Bleeding Fevers! Thrombocytopenia and Neutropenia

Bleeding Fevers! Thrombocytopenia and Neutropenia

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

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