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Borderline cytopenias

Dr Taku Sugai

Consultant Haematologist

Borderline cytopenias

• Neutropenia

• Thrombocytopenia

• Anaemia with normal haematinics

• Two recent cases of cytopenias

Neutropenia

• ANC of more than 2SD below a normal mean– Hillingdon normal range 1.8‐7.7 x 109/l

• Ethnic variation– Caucasian:  less than 1.5 x 109/l– Afro‐caribbean: less than 1.2 x 109/l

Neutrophil maturation

Common causes of Neutropenia

• Decreased neutrophil productions– Vitamin B12/Folate deficiency– Drugs

• Antibiotics(Penicillins/Cephalosporins/choloramphenicol)• Anti‐epileptic(Carbamazepine/Phenytoin)• Psychiatric drugs(Phenothiazine)• Anti‐inflammatory(Gold/Phenylbutazone)• Anti‐Thyroid drugs(Carbimazole/methylthiouracil)• Diuretics(Hydrochlorothiazide/bumetanide)• Cytotoxic agents• Alcohol

– Viral infections e.g HIV, CMV, EBV, Parvovirus, Hep B– MDS/Aplastic Anaemia/Bone marrow infiltration

• Increased peripheral destructions– Hypersplenism– Autoimmune disease(SLE/RA)

Neutrophil morphology

Neutropenia Which cases to refer?

• ANC less than 0.5 x 109/l

• Any neutropenia with history of infections

• Any cases with other cytopenias

• Drug induced neutropenia is the commonest  cause of isolated neutropenia.

Thrombocytopenia

• Platelets Below 100x 109/l

• No significant bleed until below 20 x 109/l

• Inverse relationship between platelets count  and skin bleeding time

Bleeding associated with significant  thrombocytopenia

Findings Disorder of coagulation Disorder of platelets/Thrombocytopenia

Onset of bleeding Delayed after trauma Immediate after trauma

Mucosal bleeding Rare Common

Petechiae Rare Characteristics

Deep haematomas Characteristics Rare

Haemarthrosis Characteristics Rare

Bleeding from superficial 

cuts and scratchesMinimal Persistent, often profuse

Platelets clumping

Megakaryopoiesis

Common causes of Thrombocytopenia

• Decreased platelets productions– Vitamin B12/Folate deficiency– Drugs

• Ranitidine

Valproic acid• Thiazide diuretics

Montelukast• Isotretinoin

Interferon• Quinine

Teicoplanin• Heparin

Abciximab/Oral GpIIb/IIIa inhibitors• Alcohol

– Viral infections e.g HIV, ToRCH(HHV6), EBV, Parvovirus, Hep C, Mycoplasma, 

Helicobacter– Haem neoplasm‐MDS/Aplastic Anaemia/Bone marrow infiltration

• Increased peripheral destructions– Hypersplenism– Autoimmune disease(SLE/Antiphospholipid syndrome)– ITP– HUS/TTP

Thrombocytopenia Which cases to refer?

• Platelets count less than 50 x 109/l

• Any thrombocytopenia with bleeding history

• Any cases with other cytopenias

• Drug history and virology screen would be  helpful

Anaemia WHO definition (Blanc et al, 1968)Age or Gender Group Hb threshold (g/dl)

Children (0.5‐5.0) 11

Children (5‐12yr) 11.5

Teens (12‐15yr) 12.0

Women, non‐ pregnant(>15yr)

12.0

Women, pregnant 11.0

Men (>15yr) 13.0

Anaemia with normal haematinics

• Haematological malignancies*

• Solid organ malignancies

• Haemolytic anaemia

• Anaemia of chronic disease*

• Anaemia 2ndary to renal disease

• Anaemia 2ndary to liver disease

Anaemia of chronic disease

• Hb is not less than 9g/dl• MCV is normal or mildly reduced(77‐82fl)

• MCH is usually normal

• Serum iron is reduced

• Total iron binding capacity(transferrin) reduced• Transferrin Saturation mildly reduced

• Serum Ferritin normal or increased

• CRP and ESR  usually raised(Hepcidin increased)

Anaemia of chronic disease Iron metabolism

Anaemia of chronic disease Pathogenesis

• Reduction in iron granules in bone marrow  RBC precursors

• Direct inhibition by TNFa/IL‐1/IL‐6

• Relative lack of Erythropoietin for the level of  haemoglobin(IL‐1a inhibits Epo secretion) 

Anaemia of chronic disease Treatment

• Treatment of underlying chronic disease

• Epo treatment

• Trial of iron for 3 months in selected cases

Anaemia Which cases to refer

• Unexplained anaemia with significant weight  loss

• Unexplained anaemia with other cytopenias

Case 1 Investigations

• Hb 15.9• MCV 86.8• WBC 3.0* (4‐11)• Neu 1.7* (1.8‐7.7)• Lym 0.7*(1‐4.8)• Plt 88* (140‐400)• Na 134 K4.3 U1.7 Cr57• Bil 17 ALP 74 ALT 21 Alb 37 AST34*(8‐20)

Diagnosis?

Case 1 Diagnosis

• HIV positive

• Hepatitis B positive

Case 2

• Mr KS is 32 year old Caucasian male

• Routine blood test in 2008• No history of infection/mouth ulcers

• No history of bruising• Drinks 4 units/week

Case 2 Investigations 2008

• Hb 14.2• MCV 102.6*(80‐100)

• WBC 3.1* (4‐11)

• Neu 0.9* (1.8‐7.7)• Lym 1.9*(1‐4.8)

• Plt 72* (140‐400)• Na 142 K3.8 U5.2 Cr90

Case 2 Feb2012

• 4 weeks history of SOB on exertion• 12 months history of lethargy

• Recent history of easy bruising• No history of infections• Evidence of clinical anaemia

• No organomegaly

Case 2 Investigations Feb 2012

• Hb 7.6*• WBC 1.6*• Neu 0.2*• Lymp 1.2• Plt 24*• Normal clotting• Normal renal function/LFTs• Normal Folate/B12

Diagnosis?

Case 2

Case 2 Blood film

Bone marrow aspiration and trephine  biopsy

Case 2 Bone marrow aspirate

Case 2 Bone marrow trephine

Cytogenetics

FISH for Chromosome 7

Diagnosis

• Myelodysplastic syndrome Refractory  Anaemia Excess Blasts 2(Almost AML)

• Monosomy 7

• Small PNH clone

Myelodysplastic Syndrome

• Clonal disorder of haemopoiesis• Incidence 3‐5 per 100,000/ year• Incidence >20 per 100,000/year over the age 

of 70 years.• 60% of patients over the age of 70• More common in male 1.4M to 1.0F• 15% of MDS related to previous chemo• T‐R MDS common after 5‐7 years

MDS Clinical features

• Incidental 20%

• Lethergy due to anaemia 80%

• Infections or bleed 20%

MDS Laboratory features

• Pancytopenia 30‐50%– Hb <10g/dL– Neutrophils <1.8 x 109

/L

– Platelets <100 x 109

/L

• Anaemia & thrombocytopenia/neutro 20%

• Isolated thrombocytopenia/neutropenia5%

Summary Cases to refer

• Unexplained anaemia with significant weight loss

• Unexplained anaemia with other cytopenias

• Neutropenia <0.5 x 109/l• Neutropenia with Hx of infections• Thrombocytopenia with Hx of bleeding

• Multiple cytopenias

• Detailed Drug history is essential prior to referral

Thank you Any Questions?