Haematology Flashcards
(211 cards)
1
Q
What percentage of blast cells in the peripheral blood or bone marrow is required to make a diagnosis of acute myeloid leukaemia?
A
Greater than or equal to 20%
2
Q
Promyelocytic leukaemia is a subtype or AML that requires emergency treatment. What translocation is classically associated with it?
A
t(15;17) - it’s diagnostic even with a blast count <20%. It’s and emergency due to it being associated with DIC.
3
Q
T(8:21), associated with what?
A
AML- diagnostic with a blast count <20%. Pts present younger than usual- 25-30. Good prognosis in adults, bad in children.
4
Q
Vincristine use and notable side effect?
A
Part of R-CHOP used for DLBCL treatment. Causes peripheral neuropathy.
5
Q
What does antithrombin III do?
A
It inhibits factors II, IX and X.
6
Q
What does thrombomodulin do?
A
Binds thrombin II. Thrombin II binds to Protein C which activates it. Protein C then degrades factors V and VIII.
7
Q
What causes vascular spasm?
A
Damaged epithelial cells produce endothelin. This travels to the smooth muscle layer of the vessel and binds to its receptor which causes spasm. Direct traums with foreign objects also causes smooth muscle to contract. Nociceptors responding to inflammatory signals also cause stimulation of smooth muscles causing vasospasm.
8
Q
What are the the naturally occuring plasminogen activators?
A
Urokinase and tissue plasminogen activator. Both released from sub endothelial tissue. Both normally cleared by the liver, so accumulate during liver failure.
9
Q
How does tranexamic acid work?
A
Inhibits binding of plasmin and plasminogen to fibrin. Data fo use during trauma, cardiac, orthopaedic surgery. Used in C-sections and PPH.
10
Q
What is CD38? What antibody is used to target it? What implication does this have for blood transfusion?
A
CD38 is ubiquitously expressed on plasma cells, but is relatively sparse on other cells. It is involved in the survival of clonal plasma cells responsible for multiple myeloma. It is targeted with daratumumab in the treatment of MM. One of the other cells CD38 is present on is red cells. One completing group and screening for a patient taking daratumumab, an ‘anti red cell’ ab will be detected. Fortunately, the daratumumab doesn’t have any negative impact on the function of red blood cells.
11
Q
What enzymes is responsible for the degradation of Fibrin into D-dimer and fragment E?
A
Fibrin is degraded by plasmin. Expect increased D-dimer whenever there has been a significant clotting event (either focal or diseminated) as it is produced when the fibrin cross linking is degraded by plasmin.
12
Q
What clotting pathyway is measured by the prothrombin time?
A
The extrinsic patheway. This is clotting pathway that is actvated by the exposure of sub-endothelial tissue factor. Tf cleaves factor 7 to 7a, and 7a combines with Tf to form a Xase (cleaves X to Xa). Xa combines with Va to cleave prothrombin to thormbin. Thrombin cleaves fibrinogen to fibrin and VIII to VIIIa. Factor XIII is cleaeved by factor Xa and allows fibrin cross-linking.
13
Q
What clotting pathyway and factor activity is measured by the prothrombin time?
A
The extrinsic pathway. This is the clotting pathway that is actvated by the exposure of sub-endothelial tissue factor. Tf cleaves factor 7 to 7a, and 7a combines with Tf to form a Xase (cleaves X to Xa). Xa combines with Va to cleave prothrombin to thormbin. Thrombin cleaves fibrinogen to fibrin and VIII to VIIIa. Factor VIIIa complexes with IXa, which also cleaves X->Xa. PT is used to generate the INR (patient PT/control PT).
14
Q
What to antiphospholipid abs do to the prothrombin time?
A
They bind to prothrombin and may cause hypoprothrombinaemia and prolongation of the PT. If the patient has a prolonged PT and you are testing for antiphospholipid abs, the antiphosphlipid abs may be saturated by prothrombin (the prozone effect) and not bind to the detecting ELISA abs producing a false positive.
15
Q
How does heparin work?
A
Complexes with antithrombin to make it a rapid strong inactivator of factor IIa and factor Xa. To a lesser extenet, it inhibits IXa, XIa, and XIIa (other elevments of the intrinsic pathway).
16
Q
What does Von Willebrand Factor do?
A
Allows stabilisation of factor VIII so that it can complex with IXa to cleave Xa and eventually form clots. It also participates in platelet aggregation by binding to platelet glycoprotein Ib.
17
Q
What happens in Von Willebrand Disease?
A
There is either a deficiency of Von Willebrand Factor (type 1 - most common), dysfunctional VWF (type 2, 4 subtypes - a) loss of platelet binding 10-15%, b) increased platelet binding causing thrombocytopoenia 5%, c) reduced platelet binding, d) loss of binding to factor VIII), complete absence of VWF (type 3 - rare), or lastly an anti VWF ab (acquired von Willebrand syndrome).
All of these diseases lead to excessive bleeding and should be looked for in patients with unexplained bleeding. Type 2b will also lead to thrombocytopoenia.
Most common VWD is autosomal dominant (type 1, most type 2A, most 2B). Some of the other types are autosomal recessive.
18
Q
What is the role of desmopressin in the treatment of VWD?
A
Desmopressin is synthetic vasopressin/anti-diuretic hormone. It has another effect - it increases the release of von Willebrand Factor AND factor VIII from endothelial intracellular storage sites. It has greater benefit in Type 1 disease where patients still produce functional vWF, just not in the quantities requried (cf with type 2 which is characterised by dysfunctional vWF, and type 3 where vWF is absent). It is used to allow pts with vWF to have minor surgery, or the management of minor bleeding events (e.g. heavy menstrual bleeding). Pts should be fluid restricted during treatment as they will be retaining fluid and develop hyponatraemia if too much water is consumed.
19
Q
How is severe bleeding risk managed in vWD?
A
VWF concentrates are required for major surgery are challening to control bleeding. This needs to be used if there is bleeding causing >20 Hb drop or if there is bleeding to closed compartment (intracranial, spinal, joint bleeding). Desmopressin and antifribinolytic therapy (e.g. fibrinolytic). Factor VIII may also be required.
20
Q
How are haemophilia A and B inherited?
A
X-linked recessive. A is more common than B and tends to be more severe.
21
Q
How is haemophilia C inherited?
A
Autosomal recessive. Rare cases of heterozygous patients being more susceptible to bleeding. Primarily seen in Ashkenazi Jews.
22
Q
Haemophilia A - how does it work?
A
Deficiency in factor VIII. Factor VIII is cleaved by thrombin to VIIIa which forms a complex with IXa that is necessary for the cleavage of X -> Xa. Without this critical part of the instrinsic pathway, these people bleed alot.
23
Q
Haemophilia B - how does it work?
A
Deficiency in factor IX. Factor IXa complexes with VIIIa in the intrinsic pathway to cleave X -> Xa. Factor IX deficiency leads to excessive bleeding due to a failure to effectively clot.
24
Q
Haemophilia C - how does it work?
A
Deficiency in factor XI. Factor XI cleaves IX -> IXa, which is needed to complex with VIIIa to cleave X->a and eventually form clots. These patients bleed due to a failure in the intrinsic pathway.
25
What is emicizumab? What is it used for? What is its major risk? What is the alternative?
Bispecific monoclonal ab that together factors IXa and X to overcome the missing factor VIII seen in haemaphilia A. It is able to overcome the issue with receiving factor VIII replacement in bleeding prophylaxis for haemophilia A of the development abs directed at factor VIII. The previous treatment was just to give lots of common and extrinsic pathway factors (VII and prothrombin) to bypass the role of factor VIII in the intrinsic pathway. The initial trial demonstrating its benefit was only done on haemophilia A patientes who had demonstrated the development of anti-VIII abs, and had required multipl bypass (VII and prothrombin) infusions due to bleeding events. However a follow-up trial in 2018 demonstrated benefit even in haemopilia A patients without factor VIII inhibitors.
Serious adverse effect in th 2017 NEJM study was thrombotic microangiopathy.
26
What do lupus anticoagulants do to aPTT?
They prolong it due to preventing formation of the Xa/Va complex with phospholipids. It's something that only happens in vitro, and in vivo the lupus anticoagulants actually lead to a prothrombotic state most of the time.
27
What are the typical coagulation findings in disseminated intravascular coagulopathy?
Excessive thrombin generation, fibrin production, then fibrin breakdown is occuring. Therefore, these patients have a prolonged PT, low fibrinogen, very high D-dimer, platelet consumption.
28
What is a schistocyte?
A fragmented part of red blood cell.
29
Why should transfusion be avoided in patients with autoimmune haemolytic anaemia?
Because there is significant risk of antibodies to the blood donor red blood cells. The haemolysis symptoms may also be accelerated by the addition of more red blood cells that the autoantibody may already react to.
30
What percentage of autoimmune haemolytic anaemia is primary vs secondary?
50/50 split
31
What is first line treatment of AIHA?
Prednisolone.
32
What is seoncd line treatment for AIHA?
Ritxuimab
33
What is aplastic anaemia?
Pancytopoenia with hypocellular fatty bone marrow in the absence of an abnormal infiltrate or marrow fibrosis. 70-80% of patients it's idopathic, though several inhertied/genetic disorders are charactised by AA in childhood.
34
What are the typical CBE findings in aplastic anaemia?
Hb <100, plt count <50, ANC <1.5. Need at least two of these with hypocellular marrow with no abnormal cells to make the diagnosis.
35
What's the name of the criteria used to assess severity of aplastic anaemia? What does it consider?
Camitta criteria. Marrow cellularity (less = more severe), and lower is worse for the following: ANC, plts, and reticulocyte count.
36
What is the first line treatment for severe/symptomatic aplastic anaemia?
If related haematopoetic stem cell transplant is an option, then this should be pursued. Otherwise, immunosuppression with a anti-thymocyte globulin (horse > than rabbit) given with concurrent steroids to reduce the risk of serum sickness, followed by ciclosporin A to reduce the risk of relapse.
37
What drug exposures are known to be secondary causes of aplastic anaemia?
Chloramphenicol and non-steroidal anti-inflammatory drugs. Lag time between exposure and disease presentation is usually several weeks to multiple months.
38
What other diseaseas are associated with developing aplastic anaemia?
PNH, pregnancy, eosinophilic fascitis, coeliac disease and SLE. Also some rare non-A-E hepatitis viral infections.
39
What is the pathogenesis of idiopathic aplastic anaemia?
The loss of haematopoetic cells is thought to be secondary to the effects of T cell mediated autoimmunity. Patient's with AA typically have dysfunctional Treg cells, and an increase in Th17/1/2 helper T cells, and impaired suppression of cytotoxic T cells. As such, immunosuppresion is the treatment.
40
If immunosuppression does not work in aplastic anaemia, what is the final treatment option?
Haematopoeitic stem cell transplant from an unrelated donor. Related patient haemoatopoetic stem cell transplant is sometimes considered first line management in patients for whom it is available and in whom there are no contraindications, but unrelated HST should be considered a final option in other patients.
41
What is eltrombopag?
Thrombopoetin receptor activator.
42
What adjuntive treatment can be used in aplastic anaemia to assist with thrombocytopoenia?
Eltrombopag works.
43
What does the BCL-2 protein do?
BCL-2 is a small mitochondrial membrane portein and the endoplasmic reticulum. Its role is to raise the cellular apoptotic threshold and inhibit apoptosis. It does this by inhibiting pro-apoptoci factors, such as BAX and BAK.
Normally, in B cells, BCL-2 expression is restricted to cells that through the process of somatic hypermutation by chance acquire Ig with high affinity for antigen. Then, these cells are to emerge from the germinal centres as long-lived memory B cells or will differentiate into plasma cells.
44
What is the significance of BCL-2 for haematological malignancy?
In follicular lymphoma, Ig heavy chain on on chromosome 14 is translocated with BCL on chromosome 18 in 85% of cases. Now under the control of the Ig heavy promotor, BCL-2 is over expressed in these cells in a pro-oncotic fasion, and the resultant cancer cells are able to resist apoptosis. BCL-2 overexpression is though to be implicated in a number of other haematoligcal malignancies. The anticancer drug venetoclax is an oral selective small moleculre inhibitor of BCL2.
45
What are the BAX and BAK proteins?
Pro-apoptotic factors that act by forming aggregates in the micochondrial membrane and release cycochrome c from the mitochondria into the cytoplasma, leading to the activation ocf caspase-9 and caspase 3 (the so called apoptotic executioner). Caspase 3 sets in motion irreversible apoptosis.
46
What are the current indications for venetoclax?
Acute myeloid leukaemia in combination with azacidtidne in patients >75yo or in patietn with comorbidities that preclude induction chemotherapy.
Chronic lymphocytic leukaemia/small lymphocytic lymphoma.
Off label: mantle cell lymphoma, relapsed/refractory multiple myeloma with t(11;14) translocation
47
What chromosome is BCL-2 on?
14
48
If a patient needs warfarin with INR target 2-3, but is due to have an endoscopy with mucosal biopsy in a week, what is the best course of action?
Continue warfarin. Paradoxically, a study showed that attempting to bridge with heparin in this circumstance lead to more bleeding events due to the logistics around bridging when compared with just continuing warfarin.
This same approach is true for other low bleeding risk procedures (including PCI, cardiac electrophysiology and ablation, TAVI, arthroplasy)
49
When should warfarin be stopped before major surgery?
5 days before and bridge. Give vit K if INR still 1.5-1.9 on day prior to surgery.
50
When should warfarin be restarted after major surgery?
Once haemostasis has been achieved and that patient is eating. It usually takes 5 days for therapeutic warfarin dose to be reached.
51
What is the reversal agent for dabigatran called?
Idarucizumab
52
What type of chemotherapy is fludarabine?
It's purine analog and inhibit DNA synthesis (S phase cell cycline inhibiotr).
53
What type of targeted therapy is ibrutinib?
Anti-bruton's tyrosine kinase inhibitor that antagonises cyokine, integrin and B-cell receptor mediated growth signals.
54
When should CLL treatment be commenced?
Only with advanced and symptomatic disease - progressive bone marrow failure, massive or progressive splenomegaly or lymphadenopathy autimmune anaemia or thrombocytopoenia or both not responding to steroids, B symptoms, rapidly progressive lymphocytosis (only significant feature is doublig time >30).
55
What is the first line treatment for severe and symptomatic CLL without a p53 abberation?
Fludarabine, cyclophosphamide and rituximab is standard treatmnet for patients under 65 who are fit. >65 should be given obinutuzumab and chlorambucil.
56
What is obinutuzumab?
Anti-cd20 ab. Used in CLL
57
How does chlorambucil work?
Alkylating agent. Causes cross lingking and S phase cell cycle failure. p53 accumulates as DNA errors increase and causes apoptosis.
58
What should patients with severe symptomatic CLL and a p53 aberation be managed with?
Ibrutinib (BTK inhibitor), or acalaburtinub (BTK inhibitor) or by inhibition of another p53 independent growth pathway
59
What haematological malignancy is most often assocated with DIC?
APML (90%) followed by acute lymphoblastic leukaemia (20%)
60
What solid malignancies are associated with DIC?
Mucin secreting adenocarcinomas. Tends to be associated with non-bacterial thrombic endocarditis with systemic embolism.
61
What is essential thrombocythaemia?
Myeloproliferative disease that leads to excessive platelets, but normal other cell types.
62
What are the myeloproliferative neoplasms?
Philadelphia-positive: chronic myeloid leukaemia. And Phildelphia negative: polycyaemia vera, essential thrombocytois, primary myelofibrosis.
Rarer ones are hypereosinophilic syndromes, mastocytosis and chronic myelmonocytic leukaemia (MDS/MPN overlap).
63
What is the philadelphia chromosome?
Tranlocation of chromosomes 9 and 22 t(9;22) aka BCR-ABL fusion translocation. Cause of chronic myeloid leukaemia.
64
How is CML treated?
Tyrosine kindas inhibitors - 4 generations. Imatinib is still used (first generation). The disease typically develops resistance to TKIs, and so a new TKI must be chosen. Haematopoetic stem cell transplant can be considered at all stages of the disease, but usually isn't considered until th accelerated of blast phases of the disease.
65
What is polycythamia vera?
Persistent erythrocytosis usually with increased haematorcrit. Associated with the JAK2V617F mutation.
66
What is the treatment of polcythaemia vera?
Aspirin, venesection +/- hydroxyurea or peginterferon.
67
What is the treatment target for polycythaemia vera?
Haematocrit <0.45
68
What is aquagenic pruritis? What myeloproliferative diseas is it associated with?
Itching when the skin is wet. Seen in polycyhthaemia vera.
69
What is myelodysplastic syndrome?
A disease of qualitative and quantitative defects in haematopoiesis. Characterised by clinical and clonal evolution over time. Primarily effects older adults. Can present with symptoms of leukopoenia/anaemia/thrombocytopoenia. Diagnosed on bone marrow - marked dysplasia, <20% blasts. It can transform into AML which carries a very poor prognosis.
70
How is MDS treated?
Supportive largely (growth factors, blood transfusions) and luspatercept (SMAD2/3 inhibtor- leads to more effective erythropoesis). Allogeneic haematopitic stem cell tranplantation is curative, but because of the old age that it usually occurs, patients are normally not suitable. If EPO reaches >500IU/L, giving more EPO likely won't help, so low intensity chemotherapy should be considered - azacitdine. If this fails, ATG and steroids have some evidence.
71
What is the significance of chromosome 5q31 deleation for MDS?
If this mutation is present, the patient should be considered for treatment with lenalidomide.
72
What is the significance of ring sideroblasts and the SF3B1 mutation for patients with MDS?
They respond better to luspatercept.
73
What cells are dysfunctional in primary myelofibrosis?
Uncontrolled megakaryocyte proliferation
74
Which TKI is used to provide symptom releif and increase overall survival in primary myelofirbosis?
Ruxolitinib (JAK inhibitor)
75
From a prognostic point of view, what's the difference between chronic myelomonocytic leukaemia and myelodysplastic syndrome?
High risk of transformation to AML
76
What gene mutation is mastocytosis characterised by?
KIT mutations. Imatinib is used here.
77
What driver mutations are most often seen in patients with essential thrombocythaemia?
JAK, CALR or MPL mutations.
78
How essential thrombocythaemia risk stratified?
Treatment is based on risk stratification. The criteria for risk stratifcation are age (>60 considered higher risk), presence of a driver mutation that is JAK2 or MPL increases risk. History of cardiovascular risk factors or thrombosis also increases the risk.
79
In essential thrombocythaemia, what defines very low risk disease?
Absence of a JAK2/MPL driver mutation, below age 60, no previous thrombosis, no cardiovascular risk factors.
80
How is very low risk essential thrombocythaemia treated?
Observation. If cardiovascular risk factors were present, but JAK/MPL mutations were absent, age below 60 and no previous thrombis - aspirin.
81
In essential thrombocythaemia, what defines low risk disease?
Mutations in either JAK2 or MPL, but with age <60, no previous history of thrombosis.
82
How is low risk essential thrombocythaemia managed?
Aspirin alone.
83
In essential thrombocythaemia, what defines intermediate risk disease?
Age greater than 60, in the absence of JAK2/MPL driver mutations, and in the absence of previous thrombosis.
84
How is intermediate risk essential thrombocythaemia managed?
Hydroxyurea and once daily aspirin.
85
In essential thrombocythaemia, whate defines high risk disease?
Age greater than 60, with either a JAK2/MPL driver mutation or a history of thrombosis.
86
How is high risk essential thrombocythaemia treated?
Hydroxurea and - if thrombosis was present and arterial - twice daily aspirin. If thrombosis was present and was venous, then the treatment is once daily aspirin, hydroxurea and systemic anticoagulation. In the case of age >60 and driver mutation JAK2/MPL without thrombosis, the treatment is hydroxyurea with BD aspirin.
87
How does the concept of differential time to positivity relate febrile neutropoenia management in patient with PICC or central lines?
Its the concept that time to positive culture result can be used to narrow down the source of bacteraemia. So if the line culture becomes positive at the same time or after the peripheral culture, then you may be able retain that line as it is unlikely to be the source.
88
Which heparin is more likely to be implicated in HIT?
Unfractionated heparin. Therapeutic doses are more often implicated than prophylactic doses.
89
What makes up the 4Ts for determining probability of HIT?
Thrombocytopoenia (presence or absence), timing of platelet count falle, thrombosis or other sequalae (presence or absence), other cause of thrombocytopoenia (presence or absence).
90
What are the non-heperin derived anticoagulants available for patients who have had confirmed HIT?
danaparoid, argatroban, fonaparinux, and bivalirudin
91
When a platelet transfusions indicated in HIT?
Only in the presence of clinically signigicant bleeding.
92
How long do patients with HIT require therapeutic anticoagulation for?
3 months minimum.
93
Which HIT treatment anticoagulant is best in patients with renal failure?
Argatroban
94
How long after heparin exposure does HIT typically occur?
5-10 days, but known to occur 4-15days out.
95
What is pathogenesis of herparin-induced thrombocytopoenia?
Herparin stimulates the production of antibodies to it, but that cross-react with platelet factor 4. This causes mass platelet activation and platelet depletion. Massive release of pro-coagulant platelet components leads to an excedingly high risk of thrombosis (up to 6% per day) and death.
96
What is the role of hepcidin in anaemia of chronic disease?
Hepcidin is synthesised by hepatocytes. It is upregulated by inflammatory cytokines IL-6 and IL-1. It acts at macrophages and the apical membrane of enterocytes. In both locations it binds to ferroportin and causes it to be internalised. Ferroportin is then unable to efflux iron into the plasma for it be transported to the bone marrow and used for haematopoeisis.
97
What is brentuximab vedotin work to treat Hodgkin's lymphoma?
Hodgkin's lymphoma is disease characterised by Reed-Sternberg cells. These cells almost universally express CD30. Brentuximab vedotin is an anti-CD30 monoclonal antibody bound to a chemotherapy agent which selectively delivers chemotherapy to Reed-Sternberg cells. Brentuximab vedotin can replace bleomycin in the standard first line or salvage chemotherapy regimen, reducing the risk of pulmonary toxicity.
98
What is the definition lymphocyte count for CLL?
ALC >5x10^9/L, with characteritic cells (e.g. smear cells)
99
What other haematological conditions are associated with CLL?
ITP, autoimmune haemolytic anaemia, hypogammglobulinaemia
100
What is a richter transofrmation?
It's when CLL transforms into DLBCL or Hodgkin lymphoma
101
How is DLBCL lymphoma treated?
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) - first line. Second line polatuzumab vedotin (conjugate anti-CD79b, ubiquitously expressed on DLBCL cells, with chemotherapy), CAR-T cells, bispecific T-cell engagers.
102
How is high grade follicular lymphoma treated?
Obintuzumab (potent CD-20 inhibtor) and bendamustine. Alternatively obintuzumab + CHOP.
103
Which non-hodgkin lymphoma is associated with BRAF V600E mutations?
Hariy cell leukaemia.
104
What odd blood picture finding accompanies hairy cell leukaemia?
Absolute monocytopoenia! Sometiems other cytopoenias as well.
105
What is the mutation that is seen in almost all cases plasma cells involved in Waldenstrom's macroglobulinaemia?
MYD88. The only other one implicated is CXCR4 mutatnion.
106
What mutation is classically associated with aggressive Burkitt leukaemia/lymphoma?
Translocations in the MYC gene. This is the fastest doubling time tumour known - can double in size in hours.
107
What is the role of brentuximab vedotin in the treatment of T-cell non-hodgkin lymphoma?
If the lymphoma is found to express CD30, then it should be substituted into R-CHOP in place of vincristine.
108
What is in the ABVD regime useed to treat Hodgkin lymphoma?
Doxorubicin, Bleomycin, Vincristine and Decarbazine.
109
What distribution best describes the incidence of Hodgkin's lymphoma?
Bimodal
110
What has a better prognosis, Hodgkin or non-Hodgkin lymphoma?
Hodgkin - 75% will stary in prolonged remission after initial induction chemotherapy.
111
What are the criteria used to define clinically active multiple myeloma from smouldering myeloma and MGUS?
MGUS: paraprotein <30/L with fewer than 10% bone marrow plasma cells, and no CRAB SLIM criteria. Smouldering myeloma: >30g/L and BM plasma cells 10-59%, but still no CRAB SLIM criteria. Multiple myeoma - BM plasma cells >10% with CRAB SLIM criteria.
112
What are the CRAB SLIM criteria for making a diagnosis of acitve myeloma?
C - hypercalcaemia, R - renal failure, A - anaemai, B - bone lesions, S - 60% or more plasma cells in the bone marrow, Li - light chain ratio > 100, M - Multiple focal lesions on MRI
113
What is the treatment for multiple myeloma to prevent fractures and new boney lesions?
Zoledronic acid every month!
114
What are the components of the ISS myeloma staging system?
Beta-microglobulin and albumin level.
115
When taking thalidomide, lenalidomide or pomalidomide, what should be taken to mitigate the increased risk of thrombosis?
Aspirin or apixiaban
116
What is the cytotoxic regime used as first line for the treatment of transplant eligible patients with multiple myeloma?
Borezomib, lenalidomide, and dexmethasone for 12 weeks. Followed by autologous stem cell transplant, then maintenance lenalidomide.
117
What is the cytotoxic therapy for multiple myeloma patients who are not trasplant eligible?
Gold standard: daratumumab + lenalidomide OR daratumumab + bortexomib + melphalan.
118
How does bortexomib work?
Binds to a subunit of the 26S proteosome which leads to the accumulation of pro-apoptotic intracellular signals and apoptosis.
119
How does daratumumab work?
Anti-CD38 monoclonal ab. CD38 expressed on many immune cells (B and T cells) but also red cells. Remarkably well tolerated.
120
What blood transfusion related issue needs to be considered prior to the commencement of daratumumab?
Transfusion labs need to be made aware of the patient prior to commencing, and they should have extensive studies into what their possible anti red cell abs are prior to commencing daratumumab, becuase daratumumab will come up in direct antigen screening tests as positive for a red cell antibody.
121
Is rituximab used in the treatment of Hodgkin's lymphopma?
No.
122
Is PD-1 inhibition used in the treatment of Hodgkin's lymphoma?
Yes, but not first line.
123
Were is iron predominantly absorbed?
Duodenum, followed by the proximal jejunum.
124
What type of iron is obtained from meat?
Haem iron (literally iron derived from other animal haemoglobin)
125
What type of iron is obtained from vegetables?
Non-haem iron (ferritin, haemosiderin - these things are in plants)
126
How is haem iron absorbed?
Using a specifici hephaestin and HCP1 receptors primarily located in the brush border membrane of the duodenum. Very efficient uptake.
127
What is the symbol for the ferric iron ion?
Fe3+ (it's the oxidised version of ferrous iron)
128
What is the symbol for the ferrous iron ion?
Fe2+ (it's the reduced version of ferric iron)
129
How is non-haem iron absorbed?
Most non-haem iron is ferric (Fe3+) iron. It is aborbed a little bi via the integrein-mobilferrin pathway (IMP). The remaining non-haem iron is ferrous (Fe2+) which can be absorbed by the divalent metal transporter-1 enzyme (DMT-1).
130
In what way haemochromatosis like the opposite of anaemia of chronic disease?
In HFE C282Y mutants, there is under expression of hepcidin depsite adequate iron stores, meaning that there is excessive ferroportin present in the basolateral membranes of duodenal cells and patients continue to absorb iron despite being iron replete.
131
What form must all iron be transformed into before it can be bound to transferrin and transported around the body?
Needs to all be in the ferric form (Fe3+). The conversion from ferrous Fe2+ iron to the ferric Fe3+ iron is performed by ferroxidases.
132
What is idiopathic thrombocytopoenic purpura?
Isolated thrombocypoenia with normal bone marro and the absence of other causes of thrombocyopoenia.
133
What causes idopathic thrombocytopoenic purpura?
It is acquired autoimmune disease where the thrombocytopoenia results from pathologic antiplatelt antibodies, impaired megkaryocytopoeiens and T cell-mediated destruction of platelets.
134
What might make you treat someone with ITP?
If they had meaningful bleeding or bleeding risk, or if their platelet count was less than 30.
135
What is first line treatment for patients with ITP?
Steroids for 2-4 weeks with IVIG.
136
What is second line treatment for patients with ITP?
Splenectomy and eltrombopag. Azathioprine can be used as a steroid sparing agent. There is also some evidence associated with cyclosporin and rituximab.
137
How does thaldomide work for the treatment of myeloma?
It increases the activity of natural killer cells and increases levels of interleukin 2 and inferferon gamma - all thought to promote immune control of cancer cells. There are thought to be other effects like suppressing angiogenesis, reducing the ability of cancer cells to express cellular adhesion moleculres.
138
What are the major side effects of thalidomide when used in the treatment of multiple myeloma?
Increased risk of venous thromboembolism, increased risk of secondary malignancy, peripheral and irreversible peripheral neuropathy, constipation.
139
What is the difference between the adverse effect profiles oa lenalidomide when compared to thalidomide?
Lenalidomide is thought to carry the same types of adverse effects, but they are less likely to occur. Unfortunately however, it does have a much greater increased risk of bone marrow suppression, occuring in about 25% of patients.
140
When MGUS is diagnosed, what type of immunoglobulin paraprotein carries the greatest risk of progression to multiple myeloma or another lymphoid disorder?
IgM
141
Do all multiple myeloma have a detectable paraprotein?
No. About 1% are non-secretary. This is why the diagnosis of active myeloma is actually based on bone marrow biopsy and SLiM CRAB criteria.
142
What is the role of whole body bone scan in multiple myelma?
It has no role - its ability to see myeloma lesions is worse than plain XR. Should to skeletal survey with plain XR, low dose CT, or FDG PET. Or new thing is spine and pelvis MR or whole body MR if you can get it.
143
What are the proteasome inhibiotrs used to treat multiple myeloma?
Bortezomib,and ixazombi (the -zomibs). The increase the amount of pro-apoptotic intracellular signals are in the cancer cells causing them to under controlled cell death.
144
What are the immunomodulatory drugs used for the treatment of multiple myeloma?
Thalidamide and lanelidamide (and some other -lidamides)
145
How does thae drug panobinostat work as second line treatment for multiple myeloma in combination with a proteasome inhibitor?
Panobinostat inhibits histone deacetylase. This causes greater acetylation of histone proteins in cell nuclei, and prevents DNA access for replication. This arrests the cell cycle at the G1/S phase.
146
What is the signficance of the protein SLAMF7 in the treatment of multiple myeolma?
SLAMF7 is protein that has been discovered that is unviersly present on myeloma cells, regardless of their underlying cytogenetics. A drug called eltuzumab has been developed to target this protein and stimulate death of these cells.
147
What type of chemotherapy is melphalan?
Alylating agent.
148
If a young women presents with a Budd-Chiari syndrome and and microcytosis, with normal haemoglobin and normal haematocrit, what should you suspect?
Polycythaemia vera with underying iron deficiency anaemia. Note that splanchic vascular thrombosis is a young person should also trigger a screen for PNH and inherited thrombophilia.
149
What's the classic mutation in mantle cell lymphoma?
T(11;14) translocation, leading to dergulation of cyclin D1.
150
What's the classic mutation seen in peripheral T cell lymphomas?
T (5;9) causing constiuitive ALK activation.
151
What haematological malignancy mimic is caused by parvovirus B19 infection?
Pure red cell aplasia
152
What is JC virus?
The virus that causses progressive multifocal leukoencephalopathy in profoundly immunosuppressed patients - particularly with cellular immuninity issues (haematological malignancies, HIV, natalizumab)
153
What does JC virus do in the brain?
Causes demyelination and destruction of white matter
154
How does JC virus get into cells?
Probably by the 5-HT2A receptor. This is blocked by mirtazapine, so there is some evidence this blocks viral entry.
155
What type of viruses are JV virus and BK virus?
Polyomavirus
156
What will increase the risk of graft vs host disease in an allogenic haematopoetic stem cell transplant recipient?
Prior GVHD, HLA disparity, non- T cell depleted bone marrow, male recipient from a female donor, older age of recipient or donor, recipients from peripheral blood, recipients from cord blood, having CML, more comorbidities.
157
What is sickle cell disease?
Monogenic disease caused by a mutation in the beta haemaglobin chain leading to the HbS gene and sickle haemaglobin, whichc causes sickle shaped erythrocytes that dirsupt blood flow in small vessels and cause ischaemic tissue damage. Haemolysis is also seen and, in combination with abnormal cell sequestration in the spleen, causes anaemia.
158
What are the acute veno-occlusive complications of sickel cell disease?
Pain, stroke, acute chest syndrome, renal infarction, dactylistis or bone infarction, MI, pregnancy complication, pripism, venous thromboembolism, PRES
159
What are the chronic veno-occlusive complications of sickel cell disease?
Anaemia, pain, neurological deficits and seizures, pulmonary conditions (asthma, sleep issues, pulmonary hypertension), renal impiarment, hypertension, osteoporosis, cardiomyopahty, hepatotoxicity, pigmented gallstones from chronic haemolysis, chronic leg ulcers, proliferative retinonopathy
160
What is the cause of increased risk of infection in patients with sickle cell disease?
Hypofunctioning spleen. This significantly increases risk of encapsulated organism infection (especially streptococcus pneumoniae and haemophilus influenzae).
161
What is acute chest syndrome?
Fever, chest pain, hypoxaemia, wheezing, cough or srespiratory distress in the setting of new pulmonary infiltrate and sickle cell disease. The cause is often multifactorial and includes infection, thrombosis and thrombo/fat embolism.
162
What treatments have evidence in the prevention of complications associated with sickle cell disease?
Daily hydroxyurea (or L-glutamine in those who won't tolerate hydroxyurea), pneumococcal vaccine (in addition to other vaccines), transfusions, Crizanlizumab (anti P-selectin ab) in addition to hydroxyurea, voxelotor (a HbS polymeration inhibitor + HbS increasor in O2 affinity) can be used to reduce haemolysis and reduce need for tranfusions.
163
How do you manaage acute chest syndrome?
Transfusion, oxygen, incentive spirometry, analgesia, broad spectrum abx, hydration.
164
When is exchange transfusion indicated in sickle cell anaemia?
Severe acute chest syndrome, acute stroke
165
What are the benefits of peripheral blood stem cell transplants (allografts)?
Faster engraftment, equivalent patient surivial, marked reductions in rates of relapse (graft vs cancer effect - benefit only seems to exist in related donors)
166
What are the downside to peripheral blood stem cell transplants?
No increased risk of acute graft vs host disease, but marked increase in risk of chronic graft vs host disease requiring long term glucocorticoids to control.
167
How long should DOACs be stopped before testing for thrombophilia can be done?
Thrombophilia screening should be delayed until after the thrombus is treated. Once the DOAC course is finished, thrombophilia testing can be done at least 48hrs after it has ceased.
168
How long after warfarin is stopped can thrombophilia screening be interpreted?
2 weeks
169
How long after heparin has stopped can thrombophilia screening be interpreted?
24hrs
170
Can you do thrombophilia screening whilst a patient has a thrombus?
You can, but ideally you should wait til it is treated because it will hard to interpret the results as many of the tests are impacted by the presence of an active thrombus
171
What factor deficiencies are implicated in inherited thrombophilia?
Protein C, protein S and antithrombin III loss of function mutations.
172
What gain of function mutations are associated with heritbale thrombophilia?
Factor V leiden (protein C resistant factor V), and prothombin gene mutation.
173
How far part do two test results for lupus anticoagulants need to be positive for to confirm a diagnosis of anti-phospholipid syndrome?
2 weeks.
174
What are teh clinical criteria that must be met for a diagnosis of anti-phospholipid syndrome?
One or mor vascular thrombis (arterial or venous) in the absence of vasculitis OR a pregnancy complication 1) unexplained fetal death at or beyond wk 10, OR 2) premature birth before 34 weeks due to eclampsia/pre-eclampsia or placental insfufficiency OR 3) 3 or more unexplained, consecutive, spontaneous abortions before wk 10 of gestation not related to parental chromosomal abnormalities.
175
What is the dilute Russell viper venom time?
It's a test that utilises the ability of Russell viper venom to directly activate factor X. It can be used therefore to just test the common pathway in order to detect issues affecting it. It's most common use it to test for the presence of the a lupus anticoagulant. Russell viper venom still requires uninhibited phospholipid to form clot, so if a lupus anticoagulant is present with the viper venom, the blood will fail to clot. To prove LA is the cause, this should correct when the mixture is saturated with phospholipid.
176
What effect do DOACs have on lupus anticoagulant testing?
It causes false positive lupus anticoagulant testing. This goes for direct thrombin and anti-Xa drugs. It doesn't however impact the anti-beta2-glycoprotein I or anticardioplipin antibodies.
177
What is thought to be the mechanism of TRALI in recipients of blood products?
Anti-granulocyte (anti-HNA) or anti-HLA abs in donor plasma bind to and activate reciepient leukocytes causes an inflammatory response. It's also thought that pro-inflammatory lipids that accumulate during vlood product storage likely contribute to the response.
178
What is the typical onset time of TRALI post blood product infusion?
2-6 hours
179
What group of donors are more likely to cause TRALI in recipients?
Multiparous women. They are most likley to have plasma abs to HLA and neutrophil antigens (Human neutrophil antigen/HNA antibodies).
180
What is Paget-Schroetter syndrome?
DVT in the upper limbs following strenous upper limb activity.
181
What factors are associated with upper limb DVT compared with lower limb DVT?
1) younger, 2) leaner, 3) more likely to have a diagnosis of cancer and 4) less likely to have acquired or heritary thrombophilia.
182
How are critical site threateneing, limb or vital organ threatening thrombotic events secondary to Waldenstroms hyperviscosity syndrome managed?
Plasma exchange followed by systemic cancer treatment. If haemolytic anaemis is complicating the presentation, IVIG can also be given.
183
What malignancy is trisomy 12 often associated with?
CLL
184
What is hereditary spherocytosis?
Inherited RBC membrane defects lead to red cell deformites that lead them to be damaged by the spleen and subsequnte haemolysis. This also causes progressive splenic enlargement.
185
How is hereditary spherocytosis inherited?
Autosomal dominant in abtou 75% of cases.
186
What proteins have defects in hereditary spherocytosis typically?
Ankyrin, spectrin or Band 3 red cell proteins
187
What is the mechanism by which aortic stenosis causes anaemia?
Heyde syndrome is the intestinal angiodysplasia and arteriovenous malformations secondary to pressure changes triggered by aortic stenosis. As blood has to traverse the high flow conditions in the angiodysplastic malformations, an and type 2 von Willebrands disease develops which further accelrates bleeding. Management is aortic valve replacement.
188
What condition causes target cells?
Iron deficiency anaemia
189
What leads to rouleaux formation on blood film?
Increased serum plasma, such as in multiple myeloma.
190
What cells would you find auer rods in?
These are linear bundles of granules found in myeloid cells. It is a typical finding of immature cells of acute myeloid leukaemia.
191
What is the classic blood picture seen in CML?
Leukoerythroblastic blood picture with immature myeloid cells. Basophilia, eosinophia and thrombocytosis are common.
192
What is haemaglobin?
Tetramer consisting of two heterodimers, each heterodimer has an alpha globin chain and, usually, a non-alpha globin chain and a heme molecule.
193
What are the globin components of the HbA tetramer?
2 alpha chain and 2 beta chains. This is the normal adult haemoglobin.
194
Can a homotetramer (all the same beta, gamma, zeta, epsilon or alpha globin) exist?
Yes, a beta homotetramer (Hb H) or gamma homotetramers (Barts haemoglobin) are possible. Both are bad at transporting oxygen.
195
How many genes account for alpha globin production?
2 genes HBA1 and HBA2, with a copy each from the mother and father.
196
How genes account fo beta globin production?
A single gene HBB with a copy from the mother and father.
197
What is foetal haemoglobin?
Produced as a combination of 2x alpha globins and 2x gamma globins. It takes over as the major haemoglobin at about the 14 weeks of gestation point. Foetal haemoglobin his higher oxygen affinity than adult red cells and shifts the oxygen desaturation curve to the left. It also less impacted by 2,3 DPG concentrations.
198
What does hydroxyurea do to foetal haemoglobin in the treatment of patients with sickle cell anaemia?
It causes a shift in gene expression at the beta globin locus such that gamma globin is increased in expression. This leads to more foetal haemoglobin, which is not suceptible to polymerisation and sickling.
199
Which type of thalassaemia sees high levels of circulating foetal haemoglobin?
Beta- thalassaemia.
200
In what form of thalassaemia is Hb H disease seen?
Alpha thalassaemia - in the absence of functional alpha globin, beta globin forms tetramers (Hb H). Hb H has exceedingly high O2 affinity and cannot participate in O2 tissue delivery. The genotype for Hb H disease is a-/-- (one functional alpha chain gene)
201
In what context would you Hb Barts?
Hb Barts is a gammaglobin tetramer - the result of alpha globin deficiency when foetal (Hb F, 2x alpha 2x gamma) is supposed to be present. Therefore newborns with alpha thalassaemia are likely to have Barts Hb at birth.
202
What is HBA2
Two alpha and two delta globin chains. Normal in small quatnities in adults.
203
Is thalassaemia a disease of defective globin chains or a disease of deficiency of globin chains?
It's a disease of deficiency. Alpha-thalassaemia results in a shortage of alpha globin chains, and beta-thalassaemia results in a shortage of beta-chains.
204
Which type of thalassaemis is more likley to be transufsion dependent?
Beta-thalassaemia
205
What phenotype does a thalassaemia patient with normal beta genes, and a-/-a have?
Alpha thalassaemia minor. Mild microcytic anaemia or asymptomatkic.
206
What is Hb E?
A form of haemoglobin that results from a beta globin mutation with reduced beta globin production. Causes a particularly bad thalassaemia phenotype in south east asian countries when associated with another beta mutation.
207
What is the cause of most of the complications associated with transufion dependent thalassaemia?
Haemolysis (hepatosplenomegaly), anaemia (extrmudallary haematopoeiss), thrombosis and iron overolad from transfusion. Casue problems in bascially every organ.
208
What is the role of the G1-S checkpoint?
Assessing existing DNA integrity before commiting to DNA replication
209
What is the role of the G2-M checkpoint?
Ensuring the duplicated DNA was accurate before commiting to cell devision
210
What is the Warburg effect? How is utilised by cancer cells?
The Warburg effect (also known as AEROBIC glycolysis) refers to glycolysis in the cytoplasm being preferentially used for the generation of ATP over oxidative phosphorylation in the mitochondria DESPITE the presence of O2. This takes place when there is an abundence of glucose (i.e. when glut transporters are maximally expressed in a glucose abundant microenvironment). The Warburg effect is observable for cells that are replicating in the G1 phase, as abundent glycolysisis is essential to allow for the mass production of glucose intermediates that are necessary for the duplication of cytosolic components and organelles prior to S, G2 and M phases of the cell cycle.
Cancer cells take advantage of the Warburg effect by using it continuously to sustain continuous growth. For cancer cells, it also provides a level of protection from impending hypoxia with the mass accumulation of aneorbic metabolism substrates should growth rate outstrip angiogenesis. Lastly, it leads to the production of excess lactate, lowering tumour microenvironment pH which preferentially impacts the function of immune cells and so aids in tumour protection from the immune system.
211
What is a totipotent stem cell?
A cell that can prolfierate into any cell type in a human. Only seen during embryology.
