HAematology Flashcards
What is the most common cause of renal impairment in MM
Cast nephropathy
RF for MGUS turning to MM?
M protein >1.5g/dL
Non-IgG MGUS
Abnormal serum free light chain ratio
Patients with MGUS progress to a symptomatic plasma cell proliferative disorder or lymphoproliferative disorder at a **rate of 1 percent per year. **
What does prolonged repitilase time suggest?
Inherited dysfibrinogenaemia ( others: DIC, paraproteinemia)
Markers of AML?
CD13, 33, 24, 117, MPO
Independent RF for hodgkins:
low albumin <40
Anaemia <10.5
MALE
Stage IV
WCC>15
Lt<0.6
Age >45
Syndrome of VIPoma
profound and chronic watery diarrhea and resultant dehydration, hypokalemia, achlorhydria, acidosis, flushing and hypotension (from vasodilation), hypercalcemia, and hyperglycemia.
NDAPH
NADPH maintains glutathione in its reduced form, which acts as a scavenger for dangerous oxidative metabolites.
G6PD enzyme catalyses the oxidation of Glucose-6-phophate and reduction of NADP+ to NADPH
The pentose monophosphate shunt is the only source for NADPH in red blood cells.
Lab tests suggestive of intravascular haemolysis
haemoglobinuria, methaemalbuminaemia, and urinary haemosiderin
schistocytes, fragmented cells and helmet cells
Fanconi anemia (FA) is a hereditary DNA repair disorder characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors. Patients may develop acute myeloid leukemia, often preceded by myelodysplastic syndrome. Patients are also highly predisposed to solid tumors, of the head and neck or anogenital regions. This condition is typically inherited in an autosomal recessive fashion. It is associated with chromosomal fragility.
Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development due to a mutation in P53. The classical LFS malignancies - sarcoma, cancers of the breast, brain, and adrenal glands - comprise about 80% of all cancers that occur in this syndrome.
OSLAM syndrome is a rare autosomal dominant hereditary disorder. Its name is an initialism of “osteosarcoma, limb anomalies, and erythroid macrocytosis with megaloblastic marrow syndrome”.
Gardner syndrome, also known as Gardner’s syndrome or familial colorectal polyposis, is a subtype of Familial Adenomatous Polyposis (FAP). Gardner syndrome is an autosomal dominant form of polyposis characterized by the presence of multiple polyps in the colon together with tumors outside the colon. The extracolonic tumors may include osteomas of the skull, thyroid cancer, epidermoid cysts, fibromas, as well as the occurrence of desmoid tumors in approximately 15% of affected individuals.
High risk features of ET
> 60 with JAK2 V617F mutation
Histroy of thrombosis at any age
Prognostic factors for CLL
Poor:
Unmutated IgH (CLL cells that haven’t gone through hypermutation of IgVH)
increased beta2 microglobulin
CD38+ve
MALE
Lymph doubling time <12Mo
Increased LDH
**17p deletion –> mutation in p53 **= resistance to chemo
Good:
13q del
Low CD38+ve
Low ZAD-70
Warm AIHA
Warm: most common 85%
Nucleated red cells may be seen in addition to spherocytes in warm AIHA.
IgG mediated
Haemolysis at body temp
extravascular
Causes:
- AI: SLE
- lymphoma, CLL
- Methyldopa, quinidine, penicillin
- pregnancy
Tx:
1. Supportive, folic acid and transfusion
2. Steroids
3. Rituximab
4. Splenectomy: outcomes of splenectomy are not as good as compared with ITP, with a 30-60% complete response.
Thromboembolism is common and therefore prophylactic anticoagulation should be considered
Cold AIHA
Less common
Temp <37
intravascular
Mediated by complement/IgM
Agglutination on blood film
Causes:
Infections: EBV, CMV, , mycoplasma. HCV, syphilis
Macroglobulinemia
infection tend to cause acute disease
Tx:
1. Warm, folic acid
2. Rituximab
3. PLEX (if IgM high)
4. Low dose alkylating agents (CYC or chlorambucil)
*not responsive to steroids
In warm antibody hemolytic anemia, IgG is nearly always present, and C3 (C3b and C3d) may be present as well. In cold antibody disease, C3 is present while IgG is usually absent. The test is ≥ 98% sensitive for autoimmune hemolytic anemia; false-negative results can occur if antibody density is very low or, rarely, if the autoantibodies are IgA.
Leukocyte alkaline phosphatase (LAP)
- found within mature WBC
- level increased in physiological response (leukemoid reaction) and pathologies that has **mature ** WBC (i.e. PV, ET, PMF)
- lower levels in conditions that have undeveloped WBC: CML, PNH, AML
What are rates of ICH in haemophilia?
low
What are rates of ICH in haemophilia?
low
Hereditary Spherocytosis
Autosomal Dominant defect of red blood cell cytoskeleton
- red blood cell survival reduced as destroyed by the spleen
- MCHC elevated
* jaundice, gallstones
* splenomegaly
* aplastic crisis precipitated by parvovirus infection
Degree of haemolysis is variable
Inx:
- EMA binding test and the cryohaemolysis test
- Osmotic fragility test was previously used
- To note you don’t neccesarily need these tests, if FHx and typical lab findings are seen
Tx:
Folate supplement
Splenectomy
Multiple myeloma
Poor prognostic markers for MM
High RISS score: (b2 microglobulin >5.5, albumin <35)
FISH:
17p del
p53 mutation
t4:14, 414:16, t16:20, 14:20, gain 1q, del 1p
Mantle cell lymphoma
Cyclin D1 nuclear expression
T11:14
CD 5+ 19+, 20+, FMC 7 positive
CD23-ve
Nuclear staining for cyclin D1 (BCL1) is present in >90 percent of cases
Mantle cell lymphoma and CLL are both CD5+ve
To differentiate these:
Mantle cell is** CD23-ve and CD200 -ve**
Alpha thalassaemia
Chr 11
4 genes
2 gene deletion: Cis: more common in asian and can be associated with fetal hydrops
Trans: N Hb with reduce MCV (more common in african)
3 gene deletion:
HbH (4 beta disease)
Low Hb, low MCV
Splenomegaly
nondeletional defect, such as a point mutation (ie, aa/–, where a represents the mutated alpha chain, such as hemoglobin Constant Spring). HbH disease tends to be more severe in patients with the nondeletional form.
Alpha thalassaemia
Chr 16
4 genes
2 gene deletion: Cis: more common in asian and can be associated with fetal hydrops
Trans: N Hb with reduce MCV (more common in african)
3 gene deletion:
HbH (4 beta disease)
Low Hb, low MCV
Splenomegaly
nondeletional defect, such as a point mutation (ie, aa/–, where a represents the mutated alpha chain, such as hemoglobin Constant Spring). HbH disease tends to be more severe in patients with the nondeletional form.
In patients with beta thalassaemia, co-inheritance of alpha thalassemia trait ameliorates the severity of beta thalassemia by partially normalizing the alpha to beta globin ratio without greatly affecting the amount of total hemoglobin
Beta thalassaemia
Chr 11
2 genes
Minor:
- defect in one beta allele
- Microcytosis more profound cf Hb drop
-** HbA2 high**
+/- HbF
no Tx
Major:
Defect in both alleles
Autosomal recessive
I**ncreased HbF (90-100%, **HbA2 >2.5%
Hepatosplenomegaly
Increased risk of erythroid tumour and increased marrow cavity –> pathological fractures
Good prognostic factos in AML
t8:21, t15:17 (APML)
Inv16
Mutated NPM1 without or low FLT3-ILD
Biallelic mutated CEBPA
Poor prognostic for AML
Age, ECOG correlates to reduced OS and DFS
Cytogenetics:
del5 or del7
Del5q, abn. 3q
17p abnomality
TP53 mutation
t6:9, t9:22
Wt NPM1 with FLT3-ILD high
*if it was mutated WtNPM1 then it will be intermediate risk *
*FLT3-TKD doesn’t affect prognosis
CALR mutation in Myeloproliferative disorders
CALR mutation has the best prognosis
then isolated JAK2 mutation
Triple negative confers the worse prognosis
Which conditions are reversible in haemochromostosis
Cardiomyopathy
Dermal pigmentation
Irreversible complications of haemochromatosis
- diabetes
- cirrhosis
- hypogonadism
- arthropathy
Paraneoplastic pemphigus (PNP)
rare autoimmune blistering disorder that may occur in the setting of lymphoproliferative disorders and malignancies
he disorders most frequently linked to PNP are non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman’s disease.
**Antibodies against periplakin and envoplakin **are strongly associated with PNP.
HbS
a valine is substituted for glutamic acid on the surface of the Hb S molecule in the sixth (or seventh, in the revised amino acid numbering convention) position of the beta globin chain (HBB glu6val)
HbS has the following properties:
- it is less negatively charged, due to the loss of glutamate for valine
- it polymerises with adjacent HbS
- the loss of the negative charge and the configuration of HbS makes it less soluble than HbA
- it has** lower affinity for oxygen (right-shift of the oxygen-dissociation curve)**, which increases the risk of desaturation, but improves the yield of oxygen to the tissues
- it is the result of a point mutation substituting glutamate for valine at position 6, and
it contains two α-like globins and two β-like globins and four haem molecules.
AIP
Acute intermittent porphyria
**Autosomal dominant **
defect in porphobilinogen deaminase (an enzyme involved in the biosynthesis of haem)
- results in the toxic accumulation of delta aminolaevulinic acid and porphobilinogen
Presentation: 20-40 yr old, FEMALE 5:1
Combination of abdominal, neurological and psychiatric symptoms:
abdominal: abdominal pain, vomiting
neurological: motor neuropathy
psychiatric: e.g. depression
hypertension and tachycardia common
Dx:
- Urine turns deep red on standing
- Raised urinary porphobilinogen (elevated between attacks as well)
- assay of red cells for porphobilinogen deaminase
- raised serum levels of delta aminolaevulinic acid and porphobilinogen
Tx:
- avoid triggers
- Acute attacks:
> IV haematin.haem arginate
> > IV glucose (carb load) if above not readily available
What is required for secondary haemostatis?
Negatively charged phopholypid surfce, coag factors, calcium, appropriate temp
Chimeric antigen receptor T cells (also known as CAR T cells) are T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy. Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are receptor proteins that have been engineered to give T cells the new ability to target a specific protein. The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor. CAR-T cell therapy uses T cells engineered with CARs for cancer therapy. The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to more effectively target and destroy them. Scientists harvest T cells from people, genetically alter them, then infuse the resulting CAR-T cells into patients to attack their tumors
Option A describes Bi-specific T-cell engagers (BiTEs). BiTEs form a link between T cells and tumor cells. This causes T cells to exert cytotoxic activity on tumor cells by producing proteins like perforin and granzymes, independently of the presence of MHC I or co-stimulatory molecules. These proteins enter tumor cells and initiate the cell’s apoptosis.
Option C describes PARP inhibitors. PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). PARP1 is a protein that is important for repairing single-strand breaks (‘nicks’ in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), then the replication itself can cause double strand breaks to form. Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and in tumours with BRCA1, BRCA2 or PALB2 mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don’t replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP.
Follicular lymphoma
- Histology and FISH
- nodular growth pattern and cell morphology consisting of a mixture of centrocytes and centroblasts is characteristic
- CD 19+, CD 20+
- CD5 -ve, CD 10+ve
- CD23 -ve
- BCL-6 +ve
Molecular gene rearrangements of the t(14;18) involving BCL2 can occur.
the majority has a normal serum lactate dehydrogenase (LDH) level.
PNH
- acquired disorder
- PNH is a clonal stem cell disorder resulting in deficiency of GPI-anchored proteins and intravascular haemolysis, cytopenias and thrombosis
Pathophysiology:
- GPI anchor protein to cell mb
- Complement regulating surface proteins (such as DAF) need GPI protein to attach to mb
- - thrombosis due to lack of CD59 –> platelet aggregation
- flow cytometry of blood to detect low levels of CD59 and CD55
Features:
- haemolytic anaemia
- red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
- haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day)
- **thrombosis **e.g. Budd-Chiari syndrome
- aplastic anaemia may develop in some patients
Management:
- blood product replacement
- anticoagulation
- eculizumab, a monoclonal antibody directed against terminal protein C5 It has been shown in the TRIUMPH trial to **decrease blood product support requirements and improve quality of life **in PNH, but requires meningococcal vaccination prior to commencement and is not useful acutely.
- stem cell transplantation
Fact or fiction
Levels of VWf are lower in O blood group patients.
FACT
Ruxolitinib
selective inhibitor of Janus kinase (JAK) 1 and 2
significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and** improving overall survival**
Brentuximab vedotin
- antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma
- It selectively targets tumor cells expressing the **CD30 antigen, **a defining marker of Hodgkin lymphoma and ALCL.
The major side effects include cytopenias and peripheral neuropathy
DLBCL prognostication
Age>60, elevated LDH, poor functional status, stage III/IV disease and presence of extra-nodal sites are all adverse prognostic factors in DLBCL and are used in the IPI risk calculator.
Recently the use of DNA micro-analysis has been used to predict survival also - with three subtypes identified: Germinal center B cell like; Type 3; and Activated B cell like. The “activated B cell-like DLBCL” (ABC) group has a lower overall survival rate than the “germinal centre B cell-like DLBCL” (GCB) group, with type 3 somewhere in between
Aplastic anaemia
Aplastic anaemia causes a deficiency of all blood cell types (PANCYTOPENIA): red blood cells, white blood cells, and platelets.
It is more frequent in people in their teens and twenties, but is also common among the elderly.
M=F
2 peaks: 20-25, 60
ASIANs
Causes:
- most common: Idiopathic - Autoimmune suppression of haematopoietic stem cells by T-cell mediated mechanism
- Radiation, chemotherapy, SLE
- Toxins: benzene
- Medications: Chloramphenicol, gold, sulfonamides, phenytoin, carbamazepine, quinacrine, tolbutamide
- Post- viral hepatitis
- Non-hepatitis virus: parvovirus, EBV, CMV, echovirus 3
- Pregnancy
- PNG
- Malignancy: large granular lymphocytic leukemia
- congenital: defects in telomere length (dyskeratosis congenita) or DNA repair (fanconi)
- linked to both the initiation of bone marrow failure and the propensity to later progress to myelodysplasia, PNH, or AML
Symptoms:
- hepatosplenomegaly, lymphadenopathy, or bone tenderness should not be present, and their presence should lead to questioning the diagnosis.
- will have the classic sx and signs of pancytopenia
Lab:
- pancytopenia (could be any number)
- may have: reticulocytopenia, macrocytosis,
- BM biopsy/aspirate: Hypocellular marrow
Treatment:
1. Mild: supportive care (EPO or filgrastim), transfusion, abx
2. Severe:
- defined as Nt <0.5, plt <20, reticulocyte <1%, bone marrow cellularity <20%
- young (<40y): allogeneic BMT (if you have HLA matched sibling, it’s safer)
- Old (>40y):
> ATG + cyclosporin
> Eltrombopag, a thrombopoietin mimetic, is now being added to ATG plus cyclosporine with tri-lineage hematologic responses as high as 90%.
> ATG should be used in combination with corticosteroids (prednisone or methylprednisolone 1–2 mg/kg/day orally for 1 week, followed by a taper over 2 weeks) to avoid ATG infusion reactions and serum sickness.
Cyclosporine and eltrombopag are maintained at full doses for 6 months and then stopped in responding patients.
full benefit of immunosuppression take 4mo
- 1/3 will replase after IS treatment
- Clonal hematologic disorders, such as PNH, AML, or myelodysplasia, may develop in one-quarter of patients treated with immunosuppressive therapy after 10 years of follow-up.
- Factors that predict response to ATG-cyclosporine therapy are patient’s age, reticulocyte count, lymphocyte count, and age-adjusted telomere length of leukocytes at the time of diagnosis
Polychromasia
The term ‘polychromasia’ suggests that the red cells are being stained many colours. In practice, it means that some of the red cells stain shades of bluish grey (Fig. 5-62) – these are the reticulocytes. Cells staining shades of blue, ‘blue polychromasia’, are unusually young reticulocytes. ‘Blue polychromasia’ is most often seen when there is either an intense erythropoietic drive or when there is extramedullary erythropoiesis, as, for instance, in primary myelofibrosis or carcinomatosis. It should be noted that in certain circumstances the absence of polychromasia is significant; in a patient with severe anaemia it indicates that the bone marrow response is inadequate (e.g. in aplastic anaemia and pure red cell aplasia).
What causes pancytopenia with normocellular marrow?
SLE
disseminated infection
hypersplenism
B12/folate def
MDS
Hairy cell leukemia
Hairy cell leukemia is a rare malignancy of hematopoietic stem cells differentiated as mature B lymphocytes with hairy cytoplasmic projections.
- V600E mutation in the BRAF gene is recognized as the causal genetic event of hairy cell leukemia
- median age at presentation is 55 years, 5:1 male predominance.
- Hairy cell leukemia is usually an indolent disorder whose course is dominated by pancytopenia and recurrent infections, including mycobacterial infections.
- hepatosplenomegaly
Lab:
- pancytopenia
- “hairy cells” are usually present in small numbers on the peripheral blood smear and have a characteristic appearance with numerous cytoplasmic projections.
- dry tap on BM
- immunophenotype:
> CD11c, CD20,22
> CD25
> CD103, CD123
- marked infiltration of the red pulp
Tx: indicated for symptomatic disease
1. nucleoside analog: cladribine or pentostatin
single course: 70-95% remission
2. Rituximab in relapse setting (with ot without 1)
3.** BRAF inhibitor vemurafenib** exhibits ~100% overall response rate in patients with refractory/relapsed hairy cell leukemia, with 35–40% complete remissions.
In TRALI, host neutrophils are activated by a factor in the blood product. Activation is associated with the release from neutrophils of cytokines, reactive oxygen species, oxidases, and proteases that damage the pulmonary capillary endothelium. This damage causes inflammatory (non-hydrostatic) pulmonary edema. Transfused factors responsible for host neutrophil activation can include antibodies in the blood component directed against recipient antigens, or soluble factors such as bioactive lipids that can activate neutrophils. Donor anti-leukocyte antibodies can bind to antigens on recipient neutrophils or possibly to other cells such as monocytes or pulmonary endothelial cells.
which enzymes are involved in error-free homologous recombinant repair pathway
BRAC1, BRCA 2, PALB2
Myeloproliferative disorder
General
- disease of the elderly
- includes ET, PV, IMF and CML
- Possible causative factors: **ionising radiation **
- Mutations:
JAK2, CALR, MPL
JAK2 V617F on Exon 14
if negative –> ET or MF –> check CALR + MPL –> if negative clonal testing
if negative. –> if PV: 3% JAK2 on exon 12, 13
CALR
somatic mutation on Exon 9
associated with myeloid neoplasm with thrombocytosis
Mutation of calreticulin –> activates MPL –> activates JAK/STAT pathway
Types:
1: deletion: IMF, M>F
2. Insertion: ET, younger pt, low risk of thrombosis, ^^ platelets
PV
Increased Hb and Hct +/- panmyelosis
Criteria:
Major:
1, Hb >165 (m), >160 (f)
or Hct >49% or 48%
or >25% ^ in RCM
- BM: increased cellularity with panmyelosis
- JAK2 V617F or JAK2 on Exon12
Minor:
reduced EPO
** Clinical:**
1. Hyperviscosity syndrome: parasthesia, HA, HTN, dizzy, SOB, tinnitus, visual
2. Thrombotic: DVT, PE, Budd Chiari, Stroke/TIA, MI
Arterial > Venous, RF: prior hx, >60, Leuc >15, HTN
- Bleeding
- Erythromelalgia: associated with plt >400
- Prutitus (esp. with warm shower) - mast cell degranulation and histamine release
- Epigastric sx and PUD (due to increased histamine from tissue basophils and change in gastric BF due to hyperviscosity
- gout
- Plethora
- Splenomegaly>hepatomegaly
Investigations:
1. If EPO is elevated, must exclude secondary causes:
- OSA, COPD, Pulm HTN, Smoking
- high altitude
- Eisenmenger sx
- Methemoglobunemia
- inappropriate EPO producing tumour: RCC, HCC, pheo, uterine leiomyoma, ovarian tumour, cerebral hemangioblastoma
- Leucocyte ALP will be increased, ESR will be reduced
Treatment:
Phlebotomy: aim** hct<45%**
+ daily aspirin
Low risk: <60, no thrombosis
- if microvascular sx, CV RF, leucocytosis then can consider increasing aspirin to BD
High risk: >60, hx of thrombosis: (other RF: plt >1500, WCC >15, splenomegaly, uncontrolled sx
- consider HC or IFN alpha
- if arterial thrombosis: aspirin BD
- if venous thrombosis: VKA (reduces recurrence, lifelong if splanchnic, cerebral, unprovoked proximal
- also to note, MPN pts are at higher riks of bleeding
Ruxolitinib: selective JAK1/2 inhibitor
use of failed on HC tx with splenomegaly
shown to reduce spleen size, improve sx, and reduce the need for phlebotomy
Poor prognostic factors:
- >61y
- thrombosis hx
- WCC >10.5
- abnormlal karyotype
leukaemic transformation risk: 2.3% in first 10 years, 7.9 in first 20yrs
