Bleeding fevers! Thrombocytopenia and

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 )

- Neutropenia (low ) 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

T-Cell Progenitor Mature B-Cell

Myelocyte NK-Cell Platelets Red cells T-Cell

Metamyelocyte IgM Antibody Plasma Cell Secreting B-Cell 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 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 - 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 - 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 - 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 disorders, characterized by dysplastic and ineffective 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 () on 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 / Clumping EBV IgG, IgM CMV IgG, IgM Myelodysplastic Syndrome (MDS) Serum folate Hypogranular platelets Dysplastic neutrophils Liver/Bone Profiles Specialist Tests

Acute Leukaemia (AML/ALL) Raised LFTs Myeloma Screen Circulating peripheral blasts ALT, ALP, GGT Serum protein electrophoresis (, lymphoblasts) Serum free light chains Auer rods / 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 no detectable antibody - Recognised by in spleen and destroyed

- T-cell mediated platelet destruction

- Impaired megakaryocyte (MK) function - Autoantibodies bind to MK’s and inhibit maturation - Increase destruction

- Secondary ITP; Inherited or predisposing diseases - HIV - Helicobacter pylori - SLE (and other autoimmune conditions) Bleeding fevers; Thrombocytopenia (low platelets)

Idiopathic Thrombocytopenic Purpura (ITP)

Clinical Presentation Petechiae - tiny, circular, non-raised patches that appear on the skin or mucous membrane - <5mm - WET PETECHIAE  Soft palate Purpura - tiny, circular, non-raised patches that appear on the skin or mucous membrane - 5-9mm Mucosal bleeding - Nose - Gums Isolated profound thrombocytopenia Plt <10 (without a clear cause) Bleeding fevers; Thrombocytopenia (low platelets)

Idiopathic Thrombocytopenic Purpura (ITP) Clinical Management

Children If no severe bleeding – Observe ‘Watch and Wait’ Re-assure parents will resolve with times (days)

If severe bleeding  Consultant haematology/paediatrics SOS Avoid platelet transfusions unless advised to give Bleeding fevers; Thrombocytopenia (low platelets)

Idiopathic Thrombocytopenic Purpura (ITP) Clinical Management

Acute Setting Immunosuppression EMERGENCY

High-dose steroids Azathioprine or Dexamethasone 40mg po od for 4-days only Mycophenolate mofetil (MMF) Platelet transfusion if active major bleeding Prednisolone 1mg/kg and then slow week over 4-weeks TPO agonists No indication for Intravenous Immunoglobulin (IVIg) Eltrombopag (daily tablet) routine platelet Risk of transmittable disease / reaction Romiplostim (weekly injection) transfusion in ITP (same as blood transfusion) Will be destroyed May lose response to above therapies Immunomodulatory within 6-8 hours if repeated exposure Rituximab (Anti CD20 monoclonal antibody) Bleeding fevers; Thrombocytopenia (low platelets)

Platelet Transfusion

The non-bleeding patient doesn’t (usually) need a platelet transfusion Bleeding fevers; Thrombocytopenia (low platelets)

Platelet targets Platelet Count Indication Platelet transfusion >10 All patients Routine dentistry >20 Sepsis / Acutely unwell (incl. T 38.0+) >30 Dental extraction >50 Surgery / invasive procedure Anticoagulation (Aspirin, Clopidogrel, Warfarin, DOACs) >80 (>100) Ocular or neurosurgery

DO NOT TRANSFUSE PATIENT’S WITH ITP unless active haemorrhage / life-threatening bleed  Seek Haematology advice SOS

THINK! 1x pool over 30-minutes Why is my patient thrombocytopenic? Increment 30-mins after finish Bleeding fevers; Thrombocytopenia and neutropenia

Neutropenia Bleeding fevers; Neutropenia (low neutrophils)

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; Neutropenia (low neutrophils)

Neutropenia Severity

1.5 – 7.0 x109

Mild Moderate Severe

>1.0 x109 0.5 - 1.0 x109 <0.5 x109

Unlikely to be associated with a Risk of significant infection Risk of significant infection and severe significant risk of infection atypical bacterial/fungal infections Bleeding fevers; Neutropenia (low neutrophils)

Causes

Transient Persistent

Viral infection Medications Viral infection Congenital Bone Marrow Disorders - Epstein-Barr Virus (EBV) - Anticonvulsants - Human Immunodeficiency - Fanconi anaemia - Cytomegalovirus (CMV) - Carbamazepine Virus (HIV) - Shwachman-Diamond - Human Immunodeficiency - Hepatitis B / Hepatitis C syndrome (SDS) Virus (HIV) - Antipsychotics - Pearson's syndrome - Parvovirus - Clozapine Systemic Autoimmune - Influenza - Olanzapine - Rheumatoid Arthritis Congenital Isolated Neutropenia - Lupus (SLE) - Cyclical neutropenia Usually of minimal - Antibiotics - Penicillins - Chronic idiopathic neutropenia clinical significance - Co-trimoxazole Benign Ethnic Neutropenia (BEN) - African/Caribbean Lasts <2 weeks - Antithyroid - Middle Eastern Acquired Bone Marrow Disorders - Propylthiouracil - Lymphoma Bacterial infection - Myelodysplastic Syndrome Nutritional - Brucella (MDS) - Iron deficiency - Tuberculosis - Leukaemia - Vitamin B12 / Folate - Overwhelming sepsis - Aplastic anaemia - Copper Bleeding fevers; Neutropenia (low neutrophils)

Most Concerning

Is this an Acute Leukaemia? Bleeding fevers; Neutropenia (low neutrophils)

Pluripotent Haematopoietic Stem Cell

Myeloid Stem Cell Lymphoid Stem Cell

Megakaryoblast Proerythroblast Myeloblast Genetic Lymphoblast Changes

Platelets RBC

Myeloblast Basophil Neutrophil Eosinophil Myeloblast Myeloblast

Myeloblast Myeloblast Myeloblast Myeloblast MyeloblastMyeloblast Myeloblast Myeloblast Myeloblast Myeloblast Myeloblast Bleeding fevers; Neutropenia (low neutrophils)

Pluripotent Haematopoietic Stem Cell

Myeloid Stem Cell Lymphoid Stem Cell

Megakaryoblast Proerythroblast Myeloblast Genetic Lymphoblast Changes

Platelets RBC Lymphocytes

Myeloblast Basophil Neutrophil Eosinophil Myeloblast Myeloblast

Myeloblast Myeloblast Myeloblast Myeloblast MyeloblastMyeloblast Anaemia Myeloblast Myeloblast Myeloblast Myeloblast Myeloblast Thrombocytopenia Neutropenia Bleeding fevers; Neutropenia (low neutrophils)

Myeloblast RBC

Myeloblast

Platelet

Myeloblast

Myeloblast Myeloblast RBC Myeloblast

Myeloblast

Myeloblast Myeloblast Blood film showing peripheral circulating blasts RBC Myeloblast Platelet Myeloblast

Myeloblast Myeloblast Source: http://www.virtualpathology.leeds.ac.uk/ Bleeding fevers; Neutropenia (low neutrophils) Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds

Peripheral Blood Film Source: http://www.virtualpathology.leeds.ac.uk/ Bleeding fevers; Neutropenia (low neutrophils) Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds

Peripheral Blood Film Bleeding fevers; Neutropenia (low neutrophils)

More common causes… isolated neutropenia Bleeding fevers; Neutropenia (low neutrophils)

Causes Transient Isolated Neutropenia

Viral Infection - Clinical history suggests recent viral infection - Sore throat / Cough / Coryza

- Risk factors - Blood transfusion - Unprotected sex - IVDU - HIV / Hepatitis B / Hepatitis C

Acute viral infections (e.g. Influenza, EBV) Neutropenia should resolve within 3-4 weeks

Neut >1.0 = Unlikely to be significant risk Bleeding fevers; Neutropenia (low neutrophils)

Causes Transient Isolated Neutropenia

Bacterial Infection - Overwhelming infections (proper sepsis), usually requiring ICU admission - Pancytopenia due to bone marrow suppression - Antimicrobials or direct marrow suppression

- Blood film shows immature cells () - E.g. ,

- Mycoplasma infection

Think! YOUNG PERSON IN THE ICU? Is this patient immunosuppressed?

Leukaemia? Bleeding fevers; Neutropenia (low neutrophils)

Causes Transient Isolated Neutropenia

Anticonvulsant Antipsychotic Antimicrobial

Carbamazepine Clozapine Sulphonamides Valproate Olanzapine Penicillin’s Phenothiazines Co-trimoxazole

Reduce dose / stop medication? Does the neutropenia resolve? Bleeding fevers; Neutropenia (low neutrophils)

Causes Benign Ethnic Neutropenia (BEN)

People of - African ancestry - Afro-Caribbean ancestry Mean neutrophil count 1.8 (Range: 0.8 – 3.3) No clinical significance - Arabic-Middle Eastern origin

25-50% of individuals have a lower white cell count / neutrophil count

Caucasian individuals Mean neutrophil count 3.6 (Range: 1.7 – 7.5)

Study performed on black Africans in the UK Refer people of African/Caribbean/Middle Eastern Descent Mean neutrophil count 2.6 (range: 1.1 – 6.1) if Neut persistently <1.0 x109 Bleeding fevers; Neutropenia (low neutrophils)

An approach to the adult patient with unexplained neutropenia Bleeding fevers; Neutropenia (low neutrophils)

Is the patient unwell?

Febrile / Shaking shivering / Clinically unwell

Neutropenic Sepsis

Arrange immediate admission for IV antibiotics Bleeding fevers; Neutropenia (low neutrophils)

History Physical Examination

Why was the blood test carried out in the first place? Signs of Infection - HEENT Infection history - Skin - Recurrent infections - Chest - Hospital admissions for infection - Abdomen - Genito-urinary Drug history - Neurological - New / recent drugs - Dose increases Splenomegaly - Sequestration Risk factors - Underlying extra-medullary - Unprotected sex - IVDU Other signs of underlying disease - Skin rashes (SLE) - Painful, swollen joints (RA) Bleeding fevers; Neutropenia (low neutrophils)

Neutropenia Severity

Isolated Neutropenia vs. Other cytopenias

Cytopenia Pancytopenia A reduction in one of the 3 cell lines All 3 cells lines are reduced (e.g. Low Hb, or Low neutrophils, or (Anaemia, Thrombocytopenia and Low Plt) usually, a neutropenia) Bleeding fevers; Thrombocytopenia (low platelets)

Investigations

Repeat FBC Liver/Bone/Renal Profiles Virology

Raised LFTs HIV Blood film ALT, ALP, GGT Hepatitis B surg Ag, surf Ab, core Ab Hepatitis C IgG Raised calcium ?Malignancy Haematinics EBV IgG, IgM CMV IgG, IgM Baseline renal function Iron studies Iron level, TIBC, TSat, Ferritin Specialist Tests Vitamin B12 Serum +/- MMA Myeloma Screen HAEMATOLOGY - Serum protein electrophoresis Serum folate Serum free light chains Anti-neutrophil Antibodies Genetic mutations Copper level Hep2ANA (autoimmune screen) Bleeding fevers; Neutropenia (low neutrophils)

Blood Film Findings

Blood film

Red cell White cell Platelets

Hypochromic/Microcytic  Iron deficient Hypogranular / Poorly segmented  MDS Hypogranular platelets  MDS

Macrocytic  Vitamin/B12 vs. MDS Blasts  Acute leukaemia / MDS

Left shift  Reactive (e.g. sepsis)

Reactive lymphocytes  Viral infection Autoimmune

Large granular lymphocytes  Viral infect. Bleeding fevers; Neutropenia (low neutrophils)

When to refer (isolated neutropenia)

1.5 – 7.0 x109

Mild Moderate Severe

>1.0 x109 0.5 - 1.0 x109 <0.5 x109

Investigate in primary care Urgent referral to haematology Discuss with haematology today

If the patient is unwell / clinical concern  Arrange immediate admission Is there another cytopenia? (Reduced Hb / Plt)  Urgent referral Jannah Sickle Cell PA Bleeding fevers; Thrombocytopenia and neutropenia

Thanks

@jasaunders90 | #FPAConf19 [email protected]