Bleeding fevers! Thrombocytopenia and neutropenia Faculty of Physician Associates 4th National CPD Conference Monday 21st October 2019, Royal College of Physicians, London @jasaunders90 | #FPAConf19 Jamie Saunders MSc PA-R Physician Associate in Haematology, Guy’s and St Thomas’ NHS Foundation Trust Board Member, Faculty of Physician Associates Bleeding fevers; Thrombocytopenia and neutropenia Disclosures / Conflicts of interest Nothing to declare Professional Affiliations Board Member, Faculty of Physician Associates Communication Committee, British Society for Haematology Education Committee, British Society for Haematology Bleeding fevers; Thrombocytopenia and neutropenia What’s going to be covered? - Thrombocytopenia (low platelets) - Neutropenia (low neutrophils) Bleeding fevers; Thrombocytopenia and neutropenia Thrombocytopenia Bleeding fevers; Thrombocytopenia (low platelets) Pluripotent Haematopoietic Stem Cell Myeloid Stem Cell Lymphoid Stem Cell A load of random cells Lymphoblast B-Cell Progenitor Natural Killer (NK) Precursor Megakaryoblast Proerythroblast Myeloblast T-Cell Progenitor Reticulocyte Megakaryocyte Promyelocyte Mature B-Cell Myelocyte NK-Cell Platelets Red blood cells T-Cell Metamyelocyte IgM Antibody Plasma Cell Secreting B-Cell Basophil Neutrophil Eosinophil IgE, IgG, IgA IgM antibodies antibodies Bleeding fevers; Thrombocytopenia (low platelets) Platelet physiology Mega Liver TPO (Thrombopoietin) TPO-receptor No negative feedback to liver Plt Bleeding fevers; Thrombocytopenia (low platelets) Platelet physiology Mega Liver TPO (Thrombopoietin) TPO-receptor Plt Plt Plt Plt Plt Plt Bleeding fevers; Thrombocytopenia (low platelets) Platelet physiology Mega Liver TPO (Thrombopoietin) TPO-receptor Plt Plt Plt Plt Plt Plt Bleeding fevers; Thrombocytopenia (low platelets) How bad is the thrombocytopenia? 150 – 400 x109 Severe Mild Moderate <50 149 - 100 99 - 50 ITP <30 There is little variation in platelet count for a single person A change by 98 x109 in the platelet count should prompt investigation Bleeding fevers; Thrombocytopenia (low platelets) Causes Chronic liver disease Medications Alcohol Bone Marrow Disorders - Isolated thrombocytopenia - Antibiotics - Nutritional deficiencies - Would typically cause other - Liver produces TPO - Piperacillin - Folate deficiency cytopenias - Usually mild to moderate (>50) - Vancomycin - Direct bone marrow - Leukaemia (acute) - NAFLD - Rifampicin suppression - Lymphoma - Antiepileptics - Alcoholic liver disease - Myeloma - Quinine - Myelodysplastic syndrome Infection - Metformin Nutritional Deficiencies - Viral - VitB12 deficiency - Usually associated with Autoimmune - HIV - Proton pump inhibitors (PPI) anaemia - SLE - Hepatitis B and C - Reduced nutrient - Vitamin B12 - APS - CMV and EBV absorption, incl. iron - Folate - Rheumatoid arthritis - MMR - Heparin induced (HIT) - Parvovirus - Cytotoxics - Bacterial - Chemotherapy - Direct bone marrow suppression in severe sepsis Idiopathic thrombocytopenic purpura (ITP) Thrombotic thrombocytopenic purpura (TTP) Bleeding fevers; Thrombocytopenia (low platelets) Causes Chronic Liver Disease - Liver produces TPO (hormone), which stimulates the bone marrow to produce megakaryocytes - May be the presenting feature in portal hypertension with splenomegaly - (Spleen sequestrates platelets) Chronic Alcohol Abuse - Leads to alcoholic liver disease, same as above - Direct bone marrow suppression - Should usually lead to a degree of pancytopenia - Reduced folate absorption Nutritional Deficiencies - Iron, Vitamin B12 and folate are vital for the formation of red cells in the bone marrow - Particularly Hb, but platelets also - Usually leads to a pancytopenia Bleeding fevers; Thrombocytopenia (low platelets) Causes Viral Infections Directly infect megakaryocytes, leading to apoptosis Platelet interaction with virus, causing platelet activation and consumption Direct TPO reduction from liver injury / interaction with TPO receptors - Acute - Rubella, mumps, varicella, parvovirus, Epstein-Barr virus (EBV) - Hepatitis C - Thrombocytopenia can resolve spontaneously after virus has cleared - Chronic - Human immunodeficiency virus (HIV) - direct toxicity to megakaryocytes - secondary ITP - primary HIV associated thrombocytopenia (or PHAT) - Cytomegalovirus (CMV) - Hepatitis B - Same mechanism as liver disease Bleeding fevers; Thrombocytopenia (low platelets) Causes Bacterial Infections - Overwhelming infections (proper sepsis), usually requiring ICU admission - Pancytopenia due to bone marrow suppression - Antimicrobials or direct marrow suppression - Mycoplasma infection - Helicobacter pylori infection - Tick-borne infections - Eptospirosis, brucellosis, anaplasmosis Bleeding fevers; Thrombocytopenia (low platelets) Causes Antibiotics Neurologics OTC Beta-lactam Abx Quinine Carbamazepine Vancomycin Ranitidine Phenytoin The ‘Pip’ in Pip/Taz Simvastatin Haloperidol Rifampicin Metformin Trimethoprim Proton pump inhibitors (PPIs) Aspirin/Clopidogrel/Warfarin/DOACs do not inherently reduce the platelet count Bleeding fevers; Thrombocytopenia (low platelets) Causes Heparin-induced Thrombocytopenia (HIT) - Thrombocytopenia following exposure of heparin - Rapid production of IgG antibodies, with absence of IgM antibodies - Suggesting secondary immune response - Hypothesis of sensation of antiheparin/platelet factor 4 (PF4) antibody occurs in presence of other factors (e.g. bacterial infection) UH > LMWH > Fondaparinux Bleeding fevers; Thrombocytopenia (low platelets) Causes Heparin-induced Thrombocytopenia (HIT) Diagnostic Features + Thrombocytopenia Received heparin within last 100 days 50% drop in platelet count - Typically 5-10 days - Does not need to fall below 150 x 109 - UH > LMWH > Fondaparinux Nadir ≥20 × 10⁹ Recent venous or arterial thrombosis - MI, PE, DVT, CVA, Injection site necrosis Recent orthopaedic or cardiovascular surgery Risk Assessment Absence of other causes of thrombocytopenia 4Ts score for HIT Jo et al. J Thromb Haemost. 2006 - Sepsis - Degree of thrombocytopenia - Medications (e.g. Vancomycin) - Timing of platelet count fall - Thrombosis or other sequelae Absence of bleeding - Other causes for thrombocytopenia - No or minimal petechiae/ecchymosis Bleeding fevers; Thrombocytopenia (low platelets) Causes Haematological - Myelodysplastic syndrome (MDS) - A group of malignant hematopoietic stem cell disorders, characterized by dysplastic and ineffective blood cell production - Can be cytopenia, bicytopenia or pancytopenia - Typically presents with a macrocytic anaemia and mild thrombocytopenia, that progresses - Lymphoproliferative disorders - CLL - Lymphoma Bleeding fevers; Thrombocytopenia (low platelets) Causes Haematological Thrombotic Thrombocytopenic Purpura Medical emergency New onset neurological symptoms Continuous cardiac monitoring (immediately) - Often vague - Don’t follow logical clinical pattern Immediate admission to Critical Care / Intensive Care Unit . New onset thrombocytopenia (20-30) at TTP centre . - Profound avoid delaying transfer for further investigations, unless life threatening Mild normocytic anaemia (90-100 g/L) - Intravascular haemolytic anaemia . DO NOT GIVE PLATELETS (unless discussed with haematology) Red cell fragments (schistocytes) on blood film Bleeding fevers; Thrombocytopenia (low platelets) An approach to the adult patient with unexplained thrombocytopenia Bleeding fevers; Thrombocytopenia (low platelets) Is the patient bleeding? Bleeding fevers; Thrombocytopenia (low platelets) What kind of bleeding? Mucocutaneous Bleeding Haematomas = Platelet = Coagulation System CNS Gum bleeding Skin New headache? Seizure Active Stopped Petechiae Bruising GI Spontaneous Traumatic Anaemia Epistaxis Upper GI? Lower GI? Bilateral Unilateral Normal creat / Raised urea? Acute? Chronic? Bleeding fevers; Thrombocytopenia (low platelets) Coagulation Status Mild Moderate Severe 149 - 100 99 - 50 <50 “Unlikely” to be the cause of their bleeding “Potentially” the cause of their bleeding Check coagulation status Platelet transfusion may be indicated (INR, aPTTr, Fibrinogen) (Platelets don’t solve everything) Bleeding fevers; Thrombocytopenia (low platelets) How bad is the thrombocytopenia? Mild Moderate Severe 149 - 100 99 - 50 <50 Investigate in Prim Care Not Bleeding – Same day referral to / review by Refer to haematology haematology (Send first line bloods) Bleeding – Same day discussion with haematology Bleeding fevers; Thrombocytopenia (low platelets) FBC – Plt <150 x10^9 Haematinics Virology Iron studies HIV Blood film Iron level, TIBC, TSat, Ferritin Hepatitis B surg Ag, surf Ab, core Ab Hepatitis C IgG Vitamin B12 Confirm true thrombocytopenia Serum +/- MMA Anisocytosis / Clumping EBV IgG, IgM CMV IgG, IgM Myelodysplastic Syndrome (MDS) Serum folate Hypogranular platelets Dysplastic neutrophils Liver/Bone Profiles Specialist Tests Macrocytosis Acute Leukaemia (AML/ALL) Raised LFTs Myeloma Screen Circulating peripheral blasts ALT, ALP, GGT Serum protein electrophoresis (myeloblasts, lymphoblasts) Serum free light chains Auer rods / Promyelocytes Raised calcium MAHA / TTP ?Malignancy Hep2ANA (autoimmune screen) Red cell fragments Bleeding fevers; Thrombocytopenia (low platelets) Immune thrombocytopenic purpura (ITP) Bleeding fevers; Thrombocytopenia (low platelets) Idiopathic Thrombocytopenic Purpura (ITP) - Acquired immune disorder - Isolated thrombocytopenia (<100 x109) - Primary ITP; Autoimmune in nature - Acquired anti-platelet autoantibodies (IgG) - Bind to GPIIb/IIIA receptors 30-40% patients