Haem 2 Flashcards
What are the elements of haemostasis?
Primary haemostasis
Blood coagulation
Fibrynolysis
What are the features of primary haemostasis?
Vasoconstriction
Platelet adhesion
Platelet aggregation
What constitutes coagulation?
Insoluble fibrin formation
Fibrin cross-linking
What is Fibrynolysis?
Turning plasminogen into plasmin
Which converts fibrin into fibrinogen/fibrin degrading products
What are the types of thrombosis?
Arterial
Venous
Microvascular
What is an arterial thrombus?
White clot - made of platelets and fibrin
Results in ischeamia and infarction
Secondary to atherosclerosis
What are the risk factors for arterial thrombosis?
Age Smoking Sedentary lifestyle Hypertension Diabetes mellitus Obesity Hypercholesterolaemia
How do you manage arterial thrombosis?
Primary prevention >(lifestyle/risk factor modifications) Acute presentation >Thrombolysis >Antiplatelet/anticoagulant drugs Secondary prevention
What is a venous thrombosis?
‘Red thrombus’~fibrin and red cells
Results in back pressure
Principally due to stasis and hypercoagulability
What are the risk factors of venous thrombosis?
Stasis/hypercoaguability Increasing age Pregnancy/HRT Surgery Obesity etc
What systems are used to predict venous thrombosis?
Wells score
Geneva score
What are the types of anticoagulants?
LMWH (heparin)
Coumarins (warfarin)
NOACs
What is heritable thrombophilia?
Inherited predisposition to venous thrombosis
Commonly caused by defect in prothrombin or Factor V leiden
What is microvascular thrombus?
Platelets and/or fibrin
Results in diffuse ischaemia
Principally in Disseminated Intravascular Coagulation
What is DIC (Disseminated intravascular coagulation)?
Diffuse systemic coagulation activation Occurs in: >Septicaemia >Malignancy >eclampsia Causes tissue ischaemia >Gangrene >organ failure Consumption of platelets and clotting factors leading to bleeding
What are the important parts of a bleeding history?
Do they have a bleeding disorder?
How severe is the bleeding?
How appropriate is the bleeding?
Pattern of bleeding
How do you discern the pattern of bleeding?
Platelet type >Mucosal >Epistaxis >Purpura >Menorrhagia >GI
Coagulation Factor >Articular
>Muscle Haematoma
>CNS
What are the features of haemophilia?
X-linked so only males Haemarthrosis Muscle haematoma CNS bleeding Retroperitoneal bleeding Post surgical bleeding
What are the complications of haemophilia?
Synovitis
Chronic Haemophilic Arthropathy
Neurovascular compression (compartment syndromes)
Other sequelae of bleeding (Stroke)
How do you diagnose haemophilia?
Clinical Prolonged APTT Normal PT Reduced FVIII or FIX Genetic analysis
How do you treat haemophilia?
Coagulation factor replacement FVIII/IX Now almost entirely recombinant products DDAVP Tranexamic Acid Emphasis on prophylaxis in severe haemophilia
What is von Willebrand disease?
Common (1 in 200) Variable severity Autosomal Platelet Type bleeding (mucosal) Quantitative and qualitative abnormalities of vWF 3 types, in order of severity
How do you treat von willebrand disease?
vWF concentrate or DDAVP
Tranexamic Acid
Topical applications
OCP
What bleeding disorders can you acquire?
Thrombocytopenia Liver failure Renal failure DIC Drugs related
What causes thrombocytopenia?
Decreased production
>Marrow failure
>Aplasia
>Infiltration
Increased consumption
>Immune ITP
>Non immune DIC
>Hypersplenism
What is the presentation of thrombocytopenia?
Petechia
Ecchymosis
Mucosal Bleeding
Rare CNS bleeding
What bleeding abnormalities does liver failure lead to?
Factor I, II, V, VII, VIII, IX, X, XI all affected
Prolonged PT, APTT Reduced Fibrinogen
Cholestasis -
>Vit K dept factor deficiency
»(Factor II, VII, IX, X.)
How do you correct bleeding abnormalities in liver failure?
Replacement FFP
Vitamin K
What cells make up myeloid malignancies?
Red
Platelets
Granulocytes
Monocytes
What cells make up lymphoid malignancies?
B-cells
T-cells
What is the difference between leukaemia and lymphoma?
Leukaemia generally starts in the bone marrow
Lymphoma is cancerous lymph nodes/lymph tissue
What are the acute leukaemias?
Acute lymphoblastic leukaemia (ALL)
Acute Myeloid Leukaemia (AML)
What are the chronic leukaemias?
Chronic myeloid leukaemia (CML)
Chronic lymphocytic leukaemia (CLL)
What are the malignant lymphomas?
Non-Hodgkin lymphoma (NHL) Hodgkin lymphoma (HL)
What are the groups of haematological disease?
Acute Leukaemias Chronic Leukaemias Multiple myeloma Myelodysplastic syndromes (MDS) The chronic myeloprolifertive diseases (biologically malignant)
What is the difference between acute and chronic leukaemia?
Acute - leukaemic cells don’t differentiate, whereas chronic they can
Acute is failure of bone marrow, chronic has proliferation without bone marrow failure
Acute rapidly fatal if untreated but good prognosis
Chronic is potentially curable, but often only few year survival
What are the complications of bone marrow failure?
Anaemia
- Thrombocytopenic bleeding (Purpura and mucosal membrane bleeding)
- Infection because of neutropenia (predominantly bacterial and fungal)
How can lymphoma present?
Nodal disease (lymphadenopathy) Extranodal disease Systemic symptoms >Fever >Drenching sweats >Weight loss >Prutitis >Fatigue
What causes Lymphadenopathy?
Localised and painful:
Bacterial infection in draining site
What causes Localised and painless Lymphadenopathy?
Rare infections, catch scratch fever, TB
Metastatic carcinoma from draining site- hard
Lymphoma-rubbery
Reactive, no cause identified
What causes Generalised and painful/tender Lymphadenopathy?
Viral infections, EBV, CMV, hepatitis, HIV
What causes Generalised and painless Lymphadenopathy?
Lymphoma Leukaemia Connective tissue diseases, sarcoidosis Reactive, no cause identified Drugs
What are the clinical features of multiple myeloma?
Bone pain Hyperviscosity syndrome Bleeding tendency Amyloidosis Anaemia Renal failure Recurrent infections
What is an antibody?
An immunoglobulin produced by B cells
Made up of 2 heavy chains and 2 light chains
5 types of heavy chain
What are the types of heavy chain?
IgG IgA IgM IgD IgE
What is the structure of an immunoglobulin?
Y shaped
> part of y is fab region which determines target binding
| part of Y is Fc region which is the subclass
What is a paraprotein?
monoclonal immunoglobulin present in blood or urine
When present shows proliferation of B lymphocyte somwhere in body
What immunoglobulin tests are available?
Total immunoglobulin (by subclass)
Electrophoresis
Immunofixation
Light chains
What immunoglobulins are present in myeloma + lymphoma?
Lymphoma >IgM Myeloma >IgG >IgA
What is meyloma?
Neoplastic disorder of plasma cells, resulting (usually) in excessive production of a single type of immunoglobulin (paraprotein)
More common in black population
What are the features of myeloma?
bone disease >lytic bone lesions >pathological fractures >cord compression >hypercalcaemia bone marrow failure esp. anaemia infections
What complications can arise from raised paraprotein?
Renal failure
Hyperviscosity
Hypogammaglobinaemia
Amyloidosis
How do you diagnose myeloma?
Excess plasma cells in bone marow (greater than 10%)
How do you treat meyloma?
Chemo (proteasome inhibs) Bisphosphonate therapy (zoledronic acid) Radiotherapy Steroids Autologous stem cell transplant
What is the function of the different immune cells?
Neutrophils – bacterial & fungal infection
Monocytes – fungal infection
Eosinophils – parasitic infections
T lymphocytes – fungal & viral infection, PJP
B lymphocytes – bacterial infection
How do you reduce risk of sepsis in haematological malignancy?
Prophylaxis Growth factors e.g. G-CSF Stem cell rescue/transplant Protective environment e.g. laminar flow rooms Intravenous immunoglobulin replacement Vaccination - never live
What is the prophylaxis of reducing sepsis risk?
Antibiotics (ciprofloxacin)
Anti-fungal (fluconazole or itraconazole)
Anti-viral (aciclovir)
PJP (co-trimoxazole)
What are the common gram positive causative agents?
Staphylococci - MRSSA/MRSA, coagulase negative
Streptococci viridans
What are the common gram negative causative agents?
Escherichia coli
Klebsiella spp : ESBL
Pseudomonas aeruginosa
How does neutropenic sepsis present?
Fever with no localising signs Single reading of >38.50C or 380C on two readings one hour apart Rigors Chest infection/ pneumonia Skin sepsis - cellulitis Urinary tract infection Septic shock
What is sepsis 6?
Give
Administer high flow oxygen
Give appropriate IV antibiotics within ONE hour
Start IV fluid resuscitation
Take
Assess/measure urine output
Take blood cultures, other cultures, consider source control
Measure serum lactate concentration
How do you manage neutropenic sepsis?
Broad spectrum IV antibiotics
+ vancomycin if gram positive
No response after 72 hours add antifungal
What are the myeloid malignancies?
Acute Myeloid Leukaemia (AML)
Chronic Myeloid Leukaemia (CML)
Myelodysplastic Syndromes (MDS)
Myeloproliferative Neoplasms (MPN)
What are the clinical features of AML?
Anaemia
Thrombocytopenic bleeding
Infection
How do you treat AML?
Supportive
Amto-leukaemic therapy
Allogenic stem cell transplantation
All-trans retinoic acid + arsenic trixoide (in APL)
Some targeted treatments becoming available
How does CML present?
Anaemia Splenomegaly, often massive Weight loss Hyperleukostasis - Fundal haemorrhage and venous congestion, altered consciousness, respiratory failure. Gout
What are the lab results in CML?
High (very sometimes) WCC
High platlets
Anaemia
Blood film shows all stages of white cell differentiation with increased basophils
Bone marrow is hypercellular
Bone marrow and blood cells contain the Philadelphia chromosome - t(9;22)
How do you treat CML?
Tyrokinase ihibitors >Imatinib (Glivec) > Dasatinib (Sprycel) >Nilotinib (Tasigna) >Busitinib > Ponatinib
What are myelodysplastic syndromes?
Acquired clonal disorders of the bone marrow
Commonly seen in old age
Present as macrocytic anaemia and pancytopenia
They are pre-leukaemic
They are fatal as a result of progression to bone marrow failure or AML
Treatment is supportive or stem cell transplantation for the few young patients
What are the myelodysplastic syndromes?
Polycythaemia Vera (PV) Essential Thrombocythaemia (ET) Idiopathic Myelofibrosis (IM)
What mutations are present in myelodysplastic syndromes?
All can have JAK2V617F
CALR can also be affected in ET
What are the features of polycythaemia vera?
Headaches Itch Vascular occlusion Thrombosis TIA/stroke Splenomegaly
What are the lab features of polythaemia vera?
A raised haemoglobin concentration Raise haematocrit. A tendency to have a raised WCC Raised platelet count A raised uric acid A true increase in red cell mass when the blood volume is measured
How do you treat PRV?
Venesection to keep haemocrit down
Aspirin
Hydroxcarbamide
What is essential thrombocythaemia?
Myeloproliferative disease with predominant feature of raised platelet count
Symptoms of arterial and venous thromboses, digital ischaemia, gout, headache
Mild splenomegaly
Can progress to myelofibrosis or AML
How do you treat ET?
Treated with aspirin and hydroxycarbamide or anagrelide
What are the types of lymphoma?
Hodkins
Non-hodgkins (split into high/low grade)
What is acute lymphoblastic leukaemia (ALL)?
Neoplastic disorder of lymphoblasts
Diagnosed by > 20% lymphoblasts present in bone marrow
Present with 2-3 week history of bone marrow failure or bone/joint pain
>Bone marrow failure +/- raised white cell count
>Bone pain, infection, sweats
How do you treat ALL?
Induction chemotherapy to obtain remission Consolidation therapy CNS directed treatment Maintenance treatment for 18 months Stem cell transplantation (if high risk) Newer therapies emerging -
What are the newer treatments for ALL?
Bispecifc T-cell engagers (BiTe molecules) – e.g. Blinatumumab
CAR (chimeric antigen receptor T-cells)
What are the poorer risk factors for ALL?
Increasing age Increased white cell count Immunophenotype (more primitive forms) Cytogenetics/molecular genetics t(9;22); t(4;11) Slow/poor response to treatment
How does CLL present?
Often assymptomatic at presentation Frequent findings: >Bone marrow failure (anaemia, thrombocytopenia) >Lymphadenopathy >Splenomegaly (30%) >Fever and sweats (< 25%)
Less common findings:
>Hepatomegaly
>Infections
>weight loss
What are the indications for treatment in CLL?
Progressive bone marrow failure Massive lymphadenopathy Progressive splenomegaly Lymphocyte doubling time <6 months or >50% increase over 2 months Systemic symptoms Autoimmune cytopenias
How do you treat CLL?
Cytotoxic chemotherapy e.g. fludarabine, bendamustine
Monoclonal antibodies e.g. Rituximab, obinutuzamab
Novel agents
What are the novel agents for CLL?
Bruton tyrosine kinase inhibitor eg ibrutinib
PI3K inhibitor eg idelalisib
BCL-2 inhibitor eg venetoclax
What indicates poor prognosis in CLL?
Advanced disease (Binet stage B or C) Atypical lymphocyte morphology Rapid lymphocyte doubling time (<12 mth) CD 38+ expression Loss/mutation p53; del 11q23 (ATM gene) Unmutated IgVH gene status
How do lymphomas present?
lymphadenopathy/hepatosplenomegaly
Extranodal disease
“B symptoms”
bone marrow involvement
What is hodgkin’s lymphoma assciated with?
association with Epstein Barr virus;
familial and geographical clustering
How do you treat hodgkin’s lymphoma?
Combination chemotherapy (ABVD) \+/- radiotherapy Monoclonal antibodies (anti-CD30) Immunotherapy (checkpoint inhibitors) Use of PET scan to assess response to treatment and to limit use of radiotherapy
How do you treat non’hodgkin’s lymphoma?
typically anti-CD20 monoclonal antibody
+ chemo
