Haematology Flashcards
Describe the spectrum of symptoms a patient with anaemia might describe.
Asymptomatic Fatigue Headaches, Faintness Breathlessness Angina Intermittent Claudication Palpitations
List the causes of a microcytic anaemia
Iron Deficiency
Thalassaemia
Sideroblastic Anaemia
List the causes of a normocytic anaemia
Acute Blood Loss Anaemia of Chronic Disease CKD Marrow Infiltration, Fibrosis Myelomas Mixed Defiecieny e.g. Iron and B12
List the causes of a macrocytic anaemia
Alcohol Haemorrhage/Haemolysis (increase reticulocytes) Vit B12/Folate Deficiency Hypothyroidism Pregnancy Drug Therapy
What test should always be done in a patient presenting with normocytic anaemia?
Urine and Serum Electrophoresis - looking for paraprotein for myeloma
Anaemia of chronic disease is a diagnosis on exclusion and should only be made if everything else has been ruled out.
Describe the causes of thrombocytopenia
DECREASED PRODUCTION Haematinic Deficiency e.g. B12, Folate Acute Leukaemia/Myelodysplastic Syndromes i.e. bone marrow failure INCREASED CONSUMPTION e.g. DIC, Sepsis Immune Mediated e.g. ITP Drug Induced
Describe the causes of thrombocytosis (high platelets) and how can we distinguish between them?
Can be reactive i.e. in response to infection
Can be due to a myeloproliferative neoplasm
History and Clinical Examination
Trend of platelet count (sudden increase suggests reactive,, more gradual increased suggests MPN)
Describe what a myeloproliferative neoplasm is.
Uncontrolled clonal proliferation of one or more of the cell lines in the bone marrow.
List some examples of Myeloproliferative Neoplasms
Polycythemia Vera Essential Thrombocytopenia Myelofibrosis Chronic Myeloid Leukemia N.B. these conditions grouped together as there can be transition from one disease to another and they may also transform into AML
Describe what happens in Polycythemia Vera
Alteration in pluripotent progenitor cell
Leading to excessive proliferation of erythoid (RBCs), myeloid (basophil, neutrophil, eosinophiol, macrophage) and megakaryocytic (platelets)
What mutation is commonly associated with polycythemia vera
JAK-2 - means bone marrow is continuously signalled to produce cells with or without the presence of Epo
Describe the clinical features of polycythemia vera?
Insidious onset usually >60yrs
Tiredness, depression, vertigo, tinnitus and visual disturbance
Can also get hypertension, angina, intermittent claudication and a tendency to bleed
Severe itching after a hot bath or when patient is warm is common
Spleen in palpable in 70%, hepatomegaly 50%
Thrombosis and haemorrhage are the major complications
How to you diagnose polycythemia vera?
Increased haemoglobin
Presence of JAK2 kinase mutation (taken over from marrow biopsy)
Serum epo level below normal
How is polycythemia vera treated?
Aspirin to decrease stroke risk
Venesection weekly to decrease haematocrit
Chemo with hydroxycarbamite in some with HIGH HIGH platelets- can’t venesect platelets as made too quickly - slows down marrow function
Describe Essential Thrombocytopenia
ELEVATED PLATELET COUNT
normal WBCs and RBCs
How might be patients present with essential thrombocytopenia?
Asymptomatic incidental finding
Thrombo-embolic disease
Less commonly bleeding
Describe how you diagnose essential thrombocytopenia?
JAK-2 mutation in around 50%
If negative check for calreticulin or MPL
If these both negative - do bone marrow biopsy, will show increased megakaryocytes
How do you treat Essential Thrombocytopenia?
Aspirin to decrease stroke risk
Hydroxycarbamite
Describe Myelofibrosis
Get clonal proliferation of stem cells and myeloid metaplasia in the liver, spleen and other organs, with FIBROSIS in the bone marrow (hyperplasia of abrnomal megakaryocytes which release fibroblast stimulating factors
How does Myelofibrosis Present?
Insidiously with lethargy, weakness and weight loss
Abdominal fullness from splenomegaly
Bruising, bleeding and anaemia can occur
Severe pain related to respiration may indicate peri-splenitis secondary to splenic infarction
How is Myelofibrosis Diagnosed?
Leucoerythroblastic blood film - tear drop red cells
Anaemia, Thrombocytopenia, raised WCC
Bone marrow aspiration often unsuccessful due to nature of condition
JAK-2 mutation in 50%
What is the treatment of Myelofibrosis?
Supportive - blood transfusions, folic acid, analgesia
If spleen is painful and transfusion requirements are high a splenectomy may be performed
Tx of Disease - spectrum from observation alone - bone marrow transplant
New promising therapy with JAK inhibitors
Describe the chromosomal abnormality of CML
Philadelphia Chromosome
Long arm of chromosome 22 has been shortened by reciprocal translocation with chromosome 9
Puts the BCR:ABL genes together which causes upregulation of tyrosine kinase
Describe how patients with CML present?
Peak age 40-60 Some are asymptomatic OR Symptomatic anaemia Abdo discomfort sue to splenomegaly Weight loss, fever, sweats Headaches, visual disturbance, priapism due to leucostasis
Describe how CML will progress if left untreated?
Will eventually be followed by a “blast crisis” transformation to acute leukemia or myelofirbosis
Describe how CML is diagnosed?
BLOOD TESTS
normocytic anaemia, HIGH WCC, platelets can be increased or decreased
BLOOD FILM
Neutrophilia with spectrum of mature myeloid precursors
BONE MARROW ASPIRATE
Increase cells and increase myeloid precursors
Cytogenetics reveals philadelphia chromosome
How is CML managed?
Tyrosine Kinase Inhibitor - Imantinib
Produces complete haematological response in 95% and complete cytogentic response in 80%
can be used indefinitely, although should be stopped pre-conception
Stem cell transplantation in those resistant
List the systemic effects of iron overload seen in haemochromotosis
Liver disease - hepatitis, fibrosis and cirrhosis (plus ↑risk of hepatocellular carcinoma)
Pancreatic islet cell failure → Diabetes
Accumulation in the heart → restrictive cardiomyopathy and heart failure (can be a big issue)
Deposition in joints → arthritis and joint pain
Deposition in skin → hyperpigmentation or “tanning”
Deposition in pituitary gland → hypogonadotrophic (↓FSH and LH) hypogonadism (→ ↓ sex hormone synthesis in gonads). In men this presents as erectile dysfunction, subfertility and testicular atrophy. In women it presents as menstrual irregularity/amenorrhoea and anovulation → infertility. Both sexes may experience loss of axillary, pubic and limb hair.
Describe the mutation seen in over 95% of patients with haemochromatosis
HFE1
List some of the causes of B12 deficiency
Pernicious anaemia
Diet (vegans at risk)
Conditions affecting stomach/intestines e.g. crohns, gastrectomy
Medications e.g. PPIs (stomach acid helps to break down animal proteins containing B12)
Pregnancy
Heavy Drinking
List some of the causes of Folate Deficinecy
Poor Diet (lacking green, leafy veg and brown rice)
Malabsorption e.g. coeliac, crohns,
Medication e.g. phenytoin, saulfasalazine, co-trimoxazole
Pregnancy
Heavy Drinking
What test is used to test for pernicious anaemia?
Intrinsic Factor Antibodies
How can alcohol ingestion lead to low platelets?
Signifcant alcohol intake –> liver pathology –> portal hypertension –> splenomegaly –> sequestration of platelets in spleen appearing as low platelet count
Also alcohol - direct toxic effect on bone marrow can lead to decreased platelet production
When would you see macrocytic RBCs without significant anaemia?
Hypothyroid
Alcohol
Macrocytic Anaemia + High Reticulocyte Count + Jaundice…. makes you think of what diagnosis?
Haemolytic Anaemia
When someone presents with hereditary heamolysis, what three causes should you consider?
MEMBRANE - Hereditary Spherocytosis
ENZYMES - G6PD Deficinecy
HAEMOGLOBINOPATHY - Thalassaemia
Describe how patients with haemolytic anaemia usually present?
Due to constant breakdonw of RBCs, these patients have increased bone marrow activity to replace the RBCs they are loosing
This is usually fine
However, if triggering factor e.g. infection, virus, medication
The patients can decompensate and quickly become acutely unwell with jaundice and anaemia
Describe the management of patients with haemolytic anaemia
Depends on severity
Multiple hosppital admission with decompensation by age 5 - splenectomy would be considered
(spleen breaksdonw RBCs, if remove spleen, RBCs not broken down, stops problem of haemolysis)
In less severe patients jutch treat decompensated episodes and give folate supplementation
(as bone marrow increase demand as constantly replacing RBCs)
Describe the complications associated with a splenectomy
Increased rsik of serious infection with encapsulated organisms e.g. haemophilus, streptococcus and meningococcus. These patients need to be on lifelong penicillin prophylaxis to prevent serious infection with these organisms
Describe the pathophysiology of anaemia seen in chronic kidney disease and how you would treat it
Kidney cells produce epo - stimulates cells of bone marrow to produce RBCs
In CKD kidney cells become damaged, get decreased epo, bone marrow not stimulated to produce RBCs - get normocytic anaemia
Give regular Epo injections
Describe what is seen on a leucoerythroblastic blood film and what it means
Nucleated RBCs (precursor to RBCs) and Myelocytes (precursor to granulcoytes - eosinophils and basophils) should not be seen in blood, should only be seen in bone marrow Also tear shaped RBCs - poikilocytes
Means myelofibrosis or metastatic cancer than has spread to bone marrow.
Describe Haemophilia A and its inheritance
Factor 8 Deficiency
X-Linked Recessive Inheritance
1 in 5000 males affected
Describe the presentation of Haemophilia A
Depends on the residual factor 8 level SEVERE HAEMOPHILIA (5U/dL) Usually only associated with bleeding after injury or surgery. Diagnosis in often delayed until later in life.
What laboratory findings would you expect to see in a patient with haemophilia?
Prolonged APTT (measures intrinsic pathway) Decreased levels of Factor VIII
Describe how patients with Haemophilia are managed
Prophylactic prevention of bleeds through Factor 8 infusions 3x/week
Prompt treatment of all bleeds with factor 8
In patients with mild haemophilia can give desmopressin - increase factor 8 release from endothelial cell stores, can increased circulating factor 8 by up to 4x - not effective in severe haemophilia)
Describe why it is important to know the carrier status of women with Haemophilia in the family
Up to 5% of women who carry hemophilia A have a factor 8 low enough to be considered as mild haemophilia
They will bleed with trauma and need treatment to cover surgery
Describe Haemophilia B
Also known as Christmas Disease
Deficiency of Factor 9
1 in 30,000 males affected
X-Linked recessive inheritance
Describe clinical features of Haemophilia B
Exactly the same as Haemophilia A
Have mild, moderate and severe forms,
Increased APTT and decreased factor 9 in blood
Treat with prophylactic doses of factor 9 twice weekly and factor 9 when bleeding
Desmopressin not effective
Describe von Willebrands Disease
Defective Platelet Function + Factor 8 Deficinecy
Both are due to a deficiency or abnormality of von Willebrand Factor (vWF)
vWF plays a vital role in platelet adhesion to damaged subendothelium as well as stabilising factor 8 in plasma
Describe the different types of VWD and their mode of inheritance
TYPE 1 Mild quantitatiive defect, AD TYPE 2 Qualitative defect (2a, b and m = AD, 2n = AR) TYPE 3 Severe quantitative defect = AR
Describe the clinical features of VWD
Type 1 and 2 Bleeding follows minor trauma or surgery Epistaxis and Menorrhagia often occur Haemarthroses are uncommon Type 3 More severe bleeding (but rarely see joint and muscle bleeds seen in haemophilia A)
Describe the treatment of VWD
Desmopressin given prophylactically to increase levels of vWF and Factor 8
Pooled plasma concentrations containing vWF are given to patients who are bleeding or those who are undergoing surgery
Describe the causes of VITAMIN K deficiency
INADEQUATE STORES
e.g. haemorrhagic disease of newborn or severe malnutrition
MALABSORPTION
e.g. cholestatic jaundice, leads to decreased bile salts in intestine, Vit K = a fat soluble vitamin
ORAL ANTICOAGULATION
with Vit K antagonists e.g. Warfarin
What are the consequences of haemorrhagic disease of the newborn and how are these avoided
Minor bleeding in first week of life = classical
Severe bleeding e.g. intracranial hemorrhage in 2-26 weeks of life = late
1mg of IM Vitamin K is given to all neonates
List some common acquired coagulation disorders
Vitamin K Deficiency
Liver Disease
inc Vit K deficiency in cholestasis, reduced synthesis of coag factors, thrombocytopenia through splenomegaly
DIC
Describe the pathophysiology of DIC
Occurs when the balance of procoagulant factors and anticoagulant factors is overwhelmed by a massive systemic procoagulant signal
Widespread intravascular coagulation - get platelet and coagulation factor consumption, eventually run out - get BLEEDING.
Mixture of initial thrombosis leading to organ failure - usually brain, skin and kidneys from thrombotic occlusion and hypoxia followed by bleeding tendancy
List some of the causes of DIC
Malignancy Sepsis (usually gram -ve's including meningococcal) Haemolytic transfusion reactions Obstetric causes e.g. placental abruption, amniotic fluid embolus and pre-eclampsia Trauma e.g. burns, surgery Other infections e.g. malaria falciparum Acute Liver Failure Snake Bites
Describe the blood test results you would see in a patient with severe DIC
Increased PT and APTT
Decreased fibrinogen and clotting factors
Increased D-Dimer
Decreased platelets
What are the three major causes of bone marrow failure
1) Aplastic Anaemia
2) Megaloblastic Anaemia
3) Infiltration of marrow with malignant disease (can be haematological or non-haematological)
Describe a practical approach to pancytopenia
Any significant medications - review Abdominal Ultrasound - Spleen Check Haematinics - B12, folate for megaloblastic anaemia Bone Marrow Aspirate HYPOcellular = aplastic anaemia HYPERcellular = malignancy
Describe aplastic anaemia
Pancytopenia with hypocellularity of the bone marrow
Usually acquired
Due to a decrease in pluripotent stem cells and a fault in those remaining meaning that they cannot repopulate the bone marrow.
Emergence of an abnormal clone may evolve into AML or myelodysplasia.
List the causes of aplastic anaemia
PRIMARY
Inherited, Idiopathic Acquired (67% cases)
SECONDARY
Chemicals, Drugs e.g. chemotherapy, ionising radiation, insecticides, infections e.g. hepatitis, EBV, HIV, TB
What are the clinical manifestations of Bone Marrow Failure?
Anaemia - low RBCs
Bleeding - low platelets
Infection - low WCC
What investigation would you do in a patient with aplastic anaemia?
FBCs - pancytopenia
Absence of reticulocytes (as bone marrow can’t produce anything)
Hypocellular aplastic bone marrow
Describe the treatment and prognosis of aplastic anaemia
1 - withdraw cause
2- supportive care e.g. RBC and platelet transfusions, avoiding infection whilst neutropenic
3- bone marrow transplant
4 - immunosupression
Prognosis is variable - ranges from rapid spontaneous remission to a persistent progressive pancytopenia which may result in death from infection or hemorrhage
Determinants of prognosis are severity of pancytopenia and cellularity of bone marrow.
Describe megaloblastic anaemia
Characterized by immature RBCs in the bone marrow with delayed nuclear maturation because of defective DNA synthesis = MEGALOBLASTS
How does megaloblastic anaemia lead to pancytopenia and bone marrow failure?
B12 and folate are needed for synthesis of all DNA in all cells of the body.
RBCs first affected, then platelets and white cells will be affected - leading to pancytopenia and bone marrow failure.
What non-haemotologoical malignancies commonly metastasize to the bone marrow
Breast, lung, prostate, renal, thyroid and melanoma
essentially same as bone - paired and midline organs + melanoma
What is the peak age of onset for the acute leukemias?
AML - adults, peak age 65
ALL - childhood
Describe the B symptoms of lymphoma and leukemia
Fever
Weight Loss
Night Sweats
Describe some common sites of tissue infiltration of leukemia
CNS - (cause of 50% child deaths)
Testes - swollen testes may be only presentation in young boy
Gums, skin
Thymus - SOB, tracheal narrowing, widened mediastinum on CXR - needs urgent intubation
Lymph nodes, bones
Patients with acute leukemia will have low RBCs and platelets but a high WCC, why is this?
“Blasts” - all immature white cells
Will be seen on blood film
What will the bone marrow film in a patient with acute leukemia look like?
Increased cellularity
Decreased erythropoesis
Decreased megakaryocytes
Replacement by blast cells > 20% - often approaching 100%
Neutropenic sepsis is diagnosed in any patient who…..
Has a neutrophil count
Describe the urgent actions you would do, if diagnosed a patient with neutropenic sepsis
See immediately and admit
Look for source of infection (although not always obvious in these patients)
Take FBC, U&Es, BLOOD CULTURES, and CXR
Start IVT - need lots of fluid (2-3L over first 6-8 hrs)
GIVE IMMEDIATE BROAD SPECTRUM ANTIBIOTICS
E.G. PIP TAZ
Monitor very closely and watch vital signs for evidence of deterioration
If these patients develop septic shock then the mortality is very high
Define Thrombus and Embolus
A THROMBUS is a solid mass formed in the circulation from the constituents of blood during life
An EMBOLUS is a part of a thrombus that has broken off and blocks a smaller blood vessel downstream
List some of the rsik factors for venous thromboembolic disease
Increasing age, BMI >30, Immbobility, Recent Long Haul Flight, Pregnancy and the Puerperium, Oestrogen therapy e.g. COCP, HRT, Thrombophilia, Recent Surgery, Malignancy, Anti-Phopholipid Syndrome
Describe Thrombophilia
A term describing inherited or acquired defects in haemastasis leading to a predisposition to venous or arterial thrombosis
What are the naturally occurring anticoagulants and what clotting factors do they inhibit
Protein C and Protein S - work as a complex to inhibit factor 5 and factor 8
Anti-thrombin - inhibits all other factors
Describe Virchows Triad of Thrombus Formation
HYPERCOAGULABLE STATE
VASCULAR WALL INJURY
CIRCULATORY STASIS
What is Factor V Leiden
Factor V Leiden differs from normal Factor V by a single point mutation
This variation makes Factor V less likely to be cleaved by activated protein C
Leads to a slowing of the inactivation of Factor Va, and therefore a tendency to form clots
Acts synergistically with other risk factors
How common is Factor V Leiden
Found in 2-3% of normal population and 20-30% of patients with VTE
Describe the inheritance of Protein C and S Deficiency and how it might present
Autosomal Dominant Inheritance
If HOMOZYGOUS - causes neonatal purpura fulminans, which is fatal without immediate replacement therapy
If HETEROZYGOUS -may present with DVT in young adults
Describe how you would go about diagnosing a DVT in a patient with suggestive symptoms
Review History and Examination - try and exclude other causes
Use the Wells Score to calculate risk of DVT
If Wells score suggests high risk (>2) then perform a proximal leg vein ultrasound scan and a D-dimer test
If ultrasound cannot be done and D-Dimer is high - give interim parenteral anti-coagulation until ultrasound can be performed.
Describe how you would go about diagnosing a PE in patients with suggestive symptoms
Medical History, Examination, CXR
Calculate their risk of PE using the Wells score for PE
If Wells score suggests PE is likely (>4) order a CTPA, if this cannot be done immediately give parenteral anticoagulation in the interim
If Wells score suggests not likely - do D-dimer test.
If D-dimer positive, do CTPA
List some of the causes of an isolated thrombocytopenia
Infections (bacterial and viral) Immune mediated destruction Congenital Disease Gestational Thrombocytopenia Splenomegaly Antiphospholipid antibody syndrome Drugs
What cells are classically seen on the blood film of a patient with Hodgkin Lymphoma
Reed Sternberg Cells
What are rouleaux? And in what condition might they be present on the blood film?
Stacks or Aggregations of RBCs
Occur when plasma protein levels are high
e,g, paraprotein in myeloma
Describe some of the ways that Myeloma can present?
Hypercaclcaemia & Bone Pain
Myeloma - overexpression of RANKL, RANKL activates osteoclasts, which resprob bone. Get lytic bone lesions “punched out” and hypercalcaemia
Anaemia -from replacement of normal bone marrow by tumour cells and inhibition of normal red cell production
Renal Failure - due to high plasma proteins (paraprotein)
What are auer rods? And in what conditions would they be seen on the blood film?
Clumps of granular material that form long needles in the cytoplasm of leukemic blasts. Seen in
AML
Myeloproliferative Syndromes
In any patients presenting with confusion, dehydration, nausea and vomiting what diagnosis should always be thought of
HYPERcalcaemia
In a patient who presents lymphadenopathy when should they be referred to a specialist?
Any patient with a lymph node >1cm that has lasted for >6 weeks
Any patient with generalised lymphadenopathy i.e. in two or more non-contiguous areas
If they have supraclavicular lymph nodes (v.concerning)
What initial investigations should be done in a patient presenting with lymphadenopathy?
FBC, U&Es, LFTs, ESR
Monospot - for infectious mononucleosis
Viral Screen - HIV, Hep B and Hep c - all can cause lymphadenopathy
What additional investigations should then be done, if above negative.
Blood Film (although a lot of lymphomas have abnormal blood film)
Cell Surface Markers - immunophenotyping
Lactate Dehydrogenase = non-specific marker for cell turnover - although if high in the case of this history and examination - probably means lymphoma
CXR - to check for mediastinal widening
TISSUE - FNA not enough, need excision biopsy or multiple needle cores.
Whats the difference in management in HIGH grade and LOW grade lymphomas
HIGH grade
Includes Hodgkins - need chemotherapy urgently and are curable
LOW grade
Watch and wait, do not need to treat low grade if patient is asymptomatic. Only treat when patient has symptoms. If treat low grade can get patients into remission, but they will relapse. Cannot cure it.
Describe the Ann Arbour Staging System for Lymphoma
STAGE 1 One LN region or organ STAGE 2 Two or more LN regions on the same side of the diphragm STAGE 3 LN regions on both sides of the diphragm STAGE 4 Extranodal, diffuse involvement of non-lyphatic organs/tissues e.g. bone marrow, lung, liver
Describe Tumour Lysis Syndrome and its sequale
Occurs if treatment triggers a massive breakdown on tumour cells. Leads to INCREASED serum levels of urate, potassium and phosphate
And secondary HYPOcalcaemia
Can lead to cardiac arrythmias and seizures
Urate deposition in the renal tubules can cause renal failure (hyperuricaemic nephropathy)
Describe how tumour lysis syndrome is prevented?
Vigourous hydration to maintain high urine outputs
Allopurinol can be given before treatment to protect the kidneys
How do LMWH work?
Inactivates Factor Xa
How does unfractionated heparin work?
Binds antithrombin (an endogenous inhibitor of coagulation) Which increases its ability to inhibit thrombin, Factor Xa and Factor IXa
How do you monitor Heparin?
APTT
