Haematology 2 Flashcards
What is multiple myeloma?
Malignant plasma cell disorder characterised by uncontrolled proliferation and diffuse infiltration of monoclonal plasma cells in bone marrow
These may also secrete monoclonal Ig and/or Ig fragments eg light chain
Describe why anaemia, neutropenia and thrombocytopenia are features of multiple myeloma
Bone marrow is infiltrated leading to a suppression of haematopoiesis
Describe why hypercalcaemia is a feature of multiple myeloma
Stromal cells (that adhere to myeloma cells), stimulate the production of RANKL, IL-6 and VEGF (cytokines)
RANKL stimulates osteoclast activity, causing the lytic lesions and hypercalcaemia
Describe the impact of overproduction of monocloncal Igs and light chains in multiple myeloma
These are non functioning antibodies, leading to a functional antibody deficiency - this leads to recurrent infections (particularly of the respiratory tract)
Increased serum viscosity leads to hyperviscositiy syndrome - spontaneous bleeding (gums, epistaxis, rectal bleeding), visual disturbances and headaches
What is the criteria used in multiple myeloma?
All 3 of following must be present:
- Monoclonal plasma cells in bone marrow > 10%
- Monoclonal protein in serum or urine (unless it is non-secretory in which case you need high bone marrow plasma cells > 30%)
- Evidence of organ damage (CRAB)
○ Calcium increased (>11mg/dL)
○ Renal insufficiency (creatinine clearance <40mL/min or serum creatinine >2mg/dL)
○ Anaemia (Hb <100g/L)
○ Bone lesions on MRI
How may multiple myeloma present?
Often asymptomatic Back pain Symptoms of hypercalcaemia B symptoms Anaemia symptoms Increased risk of infection (especially respiratory tract) Increased risk of petechial bleeding Foamy urine
Why is foamy urine a feature of multiple myeloma?
Bence Jones proteinuria
Free light chains (in 20%)
What investigations are done for multiple myeloma?
Serum protein electrophoresis - best initial test
Urine protein electrophoresis - looks for presence of Bence Jones’ protein
Bone marrow biopsy - confirmatory test
Bloods - U&Es (hyercalcaemia and renal insufficiency), FBC (anaemia)
Imaging for bone lesions
What does a blood smear show in multiple myeloma?
Rouleux formation = aggregation of erythrocytes looks like a stack of coins
What does serum protein electrophoresis show in multiple myeloma? What tests are requested alongside serum electrophoresis?
Monoclonal bands (paraproteins)
or
Monoclonal gammopathy of undetermined significance (MGUS)
Serum immunofixation - confirms type of paraprotein e.g. IgA or IgG
Serum free light chains - increases sensitivity of serum electrophoresis and shows presence of Bence Jones’ protein
What proteins are measured in the blood in multiple myeloma?
Elevated total proteins = one of the first signs
Paraprotein (gamma) gap = paraproteins produced by malignant plasma cells increase the difference between total serum protein and normal albumin concentration (there is an increase in non-albumin serum proteins)
Increase in ß2 microglobulin
What imaging can be useful in multiple myeloma and what may it show?
1st choice = Whole body low dose CT (WBLD CT)
- Shows osteolysis and osteopenia
X ray skeletal survey - multiple lytic lesions (punched out holes)
FDG/PET scans - areas of active osteolysis
MRI - infiltration and replacement of bone marrow
What is the name for when there is a raised level of monoclonal Ig’s in patient serum but without any accompanying clinical symptoms?
Monoclonal gammopathy of undetermined significance (MGUS)
What is the diagnostic criteria of MGUS?
Monoclonal Igs <30g/L
<10% monoclonal plasma cells in bone marrow
No organ damage (no CRAB)
What can MGUS develop into? What is the management?
Multiple myeloma (1%)
No treatment - monitor M protein levels
What is the management of asymptomatic multiple myeloma? When may this not be appropriate?
Asymptomatic - watch and wait
Unless >60% clonal cells, excessive free light chains or more than 1 bone lesion
What is the management of symptomatic multiple myeloma?
Hematopoietic stem cell transplantation (HSCT) for young patients with minimal comorbidities
MPT (Melphalan + Prednisolone + Thalidomide) or Lenalidomide + low-dose dexamethasone for those unsuitable for transplant
Bone pain:
- Bisphosphonates
- Radiation therapy of osteolytic lesions
Pancytopenia with anaemia and infection risk:
- Blood transfusions
- Granulocyte colony stimulating factor (G-CSF)
- EPO
What occurs in light chain amyloidosis in multiple myeloma and what does this lead to?
Light chains accumulate as amyloids
Leads to restrictive cardiomyopathy, renal insufficiency, macroglossia and malabsorption syndrome
What renal disease occurs in multiple myeloma?
Myeloma cast nephropathy
Light chains are directly toxic to renal tissue and protein complex (cast) formation in the distal nephron leads to tubular obstruction
20% of myeloma have Bence Jones proteins, what are the other two immunoglobulin classifications?
IgG = 50% IgA = 25%
What is the most common cause of hypercoagulability in white populations?
Factor V Leiden
What is the inheritance pattern of Factor V Leiden?
Autosomal dominant
Other than Factor V Leiden, name some inherited thromobophilias (hypercoagulablities)
Protein C deficiency Protein S deficiency Antithrombin III deficiency Hyperhomocysteinemia Plasminogen deficiency Sickle cell anaemia
Antithrombin III deficiency is usually inherited (autosomal dominant). What can cause it to be acquired?
Liver failure
Renal failure
Nephrotic syndrome = urinary loss of antithrombin
What can lead to acquired thrombophilia?
Pregnancy Inc age Smoking Obesity Surgery Immobilisation Trauma Malignancy (esp adenocarcinoma) Antiphospholipid syndrome Nephrotic syndrome OCP HRT SLE Heparin induced thrombocytopenia
What is the role of protein C?
Activated protein C inactivates factor V in the clotting cascade
This decreases the activation of thrombin (which would turn fibrinogen into fibrin creating a clot)
What is activated protein c resistance? What happens?
Factor V Leiden
Factor V does not get deactivated, so activates prothrombin to thrombin, fibrinogen gets turned to fibrin, thus there are an increase in thrombotic events
eg peripheral and cerebral vein thrombosis, recurrent pregnancy loss
What is the role of antithrombin III?
Normally binds to and inactivates thrombin and FX = inhibiting coagulation
Deficiency leads to decreased inhibition and elevated thrombin and factor X
What is the mechanism of heparin?
Indirectly inhibits the action of thrombin and factor Xa by increasing the activity of antithrombin III (an endogenous anticoagulant)
- Increases the effectiveness of antithrombin by over 1000x, reducing clot formation
Acts on the intrinsic pathway
What does heparin do to aPTT? How is this affected in those with antithrombin III deficiency?
Normally heparin increases aPTT
However in antithrombin III deficiency, there is no increase
What is hyperhomocysteinemia?
Homocysteine = amino acid produced from breakdown of proteins
Usually due to B12 or folate deficiency
Risk factor for CVD, neurodegenerative disease, NTD
What is the pathophysiology of antiphospholipid syndrome?
Acquired antibodies directed against plasma proteins bound to phospholipids
Aggregation of plasma proteins(eg clotting factors) induces venous and arterial clotting
What other conditions are linked with antiphospholipid syndrome?
SLE
RA
What complications may someone with antiphospholipid syndrome encounter?
DVTs
Portal vein thrombosis
Strokes
Miscarriages - often experience clotting inside the placenta leading to spontaneous abortions
Why is pregnancy a hypercoagulable state?
Clotting factors increase
Protein C and S decrease
Venous stasis as uterus enlarges
What risk is more associated with UFH vs LWMH?
Heparin induced thrombocytopenia
What is heparin induced thrombocytopenia?
Immune mediated adverse drug reaction caused by antibodies that activate platelets in the presence of heparin
Creating a prothrombotic state
What length of coagulation is necessary for a VTE that was
1) Provoked
2) Unprovoked
1) Provoked = 3 months
2) Unprovoked = 6 months
What may be considered if recurrent VTE / anticoagulant therapy contraindicated?
Inferior vena cava filter
What is thrombocytopenia? What are two broad causes?
Platelets < 150
Impaired platelet production in bone marrow
Increased platelet breakdown in periphery
Which cells in the bone marrow are responsible for making platelets?
Megakaryocytes
Perform thrombopoiesis
What can cause impaired platelet production in bone marrow?
Bone marrow failure Bone marrow suppression (chemo / radiotherapy /drugs) Congenital thrombocytopenias Infection Malignancy Vit B12 deficiency Folate deficiency
List some congenital thrombocytopenias
Wiskott-Aldrich syndrome
Alport syndrome
von Willebrand disease
Bernard-Soulier syndrome
List some infectious causes of impaired platelet production in bone marrow
CMV EBV Hep C HIB Mumps Rubella Parvovirus B19 Ricketts VZV
What can cause increased platelet turnover/decreased platelet survival in periphery?
Immune thrombocytopenia
DIC
TTP and HUS
Drug induced immune thrombocytopenia e.g. HIT
Preeclampsia
HELLP
Prosthetic valves causing mechanical damage
How may thrombocytopenia present?
(in increasing severity)
Asymptomatic Prolonged bleeding Scattered petecchia Spontaneous bleeding Disseminated petechial bleeding in skin and mucosa Easy bruising Haem emergency
What are petechiae?
Nonblanchable, nonpalpable, red, pinpoint macules caused by capillary inflammation and hemorrhage
How is immune thrombocytopenic purpura (ITP) diagnosed?
Diagnosis of exclusion in isolated thrombocytopenia
What is primary vs secondary ITP
Primary - idiopathic but may be triggered by infection
Secondary - lymphoma, leukaemia (esp CLL), SLE, HIV, Hep C, drug reactions
What is the pathophysiology of ITP?
IgG antibodies against glycoprotein on platelets
Platelet-antibody complex removed from circulation by spleen
Decreased platelet count
Bone marrow megakaryocytes and platelet production increases in response
ITP is common in which demographic and what onset is it usually?
Children - usually acute following infection
Women of childbearing age - insidious onset or incidental finding (>12 months)
What is the management of children with ITP?
If no bleeding or only bruising / petechiae = observation regardless of platelet count
If severe bleeding = glucocorticoids or IV Ig
What is the management of adults with ITP?
1st line - glucocortoids
or Iv Ig
2nd line - splenectomy
How do glucocorticoids help ITP?
Glucocorticoids suppress antibody production and/or stop platelet breakdown by inhibiting phagocytosis
What happens to the number of megakaryocytes in reduced bone marrow platelet production vs increased platelet turnover
Reduced production = reduced number of megakaryocytes
Increased turnover = increased number of megakaryocytes
What is pancytopenia?
A decrease in number of all cell lines in blood
i.e RBC, WBC, platelets
Pneumonic for causes of pancytopenia
PANCYTO
Paroxysmal nocturnal hemoglobinuria (PNH) Aplastic anaemia Neoplasms / near neoplasms Consumption Vitamin deficiencies Toxins / drugs / radiotherapy Overwhelming infections
What is PNH?
Disorder of stem cells that leads to an increased sensitivity to complement mediated cell lysis
How can PNH present?
Coombs test negative intravascular hemolysis (ie not autoimmune haemolysis)
Hypercoaguable state
+/- bone marrow aplasia
Why is aplastic anaemia a misnomer?
It is a disorder of stem cells thus affects all cell lines (not just RBC)
What are some causes of aplastic anaemia?
Many idiopathic
Fanconi’s anaemia
Drugs and toxins
Infections
Immune disorders
Which drugs are associated with aplastic anaemia?
Chemo Chloramphenicol Sulfa drugs NSAIDs Anti epileptics
What infections are most commonly associated with aplastic anaemia?
Parvovirus B19 most commonly
Also Hep, HIV, CMV, EBV
Which neoplasms may cause pancytopenia?
Leukaemia
Mets
Near neoplasms = myelodysplastic syndrome
What is the management of pancytopenia?
Increase each cell line
RBC transfusions
Platelet transfusions
Granulocyte colony stimulating factor
Abx for patients with fever in setting of neutropenia
What do lymphoid precursor cells produce?
B Lymphocytes
T lymphocytes
Natural killer cells
What do myeloid precursor cells produce?
Erythrocytes
Granulocytes (basophil, eosinophil, neutrophil)
Megakaryocytes
What does a left shift in blood mean?
Increase in immature progenitor cells
Usually due to infection eg increase in band neutrophils (?)
Compare ‘-cytosis’ vs ‘-emia’
A reactive increase of a cell line ends in “-cytosis” eg leukocytosis
A neoplastic increase is “emia” eg leukemia
What happens to aPPT in antiphospholipid syndrome?
Paradoxical rise in aPTT (strange as you would think short aPTT as a clotting vibe)
Lupus antibodies react with phospholipids involved in coagulation cascade - ie they get used up so can take longer to clot when doing aPTT
Normal PT
Compare pancytopenia to aplastic anaemia, what investigations would you do?
Pancyotpenia = generalised blood finding
Aplastic anaemia = distince definable disease
Do bone marrow biopsy (would be “empty” in aplastic anaemia)
Check for splenomegly
What is hypersplenism?
Increases spleen activity meaning cells are removed from blood faster - can result in a decrease of one or multiple cell lines
This leads to a reactive bone marrow hyperplasia
Splenomegaly can be caused by 3 broad causes. What are these?
1) Increased activity of spleen
2) Decreased venous drainage
3) Splenic infilatration
What can cause increased activity of the spleen?
1) Increased degradation of defective cells
- Eg haemolytic anaemias such as thalassaemia, spherocytosis, sickle cell
- Eg Polycythemia vera
2) Increased immune response to infection
3) Defective immune response
- Vasculitis
- Connective tissue disease
- RA
- SLE
- Sarcoidoisis
4) Compensatory extramedullary haemaotpoiesis within the spleen due to bone marrow deficiency
- Myelofibrosis
- Lymphoma
What can lead to decreased venous drainage which can lead to splenomegaly?
Portal hypertension
- Liver cirrhosis
- Obstruction of portal, hepatic or splenic vein
- Schistosomiasis
Which condition is linked to Philadelphia chromosome? What number and what gene?
CML
Philadelphia Chr t(9;22) resulting in the formation of a BCR-ABL fusion gene
Promotes unregulated profileration of myeloid precursor cells
What are the three phases of CML?
Chronic phase
Acclerated phase
Blast crisis
Describe the chronic phase of CML - duration and symptoms
Can persist for 10 yrs Often subclinical Symptomatic includes: - Weight loss - Fever - Night sweats - Fatigue - Splenomegaly (LUQ pain)
(not lymphadenopathy)
Which of AML or CML is characterised by recurrent infection during early stages? Why?
AML = recurrent infections
CML = granulocytes are still fully functional
Describe the accelerated phase of CML
Erythrocytopenia = anaemia
Neutropenia = infection and fever
Extreme pleocytosis (rapid increase in number of malignant cells)
- Infarctions eg splenic and MI, retinal vein occlusion
- Leukaemia priapism
- Terminal phase = myelofibrosis
MASSIVE splenomegaly
Describe the blast stage of CML
Resembles acute leukaemia
Rapid progression of bone marrow failure
- Pancytopenia
- Bone pain
Severe malaise
What is seen in a blood smear of CML
Leucocytosis Basophilia Eosinophilia Blasts = indicate accelerated phase Thrombocytosis
What is the management of CML?
Tyrosine kinase inhibitors (Imatinib) - first-line
Allogenic stem cell transplant if unsuccessful or for young patients as a curative therapy
How can CLL be differentiated from CML on presentation?
Lymphadenopathy present in CLL not CML
How else does CLL present?
B symptoms Painless LN Hepatomegaly Splenomegaly Recurrent infections Anaemia symptoms Thrombocytopenia symtpms
What is seen on a peipheral smear of CLL?
Smudge cells
Crushed Little Lymphocytes (CLL)
What is the management of CLL?
CLL = low grade malignancy, it has slow rate of cell division and disease progression
Treatment if not often necessary or unlikely to improve survival time
- Only curative tratment is stem cell transplantation
What are the two types of haematopoietic stem cell transplantation?
Autologous = removal and storage of patients own cells which are retransfused back after high dose chemo
Allogenous = transplant of stem cells from sibling or donor
When are autologous stem cell transplants indicated?
High-dose chemotherapy would destroy the bone marrow and therefore cannot be used to treat neoplastic disease without subsequent bone marrow transplantation
- So use to allow higher doses to be used eg soft tissue sarcome
Multiple myeloma
Lymphoma
What are advantages of autologous stem cell transplants?
Low risk of graft vs host disease
Low risk late post transplant infection
Low risk of graft rejection
What are disadvantages of autologous stem cell transplants?
High risk of early post transplant infection due to prolonged neutrophil infection (you’ve taken away their own bone marrow)
No graft vs tumour effect (when donour t cells attack malignant cells)
What are some indications for allogenous stem cell transplantation?
To replace abnormal but non malignant cells in the lymphohamatopoietic system eg:
Immunodeficiency
Aplastic anaemia
Thalassaemia
Also leukaemia
What are some advantages for allogenous stem cell transplantation?
Graft vs tumour effect
Low risk early post transplant infection
What are some disadvantages for allogenous stem cell transplantation?
Risk of graft vs host disease
Late post transplant infection
Inc risk of infection
Can cause chromosomal abnormalities in blood / bone marrow due to discrepancy between genotype and phenotype
Agranulocytosis vs neutropenia
Agranulocytosis = low WCC (mot commonly neutrophils)
Neutropenia = low neutrophils
Which drugs are associated with agranulocytosis?
Clozapine
Carbamazepine
Valproate
Carbimazole + other anti thyroids
What is intravascular vs extravascular haemolysis?
Intravascular = RBC within vessel
Extravascular = phagocytosis of RBC
What can be measured to check for intravascular haemolysis? Is it low or high and why?
Haptoglobin
It is low bc it is a protein which binds free Hb - if it is low then there is free Hb (as RBC have been destroyed) so this binds the haptoglobin
What can be given to increase neutrophil count in pt who are neutropenic?
Granulocyte colony stimulating factors
eg Filgrastim
Perfilgrastim
