Haematology notes Flashcards
What is the mutation involved in genetic haemochromatosis?
What is the result of this?
HFE gene mutation (HFE =High Fe) which codes for hepcidin
If mutated there is impaired production of hepcidin which causes an upregulation of ferroportin 1 transporter in enterocyte. This causes unopposed absorption of iron in the gut causing increased iron uptake.
Before giving IV iron supplements what must be checked?
What complications of IV iron?
IV iron is contraindicated in active sepsis
* Siderophilic organisms that require iron to function will thrive in iron rich enviroment
Complications
* Extravasation of iron when doing IV drip if requires multiple punctures to secure IV line. Dermal level accumulation of iron. Can do saline test to see if there is adjacent swelling post test indicating leakage.
What is the classification for amyloidosis?
- Systemic amyloidosis or localized amyloidosis
- Acquired or hereditary amyloidosis
What are the types of systemic amyloidosis?
**AL amyloidosis **(light chain amyloidosis or primary amyloidosis)
* Light chains of Ig become AL amyloid protien
* Etiology: plasma cell dyscrasias (e.g. multiple myeloma)
* Typically affects the heart, kidney, tongue, peripheral and autonomic nervous system, GIT. Rapidly progressive clinical course
AA amyloidosis (reactive amyloidosis or secondary amyloidosis)
* Serum amyloid associated protein (SAA) becomes AA amyloid protein
* Etiology: chronic inflammatory conditons (e.g. IBD, RA, SLE), chronic infections (e.g. TB, osteomyelitis), RCC, lymphomas
* May occur at any age: most common in children. Typically affects the kidney, liver and spleen, GIT, adrenal glands.
* Disease progression can be slowed by managing the underlying condition
AB2M amyloidosis (B2 microglobulin amyloidosis or haemodialysis associated amyloidosis)
* B2 microglobulin becomes AB2M amyloid protein
* Etiology: long term haemodialysis, end stage renal disease
* Features: develops 10 years after starting. Typically affects joints and tendons, manifesting with scapulohumeral periarthritis, carpal tunnel syndrome, bone cysts
ATTRmt amyloidosis (mutated transthyretin amyloidosis, ATTRv (variant) amyloidosis, or hereditary transthyretin amyloidosis)
* Transthyretin is mutated transthyretin (ATTR): autosomal dominant disease
* Familial amyloid cardiomyopathy: typical age of onset: >60 years. Affects endomyocardium
* Familial amyloid polyneuropathy. Typical age of onset: >20 years, affects peripheral and autonomic nerves
ATTRwt amyloidoisis (wild type transthyretin amyloidosis or senil cardiac amyloidosis
* Normal transthyretin (ATTRwt) –> deposition in cardiac ventricles –> cardiac dysfunction (less drastic than in AL amyloidosis
* Median age of dx is 75 years. Typically affects the heart, ligaemnts and tendons, peripheral nerves
Approach to make dx of amyloidosis?
Tissue sample: target organ (kidney/nerve) preffered in patients with single organ involvement. Abd fat inspiration or rectal mucosa preferred in patients with multiorgan and/or tissue involvement
Methods
* Congo red stain to confirm amyloid deposition
* Histology shows apple-green birefringence under polarized light
* Additional findings from an affected kidney may include deposits in glomerular mesangial areas and enlarged tubular basement membranes that can be identified via light microscopy.
Gold standard is mass spectrometry
IHC light chain (if demonstrated can indicate AL amyloidosis)
What is the etiology of AL amyloidosis?
What pathophysiology
What clinical features?
Etiology: low level expansion of a plasma cell dyscrasia (e.g. multiple myeloma, Waldenstrom macroglobulinemia)
Patho: increased production of the light chains of immunoglobulins –> deposition of amyloid light chain protein A(L) in various organs
Clinical features
* Skin: cutaneous ecchymoses around the eyes (raccoon eyes), combined with yellow waxy papules
* Heart: restrictive cardiomyopathy, HFpEF, AV block
* Kidney: nephrotic syndrome, type 2 RTA, nephrogenic DI
* Tongue: macroglossia (specific to AL amyloidosis): OSA
* ANS: autonomic neuropathy
* GIT: malabsorption, hepatomegaly
* Haematopoietic system: bleeding disorders, splenomegaly
* Musculoskeletal system: carpal tunnel syndrome (may be bilateral), shoulder pad sign
What are the diagnostic Ix for AL amyloidosis and its management
Tissue biopsy
Assessment of organ involvement, including ECG, cardiac imaging
Obtains diagnostics for plasma cell dyscrasias to identify the underlying cause
* Serum electrophoresis: monoclonal gammopathy
* Urine protien electrophoresis (UPEP) with immunofixation: Bence-Jones proteins
Suspect AL amyloidosis in patients with multiple affected organs (heart failure with preserved ejection fraction, nephrotic range protienuria, peripheral neuropathy, hepatomegaly and/or noninfectious diarrhea), and/or atypical MGUS or smoldering multiple myeloma
Management
Control of underlying plasma cell dyscrasia with chemotherapy eg. melphalan + corticosteroids, thalidomide, bortezomib
Rapidly progressive clinical course if left untreated
Median survival time without treatment is 1-2 years
What is the etiology of AA amyloidosis?
Pathophysiology?
Clinical features?
AA amyloidosis is secondary to a chronic disease, such as:
* Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis, SLE, vasculitis, familial Mediterranean fever)
* Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, osteomyelitis)
* Malignancy (e.g., renal cell carcinoma, lymphomas)
Pathophysiology
Chronic inflammatory process → ↑ production of acute phase reactant SAA (serum amyloid-associated protein) → deposition of AA (amyloid-associated) protein in various organs
Clinical features
* Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
* Adrenal glands: primary adrenal insufficiency
* Liver and spleen: hepatomegaly, splenomegaly
* Gastrointestinal tract: malabsorption
* Heart (rare): severe thickening of ventricular wall
Main feature of AA amyloidosis at dx is renal dysfunction (CKD, nephrotic syndrome). Cardiac involvement is rare.
What are the dx tests for AA amyloidosis and management?
Kidney tissue biopsy findings
* Global and segmental amyloid deposition
* Diffuse and/or focal glomerular involvement
* Enlargement of glomeruli
* Tubular atrophy
* Interstitial fibrosis
Assessment of organ involvement, including BMP, estimated GFR, urinalysis
For suspected cardiac involvement: multiparametric CMR (including late gadolinium enhancement imaging)
Identify the underlying inflammatory disosrder (if not yet known) consider: CXR, inflammatory markers (ESR, CRP)
Managaement
Treat the underlying condition to reduce AA production (mainstay of treatment) e.g. colchicine for FMF
Provide supportive care for associated complications (CKD)
What are the clinical phenotypes of ATTRmt amyloidosis, etiology and the affected sites?
What are the types of localized amyloidosis and organs affected?
What nuclear imaging used to assess severity of cardiac amyloidosis?
Tc-99m PYP (pyrophosphate) nuclear scan is useful for transthyretin amyloid (ATTR). Not useful for AL amyloidosis.
What amyloidosis associated with haemodialysis patients?
What clinical features may there be?
AB2M amyloidosis (B2 microglobulin)
Will accumulate amyloid protiens (misfolded proteins) that mainly deposit in the joints
May manifest as carpal tunnel syndrome
What are the general principles of management of sarcoidosis?
If there is heart involvement how does this affect prognosis?
Drugs used to stop the production of amyloid proteins.
If there is extensive adherence of proteins to the heart with heart failure –> difficulty in the amyloid protien disolving away from the organ.
What are the 2 types of transthyretin in amyloidosis?
Hereditary (hATTR-CM) and wild type (wATTR-CM) which is acquired
What is the initial Ix if suspicious of lymphoma?
PBS for lymphocytosis. If looks abnormal do flow cytometry (immunophenotype). If CD antigens are present it is clonal B cell in circulation (T cell is less common)
Can do light chain restriction
Or Ig rearrangement to prove those B cells are clonal
Plasma cell disorders will 90% elevated lambda chain, only 10% is kappa
If positive in peripheral blood –> already stage 4 lymphoma (as in systemic circulation)
How do you work up a patient with thrombocytosis?
Work up to rule out secondary thrombosis
* CXR (rule out CA lung)
* CEA +/-colonoscopy (rule out CA colon)
* CRP, ESR (underlying inflammation)
Wont do rheumatic work up (as expensive)
Causes of secondary thrombocytosis: infection, inflammation, malignancy, iron deficiency anemia)
How to do the workup for suspected PV?
- Peripheral blood do JAK2V617F (cytogenetics). If present in the blood does not require bone marrow biopsy –> indicates that its clonal (carries the same mutation)
- Minority of case (10%) without JAK2 V617F requires bone marrow biopsy: must do CALR exon 12
Used to rule out prefibrotic PMF or ET
What are the causes of reversed albumin: globulin ratio?
What are the causes for increased albumin/globulin ratio?
Not common and should raise suspicion in paeds
Patient with mechanical heart valve leak presents with leukopenia + increased LDH and urate (elevated to four digits). What could be the cause?
Valve related haemolysis
ITP
MUST RULE OUT HAEM MALIGNANCY since urate and LDH should not be this high
What Ix should be done and in what order for persistent lymphocytosis?
- PBS first to assess morphology (is there dysfunctional/morphological issue)
- Flow cytometry (protein expression on cells) to determine clonality (CD5 on T cell is less common: if its high most likely clonality). Can see light chain expression (kappa or lambda restricted than it is more compatible with clonal)
- IgH gene rerrangement and TCR gene rearrangement using PCR (peripheral blood of bone marrow aspirate): should have lots of variation in VDJ rearrangement and T cell receptors (shows functional immune system)
If clonal abnormality than do FISH (for prognosis not for proving clonal)
At this stage the diagnosis of clonality is already made. If it is leukemia than it necessitates bone marrow biopsy aspirate and trephine biopsy to confirm.
Why is chromosome 17p deletion bad prognosis for CLL?
- Short head of chromosome 17 contains TP53 tumor suppressor gene (any strain breaks will repair). If absent does not know how to do apoptosis.
- Will not respond to chemotherapy. As chemotherapy induces DNA breaks. So even if there is DNA breaks there is no apoptosis.
- Hence other therapy such as venetoclax which is a bcl2 inhibitor which activates BAK and BAX proteins which increases mitochondrial outer membrane permeabilization (MOMP) and induces apoptosis (bypasses cells inability to induce apoptosis by itself)
ddx for increased lymphocytosis?
- Chronic NK lymphocytosis
- Monoclonal B cell lymphocytosis
- Early phase HIV
Can leukostasis occur in CML?
Not really as CML has more mature cells hence its shape is adaptable. Even if bigger due to its adjustable shape it won’t have leukostasis.
Blasts more than 100 even if AML has high chance of leukostasis
What is a simple PE to check for hyperviscosity?
Can look at retina for engorged vessels and swollen disc (indicates microcirculation is impaired)
What does bone marrow aspirate vs trephine biopsy show?
Bone marrow aspirate = morphology
Trephine biopsy: cytology (architecture of bone marrow: to determine status of haematopoiesis: if hypo or hypercellular)
What is MDS cell count normally?
- MDS is the precursor lesion of acute leukemia
- Rate of progression to AML depends on lineage as it will definitely transform to leukemia given time
- Red cell/white cell/megakaryocytic lineage
More likely to cytopenic (gene defect): ineffective and earlier apoptosis (can be hyperproliferative but immature and doesn’t progress)
Can even have MDS/MPN overlap if both high cell count and dysplasia
What is the criteria for POEM syndrome?
What is the monoclonal gammopathy of renal significance?
Monoclonal Ig deposition but does not meet the CRAB criteria for MM (renal insufficiency is classified as creatinine clearance <40ml/min)
If IgGAM is low in suspected mutiple myeloma what may patient have?
How to can acute renal failure affect SPE?
Light chain myeloma
In acute renal failure may not be able to detect light chains in blood as all excreted out in kidney –> hence a comprehensive investigation would also include urine protein electrophoresis (not just SPE)
Lymphoma patient, what is seen and dx?
Dilated lateral ventricles
Normal 4th ventricle
Hence this is communicating hydrocephalus due to leptomeninges metastasis of lymphoma which is causing impaired reabsorption of CSF
What is management of TTP?
ADAMTS13 mutation
Tx
* Steroid
* Azathioprine
* Plasmapharesis
Mx of CMV retinitis and if resistant what drug?
- Initial is IV valganciclovir
- If resistant gene on bacteria give Foscarnet
Haematological changes in SLE?
Macrophage activation syndrome refers to haemophagocytic lymphohistiocytosis (HLH) that associates with an autoimmune disease. Inflammatory reaction due to cytokine storms provided by massive dysregulation of macrophage lymphocyte interactions –> stills disease and kawasaki disease
When may aspirin be used in procedures?
- Dental procedure
- Endoscopies with biopsies and polypectomyies
- Opthalmologic procedures
- Peripheral vascular proceure
- Neuraxial anesthesia
Warfarin can be continued for most dental procedures if INR is kept at a lower range before the procdure and close monitoring.
When to stop anticoagulants for periop management?
In minor dental procedure stop warfarin 2-3 days before procedure
If major surgery/high risk of thrombosis: stop warfarin therapy 5 days before surgery.
Resume warfarin 12-24 hours after surgery when there is adequate haemostasis.
If high risk for thrombosis consider bridging therapy with UFH (used in renal impairment) or LMWH (more effective)
Those recieving bridging therapy with UFH, stop 4-6 hours before surgery. For LMWH stop 24 hours before surgery.
Perioperative management of antiplatelet therapy in patients with coronary artery disease
Acute and long term anticoagulant for DVT management
Indications for anticoagulation: only in proximal DVRT and PE
Cancer patients: prefer LMWH over warfarin
Pregnancy: hypercoagulable state: switch to LMWH when 1st trim and >36w –> cover up to 6w postpartum
HIT: heparin C/I: start parenteral non heparin anticoagulants –> bridge to warfarin
APL: heparin followed by indefinitive warfarin (preferred over DOAC)
Early and late complications of HSCT
Infections during recovery from HSCT and mx