Haematology Flashcards
What is Antiphospholipid syndrome?
Characterized by the presence of antiphospholipid antibodies (APL) in the plasma, venous and arterial thromboses, recurrent foetal loss and thrombocytopenia
What is the aetiology of Antiphospholipid syndrome?
APL are directed against plasma proteins bound to anionic phospholipids (e.g. b2 glycoprotein-I)
APL may develop in susceptible individuals (e.g. those with rheumatic diseases such as SLE) following exposure to infectious agents
Once APL are present, a ‘second-hit’ is needed for the development of the syndrome
Complement activation is critical for pregnancy complications
What is the epidemiology of Antiphospholipid syndrome?
Can occur in patients without an underlying systemic autoimmune disease (primary APS) or with other autoimmune disease (also known as secondary APS), particularly systemic lupus erythematosus (SLE)
More common in young women
Accounts for 20% of strokes in <45-year- olds and 27% of women with >2 miscarriages
What are the presenting symptoms of Antiphospholipid syndrome?
Recurrent miscarriages History of arterial thromboses (stroke), venous throm- boses (DVT, pulmonary embolism) Headaches (migraine) Chorea (involuntary movement) Epilepsy
What are the signs of Antiphospholipid syndrome on physical examination?
Features of thrombocytopenia: petechial rash or symptoms of mucosal bleeding
Arthralgia/arthritis
Livedo reticularis: mottled purplish discoloration of the skin, which can be blanching or non-blanching on pressure
Signs of SLE (malar flush, discoid lesions, photosensitivity)
Valvular disease (cardiac murmur): UNCOMMON
What are the appropriate investigations for Antiphospholipid syndrome?
Lupus anticoagulant assays: positive on 2 occasions, 12 weeks apart, clotting assays showing effects of APL on the phospholipid-dependent factors in the coagulation cascade
ELISA testing for Anticardiolipin antibody (of IgG or IgM) and anti-b2-GPI antibodies
ANA, ds DNA, extractable nuclear antigen antibodies: elevated in SLE
Bloods:
-FBC (low platelets), ESR (usually normal), U&Es (APL nephropathy), clotting screen (prolonged APTT)
What is Aplastic anaemia?
Characterized by diminished haematopoietic precursors in the bone marrow and deficiency of all blood cell elements (pancytopaenia)- no abnormal cells
What is the aetiology of Aplastic anaemia?
Most often Idiopathic (>40%):
-May be due to destruction or suppression of stem cells by autoimmune mechanisms
Acquired:
-Drugs (chloramphenicol, NSAIDs, gold, alkylating agents, antiepileptics, sulphonamides, methotrexate), chemicals (DDT, benzene), radiation, viral infection (B19 parvovirus, HIV, EBV), paroxysmal nocturnal haemoglobinuria
Inherited:
-Fanconi’s anaemia, dyskeratosis congenita (associated with reticulated hyperpigmented rash, nail dystrophy and mucosa leukoplakia)
What is the epidemiology of Aplastic anaemia?
Annual incidence: 2–4 in per million
Can occur at any age
Slightly more common in males
What are the presenting symptoms of Aplastic anaemia?
Slow (months) or rapid (days) onset Anaemia: -Tiredness -Lethargy -Dyspnoea Thrombocytopaenia: -Easy bruising -Bleeding gums -Epistaxis Leukopenia: Increased frequency and severity of infections
What are the signs of Aplastic anaemia on physical examination?
Anaemia: Pale Thrombocytopaenia: Petechiae, bruises Leukopaenia: -Multiple bacterial or fungal infections No hepatomegaly, splenomegaly or lymphadenopathy
What are the appropriate investigations for Aplastic anaemia?
1st line:
-FBC: 2 or more cytopenias among the following:
*Hb <100 g/L (<10 g/dL)
*Platelet <50 × 10⁹/L
*Absolute neutrophil count <1.5 × 10⁹/L
Reticulocyte count: low or absent reticulocytes
Bone marrow biopsy (and cytogenetic analyses):
-Hypocellular marrow with no abnormal cell population
-Marrow space is composed mostly of fat cells and marrow stroma
-Exclusion of other causes e.g. lymphoma, leukaemia, malignancies, myeloma
Others:
Blood film: To exclude leukaemia (absence of abnormal circulating white blood cells)
What is the criteriea for severe aplastic anaemia?
Marrow showing <25 % of normal cellularity
OR
Marrow showing <50 % of normal cellularity, <30% of the cells are haematopoietic plus 2 of the following:
-neutrophils < 0.5x10⁹/L
-platelets < 20x10⁹/L
-reticulocytes < 40x10⁹/L
What is Blood product transfusion?
A lifesaving procedure to treat hemorrhages and to improve oxygen delivery to tissues
What are the indications for Blood product transfusion (red cell)?
Symptomatic anemia (causing shortness of breath, dizziness, congestive heart failure, and decreased exercise tolerance)
Acute sickle cell crisis
Acute blood loss of more than 30 percent of blood volume
What are the indications for Blood product transfusion (fresh frozen plasma)?
Can be used for reversal of anticoagulant effects
What are the indications for Blood product transfusion (Platelet transfusion)?
To prevent haemorrhage in patients with thrombocytopenia or platelet function defects
What are the indications for Blood product transfusion (Cryoprecipitate)?
Used in cases of hypofibrinogenemia, which most often occurs in the setting of massive hemorrhage or consumptive coagulopathy
What are the possible complications of Blood product transfusion?
Acute complications occur within minutes to 24 hours of the transfusion, whereas delayed complications may develop days, months, or even years later
*Infections are less common because of advances in the blood screening process
Non-infectious complications (acute): -Acute haemolytic reaction -Allergic/Anaphylactic reaction -Coagulation problems in massive transfusion -Metabolic derangements -Septic or bacterial contamination -Transfusion-associated circulatory overload Non-infectious complications (delayed): -Delayed haemolytic reaction -Iron overload -Post-transfusion purpura
Infectious complications:
- Hepatitis B virus
- Hepatitis C virus
- Human T-lymphotropic virus 1 or 2
- Human immunodeficiency virus
What is Disseminated intravascular coagulation (DIC)?
An acquired syndrome characterised by activation of coagulation pathways, resulting in formation of intravascular thrombi and depletion of platelets and coagulation factors
Thrombi may lead to vascular obstruction/ischaemia and multi-organ failure
What is the aetiology of Disseminated intravascular coagulation (DIC)?
Disease states that trigger systemic activation of coagulation may lead to DIC. Causes include:
- Sepsis/severe infection, major trauma or burns
- Some malignancies (acute myelocytic leukemia or metastatic mucin-secreting adenocarcinoma)
- Obstetric disorders (amniotic fluid embolism, eclampsia, abruptio placentae, retained dead fetus syndrome)
- Severe organ destruction or failure (severe pancreatitis, acute hepatic failure)
- Vascular disorders (Kasabach-Merritt syndrome or giant haemangiomas, large aortic aneurysms)
- Severe toxic or immunological reactions (blood transfusion reaction or haemolytic reactions, organ transplant rejection, snake bite)
What is the epidemiology of Disseminated intravascular coagulation (DIC)?
Many conditions can cause DIC, therefore, the overall incidence is difficult to determine
Seen in any severely ill patient
What are the presenting symptoms of Disseminated intravascular coagulation (DIC)?
The patient is severely unwell with symptoms of:
- The underlying disease
- Confusion
- Dyspnoea
- Evidence of bleeding
What are the signs of Disseminated intravascular coagulation (DIC) on physical examination?
Signs of the underlying aetiology, fever, evidence of shock (hypotension, tachycardia, oliguria)
Acute DIC:
-Petechiae
-Purpura
-Ecchymoses
-Epistaxis
-Mucosal bleeding
-Overt haemorrhage
-Signs of end organ damage (e.g. local infarction or gangrene), respiratory distress, oliguria caused by renal failure
Chronic DIC:
-Signs of deep venous or arterial thrombosis or embolism
-Superficial venous thrombosis, especially without varicose veins
What are the appropriate investigations for Disseminated intravascular coagulation (DIC)?
Blood:
FBC:
-Decreased platelets (due to excessive consumption)
-Decreased fibrinogen (due to excessive consumption)
-Prolonged prothrombin time
-Elevated D dimer
-Raised fibrin degradation products
Peripheral blood film:
-Red blood cell fragments (schistocytes)
Other investigations according to aetiology
What is Haemolytic anaemia?
Premature erythrocyte breakdown causing shortened erythrocyte life span (<120 days) and anaemia
What is the aetiology of Haemolytic anaemia?
Hereditary causes:
-Membrane defects e.g. Hereditary spherocytosis
-Metabolic defects e.g. G6PD deficiency
-Haemoglobinopathies e.g. Sickle cell disease, Thalassaemia
Acquired causes:
-Autoimmune: Warm and cold antibodies attach to erythrocytes causing intravascular and extravasular haemolysis
-Isoimmune: Transfusion reaction, haemolytic disease of the newborn
-Drugs: Penicillin, quinine
-Trauma: Microangiopathic haemolytic anaemia caused by red cell fragmentation in abnormal microcirculation (e.g. haemolytic uraemic syndrome, DIC, malignant hypertension, pre-eclampsia), artificial heart valves
-Infection: Malaria, sepsis
-Paroxysmal nocturnal haemoglobinuria: rare disorder resulting in an acquired RBC membrane defect and subsequent haemolysis
What is the epidemiology of Haemolytic anaemia?
Common
Genetic causes are prevalent in African, Mediterranean, Middle Eastern populations
Glucose-6-phosphate dehydrogenase deficiency, is the most common deficiency of erythrocyte enzymes that results in a shortening of the erythrocyte lifespan
-Hereditary spherocytosis is the most common inherited haemolytic anaemia in northern Europe
Warm antibody haemolytic anaemia is the most common form of autoimmune haemolytic anaemia, and affects more women than men
What are the presenting symptoms of Haemolytic anaemia?
Jaundice
Haematuria
Anaemia: fatigue, dyspnoea
Possible symptoms of systemic illness
What are the signs of Haemolytic anaemia on physical examination?
Pallor (anaemia)
Jaundice
Hepatosplenomegaly
What are the appropriate investigations for Haemolytic anaemia?
Bloods:
-FBC*: first test: (low Hb, increased reticulocytes (>1.5%), raised MCV, also elevated unconjugated bilirubin, low haptoglobin, increased mean corpuscular haemoglobin concentration-MCHC)
-Haptoglobin binds free Hb, with low plasma values suggestive of increased free Hb
-Increased LDH
Blood film:
-Leucoerythroblastic picture
-Macrocytosis
-Nucleated erythrocytes or reticulocytes
-Polychromasia
-Identifies specific abnormal cells, such as spherocytes, elliptocytes, sickle cells, fragmented erythrocytes, malarial parasites, erythrocyte Heinz bodies (denatured Hb, stained with methyl violet seen in G6PD deficiency)
Others:
-Urinalysis: Haemoglobinuria is present in intravascular haemolysis (dipstick positive for blood, no RBCs)
-LFTs: elevated in liver disease, alcoholic cirrhosis in particular
-Creatine and Urea: May also be elevated due to direct toxic effects of drugs or infection (haemolytic uraemic syndrome)
What is Haemolytic uraemic syndrome?
Characterised by microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury
There are two forms:
1. D + (diarrhoea-associated form)
2. D - (no prodromal illness identified)
What is the aetiology of Haemolytic uraemic syndrome?
An aetiological factor causing endothelial injury (glomerular capillary bed) resulting in platelet aggregation, release of unusually large vWF multimers and activation of platelets and the clotting cascade:
- FH
- Shiga toxin-producing strains of Escherichia coli,
- Infectious HUS (non-Shiga toxin-related) is caused by non-E coli organisms, including streptococcal species
- Secondary HUS: exposure to drugs (e.g., ciclosporin, some chemotherapy agents, targeted cancer agents), bone marrow transplant, and pregnancy
What is the epidemiology of Haemolytic uraemic syndrome?
Shiga toxin-producing Escherichia coli (STEC) HUS is most common in young children (<5 years), but it can be seen at any age with decreasing frequency in older children and adults
Occurs more often in summer in epidemics and is the most common cause of acute renal failure in children
What are the presenting symptoms of Haemolytic uraemic syndrome?
GI: Severe abdominal colic, watery diarrhoea that becomes bloodstained**(most common symptom)
General: Malaise, fatigue, nausea, fever <38oC
Renal: Oliguria or anuria, haematuria
What are the signs of Haemolytic uraemic syndrome on physical examination?
Pallor (from anaemia) Slight jaundice (from haemolysis) Possible abdominal tenderness
What are the appropriate investigations for Haemolytic uraemic syndrome?
FBC: anaemia, thrombocytopenia, increased LDH, low haptoglobin
Prolonged prothrombin time
Serum electrolytes: abnormalities may include hyperkalaemia, hyponatraemia, hypernatraemia, acidosis (due to bicarbonate loss), hyperphosphataemia- due to diarrhoea and acute kidney injury
Clotting: Normal Plt, APTT and fibrinogen levels, abnormality may indicate DIC
Blood smear/film: presence of schistocytes (fragmented RBCs)
Renal function/creatinine: creatinine increased
Stool culture
Blood culture, PCR
What is Haemophilia?
Are bleeding disorders from an inherited (X-linked recessive inheritance pattern) deficiency of a coagulation factor
What are the different subtypes of Haemophilia?
- Haemophilia A: (most common). Caused by a deficiency in factor VIII (8)
- Haemophilia B: Caused by a deficiency in factor IX (Christmas disease) (9)
- Haemophilia C: (rare), caused by a deficiency in factor XI (11)
What is the aetiology of Haemophilia?
Congenital haemophilia has an X-linked recessive pattern of inheritance and so boys/men are exclusively affected, although many female carriers experience bleeding symptoms requiring appropriate management
A variety of genetic mutations in the factor VIII and XI genes have been described- 30 % of cases are new mutations
Factor VIII is a vital co-factor in the intrinsic pathway of the coagulation cascade
Activated factor IX activates factor X
(converts factor X->Xa)
What is the epidemiology of Haemophilia?
Incidence of haemophilia A is 1 in 5,000 males and for haemophilia B is 1 in 30,000 males
Affects all ethnic groups and has a worldwide distribution
What are the presenting symptoms of Haemophilia?
Symptoms usually begin from early childhood
Swollen painful joints occurring spontaneously or with minimal trauma (haemarthroses)
Painful bleeding into muscles
Haematuria
Excessive bruising or bleeding after surgery or trauma
Female carriers usually asymptomatic, but may have low-enough levels to cause excess bleeding after trauma, or menorrhagia and bleeding following surgery or childbirth
What are the signs of Haemophilia on physical examination?
Multiple bruises.
Muscle haematomas
Haemarthroses
Joint deformity
Nerve palsies (nerve compression by haematoma)
Signs of iron-deficiency anaemia- pallor, Koilonychia (spoon nails)
What are the appropriate investigations for Haemophilia?
Activated partial thromboplastin time: usually prolonged; may not be prolonged in mild cases (factor levels >30%)- reflects the activity of the intrinsic and the common pathway
*Coagulation factor assays:
-Factor VIII and/or factor IX assay: decreased or absent factor VIII or IX levels; severity is based on level of factor present
-A one-stage method is more commonly used as it is simple and readily automated
Others:
-FBC: usually normal, performed to rule out thrombocytopenia as a cause of bleeding- anaemia may be present
-Prothrombin time: evaluate the extrinsic and common pathways of coagulation- normal
-Plain x-rays: used to describe the clinical progression of arthropathy, acute joint bleeding (haemarthrosis), or bone changes more consistent with chronic arthropathy
-MRI and ultrasound: may detect soft-tissue bleeding and its consequences at an early stage
What is Immune thrombocytopenic purpura (ITP)?
Syndrome characterized by immune destruction of platelets resulting in bruising or a bleeding tendency
What is the aetiology of Immune thrombocytopenic purpura (ITP)?
Often idiopathic
Acute ITP is usually seen after a viral infection in children, while the chronic form is more common in adults
Associated with:
-Infections (malaria, EBV, HIV)
-Autoimmune diseases (e.g. SLE, thyroid disease)
-Malignancies
-Drugs (e.g. quinine)
Autoantibodies that bind to platelet membrane proteins (glycoprotein IIb/IIIa and Ib/ IX) which results in thrombocytopaenia (low numbers of platelets)
What is the epidemiology of Immune thrombocytopenic purpura (ITP)?
Acute ITP presents in children between 2-7 years Chronic ITP is seen in adults
Four times more common in women
What are the presenting symptoms of Immune thrombocytopenic purpura (ITP)?
Easy bruising
Mucosal bleeding
Menorrhagia
Epistaxis
What are the signs of Immune thrombocytopenic purpura (ITP)?
Visible petechiae
Bruises (purpura or ecchymoses)
Typically, signs of other illness (e.g. infections, wasting, splenomegaly) would suggest other causes
What are the appropriate investigations for Immune thrombocytopenic purpura (ITP)?
*FBC and peripheral blood smear: platelet count <100 × 10⁹/L (<100 × 10³/microlitre), helps distinguish between rue thrombocytopenia and pseudothrombocytopenia
-Clotting screen (normal PT, APTT, fibrinogen), autoantibodies (antiplatelet antibody may be present but not used routinely for diagnosis, anticardiolipin
antibody, antinuclear antibody)
Bone marrow: To exclude other pathology. Normal or elevated megakaryocytes
Diagnosis of exclusion: Exclude myelodysplasia, acute leukaemia, marrow infiltration
What is Leukaemia, acute myeloblastic (AML)?
Malignancy of primitive myeloid lineage WBCs (myeloblasts) with proliferation in the bone marrow and blood
What is the aetiology of Leukaemia, acute myeloblastic (AML)?
- Myeloblasts, arrest at an early stage of development, with varying cyto-genetic abnormalities (e.g. gene mutations and chromosome translocations)
- Myeloblasts then undergo malignant transformation and proliferation, with subsequent replacement of normal marrow elements
- Resulting in bone marrow failure
What is the epidemiology of Leukaemia, acute myeloblastic (AML)?
*Most common acute leukaemia in adults
Incidence increases with age.
What are the presenting symptoms of Leukaemia, acute myeloblastic (AML)?
Symptoms of bone marrow failure:
-Anaemia (lethargy, dyspnoea)
-Bleeding (thrombocytopaenia) or DIC(Disseminated intravascular coagulation-blood clots form throughout the body)
-Opportunistic or recurrent infections
Symptoms of tissue infiltration:
-Gum swelling or bleeding
-CNS involvement (headaches, nausea, diplopia-double vision): especially with particular variants
What are the signs of Leukaemia, acute myeloblastic (AML) on physical examination?
Signs of bone marrow failure:
-Pallor
-Cardiac flow murmur
-Ecchymoses (discolouration of skin from bleeding underneath)
-Bleeding
-Opportunistic or recurrent infections (e.g. fever, mouth ulcers, skin infections, Pneumocytis Pneumonia- PCP)
Signs of tissue infiltration:
-Skin rashes
-Gum hypertrophy
-Deposits of leukaemic blasts may rarely be seen in the eye (chloroma), tongue and bone – in the latter may cause fractures
What are the appropriate investigations for Leukaemia, acute myeloblastic (AML)?
Bloods:
-FBC (reduced Hb, reduced platelets, variable WCC)
-Raised Uric acid
-Raised LDH
-Others: clotting studies, fibrinogen and D-dimers (when DIC is suspected)
*Blood film: AML blasts may show cytoplasmic granules or Auer rods
*Bone marrow aspirate or biopsy:
-Hypercellular with >30 % blasts (immature cells)
Immunophenotyping: Antibodies against surface antigens to classify lineage of abnormal clones
Immunocytochemistry: Myeloblasts granules are positive
[Cytogenetics: For diagnostic and prognostic information]
What is Leukaemia, acute lymphoblastic (ALL)?
Malignancy of the bone marrow and blood characterized by the proliferation of lymphoblasts (primitive lymphoid cells)
What is the aetiology of Leukaemia, acute lymphoblastic (ALL)?
- Lymphoblasts, arrest at an early stage of development, with varying cytogenetic abnormalities (e.g. gene mutations and chromosome translocations)
- Lymphoblasts then undergo malignant transformation and proliferation, with subsequent replacement of normal marrow elements
- Resulting in bone marrow failure and infiltration into other tissues
What is the epidemiology of Leukaemia, acute lymphoblastic (ALL)?
Most common malignancy of childhood.
The peak incidence occurs between 2 and 5 years of age
Second peak in the elderly
What are the risk factors/associations of Leukaemia, acute lymphoblastic (ALL)?
Environmental: radiation, viruses
Genetic: e.g. Down’s syndrome, neurofibromatosis type 1, increased risk in siblings
What are the presenting symptoms of Leukaemia, acute lymphoblastic (ALL)?
Symptoms of bone marrow failure:
-Anaemia (fatigue, dyspnoea)
-Bleeding (spontaneous bruising, bleeding gums, menorrhagia)
-Opportunistic infections (bacterial, viral, fungal, protozoal)
Symptoms of organ infiltration:
-Tender bones
-Enlarged lymph nodes
-Mediastinal compression (in T-cell ALL)
-Meningeal involvement (headache, visual disturbances, nausea)
What are the signs of Leukaemia, acute lymphoblastic (ALL) on physical examination?
Signs of bone marrow failure: Pallor -Bruising -Bleeding -Infection (e.g. fever, GI, skin, respiratory systems) Signs of organ infiltration: -Lymphadenopathy -Hepatosplenomegaly -Cranial nerve palsies -Retinal haemorrhage or papilloedema on fundoscopy -Leukaemic infiltration of the anterior chamber of the eye (mimics hypopyon) -Testicular swelling
What are the appropriate investigations for Leukaemia, acute lymphoblastic (ALL)?
Bloods:
-FBC (normochromic normocytic anaemia, reduced platelets, variable WCC)
-Raised uric acid, raised LDH, clotting screen
Blood film: Lymphoblasts evident
Bone marrow aspirate or trephine biopsy:
-Hypercellular with >30 % lymphoblasts
-Immunophenotyping: Using antibodies for cell surface antigens e.g. CD20
Lumbar puncture (and CSF analysis): For CNS involvement.
CXR: May show mediastinal lymphadenopathy, thymic enlargement, lytic bone lesions
Bone radiographs: Mottled appearance with ‘punched-out’ lesions (e.g. skull caused by leukaemic infiltration)
What are the classifications for Leukaemia, acute lymphoblastic (ALL)?
Morphologic classification(French–American–British classification):
L1: Small lymphoblasts, scanty cytoplasm.
L2: Larger, heterogenous lymphoblasts.
L3: Large lymphoblasts with blue or vacuolated cytoplasm.
What is Leukaemia, chronic myeloid (CML)?
A malignant clonal disease characterized by proliferation of granulocyte precursors in the bone marrow and blood
*distinguished from AML by its SLOWER progression
What is the aetiology of Leukaemia, chronic myeloid (CML)?
Malignant proliferation of stem cells. Three stages:
- Relatively stable chronic phase of variable duration (average of 4–6 years)
- Accelerated phase (3–9 months)
- Acute leukaemia phase (blast transformation)
What is the epidemiology of Leukaemia, chronic myeloid (CML)?
Incidence increases with age, mean 40–60 years
4 times more common in males
What are the presenting symptoms of Leukaemia, chronic myeloid (CML)?
Asymptomatic in up to 40–50 % and is diagnosed on routine blood count
Hypermetabolic symptoms:
Weight loss, malaise, sweating
Bone marrow failure symptoms: Lethargy, dyspnoea, easy bruising, epistaxis (infection is rare)
Others:
-Abdominal discomfort and early satiety
-Occasionally presents with gout or hyperviscosity symptoms (visual disturbance, headaches)
-May present during blast crisis with symptoms of AML or ALL
What are the signs of Leukaemia, chronic myeloid (CML) on physical examination?
Splenomegaly: Most common physical finding (90%)
Signs of bone marrow failure:
-Pallor
-Cardiac flow murmur
-Bleeding
-Ecchymoses (discolouration of skin from bleeding underneath)
What are the appropriate investigations for Leukaemia, chronic myeloid (CML)?
Bloods:
-FBC: grossly raised WCC, low Hb, raised basophils /eosinophils/ neutrophils, variable platelets
-Raised uric acid, low neutrophil alkaline phosphatase, high vitamin B12 and B12-binding protein
Blood film: Shows immature granulocytes in peripheral blood
Bone marrow aspirate or biopsy:
Hypercellular with raised myeloid–erythroid ratio
What is Leukaemia, chronic lymphocytic (CLL)?
Characterized by progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin
*There is an overlap between CLL and non- Hodgkin’s lymphomas
What is the aetiology of Leukaemia, chronic lymphocytic (CLL)?
Malignant cells may accumulate as a result of their inability to undergo apoptosis (partly due to overexpression of BCL2 and Fas-inhibitory molecules)
