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YEAR 3 & 5 CORE CONDITIONS > Haematology 2 > Flashcards

Haematology 2 Flashcards

1
Q

What is multiple myeloma?

A

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

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2
Q

Describe why anaemia, neutropenia and thrombocytopenia are features of multiple myeloma

A

Bone marrow is infiltrated leading to a suppression of haematopoiesis

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3
Q

Describe why hypercalcaemia is a feature of multiple myeloma

A

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

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4
Q

Describe the impact of overproduction of monocloncal Igs and light chains in multiple myeloma

A

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

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5
Q

What is the criteria used in multiple myeloma?

A

All 3 of following must be present:

  1. Monoclonal plasma cells in bone marrow > 10%
  2. Monoclonal protein in serum or urine (unless it is non-secretory in which case you need high bone marrow plasma cells > 30%)
  3. 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
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6
Q

How may multiple myeloma present?

A 
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
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7
Q

Why is foamy urine a feature of multiple myeloma?

A

Bence Jones proteinuria

Free light chains (in 20%)

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8
Q

What investigations are done for multiple myeloma?

A

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

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9
Q

What does a blood smear show in multiple myeloma?

A

Rouleux formation = aggregation of erythrocytes looks like a stack of coins

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10
Q

What does serum protein electrophoresis show in multiple myeloma? What tests are requested alongside serum electrophoresis?

A

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

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11
Q

What proteins are measured in the blood in multiple myeloma?

A

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

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12
Q

What imaging can be useful in multiple myeloma and what may it show?

A

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

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13
Q

What is the name for when there is a raised level of monoclonal Ig’s in patient serum but without any accompanying clinical symptoms?

A

Monoclonal gammopathy of undetermined significance (MGUS)

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14
Q

What is the diagnostic criteria of MGUS?

A

Monoclonal Igs <30g/L
<10% monoclonal plasma cells in bone marrow
No organ damage (no CRAB)

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15
Q

What can MGUS develop into? What is the management?

A

Multiple myeloma (1%)

No treatment - monitor M protein levels

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16
Q

What is the management of asymptomatic multiple myeloma? When may this not be appropriate?

A

Asymptomatic - watch and wait

Unless >60% clonal cells, excessive free light chains or more than 1 bone lesion

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17
Q

What is the management of symptomatic multiple myeloma?

A

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
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18
Q

What occurs in light chain amyloidosis in multiple myeloma and what does this lead to?

A

Light chains accumulate as amyloids

Leads to restrictive cardiomyopathy, renal insufficiency, macroglossia and malabsorption syndrome

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19
Q

What renal disease occurs in multiple myeloma?

A

Myeloma cast nephropathy

Light chains are directly toxic to renal tissue and protein complex (cast) formation in the distal nephron leads to tubular obstruction

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20
Q

20% of myeloma have Bence Jones proteins, what are the other two immunoglobulin classifications?

A 
IgG = 50%
IgA = 25%
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21
Q

What is the most common cause of hypercoagulability in white populations?

A

Factor V Leiden

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22
Q

What is the inheritance pattern of Factor V Leiden?

A

Autosomal dominant

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23
Q

Other than Factor V Leiden, name some inherited thromobophilias (hypercoagulablities)

A 
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
Hyperhomocysteinemia
Plasminogen deficiency
Sickle cell anaemia
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24
Q

Antithrombin III deficiency is usually inherited (autosomal dominant). What can cause it to be acquired?

A

Liver failure
Renal failure
Nephrotic syndrome = urinary loss of antithrombin

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25
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 ```
26
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)
27
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
28
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
29
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
30
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
31
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
32
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
33
What other conditions are linked with antiphospholipid syndrome?
SLE | RA
34
What complications may someone with antiphospholipid syndrome encounter?
DVTs Portal vein thrombosis Strokes Miscarriages - often experience clotting inside the placenta leading to spontaneous abortions
35
Why is pregnancy a hypercoagulable state?
Clotting factors increase Protein C and S decrease Venous stasis as uterus enlarges
36
What risk is more associated with UFH vs LWMH?
Heparin induced thrombocytopenia
37
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
38
What length of coagulation is necessary for a VTE that was 1) Provoked 2) Unprovoked
1) Provoked = 3 months | 2) Unprovoked = 6 months
39
What may be considered if recurrent VTE / anticoagulant therapy contraindicated?
Inferior vena cava filter
40
What is thrombocytopenia? What are two broad causes?
Platelets < 150 Impaired platelet production in bone marrow Increased platelet breakdown in periphery
41
Which cells in the bone marrow are responsible for making platelets?
Megakaryocytes Perform thrombopoiesis
42
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 ```
43
List some congenital thrombocytopenias
Wiskott-Aldrich syndrome Alport syndrome von Willebrand disease Bernard-Soulier syndrome
44
List some infectious causes of impaired platelet production in bone marrow
``` CMV EBV Hep C HIB Mumps Rubella Parvovirus B19 Ricketts VZV ```
45
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
46
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 ```
47
What are petechiae?
Nonblanchable, nonpalpable, red, pinpoint macules caused by capillary inflammation and hemorrhage
48
How is immune thrombocytopenic purpura (ITP) diagnosed?
Diagnosis of exclusion in isolated thrombocytopenia
49
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
50
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
51
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)
52
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
53
What is the management of adults with ITP?
1st line - glucocortoids or Iv Ig 2nd line - splenectomy
54
How do glucocorticoids help ITP?
Glucocorticoids suppress antibody production and/or stop platelet breakdown by inhibiting phagocytosis
55
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
56
What is pancytopenia?
A decrease in number of all cell lines in blood i.e RBC, WBC, platelets
57
Pneumonic for causes of pancytopenia
PANCYTO ``` Paroxysmal nocturnal hemoglobinuria (PNH) Aplastic anaemia Neoplasms / near neoplasms Consumption Vitamin deficiencies Toxins / drugs / radiotherapy Overwhelming infections ```
58
What is PNH?
Disorder of stem cells that leads to an increased sensitivity to complement mediated cell lysis
59
How can PNH present?
Coombs test negative intravascular hemolysis (ie not autoimmune haemolysis) Hypercoaguable state +/- bone marrow aplasia
60
Why is aplastic anaemia a misnomer?
It is a disorder of stem cells thus affects all cell lines (not just RBC)
61
What are some causes of aplastic anaemia?
Many idiopathic Fanconi's anaemia Drugs and toxins Infections Immune disorders
62
Which drugs are associated with aplastic anaemia?
``` Chemo Chloramphenicol Sulfa drugs NSAIDs Anti epileptics ```
63
What infections are most commonly associated with aplastic anaemia?
Parvovirus B19 most commonly Also Hep, HIV, CMV, EBV
64
Which neoplasms may cause pancytopenia?
Leukaemia Mets Near neoplasms = myelodysplastic syndrome
65
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
66
What do lymphoid precursor cells produce?
B Lymphocytes T lymphocytes Natural killer cells
67
What do myeloid precursor cells produce?
Erythrocytes Granulocytes (basophil, eosinophil, neutrophil) Megakaryocytes
68
What does a left shift in blood mean?
Increase in immature progenitor cells Usually due to infection eg increase in band neutrophils (?)
69
Compare '-cytosis' vs '-emia'
A reactive increase of a cell line ends in "-cytosis" eg leukocytosis A neoplastic increase is "emia" eg leukemia
70
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
71
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
72
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
73
Splenomegaly can be caused by 3 broad causes. What are these?
1) Increased activity of spleen 2) Decreased venous drainage 3) Splenic infilatration
74
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
75
What can lead to decreased venous drainage which can lead to splenomegaly?
Portal hypertension - Liver cirrhosis - Obstruction of portal, hepatic or splenic vein - Schistosomiasis
76
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
77
What are the three phases of CML?
Chronic phase Acclerated phase Blast crisis
78
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)
79
Which of AML or CML is characterised by recurrent infection during early stages? Why?
AML = recurrent infections CML = granulocytes are still fully functional
80
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
81
Describe the blast stage of CML
Resembles acute leukaemia Rapid progression of bone marrow failure - Pancytopenia - Bone pain Severe malaise
82
What is seen in a blood smear of CML
``` Leucocytosis Basophilia Eosinophilia Blasts = indicate accelerated phase Thrombocytosis ```
83
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
84
How can CLL be differentiated from CML on presentation?
Lymphadenopathy present in CLL not CML
85
How else does CLL present?
``` B symptoms Painless LN Hepatomegaly Splenomegaly Recurrent infections Anaemia symptoms Thrombocytopenia symtpms ```
86
What is seen on a peipheral smear of CLL?
Smudge cells Crushed Little Lymphocytes (CLL)
87
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
88
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
89
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
90
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
91
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)
92
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
93
What are some advantages for allogenous stem cell transplantation?
Graft vs tumour effect | Low risk early post transplant infection
94
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
95
Agranulocytosis vs neutropenia
Agranulocytosis = low WCC (mot commonly neutrophils) Neutropenia = low neutrophils
96
Which drugs are associated with agranulocytosis?
Clozapine Carbamazepine Valproate Carbimazole + other anti thyroids
97
What is intravascular vs extravascular haemolysis?
Intravascular = RBC within vessel Extravascular = phagocytosis of RBC
98
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
99
What can be given to increase neutrophil count in pt who are neutropenic?
Granulocyte colony stimulating factors eg Filgrastim Perfilgrastim

YEAR 3 & 5 CORE CONDITIONS (30 decks)

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