Common Haematological Problems in Primary Care

Transcription

1 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.

2 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

3 RBCs Disorders Anaemias &Others WBC Disorders Benign & Malignant Hematological Disorders Haemostatic Disorders Transfusion Medicine

4 Overview of Haematological indices Anaemia Leucocytosis & Lymphocytosis Neutropenia Thrombocytopenia Paraprotein

5 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

6 Diagnosis of anemia Complete blood count, CBC, will include: An RBC count: At birth: x 10 9 /L Males: x 10 9 /L Females: is 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)

7 CBC and RBC indices fl pg g/dl %

8 The Three Derived Indices Measurement Normal Range A. RBC count 5 million 4 to 6 B. Hemoglobin 15 g% 12 to 17 C. Hematocrit 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%

9 Diagnosis of Anaemia Hemoglobin concentration in grams/l At birth the normal range is g/l The normal range for males is g/l The normal range for females is 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 /L) x 10 At birth the normal range is In adults the normal range is

10 Diagnosis of Anaemia Mean corpuscular hemoglobin (MCH) is the average weight of hemoglobin/cell in picograms (pg= g) Hgb (in g/dl)/rbc(x /L) x 10 At birth the normal range is In adults the normal range is 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 % 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.

11 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 In adults the normal range is The MCHC is used to classify RBCs as: Normochromic (31-37) Hypochromic (<31)

12 Mean Cell Volume (MCV) RBC volume is measured by The Mean Cell Volume or MCV and RDW MCV Microcytic < 80 fl Normocyti Macrocytic c fl > 100 fl < 6.5 µ µ > 9 µ

13 Approach to Anemia CBC Reticulocyte count MCV RI < 2% RI > 2% Underproduction Increased destruction or loss MCV < 80 Microcytic MCV MCV Normocytic MCV > 100 Macrocytic Further work up Based on history, Physical, other

14 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

15 Macrocytic Anemia (MCV>100) Drug Induced (hydroxyurea, AZT, MTX, chemotherapy, anticonvulsants) B12 / folate deficiency Myelodysplastic syndrome Liver disease Alcohol abuse Reticulocytes Hypothyroidism

16 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.

17 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

18 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

19 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

20 Isolated Neutropenia Severity Categories of Neutropenia Severity Neutrophil Count Mild x10 9 /L Moderate x10 9 /L Severe <0.5 x10 9 /L

21 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

22 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)

23 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)

24 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

25 Thrombocytopenia Normal count (x10 9 /L) Mild Moderate Severe <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?

26 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

27 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

28 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

29 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.

30 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

31 Physical Findings Fever Pallor Icterus Bruising/Bleeding Lymphadenopathy Liver or spleen enlargement Generally unwell

32 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

33 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

34 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

35 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: Risk of progression to serious disease 1% per year

36 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

37 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

38 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.

39 Number of cases 0-4 How common is it in UK? 1% of All Cancers 2 nd common Haematological Malignancy Rate per 100,000 population per 100,000 Numbers of new 3-4 cases cases and in age 35 yr./gp specific Surgery incidence rates, Male cases Female cases Male rates Female rates Age at diagnosis

40 Clinical presentation

41 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

42 Myeloma

43 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 < 5.5 mg/l, any albumin Greipp et al. J Clin Oncol 2005; 23:

44 Survival Impact of Novel Agents on the Outcome in Post ASCT Relapsed/refractory Disease (n=387) Relapsed before 1998 Relapsed Relapsed Relapsed Relapsed P< Time (months) Kumar et al Blood 2008

45 Impact of New Drugs on Survival in BC Date of Diagnosis % alive at 5 years Before % 2003 and beyond 70%

46 Myeloma Drugs Drug Year of Approval (USA) Monthly Medicare Price at time of Approval Melphalan Bortezomib Lenalidomide Thalidomide Daratumomab Ixazonib

47 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

48 If unsure what to do or a Haematology patient is unwell, never hesitate to contact haematologist day or night

49 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)

50 Neutropenia The severity of neutropenia is categorised as Severity Neutrophil count (x10 9 /L) Mild Moderate Severe <0.5

51 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

52 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)

53 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

54 If unsure what to do or a Haematology patient is unwell, never hesitate to contact haematologist day or night