List II - Less Common 'Know of' Conditions Flashcards
What is disseminated intravascular coagulation (DIC)?
- Widespread activation of coagulation from release of procoagulants into circulation
What is the clotting pathway?
- Intrinsic/extrinsic pathways
- Activated Xa
- Converts prothrombin to thrombin
- Converts fibrinogen to fibrin (also thrombin activated XIII to XIIIa which crosslinks fibrin)
What is the fibrinolytic pathway?
- t-PA released from endothelial cells
- Converts plasminogen to plasmin
- Cleaves fibrin
What are the causes of DIC?
- Malignancy - leukaemia (esp. acute promyelocytic leukaemia)
- Sepsis - meningococcal septicaemia
- Trauma
- Obstetric events - retained products (>20 wks), pre-eclampsia, placental abruption, endotoxic shock, aniotic fluid embolism, placental accreta, hydatidiform mole, acute fatty liver of pregnancy
What is the pathophysiology of DIC?
- Clotting factors and platelets are consumed - increased bleeding risk
- Fibrin strands fill small vessels - haemolysing passing RBC’s
- Fibrinolysis activated
What are the signs of DIC?
- Bruising, bleeding (e.g. venepunture sites), renal failure
What are the appropriate blood investigations for DIC?
- FBC (low plts)
- Clotting screen (increased PT, increased APTT, low fibrinogen: correlates with severity)
- Raised D-dimer (fibrin degradation product)
- Blood film - schistocytes (haemolysed RBC’s)
What is the approach to the management of a patient with suspected DIC?
- A to E assessment
- A - check patency, maintain, sit up
- B - 15L o2 NRBM
- C - IV access - bloods (as above) - replace platelets if <50 - cryoprecipitate (to replace fibrinogen) - FFP (to replace clotting factors) - activated protein C (to reduce mortality if severe sepsis/multi organ failure) - treat underlying cause
What are the complications of DIC?
- Risk of death
How can DIC be prevented?
- Primary prevention - acute promyelocytic leukaemia
- Give all transretinoic acid (to reduce risk of DIC)
What is sickle cell anaemia?
- Auto-somal recessive condition that results in synthesis of and abnormal haemoglobin chain termed HbS
Who is affected by SCD?
- More common in people of African decent
- Offers some protection against malaria
- 10% of UK Afro-Caribbean’s are carriers of HbS (i.e. heterozygous) - such people are only symptomatic if severely hypoxic
- Symptoms in homozygous people dont tend to develop until 4-6 months when the abnormal HbSS molecules take over from the fetal haemoglobin
What is the pathophysiology of SCD?
- Polar amino acid glutamate is substituted by non-polar valine in each of the two beta chains (codon 6) - this decreases the water solubility of dexoy-Hb
- In the deoxygenated state the HbS molecules polymerise and cause RBC’s to sickle
- HbAS patients sickle at p02 2.5 - 4 kPa, HbSS patients at p02 5 - 6 kPa
- Sickle cells are fragile and cause infarction
What is the investigation for SCD / how is it diagnosed?
- Haemoglobin electrophoresis
How are SC crises managed?
- Analgesia e.g. opiates
- Rehydrate
- Oxygen
- Consider antibiotics if evidence of infection
- Blood transfusion
- Exchange transfusion e.g. if neurological complications
What is the longer term management of SCD?
- Hydroxyurea
- Increases the HbF levels and is used in the prophylactic management of sickle cell anaemia to prevent painful episodes
- Sickle cell patients should receive the pneumococcal polysaccharide vaccine every 5 years
What is haemophilia?
- Disorder of coagulation - meaning bleed more easily
- X-linked recessive
- Up to 30% of patients have no family history
What is the cause of haemophilia A?
- Deficiency in factor VIII
What is the cause of haemophilia B?
- Deficiency in factor IX (Christmas disease)
What are the presenting clinical features of haemophilia?
- Haemarthroses, haematomas
* Prolonged bleeding after surgery or trauma
What blood tests can be done for haemophilias?
- Prolonged APTT
* Bleeding time, thrombin time, prothrombin time normal
Which problem can occur with treatment for haemophilia A?
- Up to 10-15% of patient will develop antibodies to factor VIII treatment
What are thalassaemias?
- Group of genetic disorders characterised by a reduced production rate of either alpha or beta chains
What is beta-thalassaemia trait?
- Auto-somal recessive condition characterised by mild hypochromic, microcytic anaemia
- Usually asymptomatic
What are the clinical features of thalassaemia trait?
- Mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia
- HbA2 raised (>3.5%)
What is beta-thalassaemia major?
- Absence of beta chains
* Chromosome 11
What are the clinical features of thalassaemia major?
- Presents in first year of life with failure to thrive and hepatosplenomegaly
- Microcytic anaemia
- HbA2 and HbF raised
- HbA absent
What is the treatment of thalassaemia major?
- Repeated transfusion - iron overload
* s/c infusion of desferrioxamine
What is alpha-thalassaemia?
- Due to deficiency of alpha chains in haemoglobin
* 2 separate alpha-globulin genes are located on each chromosome 16
What determines the clinical severity of alpha-thalassaemia?
- Number of alpha globulin alleles affected
- 1 or 2 alleles affected then the blood picture would be hypochromic and microcytic, but the Hb would be typically normal
- 3 alpha globulin alleles affected results in a hypochromic microcytic anaemia with splenomegaly - known as Hb H disease
- If all 4 alpha globulin alleles are affected (i.e. homozygote) then death in utero (hyrops fetalis, Bart’s hydrops)
What is a thrombophilia?
- Blood disorder making blood more likely to clot when you dont want it to
What are the inherited thrombophilias?
Gain of function of polymorphisms
- Factor V Leiden (activated protein C resistance) - most common cause of thrombophilia
- Prothrombin gene mutation - second most common
Deficiences of naturally occurring anticoagulants
- Antithrombin III deficiency
- Protein C deficiency
- Protein S deficiency
What are the acquired thrombophilias?
- Anti-phospholipid syndrome
* Combined oral contraceptive pill
What is the relative risk of VTE according to thrombophilia?
- Factor V Leiden (heterzygous)
- P 5%, VTE risk 4%
- Factor V Leiden (homozygous)
- P 0.05%, VTE risk 10%
- Prothrombin gene mutation (heterzygous)
- P 1.5%, VTE risk 3%
- Protein C deficiency
- P 0.3%, VTE risk 10%
- Protein S deficiency
- P 0.1%, VTE risk 5-10%
- Antithrombin III deficiency
- P 0.02%, VTE risk 10-20%
How are patients screened for VTE risk in hospital?
- VTE risk assessment tool to review risk factors including:
- Medical patients - significant reduction in mobility for 3 days or more (or anticipated to have significant reduced mobility)
- Surgical/trauma patients -
- Hip/knee replacement
- Hip fracture
- General anaesthetic and a surgical duration of over 90 minutes
- Surgery of the pelvis or lower limb with a general anaesthetic and a surgical duration of over 60 minutes
- Acute surgical admission with an inflammatory/intra-abdominal condition
- Surgery with a significant reduction in mobility
- General risk factors -
- Active cancer / chemotherapy
- Aged over 60
- Known blood clotting disorder e.g. thrombophilia
- BMI over 35
- Dehydration
- One or more significant medical comorbidities e.g. heart disease, metabolic/endocrine pathologies, respiratory disease, acute infectious disease and inflammatory conditions
- Critical care admission
- Use of hormone replacement therapy (HRT)
- Use of the combine oral contraceptive pill
- Varicose veins
- Pregnant or <6 week post partum
What are the different types of VTE prophylaxis?
- Mechanical
- TED / anti-embolic compression stockings - thigh or knee height
- Intermittent pneumatic compression device
- Pharmacological
- LMWH s/c injection
- Reduced doses should be used in severe renal impairment
- Unfractionated heparin
- Alternative to LMWH for patients with CKD
What is the advice to patients pre-surgery with regard to VTE?
- Advise women to stop taking their COCP/hormone replacement therapy 4 weeks before surgery
What is the advice to patients post-surgery with regard to VTE?
- Try to mobilise patients as soon as possible after surgery
* Ensure the patient is hydrated
What is the post surgery VTE advice for patients who have had elective hip surgery?
- LMWH for 10 days followed by aspirin (75mg or 150mg) for a further 28 days
or - LMWH for 28 days combined with anti-embolism stockings until discharge
or - Rivaroxaban
What is the post surgery VTE advice for patients who have had elective knee surgery?
* Aspirin (75mg or 150mg) for 14 days or * LMWH for 14 days combined with anti-embolism stockings until discharge or * Rivaroxaban
What is the post surgery VTE advice for patients who have had fragility fractures of the pelvis, hip and proximal femur?
- NICE guidelines:
- Offer VTE prophylaxis for a month to people with fragility fractures of the pelvis, hip or proximal femur if the risk of VTE outweighs the risk of bleeding
- Choose either:
- LMWH, starting 6-12 hrs after surgery or
- Fondaparinux sodium, starting 6 hours after surgery, providing there is low risk of bleeding
What are the causes of severe thrombocytopenia?
- ITP
- DIC
- TTP
- Haematological malignancy
What are the causes of moderate thrombocytopenia?
- Heparin induced thrombocytopenia (HIT)
- Drug induced (quinine, diuretics, sulphonamides, aspirin, thiazides)
- Alcohol
- Liver disease
- Hypersplenism
- Viral infection (EBV, HIV, hepatitis)
- Pregnancy
- SLE/anti-phospholipid syndrome
- Vitamin B12 deficiency
Pseudothrombocytopenia has been reported in association with the use of EDTA as an anticoagulant
What are the features of immune thrombocytopenia in children?
- Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex
- Features in children (compared to adults)
- Typically more acute than adults
- Equal sex incidence
- May follow an infection or vaccination
- Usually a self limiting course over 1-2 weeks
What are the features of immune thrombocytopenia in adults?
- Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex
- Adults have a more chronic condition
- More common in older females
- Symptomatic patients may present as follows:
- Petechiae, purpura
- Bleeding, epistaxis
- Catastrophic bleeding e.g. intracranial is not uncommon
What is the management of ITP?
- First line treatment is oral prednisolone
- Pooled normal human immunoglobulin (IVIG) may also be used
- Splenectomy is now less commonly used
What is Evans syndrome?
- ITP in association with auto-immune haemolytic anaemia (AIHA)
Which condition is characterised by pancytopenia?
- Aplastic anaemia
What are the causes of aplastic anaemia?
- Idiopathic
- Congenital - Fanconi anaemia, dyskeratosis congenita
- Drugs - cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold
- Toxins: benzene
- Infections: parvovirus, hepatitis
- Radiation
What is the normal range for neurophils?
- 2.0 - 7.5 * 10(9)
What is considered a low neutrophil count?
- <1.5 * 10(9)
Further stratified as follows:
- Mild - 1.0 - 1.5 * 10(9)
- Moderate - 0.5 - 1.0 * 10(9)
- Severe - <0.5 * 10(9)
What are the causes of neutropenia?
- Viral
- HIV
- EBV
- Hepatitis
- Drugs
- Cytotoxics
- Carbimazole
- Clozapine
- Benign ethnic neutropenia
- Common in black African and Afro-Caribbean
- No treatment required
- Haematological malignancy
- Myelodysplastic malignancies
- Aplastic anaemia
- Rheumatological conditions
- SLE
- RA
- Severe sepsis
- Haemodialysis
What are the features of neutropenic sepsis?
- Most common 7-14 days after chemotherapy
- May be defined as a neutrophil count of <0.5 * 10 (9) in a patient having anti-cancer treatment and the presence of one of the following:
- High temperature >38c
- Other signs or symptoms that are suggestive of sepsis
What is the prophylaxis for neutropenic sepsis?
- If it is suspected that patients are likely to have a neutrophil count of <0.5 * 10(9) as a consequence of their treatment they should be offered a fluroquinolone
How should neutropenic sepsis be managed?
- Antibiotics should be started immediately, do not wait for WBC
- NICE recommends starting empirical anti-biotic therapy with pipercillin with tazobactam (Tazocin) immediately
- Many units add Vancomycin if the patient has central venous access but NICE do not support this approach
- Specialist assessment to see if management can be as outpatient (or admission)
- If patients are still febrile and unwell after 48 hours an alternative anti-biotic such as meropenem is prescribed +/- vancomycin
- If patients are not responding after 4-6 days the Christie guidelines suggest ordering investigations for fungal infections e.g. HRCT rather than just starting therapy for anti-fungal blindly
- Potential role for G-CSF in selected patients
What is G-CSF?
- Recombinant human granulocyte-colony stimulating factors used to increase neutrophil counts in patients who are neutropenic secondary to chemotherapy or other factors
- Examples - filgrastim, perfilgrastim
For patients with MM, who are suitable for stem cell transplant, what should their induction therapy consist of?
- Bortezomib and Dexamethasone
What does an autologous stem cell transplant involve for people wit MM?
- Removal of the patients own stem cells prior to chemotherapy, which are then replaced after chemotherapy
- Different from allogenic stem cell transplantation where stem cells are sourced from HLA matching donors
- Allogenic stem cell transplantation is currently only used as part of clinical trials when treating multiple myeloma
What is the most common malignancy affecting children?
- Acute Lymphoblastic Leukaemia (ALL)
- Accounts for 80% of childhood leukaemia’s
- Peak incidence is 2-5 years of age and boys are affected slightly more than girls
What are the clinical features of ALL?
Due to bone marrow failure:
- Anaemia - lethargy and pallor
- Neuropenia - frequent or severe infections
- Thrombocytopenia - easy bruising, petechiae
Others:
- Bone pain (secondary to bone marrow infiltration)
- Splenomegaly
- Hepatomegaly
- Fever in up to 50% of new cases
- Testicular swelling
What are the types of ALL?
- Common ALL (75%) CD10 present, pre-B phenotype
- T-cell ALL (20%)
- B-cell ALL (5%)
What are the poor prognostic factors for ALL?
- Age <2 yrs or >10 yrs
- WBC >20 * 10(9)/l at diagnosis
- T or B cell surface markers
- Non-caucasian
- Male sex
What is the most common form of leukaemia in adults?
- Chronic lymphocytic leukaemia (CLL) is caused by monoclonal proliferation of well differentiated lymphocytes which are almost always B-cells (99%)
What are the features of CLL?
- Often none - may be picked up as an incidental finding of lymphocytosis
- Constitutional anorexia, weight loss
- Bleeding, infections
- Lymphadenopathy more marked than chronic myeloid leukaemia
What are the investigations of CLL?
- FBC - lymphocytosis, anaemia
- Blood film - smudge cells (also known as smear cells)
- Immunophenotyping is the key investigation
What is the more common type of acute leukaemia in adults?
- Acute myeloid leukaemia (AML)
* May occur as primary disease or following a secondary transformation of a myeloproliferative disorder
What are the features of AML related to bone marrow failure?
- Anaemia: pallor, lethargy, weakness
- Neutropenia: WCC may be high, functioning neutrophil levels are low leading to frequent infections
- Thrombocytopenia: bleeding
- Splenomegaly
- Bone pain
What are the poor prognostic factors for AML?
- > 60 years
- > 20% blasts after first course of chemo
- Cytogenetics: deletions of chromosome 5 or 7
What are the features of 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)
- Auer rods (seen with myeloperoxidase stain)
- DIC or thrombocytopenia often at presentation
- Good prognosis
What is the classification of AML?
- French-American-British (FAB)
- M0 - undifferentiated
- M1 - without maturation
- M2 - with granulocytic maturation
- M3 - acute promyelocytic
- M4 - granulocytic and monocytic maturation
- M5 - monocytic
- M6 - erythroleukaemia
- M7 - megakaryoblastic
What is chronic myeloid leukaemia associated with?
- Philadelphia chromosome - present in more than 95%
- Due to a translocation between the long arm of chromosome 9 and 22 - t(9:22) (q34:q11)
- Results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene to form chromosome 22
- Resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal
What is the presentation of CML?
- Usually 60-70 years
- Anaemia - lethargy
- Weight loss and sweating are common
- Splenomegaly may be marked - abdominal discomfort
- Increase in granulocyte at different stages of maturation +/- thrombocytosis
- Decreased leucocytosis alkaline phosphatase
- May undergo blast transformation (AML in 80%, ALL in 20%)
What is the management of CML?
- Imitinab is now first line
- Hydroxyurea
- Interferon alpha
- Allogenic bone marrow transplant
What is Imitinab?
- Inhibitor of the tyrosine kinase associated with the BCR-ABL defect
- Very high response rate in chronic phase CML
