haem Flashcards
best prognosis in Acute myelogenous leukemia
t(15:17)
The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RAR α; or RARA) gene and is unique from other forms of AML in its responsiveness to all trans retinoic acid (ATRA) therapy.
Associated with a translocation denoted as t(15;17)(q22;q12).
AML strongest adverse clinical predictors
● Advanced age
● Poor performance status
● Cytogenetic and/or molecular genetic findings in tumor cells
● History of prior exposure to cytotoxic agents or radiation therapy
● History of prior myelodysplasia or other hematologic disorders such as myeloproliferative neoplasms
AML commonest gene mutation
FLT3
Ibrutinib
targeting B-cell malignancies
-selective and covalent inhibitor of the enzyme Bruton’s tyrosine kinase
treatment of mantle cell lymphoma, chronic lymphocytic leukemia and Waldenstrom’s macroglobulinemia.
ATRA cx
- differentiation syndrome
(previously called ‘retinoic acid syndrome’) which is a potentially fatal complication of induction chemotherapy in patients with acute promyelocytic leukemia (APML)
characterized by fever, peripheral edema, pulmonary opacities, hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, rash, and serositis resulting in pleural and pericardial effusions
-caused by a cytokine release syndrome or sometimes called “cytokine storm,” - inflammatory cytokines from malignant promyelocytes
The mainstay of treatment is glucocorticoid treatment. Mortality rate can be up to 30 percent without glucocorticoid therapy principally from respiratory failure or brain edema. The drug of choice would be intravenous dexamethasone 10mg twice daily.
For most patients with differentiation syndrome, ATRA could be continued but for patients with severe differentiation syndrome (eg, patients who develop progressive renal failure or respiratory distress), ATRA should be discontinued. However, once the symptoms of differentiation syndrome are completely resolved, the differentiating agent could be restarted.
With treatment, most patients demonstrate improvement within 12 hours and complete resolution of symptoms within 24 hours, although approximately 5 percent will not survive.
chronic phase of CML rx
3 phases: chronic phase, accelerated phase, or blast crisis
Treatment options:
- potential cure with allogeneic hematopoietic cell transplantation (HCT)
- disease control without cure using tyrosine kinase inhibitors (TKIs)
- palliative therapy with cytotoxic agents.
– TKIs (Imatinib, Dasatinib or Nilotinib) are the initial treatment of choice for most patients with chronic phase CML.
– Prior to TKI, other agents were much more commonly used in CML and these include hydroxyurea, interferon alpha with or without cytarabine, and busulifan.
– With the advent of HCT and the oral TKIs, the use of chemotherapeutic agents and/or interferon as primary treatment is now mostly of historic interest, although they can be of benefit to patients who are not transplantation candidates and are intolerant or refractory to treatment with TKIs.
ALL poor prognostic factors
- Presence of Mixed Lineage Leukemia (MLL), bcr-abl gene.
- Age >35 yrs or <1
- Minimal residual disease detectable at day 33 (>4 weeks).
- WBC >50,000
- Poor response to induction therapy
Philadelphia positive ALL rx
Imatinib
- Imatinib works by blocking the ABL function by interfering with ATP binding.
- superior response rates, thereby allowing more patients to proceed to Allogeneic hematopoietic cell transplantation
myelodysplastic syndrome with chromosome 5q syndrome rx
Lenalidomide
- can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities
risk score in CML
HASFORD prognostic score(Measures response post IFN α treatment): “APS BEB”
Age Platelets Spleen size Basophils Eosinophils Blasts
Imatinib s/effects
- weight gain
- Edema, muscle cramps, nausea, diarrhea, distured LFTs, rash(porphyria)
Hodgkin’s lymphoma
malignant proliferation of lymphocytes characterised by the presence of the Reed-Sternberg cell. It has a bimodal age distributions being most common in the third and seventh decades
Hodgkin’s lymphoma prognosis
Histological classification:
- nodular sclerosing: most common, good prognosis
- mixed cellularity: good prognosis
- lymphocyte predominant: best prognosis
- lymphocyte depleted: least common, worst prognosis
‘B’ symptoms also imply a poor prognosis
- weight loss > 10% in last 6 months
- fever > 38ºC
- night sweats
Other factors associated with a poor prognosis identified in a 1998 NEJM paper included:
- age > 45 years
- stage IV disease
- haemoglobin < 10.5 g/dl
- lymphocyte count < 600/µl or < 8%
- male
- albumin < 40 g/l
- white blood count > 15,000/µl
Hodgkin’s lymphoma rx
For early stage HL (Stage I-II)
- If favourable prognosis- ABVD with or without radiation therapy.
- If unfavourable prognosis- ABVD plus radiation therapy.
For advanced stage HL (Stage III-IV)
- Combination chemotherapy (ABVD or BEACOPP)
vWb
clues
combination of a petechial skin rash combined with a slightly elevated APTT and reduced factor VIII activity
majority of cases are inherited in an autosomal dominant fashion and characteristically behaves like a platelet disorder
Role of von Willebrand factor:
- large glycoprotein which forms massive multimers up to 1,000,000 Da in size
- promotes platelet adhesion to damaged endothelium
- carrier molecule for factor VIII
Types:
- type 1: partial reduction in vWF (80% of patients)
- type 2: abnormal form of vWF
- type 3: total lack of vWF (autosomal recessive)
Investigation:
- prolonged bleeding time
- APTT may be prolonged
- factor VIII levels may be moderately reduced
- defective platelet aggregation with ristocetin
Management:
- tranexamic acid for mild bleeding
- desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
- factor VIII concentrate
- type 3 von Willebrand’s disease (most severe form) is inherited as an autosomal recessive trait. Around 80% of patients have type 1 disease
Leukemoid reaction
- Dohle bodies in the white cells
The leukaemoid reaction describes the presence of immature cells such as myeloblasts, promyelocytes and nucleated red cells in the peripheral blood. This may be due to infiltration of the bone marrow causing the immature cells to be ‘pushed out’ or sudden demand for new cells
Causes:
- severe infection
- severe haemolysis
- massive haemorrhage
- metastatic cancer with bone marrow infiltration
A relatively common clinical problem is differentiating chronic myeloid leukaemia from a leukaemoid reaction. The following differences may help:
Leukaemoid reaction:
- high leucocyte alkaline phosphatase (LAP) score
- toxic granulation (Dohle bodies) in the white cells
- ‘left shift’ of neutrophils i.e. three or less segments of the nucleus
Chronic myeloid leukaemia:
* low leucocyte alkaline phosphatase (LAP) score
AL Amyloidosis
Constitutional symptoms such as weight loss and fatigue are common in AL Amyloidosis but some common presentations include the following:
1) Nephrotic syndrome- 50%.
2) Restrictive cardiomyopathy- 60%.
3) Peripheral neuropathy- Mixed sensory and motor neuropathy (20%), autonomic neuropathy (15%).
4) Hepatomegaly with elevated liver enzymes- Hepatomegaly with or without splenomegaly(70%), elevated liver enzymes (25%).
5) Macroglossia
6) Purpura- Characteristically elicited in a periorbital distribution (raccoon eyes)
7) Bleeding diathesis- Proposed mechanisms include factor X deficiency due to binding to amyloid fibrils primarily in the liver and spleen; decreased synthesis of coagulation factors in patients with advanced liver disease; and acquired von Willebrand disease.
Note: Approximately 10 percent of patients have coexisting multiple myeloma characterized by >30 percent plasma cells on bone marrow examination and/or lytic bone lesions.
Intrinsic pathway
Prekallikrein,
HMWK,
factor 8, 9, 11, 12
Extrinsic pathway
factor 3 (Tissue factor), 7
common pathway
factor 1,2, 4,5,6, 10,13
coats
APTT checks the Intrinsic pathway.
PT checks the Extrinsic pathway.
(mnemonic: Your PET is bleeding Extensively!!)
TCT checks the Common pathway.
Principles of mixing study:
If APTT is raised. Do mixing study.
Patients plasma is mixed 50:50 with normal plasma containing all clotting factors.
If correction occurs –> pt has factor deficiency.
If correction does not occur –> pt has clotting factor inhibitor present.
DDAVP
- releases vWF and FVIII from endothelial stores
Major side effect of DDAVP is hyponatremia.
Von Willebrands disease is mainly a bleeding problem.
Characterized by prolonged APTT and bleeding time with low levels of vWF and Factor VIII.
vWF serves two roles:
As the major adhesion molecule that tethers the platelet to the exposed subendothelium; and
As the binding protein for FVIII, resulting in significant prolongation of the FVIII half-life in circulation.
thrombopoeitin receptor agonist (romiplostim or eltrombopag)
-Increased platelet production in the marrow
Romiplostim is a fusion protein analog of thrombopoietin, a hormone that regulates platelet production.
Romiplostim’s effect is to stimulate the patient’s megakaryocytes to produce platelets at a more rapid than normal rate, thus overwhelming the immune system’s ability to destroy them.
As doing so involves changes to the bone marrow chemistry, a number of potentially serious side-effects may develop, including myalgia, joint and extremity discomfort, insomnia, thrombocytosis, which may lead to potentially fatal clots, and bone marrow fibrosis, the latter which may result in an unsafe decrease in the red blood count.
CYP3A4 inhibitors
- protease inhibitors
o ritonavir
o indinavir
o nelfinavir - macrolide antibiotics
o erythromycin
o telithromycin
o clarithromycin - chloramphenicol (antibiotic)
- azole antifungals
o fluconazole
o ketoconazole
o itraconazole - nefazodone (antidepressant)
- bergamottin (constituent of grapefruit juice)
- aprepitant (antiemetic)
- verapamil (calcium channel blocker)
Antiphospholipid syndrome
Characterized by thrombosis/recurrent miscarriages and present of persistently positive blood test for antiphospholipid antibodies (aPL).
Features
- venous/arterial thrombosis
- recurrent fetal loss
- livedo reticularis
- thrombocytopenia
- prolonged APTT
- other features: pre-eclampsia, pulmonary hypertension
Diagnosis: Must have persistently positive test (at least 2 positives, 6 weeks apart) to diagnose APL: - Anticardiolipin test - Lupus anticoagulant test - Anti-beta2 glycoprotein I test.
Associations other than SLE
- other autoimmune disorders
- lymphoproliferative disorders
- phenothiazines (rare)
Treatment:
For patients who have had ONE or more thrombosis: lifelong warfarin.
If pregnant: aspirin and unfractionated heparin may reduce chance of miscarriage.
BCSH guidelines
- initial venous thromboembolic events: evidence currently supports use of warfarin with a target INR of 2-3 for 6 months
- recurrent venous thromboembolic events: lifelong warfarin; if occurred whilst taking warfarin then increase target INR to 3-4
- arterial thrombosis should be treated with lifelong warfarin with target INR 2-3
antiphos primary prophylaxis
Low dose aspirin is recommended as prophylaxis if the following is present:
– SLE
– Another underlying connective tissue disorder
– History of miscarriage.
Protein C deficiency
necrosis of the skin when commenced on warfarin
MM
Dx;
presence of at least 10% clonal bone marrow plasma cells and serum or urinary monoclonal protein
common symptoms and signs at presentation:
● Anemia – 73 percent
● Bone pain – 58 percent
● Elevated creatinine – 48 percent
● Fatigue/generalized weakness – 32 percent
● Hypercalcemia – 28 percent
● Weight loss – 24 percent, one-half of whom had lost ≥9 kg
Symptoms and signs present in 5 percent or less included: paresthesias (5 percent), hepatomegaly (4 percent), splenomegaly (1 percent), lymphadenopathy (1 percent), and fever (0.7 percent).
warfarin
Warfarin inhibits vitamin K dependent synthesis of factor II,VII,IX and X.
Factor II (prothrombin) is converted to thrombin –> anti-thrombin effect
relative polycythemia, also called stress erythrocytosis or Gaisbock’s syndrome.
Patients with this syndrome characteristically are 45 to 55 years of age (a bit younger than PRV patients), smokers, obese, and hypertensive.
Modest increase in carboxyhemoglobin levels and diuretic therapy may contribute to the high-normal RBC masses and reduced plasma volumes, respectively, that are commonly seen in these patients.
High-normal erythropoietin, exclude polycythemia vera.
Renal cell carcinoma should be considered in the differential but is not the most likely diagnosis, in light of the characteristic presentation for relative polycythemia.
Sleep apnea should also be considered in the differential diagnosis, but the patient has no symptoms of excessive daytime somnolence.
The normal P50 (the Po2 at which 50% of the hemoglobin is deoxygenated) excludes a hemoglobinopathy with increased oxygen affinity.
polycythemia vera
elevated hematocrit (> 60% in men, > 57% in women), splenomegaly, elevation and immaturity of other myeloid cell lines, and the reduced erythropoietin level
myeloid metaplasia
Approximately 20% of patients with polycythemia vera (and the other myeloproliferative disorders) eventually develop myelofibrosis or myeloid metaplasia (MM), a process indistinguishable from agnogenic myeloid metaplasia (AMM).
Myeloid metaplasia is caused by progressive fibrosis of the bone marrow and a shift of hematopoiesis from the marrow to the liver and spleen. Some of the largest spleens encountered in clinical medicine are seen in AMM and MM.
These patients present with progressive cytopenia, and the smear shows characteristic teardrop-shaped red cells and a leukoerythroblastic picture.
Although these patients can progress to acute myeloid leukemia, the presence of a small percentage of myeloblasts should not suggest the diagnosis of acute leukemia in this patient at this time.
haemolysis
Causes of intravascular haemolysis:
1) Mismatched blood transfusion
2) G6PD deficiency
3) Red cell fragmentation-heart valves, TTP,DIC,HUS
4) PNH
5) Cold AIHA
- free Hb excreted in urine as haemoglobinuria, haemosiderinuria
Causes of extravascular hemolysis:
1) Haemoglobinopathies: sickle cell,thalassaemia.
2) Hereditary spherocytosis
3) Hemolytic disease of the newborn
4) Warm AIHA
Evidence of red cell breakdown:
– Hyperbilirubinemia
– Reduced haptoglobin
– Raised plasma haemoglobin (Intravascular hemolysis)
– Hamemoglobinuria (Intravascular hemolysis)
– Urinary haemosiderin (Intravascular hemolysis)
– Methalbuminemia (Intravascular hemolysis)
– Raised LDH
– Raised faecal and urinary urobilinogen
AI hemolytic anemia
DAT
- igG - warm
- igM - cold
