Haematology Notes

Primary Secondary Others Neutrophilia Neoplasia e.g. CML Infection - Bacterial infection Steroids Inflammation - autoimmune DKA Eosinophilia Neoplasia e.g. HL, T-cell Infection - Parasitic infection Idiopathic NHL Inflammation - allergic disease hyperoesinophilic syndrome Monocytosis Neoplasia e.g. CML Infection - usually chronic (e.g. TB, CMV) Basophilia Neoplasia e.g. CML Infection - pox virus Lymphocytosis Neoplasia e.g. CML/ Infection - EBV, CMV lymphoma

Coagulation Cascade Haemostasis  Vasoconstriction  Formation of loose platelet plug (primary)  Stabilisation (secondary)  Fibrinolysis

Key Diagnosic Tests Factors Investigations Common Pathway X, V, platelets, prothrombin/thrombin, PT fibrinogen/fibrin, Intrinsic Pathway VIII, IX, XI, XII APTT Extrinsic Pathway TF, VII PT

Haemorrhagic Disorders Platelet problem Coagulation problem Site of bleeding Skin, mucous Soft tissues, joints, membranes muscles Petechiae Yes No Ecchymoses Small, superficial Large, deep Hemarthrosis/muscle No Yes Bleeding after surgery Immediate Delayed (days)

Platelet Disorders  Normal count: 150-400  < 50 - petechiae, ecchymoses  < 20 - mucocutaneous bleeds (GI bleeding, haematuria) Clotting Disorders Disease Inheritance Presentation Investigations Haemophilia A (VIII X-linked < 1%: haemarthroses + deep muscle Tx: Factor concentrate, deficiency) Recessive haematoma Desmopressin (mild 1-5%: severe bleeding after injury disease) > 5%: mild bleeding after injury. Late dx Haemophilia B (IX X-linked Same features as haemophilia A Desmopressin deficiency) ineffective vWD Type 1 - AD + ↓Platelet adhesion Bleeding time prolonged partial deficiency ↓Stabilising factor for VIII:C PT & APTT – normal Type 2 - AD + loss Presents as a platelet problem of multimers  Tx: Desmopressin, VIII + altered quality vWF concentrates Type 3 - AR + complete deficiency Liver disease Malnutrition, drugs or Malabsorption causes ↓ Vit K, ↓ factor production + functional ↑ PT + APTT abnormalities Vitamin K deficiency ↓ II, VII, IX and X DIC Sepsis, Malignancy, Severe liver Prolonged PT and APTT disease, Haemolytic transfusion Prolonged TT reactions, Obstetric causes and ↑FDPs/D-dimer Trauma causes Widespread Thrombocytopenia intravascular coagulation (Consumption Tx: Support + treat of platelets + Consumption of underling cause clotting factors and fibrin generation), Secondary fibrinolysis Leads to bleeding and clotting

Thrombotic Disorders Virchow’s Triad  Hypercoagulability  Stasis  Vessel wall

Inherited Thrombophilia Features Factor V Leiden Normal pro-coagulant, abnormal anti-coagulation Prothrombin G20210A Elevated prothrombin Protein C deficiency Autosomal dominant – early thrombosis (<40y) Protein S deficiency Tx – protein C/protein S concentrate Anti-thrombin deficiency Inherited (AD) or acquired (nephrotic syndrome) Inherited present early

Acquired Thrombophilia Features Immobility/stasis Hospital in-patients, elderly with loss of mobility Surgical (tissue trauma -- pro-coagulant) Orthopaedics and gynaecology Malignancy (? pro-coagulant molecule) Anti-phospholipid syndrome Young women with: Recurrent DVT, miscarriages and stroke Hyper-oestrogen state Pregnancy/COCP/HRT Increased coagulation factors and reduced anti- coagulation factors

Anti-coagulant therapy Heparin  Aim for APPT 1.5-2.5  Immediate effect  Potentiates anti-thrombin III Warfarin  2 types:  Long term therapy o Unfractionated heparin  Vitamin K antagonist o LMWH (1 daily s.c.)  Initial procoagulant effect  Monitored with PT/INR

Anaemia  Hb < reference range for age, sex and gender of an individual. o Men < 13.5 g/dl o Women < 11.5 g/dl  Reduced red cell count (RCC)  Reduced packed cell volume (PCV)

Classical Signs  Conjunctival pallor  Post-cricoid webs (Plummer-Vinson  Koilonychia Syndrome)  Glossitis  High-flow murmur  Angular stomatitis   May be classified according to:  Size o Microcytic (IDA, thalassaemia) o Normocytic (Acute blood loss, chronic disease, leukoerythroblastic) o Macrocytic (Vitamin B12 deficiency, folate deficiency, alcoholism, hypothyroidism, liver disease)   Pathophysiology o Reduced production (Haematinic deficiency, bone marrow infiltration, chronic disease) o Reduced life-Span (Haemolysis) o Pooling (Splenomegaly)        Reduced Production  Pathology  Causes  Features  ↓Fe  Reduced intake  ↓ MCV, ↓ ferritin, ↑  Malabsorption TIBC  Blood loss  Hypochromia,  ↑Demand poikilocytosis, anisocytosis  Tx: Ferrous Sulphate, Paraenteral Fe  ↓Vit B12  ↓ intake  Macrocytosis  Impaired absorption (megaloblast)  Pernicious Anaemia (AI,  Hypersegmented ↓IF) neutrophils  Thrombocyopaenia  Peripheral neuropathy  Tx: Hydroxycobalamin  ↓Folate  ↓ intake  ↓ RBC folate  Malabsorption   ↑Demand  Tx: Folate  Drugs (methotexate, ETOH, anti-convulsants)  Bone Marrow Infiltration  Destruction/competition  Cellular with normal bone marrow  Myeloproliferation,  Can be cellular or myelofibrosis, malignant hypocellular spread   Hypocellular  Idiopathic (50%), Cytotoxic drugs + radiation, Infections, Immune  Myelodysplasia  Mild malignancy of early  Reduction in cell line myeloid progenitor cells function  Elderly  BM: increased cellularity + abnormal myeloid precursors  Anaeamia of Chronic  Chronic infection  ↓Hb, ↔/↓MCV, Disease  Chronic inflammation ↔/↑Ferritin  Malignancy   Neoplasia  Tx: Erythropoietin   Increased Destruction  Extravascular  Intravascular o Common o Rare o Occurs in spleen o Occurs in blood (macrophages)  Clinical Features  Variable  Acute episodes  No anaemia  Crises  Chronic haemolytic anaemia  Aplastic anaemia  Folate deficiency  Key haematological features  Raised unconjugated bilirubin  ↑ urinary urobilinogen  ↓ haptoglobin  Reticulocytes  ↓ LDH       Inherited:   Inherita  Features  Diagnostic tests nce  Spheroc  AD  Variable  DAT neg, osmotic ytosis fragility  Tx: Splenectomy + folate  Elliptocy  AD  Mild Course  Blood film tosis  Tx: Nil  G6PD  X-linked  Enzyme needed to produce  Heinz Bodies NADPH  Bite Cells  Used with glutathione to  DAT test – Negative protect from oxidative damage  Beutler Fluorescent  Spot test  Very common   Africa/Americans/Mediterranea ns Chronic haemolytic anaemia  Acute haemolytic episodes - Drugs - Fava beans - Infection  Sickle  Point  Shortened red cell survival  Dx: Hb cell Mutatio  • Chronic haemolysis electrophoresis + n (β  • Splenomegaly sick solubility tests globin  • Gallstones  chain)  Tx: Acute sickle  • Folate defiency crisis prevention,  • Vulnerable to aplastic Vaccination, anaemia penicillin  prophylaxis + folic  Vaso-occlusive disease acid,  • Impaired passage of cells in hydroxycarbamide  microcirculation  • Obstruction of small vessel + infarction  • Consequences  • Crises  • Organ dysfunction  Thalassa  α - Gene  β:  emia deletions  Major - homozygous (Cooley’s  β- Point anaemia), present in first year, mutation require blood transfusion s  Minor/Intermedia – heterozygous, asymptomatic, mild haemolytic picture   α:  Severity deficiency  4 - incompatible with life (hydrops fetalis)  3 - moderate anaemia + splenomegaly  1or2 - asymptomatic with mild anaemia   Haematological Malignancies  Leukaemia: malignant cells in peripheral blood/bone marrow  Lymphoma: solid tumour (malignant cells in lymph nodes)  Myeloma: malignant cells in bone marrow and production of paraprotein   Leukaemias   Subtypes  Features  Investigations  A  B cell  Children  Full blood count: L  T cell  De novo Anaemia, L  Burkitt’s  Presentation: Bone marrow failure, thrombocytopenia leukaemia Lymphadenopathy, + leucopenia, hepatosplenomegaly, Testicular Leucocytosis infiltration  Blood film: Blasts  Bone marrow biopsy: Hypercellular with blasts  Immunophenotypin g: B cell vs. T cell  Cytogenetics: Prognosis  A  M0-M7/WHO  Adults  Auer Rods M classification  De novo or secondary L  Presentation: Bone marrow failure, Bleeding tendency, GUM/Skin/CNS infiltration  C  B cell (95%)  Elderly  FBC: ↑lymphocytes L  T cell (5%)  Indolent course with good  Film: smear cells L prognosis  Marrow:  Usually presents on FBC lymphocytic infiltration   Myeloproliferative Disorders  Disease  Cell line  Features  Polycythaemia rubra vera  RBCs  Elderly  Non-specific - Tiredness, depression, vertigo, visual disturbance, Hypertension, angina, intermittent claudication  Specific – Erythomyalgia, Gout + peptic ulceration, Plethoric  Ix:↑ Hb & PCV, Erythroid hyperplasia  Tx: (keep PCV < 0.45), Venesection, Hydroxyurea +/- radioactive 32P  Essential  Platelets  Benign natural history thrombocythaemia  Features: Thrombosis (increased number), Bleeding (reduced quality)  Ix: Platelets > 1000 + hypercellular marrow  Tx - hydroxyurea  Chronic myeloid  Granulo  40 -60y leukaemia cytes  Slowly progressive course  Non-specific presentation (Generally unwell with splenomegaly+ hepatomegaly)  Ix: ↑WBC, Blood film: Granulocytes, Philadelphia chromosome  Tx: Imatinib, stem cell transplant  Myelofibrosis  Megaka  Megakaryocyte proliferation leading to ryocyte Fibrosis + Ineffective Erythropoiesis prolifera  Features: BM failure + splenomegaly tion  BM very helpful:  • Dry tap  • Fibrotic trephine biopsy  • Lack of Philadelphia chromosome   Myelodysplastic Syndromes  Disease  Features  Investigations  Lymphoma  Hodgkin’s - Reed-Sternberg  FBC: nil specific Cells  BM: Normal  Non-Hodgkin’s – B-cell or T-  cell/NK cell  Hodgkin   Radiotherapy +  Non-specific - Fatigue, loss of chemotherapy appetite, Lymphadenopathy   Specific - Fever/night sweats,  Non-Hodgkin Itching, ETOH-induced pain,  Watch and wait (follicular) Splenomegaly  Radiotherapy   Chemotherapy (e.g. CHOP)  Monoclonal antibodies (rituximab)  Stem cell transplants  Multiple Myeloma  Bone resorption  FBC: BM infiltration,  • Vertebral collapse ↑calcium  • Spinal cord compression  BM: abnormal plasma cell  • Hypercalcaemia + infiltration associations  Serum/urine electrophoresis  Paraprotein   • Infections  Tx: Treat complications, Suppress the disease  • Pneumonia +  < 65 – chemo then stem cell pyelonephritis transplant  • Hyperviscosity  > 65 - chemo roglobulin  • Visual loss  • Renal failure   Monoclonal  Often occurs in elderly  Gammopathy of  Paraprotein present but no Undetermined other symptoms/signs or Significance laboratory findings to suggest myeloma  Natural history is not well defined   Porphyria  Group of disorders caused by deficiencies in haem synthesis enzymes  The major problem is the build up of toxic haem precursors   Type  Severi  Features ty  Neurovis  Sever  Psychosis, seizures ,abdominal pain, polyneuropathy ceral e  Cutaneo  Mild  Photo-sensitive vesicular rash us   Acute Intermittent Porphyria  Archetypal neurovisceral porhyria  Autosomal dominant inheritance  Precipitated by stress  Port urine  Tx - analgesia and carbohydrates      Transfusion Complications  Type  Features  Treatment  Febrile non-haemolytic  Fever only  Slow down the transfusion reaction  No features of haemolysis  M.O.A - white cell antibodies vs. donor blood  Bacterial infection  Sudden onset fever  Stop transfusion  Very unwell  Broad spectrum antibiotics  Transfusion related acute  Sudden onset SOB &  Stop blood lung hypoxia  Ventilate  injury (rare)  No features of  M.O.A. - HLA Ab in donor haemolysis/other vs. HLA  anaphylactic features  antigen on patient WBC  Post-transfusion purpura  ~ 1 week after transfusion  IVIG  M.O.A - Patient ab. vs.  Brusing as platelets very donor platelet antigen low  Delayed haemolytic  Delayed  Treat renal failure transfusion  Features of haemolysis  Repeat CXM  reaction  (may cause renal failure)  M.O.A. - Red cell ab. not detected  Iron overload  Transfusions for many  Avoid transfusion, years Chelating agent e.g.  Damage to heart, liver and desferioxamine gonads  Viral Infections  Many possible  Screen blood  Hepatitis e.g. C/B, HIV,  Treat infection CMV, HTLV  Graft vs. host disease  Must be already  Irradiate blood (rare) immunosuppressed  M.O.A - lymphocytes from  Skin rashes, organ failure, donor vs. receipient marrow  failure 