Haem V Flashcards
X-linked recessive
Describe the three stages in myeloma pathophysiology [3]
First: Development of monoclonal gammopathy of undetermined signficicance (MGUS)
- Precancerous phase
- Initial cytogentic abnormality occurs (inciting event) due to abnormal plasma cell response to a stimulus
- Causes creation of a plasma cell clone that secretes monoclonal antibody paraprotein
- Most don’t develop to MM
Second: Smouldering myeloma
- involves abnormal plasma cells and paraproteins but no organ damage or symptoms
- It has a greater risk of progression to myeloma (about 10% per year).
Third: MGUS to MM
- Further cytogenic abnormalities
- Myeloma affects multiple bone marrow areas in the body.
Describe the clinical features of myeloma [6]
CRABBI
C – Calcium (elevated)
R – Renal failure
A – Anaemia
B – Bone lesions and bone pain
B - Bleeding
I - Infection
Describe the reasons for the following presentations in MM [6]
C – Calcium (elevated)
R – Renal failure
A – Anaemia
B – Bone lesions and bone pain
B - Bleeding
I - Infection
C – Calcium (elevated)
- Hypercalcaemia
- Increased osteoclasts activity due to cytokine activation released by myeloma cells
R – Renal failure
- Immunoglobulin light chain deposition within renal tubules
A – Anaemia
- Suppresed erythropoeisis
B – Bone lesions and bone pain
- Increased osteoclast activity causes lytic bone pain
B - Bleeding
- Due to thrombocytopenia
I - Infection
- Reduction in normal immunoglobulins
Describe the typical presentation of hyperviscosity syndrome in MM [5]
What is the classic triad? [3]
Hyperviscosity syndrome is considered an emergency. It can cause many issues:
Triad:
- neurologic abnormalities
- vision changes
- mucosal bleeding
- Blurred vision
- Headaches
- Mucosal bleeding
- Dysopnoea due to HF
- Neurological syndromes
Describe the NICE referral criteria for MM [3]
- 60+; persistent bone pain, especially in the back
- 60+; hypercalcaemia or leukopenia with a presentation consistent with MM
- Plasma viscosity and ESR consistent with MM
What test would you conduct for the following patients?
- 60+; persistent bone pain, especially in the back [3]
- 60+; hypercalcaemia or leukopenia with a presentation consistent with MM [2]
- Plasma viscosity and ESR consistent with MM [2]
60+; persistent bone pain, especially in the back:
- FBC; including Ca, plasma viscosity and ESR
60+; hypercalcaemia or leukopenia with a presentation consistent with MM
- Protein electrophoresis and a Bence-Jones protein urine test
Plasma viscosity and ESR consistent with MM
- - Protein electrophoresis and a Bence-Jones protein urine test
Describe what is meant by protein electrophoresis and a Bence-Jones protein urine test
Bence Jones protein refers to free light chains in the urine.
protein electrophoresis: test that measures specific proteins in the blood
Imaging is used to assess for bone lesions. The order of preference is? [3]
- Whole-body MRI
- Whole-body low-dose CT
- Skeletal survey (x-ray images of the entire skeleton)
Typical x-ray changes seen in patients with myeloma include? [3]
- Well-defined lytic lesions (described as looking “punched-out”) e.g. Raindrop skull
- Diffuse osteopenia
- Abnormal fractures
Describe the four stages to MM tx [4]:
- induction therapy
- autologous stem cell transplantation (ASCT)
- maintenance therapy
- managing relapse or refractory disease.
Induction therapy:
- Usually combination of three drugs:
* targeted drugs (such as thalidomide, lenalidomide, bortezomib, daratumumab)
* chemotherapy (such as cyclophosphamide or melphalan)
* steroids (such as prednisolone or dexamethasone)
Autologous stem cell transplantation (ASCT)
- removal of a patient’s own stem cells prior to chemotherapy, which are then replaced after chemotherapy
- Stem cell transplantation can be: Autologous (using the person’s own stem cells) or Allogeneic (using stem cells from a healthy donor)
Maintenance therapy:
- bortezomib or lenalidomide
- Typically given until progression.
Managing relapse or refractory disease:
- almost all patients will relapse,
pathological fractures: [] is given to prevent and manage osteoporosis and fragility fractures as these are a large cause of morbidity and mortality, particularly in the elderly.
pathological fracture: zoledronic acid is given to prevent and manage osteoporosis and fragility fractures as these are a large cause of morbidity and mortality, particularly in the elderly.
Which complications need to be managed in MM? [5]
Describe the treatment used to manage these complications [+]
pain:
- treat with analgesia (using the WHO analgesic ladder)
- Radiotherapy for bone lesions can improve bone pain
pathological fracture:
- zoledronic acid is given to prevent and manage osteoporosis and fragility fractures as these are a large cause of morbidity and mortality, particularly in the elderly.
infection
- patients receive annual influenza vaccinations
- they may also receive Immunoglobulin replacement therapy.
venous thromboembolism prophylaxis
fatigue
- if symptoms persist consider an erythropoietin analogue.
Describe the specific managment for myeloma bone disease [5]
Bisphosphonates to suppress osteoclast activity
Radiotherapy for bone lesions can improve bone pain
Orthopaedic surgery to stabilise bones (e.g., by inserting a prophylactic intramedullary rod) or treat fractures
Cement augmentation (injecting cement into vertebral fractures or lesions) to improve spine stability and pain
What is used as a prognostic tool for myeloma? [1]
Beta-2 microglobulin levels
What are the different stages for MM prognosis that are based off beta-2 microglobulin levels [3]
Stage I: median survival 62 months
Stage II: median survival 44 months
Stage III: median survival of 29 months
How do you differentiate between benign paraproteinaemia and myeloma? [1]
MGUS:
- absence of myeloma-related organ or tissue damage (predominantly renal, skeletal or bone marrow impairment).
Patients are often elderly and in good health.
Describe overall treatment plan for myelomas [3]
Describe the pathophysiology of DIC [+]
DIC does not arise by itself but instead develops on a background of some other severe pathology.
Triggers can include:
- Infectious causes (e.g. sepsis)
- non-infectious causes (e.g. malignancy or severe burns)
The triggers lead to a release of pro-inflammatory cytokines in a so-called systemic inflammatory response
These triggers lead to intravascular activation of the coagulation cascade
At the same time, widespread activation of coagulation leads to a reduction in the concentration of circulating coagulation factors.
As the concentration of available clotting factors falls, the risk of bleeding increases
Platelets are also being used up due to activation and aggregation within the circulation, which leads to thrombocytopenia
Thus, in severe DIC there is paradoxically simultaneous thrombosis and spontaneous bleeding.
Describe 7 causes of DIC [7]
Shock
Sepsis/severe infection:
- these lead to the massive release of pro-inflammatory cytokines in a systemic inflammatory response. These cytokines can activate the coagulation system.
Major trauma or burns
Malignancies:
- including both solid organ and haematological malignancies. Acute promyelocytic leukaemia (APML) is strongly associated with DIC.
Obstetric emergencies:
- including eclampsia, HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome, placental abruption, intrauterine death and amniotic fluid embolism.
Severe immune-mediated reactions:
- such as acute haemolytic transfusion reactions due to mismatched ABO antigens, organ transplant rejection and bites from certain venomous snakes.
Severe organ dysfunction:
- including acute hepatic failure and severe acute pancreatitis.
Describe the clinical features of DIC
The features of DIC can vary from a mild chronic form with little overt features to an acute and catastrophic event resulting in severe, spontaneous haemorrhage and multi-organ failure
- Bleeding from unusual sites: ears, nose, gastrointestinal tract, genitourinary tract, respiratory tract or sites of venepuncture or cannulation. Bleeding from three unrelated sites is highly suggestive of DIC.
- Widespread or unexpected bruising without a history of trauma
- Petechiae or purpura
- Livedo reticularis: a mottled lace-like patterning of the skin
- Purpura fulminans: widespread skin necrosis
- Localised infarction and gangrene for instance of the digits
Describe the typical blood picture seen in DIC [4]
Low platelets
Prolonged APTT, prothrombin and bleeding time
Fibrin degradation products are often raised
Schistocytes due to microangiopathic haemolytic anaemi
What is meant by Purpura Simplex? [1]
What are platelets, PT and APPT like in this condition? [3]
Purpura simplex is increased bruising that is due to fragile blood vessels.
Platelets:
- Normal
PT:
- Normal
APTT:
- Normal
What are platelets, PT and APPT & fibronogen like in DIC? [3]
Platelets:
- Thrombocytopenia
PT:
- Prolonged
APTT:
- Prolonged
Fibronogen:
- Decreased
Describe the three types of VWD [3]
Type 1 involves a partial deficiency of VWF and is the most common and mildest type. ~70-80%
- Functionally normal VWF, but reduced levels
- Autosomal dominant
Type 2 involves the reduced function of VWF
- Normal levels of VWF, but functionally defective
- Autosomal dominant
Type 3 involves a complete deficiency of VWF and is the most rare and severe type
- Autosomal recessive
Describe the different types of type 2 VWD [4]
Type 2A:
* VWF multimers not the right size
Type 2B:
* VWF not the right size and too active, leading to shortage of both VWF and platelets.
Type 2M:
* low or absent binding to platelet receptors
* FVIII still binds normally
Type 2N:
* WF has reduced affinity for FVIII, leading to reduced levels.
Describe the changes seen in VWD with regards to:
- FBC
- Prothrombin time
- Fibrinogen
- APTT
FBC:
- Normal
Prothrombin time:
- Normal
Fibrinogen:
- Normal
APTT:
- Normal or increased
Diagnosis is based on a history of abnormal bleeding, family history, bleeding assessment tools and laboratory investigations. Due to the various underlying causes and types, there is no single von Willebrand disease test.
Describe the typical screen used to detect VWD
FVIII assay
* Typically low but can be normal
VWF antigen (Ag):
* Diagnosis of VWD can be made when VWF levels are < 0.30 IU/ml in the context of a previous mucocutaneous bleeding history
* If levels undetectable= Type 3
VWF activity: Assessed by measuring ristocetin cofactor (RCo) and collagen binding (CB) as ratios of VWF antigen levels
* RCo/Ag and CB/Ag is >0.6 = Type 1
* RCo/Ag or CB/Ag is < 0.6 = Type 2
Describe the inheritance to a son and daughter from a male haemophilia patient and a female haemophilia patient (individually)
male haemophilia patient
- daughter will be a carrier
- son will be unaffected, as they inherit their father’s normal Y chromosome.
female haemophilia patient
- daughter has 50% chance of being carrier
- son has 50% chance of being carrier
Describe the extrinsic pathway [2]
Initiation of the coagulation cascade is usually mediated by tissue factor via the extrinsic pathway.
Tissue factor is expressed on the surface of many cells found outside blood vessels but not on the surface of circulating blood cells or the endothelium.
When the endothelium is damaged, tissue factor comes into contact with blood and combines with circulating factor VII to form a complex that leads to the activation of factor X, triggering the common pathway.
Describe the intrinsic pathway [+]
Within blood vessels, thrombin generated from previous activation of the extrinsic pathway also activates the intrinsic pathway:
- Surface contact activates factor XII
- Factor XIIa activates factor XI
- Factor XIa activates factor IX
- Factor IXa combines with factor VIIIa, platelet membrane phospholipid and Ca2+ ions to activate factor X
- Factor Xa activates the common pathway generating more thrombin
Desribe the process of the common pathway
The common pathway begins with activation of factor X (to factor Xa) via either the extrinsic pathway or the intrinsic pathway.
It is the final stage of the coagulation cascade and leads to the formation of thrombin and fibrin.
Factor Xa combines with factor V, platelet membrane phospholipids and Ca2+ ions to convert prothrombin into thrombin.
Thrombin then converts fibrinogen into fibrin strands which form an important structural component of a thrombus.
In addition to the formation of fibrin, thrombin activates many parts of the coagulation cascade via a positive feedback loop through the intrinsic pathway leading to the formation of large amounts of additional thrombin (a ‘thrombin burst’).
Describe the pathophysiology of allergic transfusion [2]
Allergic transfusion:
- hypersensitivity reaction to allergen proteins in donor plasma
- most severe form causes IgE mediated anaphylaxis
- typically manifests as urticaria
Describe what is meant by a transfusion associated graft versus host disease (Ta-GVHD) [4]
Patients who recieve a transfusion and already have impared / low lymphocyte levels as they are immunocomprimised
Residual lymphocytes from the donor can multiply in the recipient and attack the host tissue
Can cause liver, skin gut and bone marrow damage
Fatal if left untreated !
Pruritis, urticaria
Irradiated blood products are used to which blood transfusion pathology? [1]
This specifically stops which cell type?
Irradiated blood products are used to avoid transfusion-associated graft versus host disease
This reduces the risk of GvHD as it depletes T-cells.
