Haematology 2 Flashcards
What investigations are done for myeloma?
FBC: normochromic, normocytic anemia, leucopenia
Blood film: roleaux formation
ESR: raised
U&Es: often deranged
calcium: raised
ALP: normal
Serum/urine electrophoresis: paraprotein monoclonal band seen
Urine Bence-Jones protein: positive
Free immunoglobulin light chains present in the urine the precipitate and then disappear again on heating the urine
Skeletal XR: punched out lytic lesions e.g. pepper pot skull
Bone marrow biopsy: increased clonal plasma cells >10%
If under 10% then the disease may be termed ‘monoclonal gammopathy of uncertain significance’: MGUS
CT of body
B – Bence–Jones protein (request urine electrophoresis)
L – Serum‑free Light‑chain assay
I – Serum Immunoglobulins
P – Serum Protein electrophoresis
Bone marrow biopsy is necessary to confirm the diagnosis of myeloma and get more information on the disease.
What is the management for myeloma?
Supportive therapy
Chemotherapy - bortezomid, thalidomide, dexamethasone
Radiotherapy
Bone marrow stem cell transplants used if <70 as this allows higher dose chemotherapy
Patients require venous thromboembolism prophylaxis with aspirin or low molecular weight heparin whilst on certain chemotherapy regimes (e.g. thialidomide) as there is a higher risk of developing a thrombus.
What are the complications of myeloma?
Hypercalcaemia, spinal cord compression, hyperviscosity and acute renal failure
What is the prognosis for myeloma?
Original myeloma cell is very resistant so oftenrmeturns
median survival is 3-4 years
death is usually from renal failure or infection
What are lymphomas?
Malignant proliferation of lymphocytes, which most commonly accumulate in peripheral lymph nodes, but ca accumulate in teh peripheral blood or infiltrate organs
Most are derived from B cells
What proportion of lymphomas are Hodgkin’s lymphomas?
How are they differentiated?
1 in 5 or 20-25% are Hodgkin’s lymphoma
characterised by Reed-Sternburg cells: Binucleate ‘mirror cells’ on biopsy
What is the largest peak of incidence of Hodgkin’s lymphomas?
Bimodal: As young adults (20-35)
A second peak in 50-70 year olds
What are the risk factors for Hodkin’s lymphomas?
Male family history HIV EBV autoimmune condition such as SLE obese
What are the symptoms of Hodkin’s lymphoma?
B symptoms:
fever, weight loss, profuse night sweats
Alcohol - lymph node pain
mediastinal LN can have mass effects (SVC / bronchial obstruction or effects of direct extension (pleural effusion)
Fatigue Itching Cough Shortness of breath Abdominal pain Recurrent infections
What is Non-Hodgkin’s lymphoma?
Includes all lymphomas without the presence of Reed-Sternberg cells
Peak incidence is 70 years
Either high grade: divide rapidly, typically present with rapid onset lymphadenopathy
or
Low grade tumours: divide slowly, typically present more insidiously and thus tend to be widely disseminated at diagnosis, often incurable
Burkitt lymphoma
MALT lymphoma
Diffuse large B cell lymphoma (most common)
What are the symptoms of Non-Hodgkin’s lymphoma?
extra Nodal disease: 75% have superficial lymphadenopathy at presentation, can affect the oropharynx, skin, CNS, gut or lung
B symptoms: weight loss indicates disseminated disease
Bone marrow failure
What investigations can be done for Non-Hodgkin’s lymphoma?
FBC, film, ESR, LFTs, U&Es, LDH, Ca2+
lymph node dissection biopsy if possible
Image guided biopsy, laparotomy, mediastinoscopy
Staging CT
What is the management of Non-Hodgkin’s lymphoma?
chemotherapy, radiotherapy or chemo-radiotherapy
What is the prognosis for non-hodgkin’s lymphoma?
Poor prognostic signs are age >60 at presentation, disseminated disease and raised LDH
Survival = very variable
How is staging of lymphomas done?
Ann Arbor
Stage 1: Confined to one region of lymph nodes.
Stage 2: In more than one region but on the same side of the diaphragm (either above or below).
Stage 3: Affects lymph nodes both above and below the diaphragm.
Stage 4: Widespread involvement including non-lymphatic organs such as the lungs or liver.
What are myeloproliferative disorders?
These conditions occur due to uncontrolled proliferation of a single type of stem cell. They are considered a type of bone marrow cancer.
The three myeloproliferative disorders to remember are:
Primary myelofibrosis - haematopoeic stem cell
Polycythaemia vera - erythroid cells
Essential thrombocythaemia - megakaryocyte (platelet precursor)
What is essential thrombocythaemia
Clonal proliferation of megakaryocytes leading to persistently raised platelets which is often asymptomatic
The platelets have abnormal function, thus the most common presentation is with microvascular obstruction
Other symptoms may be related to bleeding or aterial / venous thrombosis
What is PCV?
Polycythemia vera
Malignant proliferation of a clone derived from one pluripotent marrow cell - Excess production of RBCs, WBCs and platelets lead to serum hyperviscosity and thrombotic complications
Diagnosed by increased red cell mass, or investigation for a JAK2 mutation
Often asymptomatic, or presents in patients >60 with arterial or venous thrombosis
What are the other rarer presentations of PCV?
Vague hyperviscosity symptoms: headache, dizziness, tinnitus, facial plethora, erythromelalgia, splenomegaly
gout - due to increased cell turnover
What’s the management of polycythaemia vera?
Venesection can be used to keep the haemoglobin in the normal range. This is the first line treatment.
Aspirin can be used to reduce the risk of developing blood clots (thrombus formation).
Chemotherapy can be used to control the disease
What are the key differentials to rule out in primary PCV?
Hypoxia and renal disease
In these secondary polycythaemia syndromes, only the red cell count is raised
What is primary myelofibrosis?
proliferation of the cell line leads to fibrosis of the bone marrow (replaced with scar tissue)
This is in response to cytokines that are released from the proliferating cells: fibroblast growth factor.
This fibrosis affects the production of blood cells and can lead to anaemia and low white blood cells (leukopenia).
Due to fibrosis, (haematopoiesis) starts to happen in other areas such as the liver and spleen.
This is known as extramedullary haematopoiesis and can lead to hepatomegaly and splenomegaly (most common presentation)
What are the symptoms of primary myelofibrosis?
B symptoms
Anaemia (except in polycythaemia)
Splenomegaly (abdominal pain)
Portal hypertension (ascites, varices and abdominal pain)
Low platelets (bleeding and petechiae)
Thrombosis is common in polycythaemia and thrombocythaemia
Raised red blood cells (thrombosis and red face)
Low white blood cells (infections)
How might disease course of Essential Thrombocythaemia and PCV change?
Essential Thrombocythaemia
and PCV both may progress to myelofibrosis or AML, but risk of this is relatively rare
What is aplastic anaemia?
Rare stem cell disorder leading to pancytopenia and hypo plastic marrow
What is the cause of aplastic anaemia?
Most commonly autoimmune (triggered by drugs, viruses or irradiation but can be inherited (Fanconi anaemia)
How Is diagnosis of aplastic anaemia done?
Bone marrow biopsy
How is aplastic anaemia managed?
Blood product transfusion and immunosuppression in autoimmune conditions
In younger patients, allogenic bone marrow transplant may be curative
What prevents platelet adhesion in homeostatic conditions?
primary haemostasis
PGI2 and NO prevent platelet adhesion
Describe the process of primary haemostasis
- If there is endothelial damage, there is exposed collagen and von Willebrand factor which leads to platelet adhesion
- Platelet adhesion leads to degranulation of the platelets, releasing ADP
- Platelets also synthesise the prostaglandin thromboxane A2 (TXA2) which causes both vasoconstriction and further aggregation
- Receptors on the platelet surface then activate the coagulation cascade, which generates fibrin to form a fibrin/platelet thrombus
What is the action of aspirin?
Low dose (75mg) aspire inhibits cyclo-oxygenase, preventing conversion of arachadonic acid to endoperoxides such as Pg12 or Txa2
How does aspirin affect Txa2 but not Pgi2?
Nuclei of endothelial cells are quickly able too secrete mRNA for PGI2 production
the anucleate platelets cannot form TXA2, so levels decrease until new platelets are formed in approximately 7 days
Low doses of aspirin every 24-48 hours thus decrease synthesis of TXA2 without massively affecting PGI2 production
What is the function of clopidogrel?
Can be used as an alternative to aspirin, or an adjunct
Works as an ADP receptor antagonist, thus preventing glycoprotein expression and platelet aggregation
What is the cause of immune thrombocytopenia?
Reduced platelet production in the bone marrow, or excessive peripheral destruction of platelets
What conditions cause reduced production of platelets?
Aplastic anaemia
Marrow infiltration
Marrow suppression
What conditions cause excess destruction of platelets?
ITP other immune causes: SLE, CLL, viruses TTP HUS Sequestration: hypersplenism
What is the presentation of immune thrombocytopenia?
Bruising / purpura of the skin
Epistaxis / haemorrhage
When does ITP arise in children / adults?
In children, usually acute and self-limiting, following a virus or immunisation
In adults. usually less acute, classically in women with other autoimmune disorders
What investigations are done for ITP?
FBC - thrombocytopenia
Bone marrow examination: not in children normally. but normal/increased megakaryocytes numbers found - otherwise normal
Platelet autoantibodies: positive in 70% patients but does not confirm diagnosis
What is the management for ITP?
Children are not usually treated
If clinically necessary, they may be treated with prednisolone or IVIG.
Chronic thrombocytopenia = rare and requires specialist management
In adults, corticosteroids = first line
IVIG if rapid rise in platelets is required
Splenectomy may be second line
Platelet transfusions are reserved for extreme haemorrhage
What lab tests are used to test the clotting system?
PT
INR
APTT
TT
What does PT test?
The extrinsic pathway - by addition of a tissue factor substitute to the patient’s plasma
What conditions cause prolonged PT?
Liver disease, or if the patient is on warfarin
What does INR test?
Ratio of a patient’s PT to a normal control whilst using an international reference preparation (standardises laboratories worldwide)
0.9-1.1 = normal range
Used for warfarin testing
What does APTT entail?
Add-on of a surface activator to the plasma
What does APTT test?
Intrinsic pathway
Monitoring for unfractionated heparin
What is thrombin time?
Addition of thrombin to the patient’s plasma
What causes prolonged thrombin time
Prolonged with fibrinogen deficiency or abnormal function or inhibitors such as heparin
Where are clotting factors synthesised?
the liver
What is factor 1?
Fibrinogen
What is factor II
Prothrombin (so thrombin is IIa)
What is the end result of the intrinsic / extrinsic pathways?
Both lead to a common pathway that leads to production of fibrin and thus a thrombus can be formed
Where is Vitamin K found?
Leafy green vegetables, dairy products and soya beans
Which clotting factors is vitamin K a necessary co-factor for?
2, 7, 9, 10
What is the result of vitamin K deficiency?
Clotting factor deficiencies –> increased PT and haemorrhage
What can vitamin K deficiencies arise from ?
Malabsorptive conditions (fat soluble, cholestatic jaundice or antibiotics
DRAW OUT THE CLOTTING CASCADE
wot r u waiting for, go draw
What are the inhibitors of coagulation?
Anti-thrombin III: serine protease inhibitor, potentiated by heparin
Activated Protein C (APC): also generated by vitamin K, and activated by thrombin
How does APC act?
Acts with the co-factor protein S to induce fibrinolysis
Destroys factor V and VIII, reducing further thrombin generation and also inhibits stabilisation of the fibrin clot
How does fibrinolysis occur?
Plasminogen is converted to plasmin by tissue plasminogen activator (t-PA_
Many mediators including thrombin and APC stimulate the release of t-PA
Plasmin is a serine protease that breaks down fibrinogen and fibrin into fibrin degradation products e.g. D-dimer
What does D-dimer presence in the plasma indicate?
D-dimers = fibrinolysis degredation products: significant thrombus breakdown in the body
What is Haemophilia A?
Factor VIII deficiency
Xlinked recessive
BUT high rate of new mutations
What is Haemophilia B?
Factor IX deficiency
X linked recessive
What are the clinical features of haemophilia?
Major bleeds following minor trauma
Recurrent haemoarthroses leading to crippling arthropathies
Compartment syndrome / nerve palsies can develop due to pressure effects
How Is diagnoses of haemophilia done?
Raised APTT
Low factor VIII / IX on assays
What is the management of haemophilia?
Avoid NSAIDs and IM injections
Minor bleeding - compression and elevation, desmopressin raises factor VIII levels and may be sufficient
Major bleeding (e.g. haemoarthrosis): infusion of recombinant factor VIII / IX to raise factor levels to 50% of normal
Life threatening bleeds - raise to 100% of normal
What are the other causes of factor deficiency?
vWD, liver disease, DIC, vitamin K deficiency or anticoagulant drugs
Most common inherited disorder = VWD
What is von willebrand’s disease?
Absence of vWF or presence of abnormally functioning vWF due to autosomal dominant condition
Gives symptoms of platelet type disorder: epistaxis, menorrhagia, with haemoarthrosis rare in vWF
What is the mode of inheritance of von willebrand’s disease?
Autosomal recessive: cormpleteabsence of detectable vWF (20%)
Autosomal dominant: less severe depletion of vWF (80%)
Which tests are changed in Vwd?
APTT is increased but INR and platelets are within normal limits
What is the management of vwd?
Desmopressin can be used to stimulates the release of VWF
VWF can be infused
Factor VIII is often infused along with plasma-derived VWF
Women with VWD that suffer from heavy periods can be managed by a combination of:
Tranexamic acid Mefanamic acid Norethisterone Combined oral contraceptive pill Mirena coil
What history points should be covered when investigating a bleeding disorder?
site of bleed - muscle/joint bleeds: coagulation issues
purpura, epistaxis, menorrhagia, GI haemorrhage: platelet issue / vWd
recurrent bleeds at one site: ?local endothelial abnormality
Duration of hx / fh: congenital/acquired
seriousness
surgical hx - bleeding that starts immediately after is suggestive of platelet issue
PMH: renal/liver failure
Drug hx: Anticoagulation, steroids, NSAIDs
How should patient with ?bleeding disorder be examined?
Skin: bruises, purpura, telangiectasia
Joints: any evidence of haemoarthrosis
Abdomen: splenomegaly, evidence of hepatic dysfunction
What is warfarin?
Vitamin K antagonist
Inhibits the enzyme responsible for regenerating ‘active’ vitamin K, thus producing an anti-coagulativestate analogous to vitamin K deficiency
How long does warfarin take to have an effect?
up to 5 days
has an initial prothrombotic effect so should always be combined with a heparin agent until INR is within the Therapeutic range
In which patients is warfarin contra-indicated in?
Peptic ulcer disease
bleeding disorders
severe hypertension
pregnancy
What are the target INRs for prophylactic use of warfarin?
Single DVT/PE: 2-3
AF: 2-3
Recurrent DVT/PE: 3-4
Prosthetic metal heart valves: 3-4
How is warfarin initiated?
Loading dose given with INR measured on alternate dats and dose titrated according to INR
Name three NOACS commonly used?
Dabigatran, Apixaban and rivaroxaban
How do NOACs work?
Apixaban and rivaroxaban = competitive factor Xa antagonists
Dabigatran = reversible competitive antagonist of thrombin (IIa)
What are the advantages of NOACs?
Rapid onset of coagulation effects
more predictable pharmacokinetics
lower potential for clinically important interactions with food, lifestyle and other drugs
No need for routine coagulaitonmonitoring
What are the disadvantages of NOACs?
?Increased risk of GI bleed
NO antidotes
How should over anticoagulation be managed in a patient taking warfarin?
INR measurement:
If 4.6-6 - reduce dose of warfarin / omit dose, restart when INR <5
If 6-8: stop warfarin, restart when INR<5
If >8: with no bleed / minor bleed, stop warfarin and give vitamin K
Also give 0.5-2mg oral vitamin K if risk factors for bleeding
If major bleed, stop warfarin, give 5-10mg vitamin K IV plus octaplex (Prothrombin complex concentrate) or FFP according to local guidelines
Give an example of a LMWH?
Exoxaparin (SC)
How do LMWH work?
Inactivate Xa (but not thrombin) no lab monitoring required, but if requited, then anti Xa levels used
Can accumulate in renal failure - lower dose prophylactically
What is the purpose of UFH?
If high risk of bleeding - anticoagulation can be terminated rapidly
In CKD
What is the mode of action of UFH?
Potentiates anti-thrombin III
Increases its ability to inhibit thrombin, factor Xa and IXa
How is UFH monitored?
APTT
should be checked at 6 hours, aiming for APTT of 1.5-2.5
What are the side effects of UFH?
Common to both LMWH and UFH but less common in LMWH
Bleeding e.g. GI, operative site, intracranial
heparin induced thrombocytopenia (HIT)
Osteoporosis with long term use
Hyperkalaemia
What are the contraindications for heparin?
bleeding disorders, platelets <60x10^9, previous HIT, peptic ulcer
How should overanticoagulaiton with heparins be treated?
Stop infusion
Give protamine sulphate
How is thrombolysis achieved?
Streptokinase: purified fraction of filtrate obtained from haemolytic streptococci
Alteplase - recombinant tissue type plasminogen activator, leading to increased plasminogen activation and fibronlysis
What are the contra-indications to thrombolysis?
Active bleeding: any sign of cerebral haemorrhage in stroke suspected aortic dissection in ACS Severe hypertension (>200/120) Recent head trauma recent surgery Pregnancy or recent delivery severe liver disease / oesophageal varices Prolonged /traumatic CPR
What is thrombophilia?
Inherited / acquired coagulopathy, predisposing to thrombosis, usually venous
What are the causes of thrombophilia?
Inherited: APC resistance, factor V Leiden mutation
Antithrombin III deficiency
Prothrombin gene mutation
Acquired: APL syndrome
What are the indications for screening for thrombophilia?
Arterial thrombosis <50
Venous thrombosis <40 with no risk factors
Familial VTE
Recurrent unexplained VTE
Unusual site of thrombosis e.g. mesenteric or portal vein thrombosis
Recurrent fetal loss
What investigations can be done for thrombophilia?
FBC
clotting
fibrinogen concentration +/- APC resistance test
lupus anticoagulant / anti-cardiolipin antibodies
Antithrombin and protein C/S assays for deficiency
Factor V Leiden mutation PCR if APC resistance test = positive
PCR for prothrombin gene mutation
What is DIC?
Systemic activation of of the coagulation pathways, leading to extensive intravascular coagulation and fibrin clot development
There is thrombotic occlusion of the arterial microvasculature
Depletion of clotting factors + consumption of platelets = ++HAEMORRAHAGE
Organ failure ensues
What are the causes of DIC?
Infection Trauma Malignancy Obstetric complications (amniotic fluid emboli, pre-eclampsia) Severe liver failure Tissue destruction (pancreatitis/burns) Toxic / immunogenic stimuli
What are the clinical features of DIC?
Bruising
Excessive bleeding from any site: e.g. venipuncture wounds
renal failure
What are the investigations for DIC
Low platelets, low fibrinogen
Raised PT and APTT
Raised D dimer
Blood film: broken RBCs (schistocytes)
What is the treatment for DIC?
Treat the cause
Aggressive resuscitation, replacing platelets, coagulation factors (FFP) and fibrinogen (cryoprecipitate)
Protein C: reduces mortality in multi-organ failure / severe sepsis
How are blood groups determined?
By antigens on the surface of red cells, with the ABO / rhesus groups the 2 major blood groups
Describe the ABO system
Red cells either A, B, AB or O
named according to surface antigens
Carry IgM antibodies against any antigen that they do not carry.
O blood group contains anti-A and anti-B antibodies
AB = both A and B antigens
AB group blood will not carry any anti-A or anti-B antibodies
Describe the rhesus system?
RBC either show the rhesus D antigen or not (+ve or -ve)
If a rhesus negative individual Is exposed to rhesus positive blood products, they can develop IgG antibodies directed against the rhesus D antigen
If exposed AGAIN, there will be haemolysis
What are the principles of cross matching blood?
Blood grouping: ABO and RhD groups of the patient are determined
Antibody screening: patient serum/plasma screened for atypical antibodies that would cause significant haemolysis of transfused cells
Tested using at least 2 group O donors expressing a wide range of antigens
What is the indirect agglutination test?
Donor RBCs added to patient’s serum, then Coomb’s reagent is added, agglutination indicates that the patients serum has antibodies for the donor RBCs
This test is always performed pre-transfusion
What is the direct agglutination test?
Patient’s ‘washed’ RBCs are added to Coomb’s reagent and if they agglutinate, that indicates that there is an autoimmune haemolytic process occurring with the RBCs coated with immunoglobulins
‘Coomb’s test’
Which blood products need to be cross matched?
ALL except platelets
What is a group and save?
Antibody screen performed to confirm negative so appropriate blood can be made available
undergoing elective surgery where transfusion not expected
What is the massive transfusion protocol?
2 Units of O negative blood to be made available immediately
Blood of the same ABO / rhesus group will be available in 10-15 minutes
fully cross-matched blood will be available within 45 minutes
When are packed red cells given?
Given with crystalloids/colloids in acute blood loss
When are platelet concentrates given?
TO treat bleeding in severe thrombocytopenia or prophylactically in patients with bone marrow failure
When is FFP given?
Contains all the coagulation factors present in fresh plasma, so is used mainly for replacement of coagulation factors in acquired deficiencies e.g. liver disease, TTP, warfarin overdose where vitamin K would be too slow
What is cryoprecipitate and when is it given?
FFP without supernatant,
Highly concentrated fibrinogen
useful in conditions such as DIC where the fibrinogen is very low
What are factor VII and IX concentrates used for?
Specific factor concentrates, used in haemophilia / vWD
What is albumin used for?
In severe hypoalbuminaemia where the patient is overloaded and resistant to diuretics
What is IVIG used for?
Either normal / specific to prevent infections in hypogammaglobulinaemia or other conditions such as ITP
What kind of transfusion reactions can patients get?
Acute haemolytic reaction
Allergy/anaphylaxis
Bacterial contamination
Transfusion-related acute lung injury
Non-haemolytic febrile transfusion reaction
Fluid overload
What are the symptoms of acute haemolytic reaction?
agitation, raised temperature, low BP, abdominal/chest pain, or signs of DIC
How should an acute haemolytic reaction be monitored?
STOP transfusion
A-E resuscitation, give 0.9% saline
How should allergic transfusion reaction be monitored?
If simple allergy (urticaria/itch), slow/stop and give chloramphenamine
If anaphylaxis, stop and treat as such
What are the symptoms of ?bacterial contamination reaction
sepsis and rigors
How should bacterial contamination reaction be monitored?
Stop transfusion
Start sepsis protocol, sending the blood unit to the lab as well as cultures from the patient
What is TRALI?
Transfusion related acute lung injury
ARDS due to antibodies in the donor plasma, suggested by dyspnoea and CXR white out
What are the symptoms of non-haemolytic febrile transfusion reaction?
Shivering and fever usually 0.5-1 hour after starting transfusion
Slow the transfusion, administer antipyretic and monitor closely
How should fluid overload be managed?
Slow or stop transfusion
Give oxygen and a diuretic
If the patient is not hypovolaemic, it is often standard practice to co-prescribe furosemide to prevent overload
Consider exchange transfusion
Which blood bottle is used for cross match?
PINK
What are the important principles of requesting blood products?
Ensure a blood sample has been taken
Consent the patient for transfusion
Benefits/indications
Risks of infection: HIV 3 million, HBV 2/100,000
Non-infectious risks: transfusion reactions
Right to refuse e.g. Jehovah’s witnesses
Specific form
