AGENDA FRACP Lecture Series z Lecture 1 – Bleeding disorders z Lecture 2 – Neutropenia and Thrombocytopenia z For each of these conditions the following should be addressed Nalini Pati z Clinical presentation z Initial investigations Consultant haematologist z Initial management z Potential complications z Therapeutic options z Indications for referral Investigations Haemophilia z Screening z PFA – 100 z What haemophilia was. investigations z Blood group z FBE z z Von Willebrand’s What haemophilia is. screen z APTT z What are the main problems with z PT / INR z Factor XIII haemophilia today. z Fibrinogen z TCT 1 2 Haemophilia Carrier Woman Healthy Man XH X X Y X X X X X Y X Y H H Carrier Girl Healthy Girl Haemophilic Boy Healthy Boy Haemophilia Haemophilia ––WorldWorld Healthy Woman Haemophilic Man Perspective z An estimated 250,000 patients in the world population. X X X Y H z Only about 50, 000 receive specific treatment. X X X X X Y X Y z Australia has approximately 1800 patients H H with haemophilia Carrier Girl Carrier Girl Healthy Boy Healthy Boy Haemophilia Management 2008 Haemophilia Prophylaxis z Clotting factor replacement is the cornerstone of z Prophylaxis treatment z Regular infusions of (recombinant) clotting z Recent (October 2004) Federal and State Government consensus to fund recombinant FVIII and FIX for all factor concentrate to prevent joint and muscle patients with haemophilia in Australia bleeds z Clotting factor needs to be given directly into the into veins z Majority of children begin prophylaxis after the first or second joint bleed z Factor replacement can be given for treatment AND prevention (prophylaxis) of bleeds z The use of early prophylaxis has significantly reduced the complication of joint disease 3 FVIII and FIX Inhibitors z Most serious complication z FVIII or FIX proteins recognised as “foreign” z Stimulating immune response and formation of IgG z Occurs in 30% patients severe haemophilia A and 5% patients haemophilia B FVIII and FIX Inhibitors Haemophilia 2008 z Renders treatment and prophylaxis ineffective z Whilst inhibitors in haemophilia are still a major problem, the modern management z Limited treatment options and return to the of haemophilia prevents the traditional “natural history of haemophilia” complications of joint disease z Current treatment option to treat haemorrhage in z The availability of recombinant clotting patients with haemophilia (rFVIIa – NovoVII) factor concentrate limits the risk of particularly expensive transfusion transmitted viral disease Structure of Haemophilia Care in Australia z National Blood Authority provides funds for clotting factor concentrate z 30% state / 70% federal z Management run through haemophilia Diagnos is TitiTransition individual treatment centers 4 12 – 24 months of age • Onset of joint bleeds Diagnos is TitiTransition Diagnos is TitiTransition < 12 months of age • Addressing psychological impact of X linked recessive disorder 2 years – 5 years • Commencement of home based therapy Diagnos is TitiTransition Diagnos is TitiTransition > 5 years • Are boys with hemophilia as active, fit and happy as their peers? Modern Morbidities of Haemophilia Virchow’s Triad in Haemophilia z Impact on family functioning Vessel Wall z Support of home based therapy z Complications of central venous lines z Activity levels z Bone density z Maintenance of Healthy Weight Thrombosis z Maximizing Education Potential Blood Blood composition Flow 5 Activity Levels Bone Density z In the modern era of haemophilia z Importance of musculomusculo--skeletalskeletal integrity management, are boys with haemophilia (including maintaining adequate bone as active as their peers? density) z What are the implications of reduced z Patients with haemophilia may be at risk of levels of activity in boys with haemophilia? developing reduced bone density z Bone density z Reduced weight bearing exercise z Maintenance of Healthy Weight z Prolonged periods of immobility Figure 1 Bone mineral density (BMD) of lumbar spine and total body and bone mineral apparent density (BMAD) of lumbar spine plotted by age in boys and girls. The bold line represents the fitted line, the thin lines represent {+/-}2 SD. Bone Density van der Sluis, I M et al. Arch Dis Child 2002;87:341-347 Bone Density Maintenance of Healthy Weight z Obesity is a major public health problem z Greater access to calorie dense foods z Reduced activity (greater access to sedentary pastimes) 6 Risk Factors Maintenance of Healthy Weight z Are boys with haemophilia more prone to becoming overweight? z Predisposed to becoming overweight on the basis of reduced physical activity Maintenance of Healthy Weight in Changing Morbidities of Haemophilia Haemophilia z Implications for patients with haemophilia and obesity significant z As a result of the major advances in haemophilia care there is the opportunity z Complicated venous access to focus on a different range of co- z Increased clotting factor usage morbidities z Exacerbation of established joint disease Von Willebrand disease z Type 1 z 80% z Mild to moderate quantitative reductions in VWF von Willebrand’s disease levels z T2Type 2 z 20% z Qualitative defects z Type 3 z Virtual deficiency of VWF 7 Type 1 VWD Type 1 VWD z Prospective studies have suggested 1% of z VWD is an inherited disease that causes population affected bleeding and type 1 VWD is a quantitative deficiency of VWF. z Ter tiary re ferra l cen tres 1 in 10, 000 Type 1 VWD (ISTH) Von Willebrand Disease in the Neonate z All of the following criteria must be met z A significant history of mucocutaneous bleeding z VWF:Ag and CBA increased in the z Laboratory tests compatible with type I VWD neonatal population z Either a positive family history or an appropriate genetic mutation z Reach adult levels by 6 months of age Royal Children’s Hospital Royal Children’s Hospital Type VWD 1 VWD z Vast majority of patients have Type 1 z Patients referred from surgical services, VWD adolescent gynaecology and external ggpeneral practitioners z Type 2 VWD z ? 4 patients z Routine investigations z Type 3 VWD z Family testing performed as routine z 1 patient z DDAVP challenge performed as routine 8 DDAVP challenge Management of VWD z Relative contraindication in children less than 2 z Non transfusional therapies years of age z DDAVP z Thirty minute infusion of 0.3 mcg / kg (maximum z Sustain increase in FVIII / VWF 8 – 10 hours 20 mcg) z Given 12 – 24 hourly depending on documented response z VWF: Ag a t 30 m inu tes, 1 hour an d 4 hours z Tachyphylaxis after 4 doses z Restriction of fluid input over 12 hours following z Antifibrinolytics infusion z Transfusional therapies z One patient (10 months of age) developed seizures z BIOSTATE (AHF) secondary to hyponatramia following treatment with DDAVP Biostate Thrombocytopenia z Plasma derived FVIII / VWF z Inherited z Ratio of FVIII : VWF of 2:3 (product insert suggests Biostate ratio of 1:2) z Acquired (ITP) z 20 000 units on stock at all times at RCH Case Case z 3 week old male infant presenting with z Family history marked thrombocytopenia in the setting of z No significant history of bleeding, known possible vascular tumour of lower limb platelet disorders z Youngest of five children z Previous six miscarriages z Antenatal history z Largely unremarkable z Mother on aspirin for recurrent miscarriages z Consanguineous parents 9 Case z Presenting history z Presented at birth with large, fleshy vascular(?) lesion affecting the lower limb z Referred to paediatrician z Possible kaposiform haemangioendothelioma (KHE) z Treated with corticosteroids z Referred to haematology due to persistent thrombocytopenia Case z Initial investigations z Slightly anaemic, neutropenic and markedly thrombocytopenic z No evidence of coagulation activation z Ultrasound showed lesion in right cerebral hemisphere, confirmed on MRI as bleed (antenatal) z Managed with platelet transfusion with good response 10 Case Congenital Thrombocytopenia: “Tools” available for assessment z Progress z Platelet count & sizing z Reticulated platelets z Persistent marked thrombocytopenia despite involution of vascular lesion z Electron microscopy z Bone marrow aspiration and z Repeated bone marrow examination showing immunohistochemistry normocellular bone marrow but (?) decreasing megakaryocytes (confirmed on z Flow cytometry for platelet glycoproteins immunohistochemistry CD61) z Assessment of platelet function z PFA 100 z Patient “well” and not bleeding z Aggregometry z Molecular markers Platelet counting and sizing Platelet Counting & Sizing (Coulter principle) z Platelet count is not directly measured – derived RBCs from platelet histogram z Any particle sized between 2 to 20 fl is counted as a + - platelet z Any particle sized outside of 2 to 20 fl is not counted as a platelet PLT Cross section of Oscilloscope screen RBC aperture (60x50 micron) 11 Reticulated Platelets z “Immature platelets” z Larger mean platelet volume with higher RNA content z Flow cytometric method using the membrane permeable flurochrome thiazole orange to stain RNA z Sensitivity improved by using gating techniques incorporating CD61 z Reported as a percentage (lack of widely accepted standardization of normal values) Reticulated Platelets Bone Marrow Aspiration z May have a role in the distinguishing z Performed under general anaesthetic patients with ITP / consumptive states z Limited morbidity from those with decreased platelet production z Provides quantitative information with lim ite d qua lita tive in forma tion (corre la tion of