Haematology Flashcards
What percentage of blast cells in the peripheral blood or bone marrow is required to make a diagnosis of acute myeloid leukaemia?
Greater than or equal to 20%
Promyelocytic leukaemia is a subtype or AML that requires emergency treatment. What translocation is classically associated with it?
t(15;17) - it’s diagnostic even with a blast count <20%. It’s and emergency due to it being associated with DIC.
T(8:21), associated with what?
AML- diagnostic with a blast count <20%. Pts present younger than usual- 25-30. Good prognosis in adults, bad in children.
Vincristine use and notable side effect?
Part of R-CHOP used for DLBCL treatment. Causes peripheral neuropathy.
What does antithrombin III do?
It inhibits factors II, IX and X.
What does thrombomodulin do?
Binds thrombin II. Thrombin II binds to Protein C which activates it. Protein C then degrades factors V and VIII.
What causes vascular spasm?
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.
What are the the naturally occuring plasminogen activators?
Urokinase and tissue plasminogen activator. Both released from sub endothelial tissue. Both normally cleared by the liver, so accumulate during liver failure.
How does tranexamic acid work?
Inhibits binding of plasmin and plasminogen to fibrin. Data fo use during trauma, cardiac, orthopaedic surgery. Used in C-sections and PPH.
What is CD38? What antibody is used to target it? What implication does this have for blood transfusion?
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.
What enzymes is responsible for the degradation of Fibrin into D-dimer and fragment E?
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.
What clotting pathyway is measured by the prothrombin time?
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.
What clotting pathyway and factor activity is measured by the prothrombin time?
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).
What to antiphospholipid abs do to the prothrombin time?
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.
How does heparin work?
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).
What does Von Willebrand Factor do?
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.
What happens in Von Willebrand Disease?
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.
What is the role of desmopressin in the treatment of VWD?
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.
How is severe bleeding risk managed in vWD?
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.
How are haemophilia A and B inherited?
X-linked recessive. A is more common than B and tends to be more severe.
How is haemophilia C inherited?
Autosomal recessive. Rare cases of heterozygous patients being more susceptible to bleeding. Primarily seen in Ashkenazi Jews.
Haemophilia A - how does it work?
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.
Haemophilia B - how does it work?
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.
Haemophilia C - how does it work?
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.
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.
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.
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.
What is a schistocyte?
A fragmented part of red blood cell.
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.
What percentage of autoimmune haemolytic anaemia is primary vs secondary?
50/50 split
What is first line treatment of AIHA?
Prednisolone.
What is seoncd line treatment for AIHA?
Ritxuimab
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.
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.
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.
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.
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.
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.
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.
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.
What is eltrombopag?
Thrombopoetin receptor activator.
What adjuntive treatment can be used in aplastic anaemia to assist with thrombocytopoenia?
Eltrombopag works.
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.
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.
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.
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
What chromosome is BCL-2 on?
14
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)
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.
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.
What is the reversal agent for dabigatran called?
Idarucizumab
What type of chemotherapy is fludarabine?
It’s purine analog and inhibit DNA synthesis (S phase cell cycline inhibiotr).
What type of targeted therapy is ibrutinib?
Anti-bruton’s tyrosine kinase inhibitor that antagonises cyokine, integrin and B-cell receptor mediated growth signals.
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).
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.
What is obinutuzumab?
Anti-cd20 ab. Used in CLL
How does chlorambucil work?
Alkylating agent. Causes cross lingking and S phase cell cycle failure. p53 accumulates as DNA errors increase and causes apoptosis.
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
What haematological malignancy is most often assocated with DIC?
APML (90%) followed by acute lymphoblastic leukaemia (20%)
What solid malignancies are associated with DIC?
Mucin secreting adenocarcinomas. Tends to be associated with non-bacterial thrombic endocarditis with systemic embolism.
What is essential thrombocythaemia?
Myeloproliferative disease that leads to excessive platelets, but normal other cell types.
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).
What is the philadelphia chromosome?
Tranlocation of chromosomes 9 and 22 t(9;22) aka BCR-ABL fusion translocation. Cause of chronic myeloid leukaemia.
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.
What is polycythamia vera?
Persistent erythrocytosis usually with increased haematorcrit. Associated with the JAK2V617F mutation.
What is the treatment of polcythaemia vera?
Aspirin, venesection +/- hydroxyurea or peginterferon.
What is the treatment target for polycythaemia vera?
Haematocrit <0.45
What is aquagenic pruritis? What myeloproliferative diseas is it associated with?
Itching when the skin is wet. Seen in polycyhthaemia vera.
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.
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.
What is the significance of chromosome 5q31 deleation for MDS?
If this mutation is present, the patient should be considered for treatment with lenalidomide.
What is the significance of ring sideroblasts and the SF3B1 mutation for patients with MDS?
They respond better to luspatercept.
What cells are dysfunctional in primary myelofibrosis?
Uncontrolled megakaryocyte proliferation
Which TKI is used to provide symptom releif and increase overall survival in primary myelofirbosis?
Ruxolitinib (JAK inhibitor)
From a prognostic point of view, what’s the difference between chronic myelomonocytic leukaemia and myelodysplastic syndrome?
High risk of transformation to AML
What gene mutation is mastocytosis characterised by?
KIT mutations. Imatinib is used here.
What driver mutations are most often seen in patients with essential thrombocythaemia?
JAK, CALR or MPL mutations.
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.
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.
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.
In essential thrombocythaemia, what defines low risk disease?
Mutations in either JAK2 or MPL, but with age <60, no previous history of thrombosis.
How is low risk essential thrombocythaemia managed?
Aspirin alone.
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.
How is intermediate risk essential thrombocythaemia managed?
Hydroxyurea and once daily aspirin.
