Haematology Flashcards
Disseminated intravascular coagulation
Pathophysiology
- Hemostasis goes out of control
- Various blood clots form –> organ ischaemia (kidneys, liver, lungs, brain)
- These clots consume platelets and clotting factors
- Therefore the rest of the blood is low on these factors
- Fibrin degradation products in the circulation (from breakdown of the clots) also interferes with new clot formation
- Therefore resulting in bleeding with even the slightest damage to vessel walls
= Bleeding and clotting
Disseminated intravascular coagulation
Investigations
- Decreased platelets
- Decreased fibrinogen
- Prolonged prothrombin time (PT)
- Prolonged activated partial thromboplastin time (APTT)
PT and PTT reflect low circulating coagulation factors - Elevated D-Dimer (fibrin degradation product)
- Schistocytes due to microangiopathic haemolytic anaemia
Disseminated intravascular coagulation
When might you see chronic DIC
- Solid tumours
- Large aortic aneurysms
Disseminated intravascular coagulation
What would you see on investigations
- Relatively normall findings due to compensation
Disseminated intravascular coagulation
Management
Focus on underlying cause
- Support underlying organs (ventilator, haemodynamic support, tranfusions if needed)
Disseminated intravascular coagulation
Causes
- Sepsis
- Trauma
- Obstetric complications, e.g. HELLP syndrome, amniotic fluid embolism
- Malignancy
Can all initially tip the balance in favour of clotting –> starting the process of DIC
Haemophilia
Pathophysiology
- Deficiency of clotting factors
- Leading to bleeding
Haemophilia
Inheritance
X-linked recessive
- All of the X chromosomes need to have the abnormal gene
- Men only require one abnormal copy as they only have one X chromosome
- Women require two abnormal copies
- If they only have one copy –> carrier
- Almost exclusively affects males as for a female to be affected it would require an affected father and an affected/carrier mother
Haemophilia
Features
- Excessive bleeding in response to minor trauma
- Risk of spontaneous hemorrhage
- Haemoarthroses (bleeding into joints)
- Haematomas
- Prolonged bleeding after trauma/surgery
- Cord bleeding in neonates
- Bleeding of gums, GI tract, UT (haematuria), retroperitoneal space, intracranial
KEY presentation of severe disease = spontaneous bleeding into joints and muscles
Haemophilia
Investigations
- Prolonged APTT
- Bleeding time, thrombin time and prothrombin time all normal
- Genetic testing
Haemophilia
Management
Prophylactically:
- Replace clotting factors via IV
- Complication = formation of antibodies against the clotting factor, making it ineffective Tx
Acutely:
- Infusions of affected factor (VIII or IX)
- Desmopressin to stimulate release of von Willebrand factor
- Antifibrinolytics, e.g. tranexamic acid
Haemophilia
Types
- Type A = deficiency in factor VIII
- Type B = deficiency in factor IX (Christmas disease)
Hyposplenism
Causes
- Splenectomy
- Sickle-cell
- Coeliac disease, dermatitis herpetiformis
- Graves’ disease
- Systemic lupus erythematosus
- Amyloid
Hyposplenism
Features on blood film
- Howell-Jolly bodies
- Siderocytes
Splenectomy
Post-splenectomy risks
- Pneumococcus
- Haemophilus
- Meningococcus
- Capnocytophaga canimorsus (dog bites)
Splenectomy
Vaccination
If elective, should be done 2 weeks prior to operation:
- Haemophilus influenza Type B (HiB)
- Meningitis A&C
Also:
- Annual influenza
- Pneumococcal every 5 years
Splenectomy
Antibiotic prophylaxis
- Penicillin V for at least 2 years or until 16 yrs old
- Can sometimes be for life
Splenectomy
Indications
- Trauma (1/4 = iatrogenic)
- Spontanous rupture (EBV)
- Hypersplenism (hereditaory sphero/elliptocytosis)
- Malignancy (lymphoma, leukaemia)
- Splenic cysts, hydatid cysts, splenic abscesses
Splenectomy
Complications
- Haemorrhage - from SHORT GASTRIC or SPLENIC HILAR vessels
- Pancreatic fistula (from iatrogenic damage to tail)
- Thrombocytosis - prophylactic aspirin
- Encapsulated bacteria infection (strep pneumo, haem influenza, Neisseria meningitidis)
Splenectomy
Post-splenectomy changes
- Platelets will rise first
- Blood film will change after following weeks
- Howell-Jolly bodies will appear on the film
- May also see target cells, pappenheimer bodies
- Increased risk of post-splenectomy sepsis -> prophylactic Abx and pneumococcal vaccine
Splenectomy
Post-splenectomy sepsis
- Typically occur with encapsulated organisms
- Risk is greatest in < 16 yrs and > 50 yrs
- Tx = Penicillin V 500 mg BD and Amoxicillin 250 mg BD
Splenectomy
Travel
- Asplenic individuals travelling to malaria endemic areas are at high risk and should have both pharmacological and mechanical protection
Myeloproliferative disorders
Umbrella term for what?
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
Myeloproliferative disorders
Pathophysiology
- Uncontrolled proliferation of a single type of stem cell
- Considered a type of bone marrow cancer
Myeloproliferative disorders
Cell lines and diseases
- Primary myelofibrosis = fibroblasts (monocytes, eosinophils, neutrophils, basophils)
- Polycythemia vera = erythrocytes (RBCs)
- Essential thrombocythaemia = megakaryocytes (platelets)
Myeloproliferative disorders
Complications
Have the potential to progress and transform into acute myeloid leukemia (AML)
Myeloproliferative disorders
Associated mutations
- JAK2
- MPL
- CALR
Myelofibrosis
Pathophysiology
- Can be the result of primary myelofibrosis, polycythemia vera or essential thrombocytopenia
- Proliferation of haematopoietic stem cell
- Resultant release of platelet-derived growth factors –> stimulates fibroblast growth factor
- Leads to fibrosis of the bone marrow, replaced by scar tissue
- Can lead to low production of blood cells –> anaemia and leukopenia
- Haematopoiesis starts occurring in liver and spleen (extramedullary haematopoiesis)
- Can lead to hepatosplenomegaly and portal hypertension
- If this occurs around the spine it can result in spinal cord compression
Myelofibrosis
Features
- Symptoms of anaemia
- Massive splenomegaly
- Hypermetabolic symptoms - weight loss, night sweats
Myelofibrosis
Investigations
- Anaemia
- High WBC and platelet count in early disease
- May be low in later disease
- High urate and LDH (increased cell turnover)
Blood film:
- TEARDROP POIKILOCYTES
- Poikilocytosis (varying sizes)
- Immature red and white cells (blasts)
Bone marrow biopsy:
- Usually ‘dry’ as it has turned to scar tissue
- Therefore, need trephine biopsy
- Genetic testing: JAK2, MPL and CALR
Myelofibrosis
Management
- Allogenic stem cell transplantation (potentially curative but carries risks)
- Chemotherapy (improves symptoms and slow progression but not curative)
- Supportive management of anaemia, splenomegaly, portal HTN
Polycythaemia vera
Pathophysiology
- Clonal proliferation of a marrow stem cell, erythroid cells
- Leads to an increased in red cell volume
- Often accompanied by overproduction of neutrophils and platelets
- INcidence peaks in 6th decade
Polycythaemia vera
Features
- Hyperviscosity
- Pruritus, typically after a hot bath
- Splenomegaly
- Haemorrhage (secondary to abnormal platelet function)
- Plethoric appearance
- Conjunctival plethora
- Hypertension in a third of patients
- Low ESR
- Ruddy complexion
Polycythaemia vera
Investigations
- FBC: raised haematocrit, neutrophils, basophils, platelets (in 1/2), raised red cell mass
- JAK2 mutation (92%)
- Serum ferritin
- Renal and liver function test
- Low ESR
- Raised leukocyte alkaline phosphate
Polycythaemia vera
Management
- Venesection to keep Hb in normal range = 1st line
- Aspirin to reduce risk of blood clots
- Chemo to control disease (hydroxyurea or phosphorus-32)
Polycythaemia vera
JAK-2 positive diagnostic criteria
Requires both
- High haematrocrit (> 0.52 in men, > 0.48 in women) OR raised red cell mass (> 25% above predicted)
- Mutation in JAK2
Polycythaemia vera
JAK-2 negative diagnostic criteria
Requires A1 + A2 + A3 + either another A or two B criteria
A1: Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women
A2: Absence of JAK2 mutation
A3: No cause of secondary erythrocytosis
A4: Palpable splenomegaly
A5: Presence of aquired genetic abnormality (excluding BRC-ABL) in haemopoietic cell
B1: Thrombocytosis (platelets > 450)
B2: Neutrophils > 10 in non-smokers, >12.5 in smokers
B3: Radiological evidence of splenomegaly
B4: Endogenous erythroid colonies or low serum erythropoietin
Essential thrombocytosis
Pathophysiology
- Essential thrombocytosis is one of the myeloproliferative disorders which overlaps with chronic myeloid leukaemia, polycythaemia rubra vera and myelofibrosis.
- Megakaryocyte proliferation results in an overproduction of platelets.
Essential Thrombocytosis
Features
- Platelet count > 600
- Both thrombosis and haemorrhage
- Burning sensation in the hands
- JAK2 mutation in 50%
Essential Thrombocytosis
Investigations
Raised platelet count (more than 600 x 10^9/l)
Essential Thrombocytosis
Management
- Aspirin to reduce risk of thrombus formation
- Chemo to control disease
- Hydroxyurea to reduce platelet count
- Interferon-alpha in younger patients
Thrombocytosis
Define
Thrombocytosis is an abnormally high platelet count, usually > 400 * 10^9/l
Thrombocytosis
Causes
- Reactive: platelets are an acute phase reactant - platelet count can increase in response to stress such as a severe infection, surgery. Iron deficiency anaemia can also cause a reactive thrombocytosis
- Malignancy
- Essential thrombocytosis, or as part of another myeloproliferative disorder such as chronic myeloid leukaemia or polycythaemia rubra vera
- Hyposplenism
Myelodysplastic syndrome
Pathophysiology
- Myeloid bone marrow cells do not mature properly
- Therefore do not produce healthy blood cells
- Pre-leukaemia –> may progress to AML
Myelodysplastic syndrome
Features
Bone marrow failure:
- Anaemia - pallor, fatigue, SOB
- Neutropenia (low neutrophils) - frequent/severe infections
- Thrombocytopenia (low platelets) - purpura or bleeding
Myelodysplastic syndrome
Investigations
- FBC: anaemia, neutropenia, thrombocytopenia
- Blood film: Blasts
- Bone marrow aspiration and biopsy
Myelodysplastic syndrome
Management
- Watchful waiting
- Supportive treatment with blood transfusions if severely anaemic
- Chemotherapy
- Stem cell transplantation
Myelodysplastic syndrome
Epidemiology
- More common with age (> 60 yrs)
- More common in those who have previously had chemo or radio therapy
Polycythaemia
Types
- Relative
- Primary (polycythaemia vera)
- Secondary
Causes of relative polycythaemia
- Dehydration
- Stress - Gasibock syndrome
Causes of primary polycythaemia
- Polycythaemia vera (proliferation of a marrow stem cell, erythroid cells)
Causes of secondary polycythaemia
- COPD
- Altitude
- Obstructive sleep apnoea
- Excessive erythropoietin:
- Cerebellar hemangioma
- Hypernephroma
- Hepatoma
- Uterine fibroids –> menorrhagia –> blood loss
How to differentiate between true (primary and secondary) and relative polycythaemia?
RED CELL MASS
In true polycythaemia the total red cell mass in males > 35 ml/kg and in women > 32 ml/kg
Thrombocytopenia
Pathophysiology
- Low platelet count
- Can either be due to low production or excess destruction
Thrombocytopenia
Problems with production
- Sepsis
- B12 or folic acid deficiency
- Liver failure –> reduced thrombopoietin production
- Leukaemia
- Myelodysplastic syndrome
Thrombocytopenia
Problems with destruction
- Alcohol
- ITP
- TTP
- Heparin-induced thrombocytopenia
- Haemolytic-uraemic syndrome
- DIC (using them up rather than destruction)
- Medications:
- Sodium valproate
- Clozapine
- Methotrexate
- Isotretinoin
- Antihistamines
- PPIs
Thrombocytopenia
Features
Platelets < 50 x 109/L
- Easy or spontaneous bruising and prolonged bleeding times
- Nosebleeds, bleeding gums, heavy periods, easy bruising or blood in the urine or stools
Platelet counts < 10 x 109/L
- High risk for spontaneous bleeding
- Spontaneous intracranial haemorrhage or GI bleeds are particularly concerning
Differentials of abnormal or prolonged bleeding
- Thrombocytopenia (low platelets)
- Haemophilia A and haemophilia B
- Von Willebrand Disease
- Disseminated intravascular coagulation (usually secondary to sepsis)
Causes of severe thrombocytopenia
- ITP
- DIC
- TTP
- Haematological malignancy
Causes of moderate thrombocytopenia
- HIT
- Drug-induced
- Alcohol
- Liver disease
- Hypersplenism
- Viral infection (EBV, HIV, hepatitis)
- Pregnancy
- SLE
- Antiphospholipid syndrome
- Vit B12 deficiency
Immune thrombocytopenia
Pathophysiology
- Antibodies are created against platelets
- Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex
Immune thrombocytopenia
Epidemiology
- More common in older females
Immune thrombocytopenia
Features
- May be detected incidentally
- Petichae, purpura
- Bleeding (e.g. epistaxis)
- Catastrophic bleeding (e.g. intracranial) = rare
Immune thrombocytopenia
Investigations
Platelets
Immune thrombocytopenia
Management
- Prednisolone = 1st line
- IV normal human immunoglobulin (IVIG): raises platelet count quicker than Pred so may be used if active bleeding or urgent invasive procedure is required
- Rituximab (monoclonal antibody against B cells)
- Splenectomy (now less common)
Immune thrombocytopenia
Other names for it
Autoimmune thrombocytopenic purpura
Idiopathic thrombocytopenic purpura
Primary thrombocytopenic purpura
Thrombotic Thrombocytopenic Purpura
Pathophysiology
- Abnormaly large or ‘sticky’ multimers of von Willebrand’s factor
- Causes platelets to clump in the vessels
- Deficiency of ADAMTS13 (normally present to break down multimers of von Willebrand’s factor)
- Platelets are used up here and therefore can not form clots –> bleeding
- The blood clots also break up RBCs leading to haemolytic anaemia
Thrombotic Thrombocytopenic Purpura
Features
- Fever
- Fluctuating neuro signs (microemboli)
- Microangiopathic hemolytic anaema
- Thrombocytopenia
- Renal failure
Thrombotic Thrombocytopenic Purpura
Causes
Deficiency in the ADAMTS13 can be autoimmune disease or inherited genetic mutation
- Post-infection, e.g. urinary, GI
- Pregnancy
- Tumours
- SLE
- HIV
- Drugs:
- Ciclosporin
- Oral contraceptive pill
- Penicillin
- Clopidogrel
- Aciclovir
Thrombotic Thrombocytopenic Purpura
Investigations
Platelets
Hb (low)
Renal function
Thrombotic Thrombocytopenic Purpura
Management
- Plasma exchange
- Steroids
- Rituximab (monoclonal antibody against B cells)
Heparin Induced Thrombocytopenia (HIT)
Pathophysiology
- Development of antibodies against platelets in response to exposure to heparin
- Specifically target platelet factor 4 (PF4)
- Therefore are anti-PF4/heparin antibodies
- HIT antibodies bind to platelets and activate clotting mechanisms -> hypercoagulable state -> thrombosis
- BUT they also break down platelets causing thrombocytopenia
CLINICALLY: A patient on heparin has low platelets but forms unexpected blood clots –> HIT
Heparin Induced Thrombocytopenia (HIT)
Diagnosis
Test for HIT antibodies
Heparin Induced Thrombocytopenia (HIT)
Management
- Stop heparin
- Use an alternative anticoagulant, guided by a specialist
G6PD Deficiency
Pathophysiology
- G6PD is responsible for helping to protect cells from damage by reactive oxygen species (ROS)
- Reduced G6PD –> reduced NADPH –> reduced glutathione –> reduced RBC susceptibility to oxidative stress –> RBC haemolysis
- Periods of acute stress lead to higher production of ROS –> acute haemolytic anaemia
- X linked recessive pattern
G6PD Deficiency
Triggers
- Broad beans (fava beans)
- Infection
- Recent course one of the following drugs:
- Anti-malarials - primaquine
- Ciprofloxacin
- Nitrofurantoin
- Trimethoprim
- Sulph-group drugs: sulphonamides, suphasalazine, sulphonylureas
G6PD Deficiency
Epidemiology
- More common in Mediterranean, Middle Eastern and African patients
- Inherited in an X linked recessive pattern (usually affects males)
G6PD Deficiency
Features
- Anaemia
- Intermittent jaundice (in response to triggers)
- Neonatal jaundice
- Intravascular haemolysis
- Gallstones
- Splenomegaly
G6PD Deficiency
Investigations
- Blood film: Heinz bodies (= blobs of denatured hemoglobin)
- May also see bite and blister cells
- Diagnosis = G6PD enzyme assay
- Levels should be checked around 3 months after an acute episode of hemolysis
- RBCs with the most severely reduced G6PD activity will have hemolysed → reduced G6PD activity → not be measured in the assay → false-negative results
G6PD Deficiency
Management
- Avoid triggers where possible
- Usually self-limiting
Hereditary spherocytosis
Pathophysiology
- Deficiency in RBC membrane proteins
- Caused by genetic lesions
- Spleen destroys them due to their odd shapes
- Autosomal dominant
Hereditary spherocytosis
Epidemiology
- Autosomal dominant
- More common in Northern Europeans
Hereditary spherocytosis
Features
- Failure to thrive (children)
- Jaundice
- Gallstones
- Splenomegaly
- Asplastic crisis precipitated by PARVOVIRUS (more severe haemolysis, anaemia and jaundice, no response from bone marrow to make new cells)
- Degree of haemolysis = variable
Hereditary spherocytosis
Investigations
- Family history
- Blood film: spherocytes or elliptocytes (another membranopathy with similar patho)
- Elevated mean corpuscular haemoglobin concentration (MCHC) on FBC
- Reticulocutes will be raised due to rapid turnover of RBCs (NOT in an aplastic crisis)
Hereditary spherocytosis
Management
- Folate supplementation
- Splenectomy
- Removal of gallbladder (cholecystectomy) if required
- Transfusions may be needed in acute crises
Hereditary Elliptocytosis
Exactly the same as spherocytosis except ellipse shaped RBCs
Also autosomal dominant
Von Willebrand Disease
Pathophysiology
- von Willebrand = large glycoprotein that form massive mU\
- Usually released from Weibel-Palade bodies in endothelial cells
- Promotes platelet adhesion to damaged endothelium
- Carrier molecule for factor VIII
(ADAMST13 balances the adhesion and prevents multimers from getting too big)
Von Willebrand Disease
Epidemiology
- Most common inherited cause of abnormal bleeding
- Autosomal dominant (most of the underlying causes)
Von Willebrand Disease
Types
- Type 1: Partial reduction in vWF (80% - autosomal dominant)
- Type 2: Abnormal form of vWF (autosomal dominant)
- Type 3: Total lack of vWF (autosomal recessive)
Von Willebrand Disease
Features
- Bleeding gums with brushing
- Epistaxis
- Heavy menstrual periods
- Heavy bleeding during surgical operations
- Family history !!
Von Willebrand Disease
Investigations
- Prolonged bleeding time
- APTT may be prolonged
- Factor VIII levels may be moderately reduced
- Defective platelet aggregation with ristocetin
Von Willebrand Disease
Management
- Desmopressin can stimulate the release of vWF from Weibel-Palade bodies in endothelial cells
- VWF can be infused
- Factor VIII infusion (along with plasma-derived VWF)
- Tranexamic acid or mefenamic acid or mild bleeding
- Could manage heavy periods with norethisterone, COCP, mirena coil, or ultimately hysterectomy
What is Osler-Weber-Rendu syndrome also known as?
Hereditary hemorrhagic telangiectasia
What is Osler-Weber-Rendu syndrome?
Characterized by (as the name suggests) multiple telangiectasia over the skin and mucous membranes
The inheritance pattern of Osler-Weber-Rendu syndrome?
Autosomal dominant
Diagnostic criteria of Osler-Weber-Rendu syndrome?
If 2 –> possible diagnosis
If 3+ –> definite diagnosis
- Epistaxis (spontaneous, recurrent nosebleeds)
- Telangiectases (multiple characteristic sights - lips, oral cavity, fingers, nose)
- Visceral lesions (GI telangiectasia, pulmonary AV malformations, hepatic AVM, cerebral AVM, spinal AVM)
- Fx - first-degree relative with HHT
What is telangiectasia
Dilated or broken blood vessels located near the surface of the skin or mucous membranes
Lymphoma
Pathophysiology
- Group of cancers that affect the lymphocytes inside the lymphatic system
- Cancerous cells proliferate within the lymph nodes
- Cause the lymph nodes to become abnormally large (lymphadenopathy)
Lymphoma
Types
- Hodgkins
- Non-hodgkins (including Burkitt’s)
Hodgkin’s Lymphoma
Epidemiology
- 1 in 5 lymphomas = Hodgkins
- Bimodal age distribution: 20 yrs and 75 yrs
Hodgkin’s Lymphoma
Risk factors
- HIV
- EBV
- Autoimmune conditions, e.g. RA and sarcoidosis
- Fx
Hodgkin’s Lymphoma
Features
- LYMPHADENOPATHY - sometimes pain when drinking alcohol, normally painless, non-tender, rubbery, asymmetrical
- Fatigue
- Itching
- Cough/SOB
- Abdo pain
- Recurrent infections
- Hepatosplenomegaly
B symptoms:
- Fever (Pel-Ebstein: fever than rises and falls every 7-10 days)
- Weight loss
- Night sweats
Hodgkin’s Lymphoma
Investigations
- Raised LDH (not specific)
- Normocytic anaemia
- Eosinophilia
- Lymph nodes biopsy
- REED STERNBERG CELLS (abnormally large B cells that have multiple nuclei –> owl-looking)
- CT, MRI, PET scan
Hodgkin’s Lymphoma
Staging
ANN ARBOR STAGING
1: Confined to one region of lymph nodes
2: More than one region but same/one side of diaphragm
3: Affects lymph nodes both above and below diaphragm
4: Widespread involvements, including non-lymphatic organs, e.g. lungs, liver
Hodgkin’s Lymphoma
Classification (A/B)
A = no systemic features (apart from pruritus)
B = B symptoms present
- Weight loss > 10% in last 6 months
- Fever > 38 degress
- Night sweats (poor prognosis)
Hodgkin’s Lymphoma
Poor prognostic factors
- B symptoms
- Age > 45 yrs
- Stage IV disease
- Hb < 10.5
- Lymphocytes < 600 or < 8%
- Male
- Albumin < 40
- WBC > 15,000
- Raised ESR
Hodgkin’s Lymphoma
Histological types (and prognosis)
Nodular sclerosing
- Most common
- More common in women
- Associated with lacunar cells
- Good prognosis
Mixed cellularity
- Around 20%
- Associated with large numbers of RS cells
- Good prognosis
Lymphocyte predominant
- Best prognosis
Lymphocyte depleted
- Worst prognosis
Hodgkin’s Lymphoma
Management
Chemotherapy and radiotherapy
- Chemo: risk of leukaemia and infertility
- Radio: risk of cancer, damage to tissues, hypothyroidism
Chemo = AVBD
- Doxorubicin hydrochloride (Adriamycin)
- Bleomycin sulfate
- Vinblastine sulfate
- Dacarbazine
Early = 2-4 cycles Advanced = 6-8 cycles
Non-Hodgkins Lymphoma
Epidemiology
- 6th most common cancer in UK (more common than hodgkins)
- Typically in the elderly (> 75 yrs)
- More common in men
Non-Hodgkins Lymphoma
Risk factors
- EBV
- H.plyor (MALT lymphoma)
- Hep B or C
- Exposure to pesticides or specific chemical (trichloroethylene)
- Fx
- Hx of chemo/radiotherapy
- Autoimmune diseases (SLE/sjogrens/coeliac)
- Immunodeficiency (HIV/DM/tranplant)
Non-Hodgkins Lymphoma
Features
Same as Hodgkins - only differentiated by biopsy
- Painless lymphadenopathy (non-tender, rubbery, asymmetrical)
- Constitutional/B symptoms (fever, weight loss, night sweats, lethargy)
- Extranodal Disease - gastric (dyspepsia, dysphagia, weight loss, abdominal pain), bone marrow (pancytopenia, bone pain), lungs, skin, central nervous system (nerve palsies)
- Signs of weight loss
- Palpable abdominal mass - hepatomegaly, splenomegaly, lymph nodes
- Testicular mass
- Fever
Non-Hodgkins Lymphoma
Investigations
- Raised LDH
- Raised ESR
- Normocytic anemia
- Lymph node biopsy
- Burkitt’s may have starry sky appearance
- CT TAP to assess staging
Non-Hodgkins Lymphoma
Staging
ANN ARBOR STAGING
1: Confined to one region of lymph nodes
2: More than one region but same/one side of diaphragm
3: Affects lymph nodes both above and below diaphragm
4: Widespread involvements, including non-lymphatic organs, e.g. lungs, liver
Plus A or B for absence/presence of B symptoms
Non-Hodgkins Lymphoma
Management
- May just be watchful waiting
- Chemo: R-CHOP
- Rituximab
- Cyclophosphamide
- Doxorubicin Hydrochloride
- Vincristine (Oncovin)
- Prednisolone
- Flu/pneumococcal vaccines
- Neutropenia may require prophylactic Abx
- Stem cell transplantation
Non-Hodgkins Lymphoma
Complications
- Bone marrow infiltration causing anaemia, neutropenia or thrombocytopenia
- Superior vena cava obstruction
- Metastasis
- Spinal cord compression
- Complications related to treatment e.g. Side effects of chemotherapy
Non-Hodgkins Lymphoma
Prognosis
- Low-grade non-Hodgkin’s lymphoma has a better prognosis
- High-grade non-Hodgkin’s lymphoma has a worse prognosis but a higher cure rate
Non-Hodgkins Lymphoma
Types and cells involved and additional symptoms
- Mantle cell (Mature B cell lymphoma)
- B-cell follicular (Mature B cell lymphoma)
- Diffuse Large B-Cell (B cell) - bowel symptoms
- Burkitt’s (B cell) - abdo/testicle/CNS mass
- T and NK cell (T cell)
Lymphoma
Factors that might help differentiate between Hodgkins and non-Hodgkins before biopsy
- Lymphadenopathy in Hodgkin’s lymphoma can experience alcohol-induced pain in the node
- ‘B’ symptoms typically occur earlier in Hodgkin’s lymphoma and later in non-Hodgkin’s lymphoma
- Extra-nodal disease is much more common in non-Hodgkin’s lymphoma than in Hodgkin’s lymphoma
Burkitt’s Lymphoma
Types
Endemic (African):
- Maxilla or mandible
Sporadic form:
- Abdo (ileo-caecal) tumours are most common
- Most common in HIV patients
Burkitt’s Lymphoma
Genetics
- Associated with c-myc gene
- Translocation t(8:14)
- EBV is strongly implicated in African form
Burkitt’s Lymphoma
Microscopy findings
- Starry sky appearance
- Lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells
Burkitt’s Lymphoma
Management
- Chemo
- Produced rapid response which may lead to TUMOUR LYSIS SYNDROME
- Give Rasburicase before chemo to reduce chance of this
Chemotherapy side effects
- Alopecia
- Nause and vomiting
- Fatigue
- Neutropenia
Use ONDANSETRON (5HT3 antagonist)
Myeloma
Pathophysiology
- Proliferation of plasma cells
- Type of B lymphoycte that produce antibodies
- Cancer in a specific type of plasma cell results in large quantities of a single type of antibody being produced (antibodies = immunoglobulins)
- Multiple myeloma = where myeloma affects multiple areas of the body
Myeloma
Risk factors
- Older age
- Males
- Black African ethnicity
- Fx
- Obesity
Myeloma
Features
CRABBI
C: Calcium - hypercalcemia (bones, groans, psych moans, stones)
- Occurs due to increased osteoclast activity within bones
- Leads to constipation, nausea, anorexia, confusion
R: Renal failure
- Light chain deposition within renal tubules (BENCE JONES)
- Renal damage -> dehydration and thirst
- Other causes: amyloidosis, nephrolithiasis, nephrocalcinosis
A: Anaemia
- Bone marrow crowding suppresses erythropoiesis
- Fatigue and pallor
B: Bone lesions/pain
- Bone marrow infiltration by plasma cells and cytokine-mediated osteoclast overactivity –> lytic bone lesions
- Pain (espeically back), increased fragility fractures
B: Bleeding/bruising
- Bone marrow crowding –> thrombocytopenia
I: Infection
- Reduction in production of normal immunoglobulins –> increased susceptibility to infection
- Infiltration of bone marrow –> neutropenia
Myeloma
Investigations
- FBC: thrombocytopenia, neutropenia, anaemia (low RBCs), raised ESR
- U&Es: Raised urea and creatinine
- Raised calcium
- Plasma viscosity
If any of above +ve or myeloma still suspected: BLIP
- B: Bence Jones protein in urine (urine electophoresis)
- L: serum Light chain assay
- I: serum Immunoglobuilins
- P: serum Protein electrophoresis
Bone marrow biopsy needed to confirm the diagnosis (significantly raised plasma cells)
Whole-body MRI or CT or skeletal survey for bony lesions
Myeloma
General management
Myeloma = chronic relapsing and remitting malignancy which is currently deemed incurable. Management aims to control symptoms, reduce complications and prolong survival.
For those suitable for stem cell transplantation, induction therapy:
- Bortezomid and Dexamethasone
For those NOT suitable:
- Thalidomide + Alkylating Agent + Dexamethasone
For relapses:
- Bortezomib monotherapy
- May be suitable for repeat stem cell transplant
VTE prophylaxis
What are the different type of immunoglobulins
They come in 5 main types: A, G, M, D and E
What are immunoglobulins
- Complex molecules made up of two heavy chains and two light chains arranged in a Y shape
- They help the immune system recognize and fight infections by targeting specific proteins on the pathogen.
What are immunoglobulins
- Complex molecules made up of two heavy chains and two light chains arranged in a Y shape
- They help the immune system recognize and fight infections by targeting specific proteins on the pathogen.
What can occur as a result of hyperviscotiy in myeloma?
- Easy bruising
- Easy bleeding
- Reduced or loss of sight due to vascular disease in the eye
- Purple discolouration to the extremities (purplish palmar erythema)
- Heart failure
What can occur as a result of hyperviscosity in myeloma?
Results in vascular stasis and hypo-perfusion
- Easy bruising
- Easy bleeding
- Reduced or loss of sight due to vascular disease in the eye
- Purple discolouration to the extremities (purplish palmar erythema)
- Heart failure
Myeloma
X-Ray signs
- Punched out lesions
- Lytic lesions
- Raindrop skull - caused by many punched out (lytic) lesions throughout the skull, gives appearance of raindrops splashing on surface (salt and pepper too)
Myeloma
Complications
- Pain (Tx = analgesia)
- Pathological fracture
- Infection
- Renal failure
- Anaemia
- Hypercalcaemia
- Peripheral neuropathy
- Spinal cord compression
- Hyperviscosity
Myeloma
Management of bone disease
- Bisphosphonates (Zolendronic Acid)
- Radiotherapy to bone lesions
- Orthopaedic surgery can stabilize bones (e.g. inserting prophylactic intramedullary rod)
- Cement augmentation (inject cement into vertebral fractures or lesions to improve spine stability and pain)
Myeloma
Prognosis
- Incurable
- Patients always relapse
Leukaemia
Pathophysiology
Rapid proliferation of immature blood blast cells (precursors of RBCs, WBCs, platelets) in the bone marrow that are non-functional (defective)
- A genetic mutation in one of the precursor cells in the bone marrow leads to excessive production of a single type of abnormal white blood cell
- -> Less energy, space and food for creating and maintaining healthy cells
- Results in a PANCYTOPENIA - low RBCs (anaemia), low WBCs (leukopenia) and low platelets (thrombocytopenia)
Acute myeloid leukemia
Epidemiology
- Most common acute leukaemia in ADULTS
- Myeloid blast cell proliferation
- Associated with radiation, Downs syndrome
- Can be a long-term complication of chemo (e.g. lymphoma)
- Can be the result of myeloproliferative disorders, e.g. polycythemia vera/myelofibrosis
Acute myeloid leukemia
Features
Bone marrow failure:
- Anaemia (low RBCs)
- Infection, fever, mouth ulcers (low WBCs)
- Bleeding + bruising (low platelets)
Marrow infiltration:
- Bone pain
- Splenomegaly
- Gum hypertrophy and bleeding
Acute myeloid leukemia
Investigations
- Blood film: BLAST CELLS and AUER RODS
- Same as ALL apart from HIGH WCC and low neutrophils
Acute myeloid leukemia
Management
- Chemo (daunorubicin, cytarabine)
- Supportive - tranfusions
- Allopurinol to prevent tumour lysis syndrome
- Treat infections
- Bone marrow transplant
Acute myeloid leukemia
Poor prognostic factors
- > 60 years
- > 20% blasts after first course of chemo
- Cytogenetics: deletions of chromosome 5 or 7
Chronic myeloid leukaemia
Epidemiology/associations
- Most often in adults (40-70 yrs)
- Slight male predominance
- > 80% have Philadelphia chromosome = t(9:22)
Chronic myeloid leukaemia
Features
INSIDIOUS ONSET
- Anaemia
- Weight loss
- Fatigue
- Fever
- Sweats
- Gout
- Bleeding
- SPLENOMEGALY - often massive
Chronic myeloid leukaemia
Phases
- Chronic phase - can last around 5 yrs, often asymptomatic, may be diagnosed incidentally
- Accelerated phase - abnormal blast cells take up a high proportion of cells in bone marrow and blood (10-20%), more symptoms, anaemia, immunocompromised
- Blast phase - even higher proportion of blast cells (> 30%), severe symptoms, pancytopenia, often fatal
Chronic myeloid leukaemia
Investigations
- PHILADELPHIA CHROMOSOME
- Decreased leukocyte alkaline phosphate
- Very high WCC - whole spectrum of myeloid cells - neutrophils, basophils, eosinophils, myelocytes
Chronic myeloid leukaemia
Managements
- IMATINIB (inhibitor of tyrosine kinase) = 1st line
- Hyroxyurea
- Interferon-alpha
- Allogenic bone marrow transplant
What is the philadelphia chromosome?
- Translocation between the long arm of chromosome 9 and 22 –> t(9:22)
- Results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene on chromosome 22
- Outcome = BCR-ABL gene
- Codes for a fusion protein that has excessive tyrosine kinase activity
Acute lymphoblastic leukemia
Epidemiology
- Most common in children
- Peak = 2-5 yrs old
- Boys slightly more commonly affected
- Usually B-lymphocytes
- Associated with Down’s syndrome and ionising radiation during pregnancy
Acute lymphoblastic leukemia
Features
Marrow failure:
- Anaemia
- Infection
- Bleeding
Organ infiltration
- Bone pain
- Hepatosplenomegaly
- Lymphadenopathy
- Headache and cranial nerve palsy
- Mediastinum masses
- testicular swelling
- Fever is present in up to 50% of new cases
Acute lymphoblastic leukemia
Investigations
- Blast cells on blood film
- Philadelphia chromosome in 30% of adults, 3-5% of children (poor prognostic factor)
- LP to look for CNS involvement
Acute lymphoblastic leukemia
Types
If all B-cells –> Children
If all T-cells –> Adult
Acute lymphoblastic leukemia
Management
- Supportive - transfusion
- Chemo (vincristine, pred)
- If CNS –> Methotrexate
- Allopurionl to prevent tumor lysis
- Treat infections quickly
- Bone marrow transplant
Acute lymphoblastic leukemia
Poor prognostic factors
- Age < 2yrs r > 10 yrs
- WBC > 20 at diagnosis
- T or B cell surface markers
- Non-Caucasian
- Male sex
Chronic lymphocytic leukaemia
Epidemiology
- MOST COMMON LEUKAEMIA
- Most common in the elderly
- Accumulation of mature B-lymphocytes that have escaped programmed cell death and undergone cell cycle arrest
Chronic lymphocytic leukaemia
Features
- Oftrn asymptomatic!
- Anaemic or infection prone
- If severe: weight loss, sweats, anorexia
- Hepatosplenomegaly
- Lymphadenopathy - more marked than CML
Chronic lymphocytic leukaemia
Investigations
- FBC: lymphocytosis, anaemia
- SMUDGE CELLS or SMEAR CELLS (during process of preparing the film, fragile WBCs rupture and leave smudge on film)
Chronic lymphocytic leukaemia
Complications
- Can transform into high-grade lymphoma. This is called Richter’s transformation.
- Can cause WARM AUTOIMMUNE HAEMOLYTIC ANAEMIA
- Hypogammaglobulinemia (recurrent infections)
What is Richter transformation
Ritcher’s transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin’s lymphoma. Patients often become unwell very suddenly.
Ritcher’s transformation is indicated by one of the following symptoms:
- Lymph node swelling
- Fever without infection
- Weight loss
- Night sweats
- Nausea
- Abdominal pain
Chronic lymphocytic leukaemia
Management
- 1st line = Fludarabine and Rituximab +/- Cyclophosphamide
- Human IV immunoglobulin
- Blood transfusions
- Bone marrow transplant
Chronic lymphocytic leukaemia
Prognosis
Rule of three
- 1/3 never progress
- 1/3 progress slowly
- 1/3 progress rapidly
Age of different leukaemias
ALL CeLLmates have CoMmon AMbitions
- <5 and >45: ALL
- Over 55: CLL
- Over 65: CML
- Over 75: AML
Investigations for all leukaemias
- FBC
- Blood film
- LDH - not specific
- Bone marrow biopsy
- CXR - infection of mediastinum lymphadenopathy
- Lymph node biopsy
- LP is CNS involvement
- CT, MRI, PET to stage and assess
Types of bone marrow biopsy
- Aspiration: take liquid sample full of cells
- Trephine: solid core sample - better assessment of cells and structure
Where is the bone marrow biopsy usually taken from?
The iliac crest
Causes of pathological fractures
- Metastatic tumor (breast, lung, thyroid, renal, prostate)
- Bone disease (osteogenesis imperfecta, osteoporosis, metabolic bone disease, Paget’s disease)
- Local benign condition (chronic osteomyelitis, solitary bone cyst)
- Primary malignant tumours (chonqdrosarcoma, osteosarcoma, Ewing’’s tumour)
- Myeloma (salt and pepper/raindrop skull)
Which vessels might bleed following a splenectomy?
- Short gastric
- Splenic hilar
What would prompt an urgent FBC in young people?
- Pallor
- Persistent fatigue
- Unexplained fever
- Unexplained persistent infections
- Generalised lymphadenopathy
- Persistent or unexplained bone pain
- Unexplained bruising
- Unexplained bleeding
How quickly do you prescribe RBCs in a non-urgent scenario?
90-120 minutes
Transfusion threshold for patients without ACS?
70 g/L
Transfusion threshold for patients with ACS?
80 g/L
Target after transfusion for those without ACS?
70-90 g/L
Target after transfusion for those with ACS?
80-100 g/L
Inherited causes of thrombophilia?
- Most common = Factor V Leiden (activated protein C resistance)
- 2nd most common = prothrombin gene mutation
- Antithrombin III deficiency
- Protein C deficiency
Protein S deficiency
Acquired causes of thrombophilia?
- Antiphospholipid syndrome
- COCP
What are irradiated blood products?
- Depleted of T-lymphocytes
- Avoid transfusion-associated graft versus host disease
- Used in intra-uterine, neonates, bone marrow/stem cell transplants, immunocompromised, patients with/prev Hodgins Lymphoma
Tx of neutropenic sepsis?
IV piperacillin with tazobactam
