an increased risk of venous thrombosis Almost exclusively found in Caucasians ● Carriers have a 2- to 3-fold increased risk of venous thrombosis ● Found in approximately 6% of patients with venous thrombosis ● As factor V Leiden and prothrombin 20210A both are common, compound heterozygotes are not exceedingly rare, have 20-fold increased risk of thrombosis compared to individuals with neither mutation Khan &Dickermann;J.Thrombosis,2006 Weak genetic risk factors Several genetic factors have a weak effect on thrombosis, i.e. with relative risks between 1.0 and 1.5 The C>T variant at position 677 in MTHFR renders the enzyme thermolabile, resulting in slightly elevated homocysteine levels The variant is common (10% of the general population are carriers), but effect on homocysteine levels is small, which may explain conflicting results about effect of carriership on risk of thrombosis A meta-analysis suggested weak effect (relative risk 1.20), but large single study (the MEGA study) showed no association at all N.A.Goldenberg , Hematology 2008;F. R. Rosendaal and P. H. Reitsma ; JTH 2009 Prevalence of inherited thrombophilia and relative risk estimates for various clinical manifestations Antithrombin Protein C Protein S F2 G20210A Lupus Anticardiolipin Factor V Leiden deficiency deficiency deficiency mutation anticoagulant antibodies Prevalence in the general 0·02% 0·2% 0·03–0·13% 3-7% 0·7–4% 1–8% 5% population Relative risk for a first venous 5–10 4–6·5 1–10 20% 2–3 3–10 0·7 thrombosis Relative risk for recurrent 1·9–2·6 1·4–1·8 1·0–1·4 1.4 1·4 2–6 1–6 venous thrombosis Relative risk ???No No No consistent for arterial consistent 1.3 0·9 10 1·5–10 association association thrombosis association S. Middeldorp ,ASH Education Book 2016 Prevalence of genetic defects among Caucasians Incident VTE (%) recurrent VTE (%) Normal population Activated Protein C resistance (Factor V 20 40–50 3–7 Leiden) Prothrombin G20210A mutation 3–8 15–20 1–3 Antithrombin deficiency 1–2 2–5 0.02–0.04 Protein C deficiency 2–5 5–10 0.2–0.5 Protein S deficiency 1–3 5–10 0.1–1 Khan and Dickerman ;Thrombosis Journal 2006 HYPERHOMOCYSTEINEMIA INHERITED ● Homozygous cystathionine synthetase deficiency (severe)---premature atherosclerosis , arterial and venous thrombosis ● Heterozygous ● Others : remethylation pathways defects ACQUIRED ● Nutritional deficiencies : B12 ,folic acid, pyridoxine ( cofactors of homocysteine metabolism) ● Relative deficiency in chronic hemolytic anemias ● Drugs that interfere with metabolism of these factors The antiphospholipid syndrome (APS) ● APS is autoimmune condition characterized by the persistent presence of antiphospholipid antibodies (aPL), in association with thrombosis (which can be arterial, microvascular or venous) and/ or pregnancy morbidity ● APS can occur alone when it is known as