23 rd March 2019 GP Hot Topics In Primary Care Common Haematological Problems in Primary Care Dr Samar Kulkarni Consultant Haematologist-Oncologist and The Christie Private Care Manchester, UK.
Haematology? Haematology is the study of formed elements in blood including The white blood cells (leukocytes) The red blood cells (erythrocytes) The platelets (thrombocytes) All are derived from pluripotent stem cell in the bone marrow Bone marrow is the predominant site of pathology
RBCs Disorders Anaemias &Others WBC Disorders Benign & Malignant Hematological Disorders Haemostatic Disorders Transfusion Medicine
Overview of Haematological indices Anaemia Leucocytosis & Lymphocytosis Neutropenia Thrombocytopenia Paraprotein
Definition of Anaemia Anaemia is a functional inability of the blood to supply the tissue with adequate O 2 for proper metabolic function Anaemia is not a disease, but rather the expression of an underlying disorder or disease
Diagnosis of anemia Complete blood count, CBC, will include: An RBC count: At birth: 3.9-5.9 x 10 9 /L Males: 4.5-5.9 x 10 9 /L Females: is 3.8-5.2 x 10 9 /L Hematocrit (Hct) or packed cell volume in % or At birth: 42-60% (42-60) Males: 41-53% (41-53) Females: 38-46% (38-46)
CBC and RBC indices 80-96 fl. 27-33 pg. 33-36 g/dl 12.0-13.6%
The Three Derived Indices Measurement Normal Range A. RBC count 5 million 4 to 6 B. Hemoglobin 15 g% 12 to 17 C. Hematocrit 45 38 to 50 A x 3= B x 3 = C (if not then micro or macrocytosis or hypochromia) MCV C A x 10 = 90 fl MCH B A x 10 = 30 pg MCHC B C x 100 = 33%
Diagnosis of Anaemia Hemoglobin concentration in grams/l At birth the normal range is 135-200 g/l The normal range for males is 135-175 g/l The normal range for females is 120-160 g/l RBC indices Use results of the RBC count, hematocrit, and hemoglobin to calculate 4 parameters: Mean corpuscular volume (MCV) is the average volume/rbc in femtoliters (10-15 L) Hct (in %)/RBC (x 10 12 /L) x 10 At birth the normal range is 98-123 In adults the normal range is 80-100
Diagnosis of Anaemia Mean corpuscular hemoglobin (MCH) is the average weight of hemoglobin/cell in picograms (pg= 10-12 g) Hgb (in g/dl)/rbc(x 10 12 /L) x 10 At birth the normal range is 31-37 In adults the normal range is 26-34 Red cell distribution width (RDW) is a measurement of the variation in RBC cell size Standard deviation/mean MCV x 100 The range for normal values is 11.5-14.5% A value > 14.5 means that there is increased variation in cell size above the normal amount (anisocytosis) A value < 11.5 means that the RBC population is more uniform in size than normal.
Diagnosis of Anaemia The MCV is used to classify RBCs as: Normocytic (80-100) Microcytic (<80) Macrocytic (>100) Mean corpuscular hemoglobin concentration (MCHC) is the average concentration of hemoglobin in g/dl (or %) Hgb (in g/dl)/hct (in %)x 100 At birth the normal range is 30-36 In adults the normal range is 31-37 The MCHC is used to classify RBCs as: Normochromic (31-37) Hypochromic (<31)
Mean Cell Volume (MCV) RBC volume is measured by The Mean Cell Volume or MCV and RDW MCV Microcytic < 80 fl Normocyti Macrocytic c 80-100 fl > 100 fl < 6.5 µ 6.5-9 µ > 9 µ
Approach to Anemia CBC Reticulocyte count MCV RI < 2% RI > 2% Underproduction Increased destruction or loss MCV < 80 Microcytic MCV MCV 81 99 Normocytic MCV > 100 Macrocytic Further work up Based on history, Physical, other
The definitive test is serum ferritin Low serum ferritin (<12 ug/l)is diagnostic of iron deficiency Although ferritin is an acute phase reactant, it will still be low in iron deficiency Also, high TIBC Fe saturation = Fe/TIBC < 10% in Fe deficiency If ferritin is indeterminate Low serum Fe is not in itself diagnostic, neither is marrow staining Anisocytosis (heterogeneous in shape) and poikilocytosis (abnormal shape) Reactive thrombocytosis Iron Deficiency Anemia
Macrocytic Anemia (MCV>100) Drug Induced (hydroxyurea, AZT, MTX, chemotherapy, anticonvulsants) B12 / folate deficiency Myelodysplastic syndrome Liver disease Alcohol abuse Reticulocytes Hypothyroidism
Leucocytosis Leucocytosis does not mean haematological malignancy Careful history Fevers, diarrhoea, drugs, smoking Examine Skin, liver, spleen, lymph nodes Ask for a blood film What is the white cell differential? What do the white cells look like? Is the rest of the FBC normal? Consider repeating the blood count 2-4 weeks.
Lymphocytosis Lymphocyte Count Investigation >10 x 10 9 /L Refer to haematology for investigation >3.5 and <10 x 10 9 /L Rest of blood count normal No lymphadenopathy or splenomegaly >3.5 and <10 x 10 9 /L and anaemia or thrombocytopenia or lymphadenopathy or splenomegaly Repeat FBC and Blood film in 3-6 months: If lymphocytes are lower or the same level: no further investigation or monitoring; repeat blood count in 1 year If lymphocytes are > 10 x10 9 /L: refer to haematology for investigation Refer to haematology for investigation
Asymptomatic lymphocytosis Early CLL - Stage A Normal Hb, neutrophils, platelets, no organomegaly Does not require treatment (usually) Increased risk of bacterial infection and zoster Annual flu vaccination and consider for Pneumovax May increase risk of other malignancies Clinical assessment and monitor blood count every few months initially
Chronic Lymphocytic Leukaemia (CLL) Accumulation of mature B cells Commonest leukaemia (4/100,000/year) Symptoms/signs often none, found on routine FBC May have enlarged rubbery non tender lymphadenopathy, hepato/spleomegaly and systemic symptoms Investigations Flow-cytometry, can cause autoimmune haemolysis and pancytopenia
Isolated Neutropenia Severity Categories of Neutropenia Severity Neutrophil Count Mild 1.0-1.5 x10 9 /L Moderate 0.5-1.0 x10 9 /L Severe <0.5 x10 9 /L
Causes of Neutropenia Transient Viral infections neutropenia usually lasts 2 weeks and rarely cause clinical problems Occasionally, the neutropenia may persist for months. Persistent Benign ethnic neutropenia Individuals of African-Caribbean or Middle Eastern descent Viral infections EBV, HIV, hepatitis Autoimmuine disorders Drugs Splenomegaly ( +liver disease) Haematological diseases Myelodysplasia, leukaemia, lymphoma, myeloma, B12/folate deficiency etc. Rare congenital
Evaluation of a patient with Neutropenia History: Symptoms or history of recurrent infection Drug history Family history of infections Records of past FBCs (chronicity of the neutropenia) Risk factors for HIV, TB Examination: Signs of infection: oral mucosa, skin rashes, abscesses, lung infections, perianal/genital area Splenomegaly Other signs of underlying medical problems (SLE, malignancy)
Investigations: Evaluation of Neutropenia Repeat FBC with differential Blood film (do the cells look normal?) Paul Bunnell (IMST) B12, folate Autoantibody screen & rheumatoid factor HIV testing if clinical risk factors are present Blood cultures if the patient is pyrexial (in which case send to hospital)
First checks- When to seek further advice or refer to Haematology? How severe is the neutropenia? Are there any other abnormalities of the blood count? Does the patient have any symptoms relating to the neutropenia? How long has the neutropenia persisted for? Consider referral if- Persistent neutropenia <1.3 x 10 9 /L over 6-8 weeks with no obvious cause Neutropenia associated with severe and/or recurrent infection Neutropenia associated with other full blood count abnormalities Neutropenia associated with splenomegaly (NOT due to liver disease fulfils 2 week wait criteria) Suspected underlying haematological disease: i.e. clinical symptoms or on blood film
Thrombocytopenia Normal count (x10 9 /L) Mild Moderate Severe 150-400 100-150 30-100 <30 Consider Is the low platelet count acute or chronic? Are there associated abnormalities of other blood counts? Has the FBC been repeated? Does the patient have a history suggestive of infection, autoimmune disease, or malignancy?
Thrombocytopenia Medication history (the list is endless!)? Examine for spleen, lymph nodes, skin rashes, musculoskeletal abnormalities Request blood film: Platelet clumping May-Hegglin (large platelets that machine doesn t count) Hypersegmented neutrophils & macrocytosis (B12 / folate deficiency) Lymphocytosis etc. -? CLL Macrocytosis and Pelgeroid neutrophils - MDS
Thrombocytopenia Isolated thrombocytopenia, normal blood film and physical examination: bone marrow test may not be necessary If patient is asymptomatic: monitoring with serial blood counts is required Most patients with isolated mild thrombocytopenia do not develop clinical disease Those that do, the commonest group is autoimmune in origin Consider HIV and Hepatitis C as an underlying cause without other explanation
Leukaemia Acute leukemia is characterized by an abnormal proliferation of immature white blood cells, called blasts or progenitor cells Two main forms of acute leukemia Acute lymphoblastic leukemia A cancer at the earliest stages of lymphocyte maturation Occurs more often in the young Acute nonlymphoblastic leukemia Usually a malignancy of the myeloblast More common in adults
A B C D A : Picture of bone marrow smear (control) B : Acute lymphoid leukemia (ALL); Proliferation of small lymphoblasts. C : Acute myeloid leukemia (AML); Proliferation of large myeloblasts. D : Chronic myeloid leukemia (CML); Proliferation of granulocytes at various stages of maturation.
Functional Presentation of Leukaemia Leukaemia present with signs and symptoms of Anaemia Neutropenia with infection and fever Thrombocytopenia with bleeding Patients may present critically unwell
Physical Findings Fever Pallor Icterus Bruising/Bleeding Lymphadenopathy Liver or spleen enlargement Generally unwell
Disorder Associated with Monoclonal Protein Neoplastic cell proliferation Multiple myeloma Solitary plasmacytoma Waldenstrom macroglobulinemia Heavy chain disease Primary amyloidosis Undetermined significance Monoclonal gammopathy of undetermined significance (MGUS) Transient M protein Viral infection Post-valve replacement Malignacy Bowel cancer, Breast cancer Immune dysregulation HIV, Old age Chronic inflamation
Paraproteins Does the patient have symptoms? Does the patient have clinical signs (e.g. nodes)? How high is the paraprotein concentration? What sort of paraprotein is it? IgA / IgG ~ Myeloma IgM / IgG ~ Lymphoma Are the other Igs suppressed? Is the blood count normal? Are the renal function and calcium normal? Most paraproteins are incidental and usually represent MGUS
Monoclonal Gammopathy of Undetermined Significance (MGUS) Common, age-related Prevalence: 3.2% in persons over 50 yrs old (Minnesota) Approximately 5% in age above 70yr Higher prevalence in African populations.? Association with inflammatory states: obesity, Gaucher s disease Increased risk for thrombosis and fractures Risk of progression in entire population: 1% per year Risk factors for progression: %PC, level M spike, raised free light chain, IgA protein,?decline in uninvolved Ig s
Probability of Progression among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy of Undetermined Significance (MGUS) Was Diagnosed from 1960 through 1994 Kyle, R. A. et al. N Engl J Med 2002;346:564-569 Risk of progression to serious disease 1% per year
1% of people > 50 yrs age 10% of people > 80 yrs age 10% will develop myeloma How to monitor? MGUS: How to Monitor 6 monthly FBC, U&E, calcium, and paraprotein quantitation Refer to haematology if- Falling Hb, Rising urea or calcium, Rising paraprotein, bone pain, lymphadenopathy
Criteria for Diagnosis MGUS <3 g M spike <10% PC Smoldering MM 3 g M spike OR 10% PC Active MM 10% PC M spike + AND AND CRAB Negative CRAB: Positive CRAB: Calcium, Renal, Anaemia, Bones Kyle RA. N Engl J Med 2002; 346: 564
Myeloma Malignant clonal proliferation of plasma cells Incidence 5/100,000, peak age 70 years Symptoms and signs: - Osteolytic bone lesions backache, pathological fractures. - Hypercalcaemia - Anaemia, thrombocytopenia, neutropenia - Recurrent bacterial infections - Renal impairment (light chain deposition) - Can present acutely with cord compression, hyperviscocity or renal failure.
Number of cases 0-4 How common is it in UK? 1% of All Cancers 2 nd common Haematological Malignancy 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Rate per 100,000 population 400 5 per 100,000 Numbers of new 3-4 cases cases and in age 35 yr./gp specific Surgery incidence rates, 300 70 60 50 200 Male cases Female cases Male rates Female rates 40 30 100 20 10 0 0 Age at diagnosis
Clinical presentation
Diagnostic Evaluation History and physical examination Blood work-up Full blood count Urea, Creatinine, Calcium, Albumin Serum protein electrophoresis (SPEP) and immunofixation Serum free light chains 2 -microglobulin Urine Bence Jone Protein Skeletal survey Bone marrow examination with cytogenetics
Myeloma
International Staging System (ISS) For Symptomatic Myeloma Stage I Criteria β2m < 3.5 mg/l albumin 3.5 g/dl Median Survival (mo) 62 II* Not stage I or III 44 III β2m 5.5 mg/l 29 *β2m < 3.5 mg/l and albumin < 3.5 g/dl or β2m 3.5 - < 5.5 mg/l, any albumin Greipp et al. J Clin Oncol 2005; 23: 3412-20
Survival Impact of Novel Agents on the Outcome in Post ASCT Relapsed/refractory Disease (n=387) 1.0 0.8 0.6 Relapsed before 1998 Relapsed 1998 1999 Relapsed 2000 2001 Relapsed 2002 2003 Relapsed 2004 2005 0.4 P<0.001 0.2 0.0 0 20 40 60 80 100 Time (months) Kumar et al Blood 2008
Impact of New Drugs on Survival in BC Date of Diagnosis % alive at 5 years Before 2003 50% 2003 and beyond 70%
Myeloma Drugs Drug Year of Approval (USA) Monthly Medicare Price at time of Approval Melphalan 1992 20 Bortezomib 2003 2500 Lenalidomide 2005 5500 Thalidomide 2006 3500 Daratumomab 2016 6000 Ixazonib 2016 2000
Suspected Haematological Cancers Combinations of the following symptoms and signs may suggest haematological cancer Fatigue Drenching night sweats Fever Weight loss Generalised pruritus Breathlessness Bruising Bleeding Recurrent infections Bone pain Alcohol-induced pain Abdominal pain Lymphadenopathy Splenomegaly Hepatomegaly
If unsure what to do or a Haematology patient is unwell, never hesitate to contact haematologist day or night
CBC Components Red Blood Cells (RBCs) Haematocrit (Hct) Haemoglobin (Hgb) Mean Corpuscular Volume (MCV) Mean Corpuscular Haemoglobin(MCH) Mean Corpuscular Haemoglobin Concentration (MCHC) Red cell distribution width (RDW) White Blood Cells (WBCs) Platelets Mean Platelet Volume (MPV)
Neutropenia The severity of neutropenia is categorised as Severity Neutrophil count (x10 9 /L) Mild 1.0-1.5 Moderate 0.5-1.0 Severe <0.5
Causes of Neutropenia Transient Viral infections: usually lasts 2 week seldom any clinical problems Occasionally may persist for months Persistent Benign ethnic neutropenia- African-Caribbean or Middle Eastern descent Viral infections : EBV, HIV, hepatitis Autoimmune disorders: SLE, RA Drugs: A long list! Splenomegaly Haematological diseases: MDS, leukaemia, lymphoma, myeloma, B12/folate deficiency
Evaluation of a patient with neutropenia History: History of recurrent infection? Drug history Family history of infections Records of past FBCs to establish the chronicity of the neutropenia Risk factors for HIV, TB Examination: Signs of infection: oral mucosa, skin rashes, abscesses, lung infections, perianal/genital area Splenomegaly Other signs of causative medical problems (SLE, malignancy)
First check: How severe? Neutropenia When to seek advice or refer to Haematology? Any other abnormalities of the blood count? Any symptoms relating to the neutropenia? How long has it persisted? Consider referral if: Persistent neutropenia <1.3 x 10 9 /L over 6-8 weeks Associated severe and/or recurrent infection Associated other full blood count abnormalities Associated splenomegaly (NOT due to liver disease fulfils 2 week wait criteria) Suspected underlying haematological disease clinical symptoms
If unsure what to do or a Haematology patient is unwell, never hesitate to contact haematologist day or night