1
Q
best prognosis in Acute myelogenous leukemia
A
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).
2
Q
AML strongest adverse clinical predictors
A
● 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
3
Q
AML commonest gene mutation
A
FLT3
4
Q
Ibrutinib
A
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.
5
Q
ATRA cx
A
- 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.
6
Q
chronic phase of CML rx
A
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.
7
Q
ALL poor prognostic factors
A
- 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
8
Q
Philadelphia positive ALL rx
A
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
9
Q
myelodysplastic syndrome with chromosome 5q syndrome rx
A
Lenalidomide
- can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities
10
Q
risk score in CML
A
HASFORD prognostic score(Measures response post IFN α treatment): “APS BEB”
Age Platelets Spleen size Basophils Eosinophils Blasts
11
Q
Imatinib s/effects
A
- weight gain
- Edema, muscle cramps, nausea, diarrhea, distured LFTs, rash(porphyria)
12
Q
Hodgkin’s lymphoma
A
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
13
Q
Hodgkin’s lymphoma prognosis
A
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
14
Q
Hodgkin’s lymphoma rx
A
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)
15
Q
vWb
A
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
16
Q
Leukemoid reaction
A
- 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
17
Q
AL Amyloidosis
A
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.
18
Q
Intrinsic pathway
A
Prekallikrein,
HMWK,
factor 8, 9, 11, 12
19
Q
Extrinsic pathway
A
factor 3 (Tissue factor), 7
20
Q
common pathway
A
factor 1,2, 4,5,6, 10,13
21
Q
coats
A
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.
22
Q
DDAVP
A
- 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.
23
Q
thrombopoeitin receptor agonist (romiplostim or eltrombopag)
A
-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.
24
Q
CYP3A4 inhibitors
A
- 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)
25
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
26
antiphos primary prophylaxis
Low dose aspirin is recommended as prophylaxis if the following is present:
– SLE
– Another underlying connective tissue disorder
– History of miscarriage.
27
Protein C deficiency
necrosis of the skin when commenced on warfarin
28
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).
29
warfarin
Warfarin inhibits vitamin K dependent synthesis of factor II,VII,IX and X.
Factor II (prothrombin) is converted to thrombin --> anti-thrombin effect
30
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.
31
polycythemia vera
elevated hematocrit (> 60% in men, > 57% in women), splenomegaly, elevation and immaturity of other myeloid cell lines, and the reduced erythropoietin level
32
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.
33
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
34
AI hemolytic anemia
DAT
- igG - warm
- igM - cold
35
macrocytic anemia
Megaloblastic marrow:
– B12 deficiency
– Pernicious anemia
– Folate deficiency
– Congenital enzyme deficiencies in DNA synthesis (e.g. orotic aciduria),
– Drugs: hydroxyurea, azathioprine, zidovudine
– Myelodysplasia due to dyserythropoiesis.
```
Normoblastic marrow:
Physiological: Pregnancy.
Pathological causes:
– alcohol excess
– liver disease
– Reticulocytosis
– Hypothyroidism
– aplastic anaemia
– sideroblastic anaemia
– pure red cell aplasia
– Drugs (e.g. cytotoxics azathioprine)
– Spurious (agglutinated red cells measured on red cell counters)
– Cold agglutinins due to autoagglutination of red cells.
```
NOTE:
Megaloblast:
Peripheral blood film shows oval macrocytes with hypersegmented polymorphs with six or more lobes in the nucleus.
Bone marrow shows megaloblastic erythropoeisis.
Normoblast:
Normal serum B12 and folate.
Normoblastic bone marrow.
36
IDA
```
– Low serum iron.
– Increased TIBC.
– Increased Transferrin.
– Low transferrin saturation.
– Low Ferritin (confirms the diagnosis)
– High Serum soluble transferrin receptors
```
Features
* koilonychia
* atrophic glossitis
* post-cricoid webs
* angular stomatitis
Blood film
* target cells
* ‘pencil’ poikilocytes
* if combined with B12/folate deficiency a ‘dimorphic’ film occurs with mixed microcytic and macrocytic cells
37
Haemolytic uraemic syndrome
MAHA + Thrombocytopenia + Renal failure = HUS
MAHA (microangiopathic haemolytic anemia)
Blood film:
- fragmented RBC with Helmet cells
38
Thalassemia
- α/β globin chain imbalance
In Thalassaemia, the reduced rate of synthesis of one globin chain(either α/β globin chain) leads to unbalance synthesis with an excess of normal chain resulting in ineffective erythropoeisis and haemolysis.
genetic defect :
- α thalassaemia - gene deletion
- β-thalassaemia - point mutation
39
alpha+ thalassaemia trait
clues
| mild anemia and HbH inclusions
40
β-thalassaemia trait
clue: presence of HbA2
HbA2 is made up of α2δ2, so when the body is depleted of β globin chain, it compensates by producing a different form of hemoglobin other than the normal HbA (α2β2).
41
Hb types
```
Normal hemoglobin is HbA (α2β2)
Minor hemoglobin is HbA2 (α2δ2)
Fetal hemoglobin is HbF (α2γ2)
Hb H (β4)
Hb Barts (γ4)
```
42
Acute sickle chest syndrome
- most common cause of death after puberty.
Presents with sob,hypoxia,pulmonary infiltrates.
Treatment is with analgesia, oxygen, hydration, exchange transfusion and ventilatory support.
Hydroxycarbamide (hydroxyurea) is the first drug which has been widely used as therapy for sickle cell anaemia. It acts by increasing Hb F concentrations.
Hydroxycarbamide has been shown in trials to reduce the episodes of pain, the acute chest syndrome, and the need for blood transfusions.
Bone marrow transplantation has been used to treat sickle cell anaemia. Children and adolescents younger than 16 years of age who have severe complications (strokes, recurrent chest syndrome or refractory pain) and have an HLA-matched donor are the best candidates for transplantation.
43
Types of transfusion reactions
```
1) Acute transfusion reactions
Hemolytic transfusion reaction.
– caused by ABO incompatibility.
– donor RBC antigen reacts with recipients pre-existing alloantibody.
Management: DAT, Repeat X-match.
```
Febrile non-hemolytic transfusion reaction (FNHTR):
– caused by donor’s leukocyte reacting to recipients antibody.
– self limited without complication.
Transfusion Related Acute Lung Injury (TRALI):
– Mainly due to donor’s antibody reacting to recipient’s leucocyte (In 85% of cases) (Opposite to FNHTR)
– Identify the donor and inform public health- Tell him/her to STOP donating blood please!!
2) Delayed transfusion reactions:
Transfusion associated Graft Versus Host Disease (GVHD)
– due to recipient unable to mount an immune response to donor’s Lymphocyte
– high mortality (>85%)
– Mx: Use irradiated product.
44
hyperviscosity syndrome, a complication of Waldenstrom’s macroglobulinemia
clin fx;
1) Patient’s advanced age (The median age at diagnosis is 64 years old).
2) Symptoms of hyperviscosity syndrome- blurring or loss of vision, headache, vertigo, nystagmus, dizziness, tinnitus, sudden deafness, diplopia, or ataxia
3) Bruising and epistaxis due to low platelet count.The most common presenting features in WM include weakness, fatigue, weight loss, and chronic oozing of blood from the nose or gums.
3) Fundoscopy findings typically shows dilated, segmented and tortuous retinal veins. Other retinal lesions, including hemorrhages, exudates, and papilledema. Central retinal vein thrombosis can also occur.
4) Lab findings: Anemia, Neutropenia, Thrombocytopenia. Blood film showing macrocytosis with marked rouleaux formation. Raised IgM kappa paraprotein.
The only effective treatment for the hyperviscosity syndrome is the removal of IgM from the circulation via plasmapheresis. The large size of the IgM molecule restricts it mainly to the intravascular space such that it can be rapidly removed with plasmapheresis resulting in prompt alleviation of symptoms.
For patients who present with symptoms due to hyperviscosity, or who develop hyperviscosity during treatment, immediate institution of therapeutic plasmapheresis is required. Red blood cell transfusions should be avoided, if possible, prior to plasmapheresis since they might further increase serum viscosity. Once plasmapheresis is complete, patients will need to initiate chemotherapy to control the malignant clone.
45
Pure red cell aplasia
normochromic, normocytic anemia with elevated EPO levels.
Erythroblasts will be absent in the bone marrow
46
vit K dependant factors
2,7, 9,10
| protein C/ S
47
Essential thrombocytosis
Features
* platelet count > 600 * 109/l
* both thrombosis (venous or arterial) and haemorrhage can be seen
* a characteristic symptom is a burning sensation in the hands
* a JAK2 mutation is found in around 50% of patients
Management
* hydroxyurea (hydroxycarbamide) is widely used to reduce the platelet count
* interferon-α is also used in younger patients
* low-dose aspirin may be used to reduce the thrombotic risk
myeloproliferative disorder associated with an increase in number and size of circulating platelets.
Half of all patients are asymptomatic, but clinical presentations include thrombosis and bleeding. There are no pathognomonic features and it is a diagnosis of exclusion.
Principles of treatment:
1) Group patients into low , intermediate or high risk:
Features of Low and intermediate risk:
– asymptomatic with no high-risk features
– aged 40-60 years are intermediate risk.
Features of high risk:
– age >60 years,
– platelet count >1,500,000/microlitre,
– previous thrombotic or haemorrhagic events.
2) Pregnant/Non-pregnant and low risk:
– Lifestyle modification (smoking cessation and weight control)
– Regular blood counts every 3 months to monitor platelet count
– For mild vasomotor symptoms (e.g. headache, digital ischaemia, erythromelalgia, livedo reticularis) and to decrease the risk of thrombosis, low-dose aspirin may be sufficient.
3) Non pregnant and high risk:
–Hydroxyurea and anti-platelet treatment is first line treatment.
– plus lifestyle modification and 3 monthly bloods.
Other options include **anagrelide, interferon alfa 2b, radio phosphorus.
4) Pregnant and high risk:
– Interferon alpha 2b and anti-platelet treatment is first line.
(contraindicated in patients with thyroid and/or mental disorders)
-plus lifestyle modification and 3 monthly bloods
*Hydroxyurea is an antineoplastic that may cause inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor. It is S-phase specific.
** Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III that reduces platelet production and, at higher than therapeutic doses, inhibits platelet aggregation.
48
Indication for Platelets
– thrombocytopenia (chemo/cancer/consumption)
– defective platelet function
– to prepare patient for surgery if platelet <50
– DO NOT use in ITP.
49
Indications for fresh frozen plasma
– contains ALL the coagulation factors present in fresh plasma.
– Used for correction of bleeding where multiple coagulation factor deficiencies are present:
DIC, liver dysfunction, dilutional coagulopathy, TTP (To replace ADAMS13 enzyme).
50
Indications for cryoprecipitate
– consists of fibrinogen, vWF, Factor VIII, Factor XIII, Fibronectin. (The 5 F’s)
– Used in fibrinogen deficiencies, dysfibrinogenemia,DIC (basically conditions that give you low fibrinogen).
51
Indications for Prothrombinex
– Consists of Vitamin K dependent factors: Factor II, VII,IX, X.
– Used in warfarin reversal.
– DO NOT use in thrombosis, DIC or AMI.
52
Indications for Recombinant Factor VIIa
– Consists of activated recombinant factor VII.
– Used to control bleeding or for procedural prophylaxis in patients with inhibitors to coagulation factors VIII or IX.
– DO NOT use in recent DIC, AMI or Stroke.
53
Desmopressin
– Increases vWF and F 8 levels
– used in vWD.
54
Tranexamic acid
– displaces plasminogen from fibrin and inhibits fibrinolysis.
– used for mucosal bleeding.
55
Hereditary hemorrhagic telangiectasia
| -Also known as Osler-Weber-Rendu syndrome
- autosomal dominant condition characterised by (as the name suggests) multiple telangiectasia over the skin and mucous membranes. Twenty percent of cases occur spontaneously without prior family history.
There are 4 main diagnostic criteria. If the patient has 2 then they are said to have a possible diagnosis of HHT. If they meet 3 or more of the criteria they are said to have a definite diagnosis of HHT:
1. epistaxis : spontaneous, recurrent nosebleeds
2. telangiectases: multiple at characteristic sites (lips, oral cavity, fingers, nose)
3. visceral lesions: for example gastrointestinal telangiectasia (with or without bleeding), pulmonary arteriovenous malformations (AVM), hepatic AVM, cerebral AVM, spinal AVM
4. family history: a first-degree relative with HHT
56
Blood films: typical pictures
Hyposplenism e.g. post-splenectomy
* target cells
* Howell-Jolly bodies
* Pappenheimer bodies
* siderotic granules
* acanthocytes
* schizocytes
Iron-deficiency anaemia
* target cells
* ‘pencil’ poikilocytes
* if combined with B12/folate deficiency a ‘dimorphic’ film occurs with mixed microcytic and macrocytic cells
Myelofibrosis
* ‘tear-drop’ poikilocytes
Intravascular haemolysis
* schistocytes
Megaloblastic anaemia
* hypersegmented neutrophils
57
Sickle-cell crises
Four main types of crises are recognised:
* thrombotic, ‘painful crises’
* sequestration
* aplastic
* haemolytic
Thrombotic crises
* also known as painful crises or vaso-occlusive crises
* precipitated by infection, dehydration, deoxygenation
* infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and brain
Sequestration crises
* sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia
* acute chest syndrome: dyspnoea, chest pain, pulmonary infiltrates, low pO2 – the most common cause of death after childhood
Aplastic crises
* caused by infection with parvovirus
* sudden fall in haemoglobin (without appropriate rise response in reticulocytes)
Haemolytic crises
* rare
* fall in haemoglobin due an increased rate of haemolysis
58
Paroxysmal nocturnal haemoglobinuria
Pathophysiology
* GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
* complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
* thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation
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
Diagnosis
* flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham’s test as the gold standard investigation in PNH
* Ham’s test: acid-induced haemolysis (normal red cells would not)
Management
* blood product replacement
* anticoagulation
* eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis
* stem cell transplantation
59
Hereditary spherocytosis
Basics
* most common hereditary haemolytic anaemia in people of northern European descent
* autosomal dominant defect of red blood cell cytoskeleton
* the normal biconcave disc shape is replaced by a sphere-shaped red blood cell
* red blood cell survival reduced as destroyed by the spleen
Presentation
* failure to thrive
* jaundice, gallstones
* splenomegaly
* aplastic crisis precipitated by parvovirus infection
* degree of haemolysis variable
Diagnosis
* osmotic fragility test
Management
* folate replacement
* splenectomy
60
Haemochromatosis
autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6
raised ferritin and iron, associated with a transferrin saturation of greater than 60% and a low total iron binding capacity
Diagnostic tests
* molecular genetic testing for the C282Y and H63D mutations
* liver biopsy: Perl’s stain
Typical iron study profile in patient with haemochromatosis
* transferrin saturation > 55% in men or > 50% in women
* raised ferritin (e.g. > 500 ug/l) and iron
* low TIBC
Monitoring adequacy of venesection
* BSCH recommend ‘transferrin saturation should be kept below 50% and the serum ferritin concentration below 50 ug/l’
Joint x-rays characteristically show chonedrocalcinosis
general population screening test:
- transferrin saturation is considered the most useful marker.
- Ferritin should also be measured but is not usually abnormal in the early stages of iron accumulation
- testing family members: genetic testing for HFE mutation
61
Polycythaemia
Polycythaemia may be relative, primary (polycythaemia rubra vera) or secondary
Relative causes
* dehydration
* stress: Gaisbock syndrome
Primary
* polycythaemia rubra vera
Secondary causes
* COPD
* altitude
* obstructive sleep apnoea
* excessive erythropoietin: cerebellar haemangioma, hypernephroma, hepatoma, uterine fibroids**
To differentiate between true (primary or secondary) polycythaemia and relative polycythaemia red cell mass studies are sometimes used. In true polycythaemia the total red cell mass in males > 35 ml/kg and in women > 32 ml/kg
**uterine fibroids may cause menorrhagia which in turn leads to blood loss – polycythaemia is rarely a clinical problem
62
Acute lymphoblastic leukaemia: prognostic features
Good prognostic factors
* French-American-British (FAB) L1 type
* common ALL
* pre-B phenotype
* low initial WBC
Poor prognostic factors
* FAB L3 type
* T or B cell surface markers
* Philadelphia translocation, t(9;22)
* age < 2 years or > 10 years
* male sex
* CNS involvement
* high initial WBC (e.g. > 100 * 109/l)
* non-Caucasian
Philadelphia translocation, t(9;22) – good prognosis in CML but poor prognosis in AML + ALL
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Tumour lysis syndrome
Burkitt’s lymphoma is a common cause of tumour lysis syndrome
Tumour lysis syndrome occurs as a result of cell breakdown following chemotherapy. This releases a large quantity of intracellular components such as potassium, phosphate and uric acid.
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Burkitt’s lymphoma
Burkitt’s lymphoma is a high-grade B-cell neoplasm. There are two major forms:
* endemic (African) form: typically involves maxilla or mandible
* sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV
Burkitt’s lymphoma is associated with the c-myc gene translocation, usually t(8:14). The Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of Burkitt’s lymphoma and to a lesser extent the sporadic form.
Management is with chemotherapy. This tends to produce a rapid response which may cause ‘tumour lysis syndrome’.
Complications of tumour lysis syndrome include:
* hyperkalaemia
* hyperphosphataemia
* hypocalcaemia
* hyperuricaemia
* acute renal failure
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Heparin-induced thrombocytopaenia (HIT)
* immune mediated – antibodies form which cause the activation of platelets
* usually does not develop until after 5-10 days of treatment
* despite being associated with low platelets HIT is actually a prothrombotic condition
features include a greater than 50% reduction in platelets, thrombosis and skin allergy
treatment options include alternative anticoagulants such as lepirudin and danaparoid
Both unfractionated and low-molecular weight heparin can cause hyperkalaemia. This is thought to be caused by inhibition of aldosterone secretion.
Heparin overdose may be reversed by protamine sulphate, although this only partially reverses the effect of LMWH.
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CML
The Philadelphia chromosome is present in more than 95% of patients with chronic myeloid leukaemia (CML). It is due to a translocation between the long arm of chromosome 9 and 22 – t(9:22)(q34; q11). This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal
Presentation (40-50 years)
* middle-age
* anaemia, weight loss, abdo discomfort
* splenomegaly may be marked
* spectrum of myeloid cells seen in peripheral blood
* decreased neutrophil alkaline phosphatase
* may undergo blast transformation (AML in 80%, ALL in 20%)
Management
* imatinib is now considered first-line treatment
* hydroxyurea
* interferon-alpha
* allogenic bone marrow transplant
Imatinib
* inhibitor of the tyrosine kinase associated with the BCR-ABL defect
* very high response rate in chronic phase CML
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Chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is caused by a monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%)
Features
* often none
* constitutional: anorexia, weight loss
* bleeding, infections
* lymphadenopathy more marked than CML
Complications
* hypogammaglobulinaemia leading to recurrent infections
* warm autoimmune haemolytic anaemia in 10-15% of patients
* transformation to high-grade lymphoma (Richter’s transformation)
Investigations
* blood film: smudge cells
* immunophenotyping
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AML
Acute myeloid leukaemia is the more common form of acute leukaemia in adults. It may occur as a primary disease or following a secondary transformation of a myeloproliferative disorder.
Poor prognostic features
* > 60 years
* > 20% blasts after first course of chemo
* cytogenetics: deletions of chromosome 5 or 7 (MOST IMPORTANT)
Acute promyelocytic leukaemia M3
* associated with t(15;17)
* fusion of PML and RAR-alpha genes
* presents younger than other types of AML (average = 25 years old)
* DIC or thrombocytopenia often at presentation
* good prognosis
Classification – French-American-British (FAB)
* MO – undifferentiated
* M1 – without maturation
* M2 – with granulocytic maturation
* M3 – acute promyelocytic
* M4 – granulocytic and monocytic maturation
* M5 – monocytic
* M6 – erythroleukaemia
* M7 – megakaryoblastic
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Multiple myeloma
neoplasm of the bone marrow plasma cells.
The peak incidence is patients aged 60-70 years.
Clinical features
* bone disease: bone pain, osteoporosis + pathological fractures (typically vertebral), osteolytic lesions
* lethargy
* infection
* hypercalcaemia (see below)
* renal failure
* other features: amyloidosis e.g. Macroglossia, carpal tunnel syndrome; neuropathy; hyperviscosity
Diagnosis is based on:
* monoclonal proteins in the serum and urine (Bence Jones proteins)
* increased plasma cells in the bone marrow
* bone lesions on the skeletal survey
Hypercalcaemia in myeloma
* due primarily to increased osteoclastic bone resorption caused by local cytokines released by the myeloma cells
* other contributing factors include impaired renal function, increased renal tubular calcium reabsorption and elevated PTH-rP levels
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Venous thromboembolism: risk factors
Common predisposing factors include malignancy, pregnancy and the period following an operation. The comprehensive list below is partly based on the 2010 SIGN venous thromboembolism (VTE) guidelines:
General
* increased risk with advancing age
* obesity
* family history of VTE
* pregnancy (especially puerperium)
* immobility
* hospitalisation
* anaesthesia
* central venous catheter: femoral >> subclavian
Underlying conditions
* malignancy
* thrombophilia: e.g. Activated protein C resistance, protein C and S deficiency
* heart failure
* antiphospholipid syndrome
* Behcet’s
* polycythaemia
* nephrotic syndrome
* sickle cell disease
* paroxysmal nocturnal haemoglobinuria
* hyperviscosity syndrome
* homocystinuria
Medication
* combined oral contraceptive pill: 3rd generation more than 2nd generation
* hormone replacement therapy
* raloxifene and tamoxifen
* antipsychotics (especially olanzapine) have recently been shown to be a risk factor
recurrent VTE:
* previous unprovoked VTE
* male sex
* obesity
* thrombophilias
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Chronic lymphocytic leukaemia: management
Indications for treatment
* progressive marrow failure: the development or worsening of anaemia and/or thrombocytopenia
* massive (>10 cm) or progressive lymphadenopathy
* massive (>6 cm) or progressive splenomegaly
* progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months
* systemic symptoms: weight loss > 10% in previous 6 months, fever >38ºC for > 2 weeks, extreme fatigue, night sweats
* autoimmune cytopaenias e.g. ITP
Management
* patients who have no indications for treatment are monitored with regular blood counts
* fludarabine, cyclophosphamide and rituximab (FCR) has now emerged as the initial treatment of choice for the majority of patients
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Haematological malignancies: infections
Viruses
* EBV: Hodgkin’s and Burkitt’s lymphoma, nasopharyngeal carcinoma
* HTLV-1: Adult T-cell leukaemia/lymphoma
* HIV-1: High-grade B-cell lymphoma
Bacteria
* Helicobacter pylori: gastric lymphoma (MALT)
Protozoa
* malaria: Burkitt’s lymphoma
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Polycythaemia rubra vera
- myeloproliferative disorder --> increase in red cell volume, often accompanied by overproduction of neutrophils and platelets.
It has recently been established that a mutation in JAK2 is present in approximately 95% of patients with PRV and this has resulted in significant changes to the diagnostic criteria.
The incidence of PRV peaks in the sixth decade.
Features
* hyperviscosity
* pruritus, typically after a hot bath
* splenomegaly
* haemorrhage (secondary to abnormal platelet function)
* plethoric appearance
* hypertension in a third of patients
The discovery of the JAK2 mutation has made red cell mass a second-line investigation for patients with suspected JAK2-negative polycythaemia rubra vera
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TTP
Pathogenesis of thrombotic thrombocytopenic purpura (TTP)
* abnormally large and sticky multimers of von Willebrand’s factor cause platelets to clump within vessels
* in TTP there is a deficiency of caspase which breakdowns large multimers of von Willebrand’s factor
* overlaps with haemolytic uraemic syndrome (HUS)
Features
* rare, typically adult females
* fever
* fluctuating neuro signs (microemboli)
* microangiopathic haemolytic anaemia
* thrombocytopenia
* renal failure
Causes
* post-infection e.g. urinary, gastrointestinal
* pregnancy
* drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
* tumours
* SLE
* HIV
Management
* no antibiotics – may worsen outcome
* plasma exchange is the treatment of choice
* steroids, immunosuppressants
* vincristine
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Livedo reticularis
antiphospholipid syndrome and cholesterol embolism
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ITP
Idiopathic thrombocytopenic purpura (ITP) is an immune mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb-IIIa or Ib complex.
ITP can be divided into acute and chronic forms:
Acute ITP
* more commonly seen in children
* equal sex incidence
* may follow an infection or vaccination
* usually runs a self-limiting course over 1-2 weeks
Chronic ITP
* more common in young/middle-aged women
* tends to run a relapsing-remitting course
Evan’s syndrome
* ITP in association with autoimmune haemolytic anaemia (AIHA)
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Sideroblastic anaemia
Sideroblastic anaemia is a condition where red cells fail to completely form haem, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired
Congenital cause: delta-aminolevulinate synthase-2 deficiency
Acquired causes
* myelodysplasia
* alcohol
* lead
* anti-TB medications
Investigations
* hypochromic microcytic anaemia (more so in congenital)
* bone marrow: sideroblasts and increased iron stores
Management
* supportive
* treat any underlying cause
* pyridoxine may help
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Factor V Leiden mutation
Activated protein C resistance
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MGUS
Monoclonal gammopathy of undetermined significance (MGUS, also known as benign paraproteinaemia and monoclonal gammopathy) is a common condition that causes a paraproteinaemia and is often mistaken for myeloma. Differentiating features are listed below. Around 10% of patients eventually develop myeloma at 5 years, with 50% at 15 years
Features
* usually asymptomatic
* no bone pain or increased risk of infections
* around 10-30% of patients have a demyelinating neuropathy
Differentiating features from myeloma
* normal immune function
* normal beta-2 microglobulin levels
* lower level of paraproteinaemia than myeloma (e.g. < 30g/l IgG, or < 20g/l IgA)
* stable level of paraproteinaemia
* no clinical features of myeloma (e.g. lytic lesions on x-rays or renal disease)
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Haematological malignancies: genetics
t(9;22) – Philadelphia chromosome
* present in > 95% of patients with CML
* this results in part of the Abelson proto-oncogene being moved to the BCR gene on chromosome 22
* the resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal
* poor prognostic indicator in ALL
t(15;17)
* seen in acute promyelocytic leukaemia (M3)
* fusion of PML and RAR-alpha genes
t(8;14)
* seen in Burkitt’s lymphoma
* MYC oncogene is translocated to an immunoglobulin gene
t(11;14)
* Mantle cell lymphoma
* deregulation of the cyclin D1 (BCL-1) gene
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Hyposplenism
Causes
* splenectomy
* sickle-cell
* coeliac disease, dermatitis herpetiformis
* Graves’ disease
* systemic lupus erythematosus
* amyloid
Features
* Howell-Jolly bodies
* siderocytes
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thrombocytopenia
Causes of severe thrombocytopenia
* ITP
* DIC
* TTP
* haematological malignancy
Causes of moderate thrombocytopenia
* heparin induced thrombocytopenia (HIT)
* drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides)
* alcohol
* liver disease
* hypersplenism
* viral infection (EBV, HIV, hepatitis)
* pregnancy
* SLE/antiphospholipid syndrome
* vitamin B12 deficiency
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Sjogren’s syndrome
Sjogren’s syndrome is an autoimmune disorder affecting exocrine glands resulting in dry mucosal surfaces. It may be primary (PSS) or secondary to rheumatoid arthritis or other connective tissue disorders, where it usually develops around 10 years after the initial onset. Sjogren’s syndrome is much more common in females (ratio 9:1). There is a marked increased risk of lymphoid malignancy (40-60 fold)
Features
* dry eyes: keratoconjunctivitis sicca
* dry mouth
* vaginal dryness
* arthralgia
* Raynaud’s, myalgia
* sensory polyneuropathy
* renal tubular acidosis (usually subclinical)
Investigation
* rheumatoid factor (RF) positive in nearly 100% of patients
* ANA positive in 70%
* anti-Ro (SSA) antibodies in 70% of patients with PSS
* anti-La (SSB) antibodies in 30% of patients with PSS
* Schirmer’s test: filter paper near conjunctival sac to measure tear formation
* histology: focal lymphocytic infiltration
* also: hypergammaglobulinaemia, low C4
Management
* artificial saliva and tears
* pilocarpine may stimulate saliva production
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Thrombophilia: causes
Inherited
* activated protein C resistance (factor V Leiden)
* antithrombin III deficiency
* protein C deficiency
* protein S deficiency
Acquired
* antiphospholipid syndrome
* the Pill
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Hairy cell leukaemia
Hairy cell leukaemia is a rare malignant proliferation disorder of B cells. It is more common in males (4:1)
Features
* pancytopenia
* splenomegaly
* skin vasculitis in 1/3 patients
* ‘dry tap’ despite bone marrow hypercellularity
* tartrate resistant acid phosphotase (TRAP) stain positive
Management
* chemotherapy is first-line: cladribine, pentostatin
* immunotherapy is second-line: rituximab, interferon-alpha
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Leucocyte alkaline phosphatase
Raised in
* myelofibrosis
* leukaemoid reactions
* polycythaemia rubra vera
* infections
* steroids, Cushing’s syndrome
* pregnancy, oral contraceptive pill
Low in
* chronic myeloid leukaemia
* pernicious anaemia
* paroxysmal nocturnal haemoglobinuria
* infectious mononucleosis
