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 treaments for VWD [4]
- Desmopressin (first line) (stimulates the release of vWF from endothelial cells.
- Tranexamic acid
- Von Willebrand factor infusion
- Factor VIII plus von Willebrand factor infusion
Describe the treatment algorithm for patient with VWD during an active bleed? [2]
1st line :
* administration of tranexamic acid and desmopressin
* Both can be used as prophylaxis prior to surgery
2nd line:
* if the patient is non responsive to desmopressin, a VWF-FVIII concentrate should be used
* Also used as prophylaxis prior to surgery
* In menorrhagia, hormonal management and use of IUD can be considered
Describe the pathophysiology of haemophilia [5]
Deficiency of either Factor VIII or IX interferes with the intrinsic pathway of the coagulation cascade
This leads to a decreased activation of Factor X to Factor Xa, reducing the generation of thrombin
Thrombin is critical for converting fibrinogen to fibrin, a protein that provides the structural integrity of a clot.
As a result of inadequate thrombin generation, the conversion of soluble fibrinogen to insoluble fibrin is compromised, rendering the clot fragile and susceptible to premature lysis
Therefore, the platelet plug, lacking the stabilising meshwork of fibrin, fails to halt the bleeding effectively.
Describe the typical presentation of haemophilia A & B
-
Haemarthrosis (bleeding into a joint)
Up to 80% of haemorrhages in haemophilia patients
Muscular haematomas (15% of all hemorrhages in haemophilia patients) - commonly leg muscles (quadriceps, calves) - Patients can bleed excessively in response to minor trauma
- spontaneous bleeding without any trauma.
- intracranial haemorrhage
- haematomas
- cord bleeding in neonates
Describe how haemophilia can present in neonates [3]
Prolonged bleeding after circumcision
Intracranial bleeding (up to 5% of severe cases); can be due to trauma from delivery ie forceps
Prolonged bleeding after heel prick testing
Diagnosis of haemophilia is based on bleeding scores, coagulation factor assays and genetic testing.
Describe the results seen for these [+]
Clotting Studies
* Prolonged activated partial thromboplastin time (aPTT)
* Normal bleeding time (BT)
* Normal fibronogen levels
* Normal VWF levels
* A normal prothrombin time (PT) rules out extrinsic and common coagulation pathway pathologies that could present similarly; e.g. liver disease; vitamin k deficiency; DIC
* Reduced factor VII or factor IX activity level for Haem. A & B respectively
Describe the managment of haemophilia A & B [2]
Desmopressin (DDAVP)
* can be used in acute episodes of mild haemophilia A to promote the function of von Willebrand factor (which in turn promotes factor VIII activity) and only if bleeding persists would coagulation factor concentrates be used.
In more severe disease: replace the missing coagulation factors
* In haemophilia A, coagulation factor VIII needs to be replaced
* in haemophilia B, coagulation factor IX needs to be replaced
Fresh frozen plasma or cryoprecipitate may be needed alongisde factor infusions
Analgesia
- Paracetamol
- Opioids
- avoid the use of aspirin and NSAIDs due to their increased risk of bleeding
Describe what is meant by a factor inhibitor [1]
When antibodies develop to the replacement coagulation factors (so have to increase the concentration of coagulation factors adminstered)
How do you manage patients with severe haemophilia before surgery? [2]
Which surgeries is this particularly needed for? [2]
Patients with severe haemophilia are at high risk of bleeding during and after surgery.
- For this reason, their factor activity should be increased to 50-100% for 2-7 days before surgery, and closer to 100% for surgery on the brain or prostate.
- Tranexamic acid can be considered as this inhibits fibrinolysis without increasing thrombosis risk in healthy individuals.
What is the inheritance pattern of haemophilia? [1]
X-linked recessive inheritance pattern
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
Why should factor exposure be initially given in a specialist centre? [1]
The immune response can result in anaphylaxis on exposure to any factor product, so first exposure should always take place in a specialist centre.5
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 how the clotting cascade is regulated [2]
Protein C is produced in response to thrombin binding to the receptor thrombomodulin on the vascular endothelium.
This leads to protein S activation which then breaks down factors Va and VIIIa in a negative feedback loop.
Antithrombin is a natural anticoagulant that is produced by the liver and destroys factors XIa, Xa and thrombin.
Describe the MoA of heparin and fondaparinux [1]
Heparin and fondaparinux enhance the natural effects of antithrombin in inhibiting thrombin and factor Xa.
Antithrombin is a natural anticoagulant that is produced by the liver and destroys factors [] and [].
Antithrombin is a natural anticoagulant that is produced by the liver and destroys factors XIa, Xa and thrombin.
What are reasons for a prolonged PT time? [3]
- Disseminated intravascular coagulation (DIC)
- Vitamin K deficiency (Factor VII is the vitamin K dependent clotting factor with the shortest half-life)
- Chronic liver disease
Causes of a prolonged APPT include? [4]
- Disseminated intravascular coagulation (DIC)
- Clotting factor deficiencies (e.g. haemophilia A or B)
- Lupus anticoagulant
- Von Willebrand’s disease
Describe what is meant by Factor V Leiden [1]
Factor V Leiden is a common genetic mutation to the gene coding for Factor V.
It increases the resistance of factor V to activated protein C making it more difficult to break down and therefore leading to an increased tendency to clot.
What is the 1/2 life of doacs? [1]
When is the peak anticoagulant effect of doac? [1]
Half life:
- ~ 12hrs
Peak AC effect:
- 2hrs
Describe the pathophysiology of acute haemolytic reaction [4]
Acute haemolytic reaction:
- Results from ABO incompatibility
- Preformed antibodies to donor antigens results in complement activation
- Causes intravascular haemolysis & associated severe acute inflammatory cascade
- This can result in DIC, shock or acute renal failure
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 how an allergic transfusion occurs in IgA deficiency patients [1]
anaphylactic reaction (technically anaphylactoid, as it is not IgEmediated) can occur as a result of anti-IgA antibodies in the recipient interacting with donor IgA.
Describe the pathophysiology of a non-haemolytic febrile reaction [2]
- Interaction between recipient antibodies directed against leukocytes
present in the red-cell or platelet unit transfused. - may also result from the transfusion of proinflammatory substances
including cytokines, complement fragments, and lipid compounds that are contained in the
transfused unit’s plasma supernatant
Describe the pathophysiology of TRALI [1]
Transfusion-related acute lung injury (TRALI):
- Anti-leucocyte antibodies in donor react with recipient WBCS
- Patients are usually ill, which primes their WBCS
Non-cardiogenic pulmonary oedema thought to be secondary to increased vascular permeability caused by host neutrophils that become activated by substances in donated blood
Describe the pathophysiology of TACO [1]
How long does it occur after transfusion? [1]
TACO
* Pulmonary oedema due to excessive rate of transfusion with pre-existing heart failure
* ~ 12hrs after
Describe what is meant by a delayed haemolytic reaction [1]
How long after a transfusion does it occur? [1]
What are four features of this? [4]
- Antibodies directed agaisnt other red cell antigens (asides from ABO antigens)
- 7-10 days after transfusion
- Causes extravascular haemolysis:
1. Falling Hb
2. Jaundice
3. Dark urine
4. Fever
Bacterial sepsis via bacterial contamination occurs via transfusion of which types of products? [1]
What are the clinical consequences of this? [1]
Bacteria from donor’s skin (such as Staphylcoccus) becomes infected in blood.
Most commonly occurs in platelet transfusions because these need to be kept at room temp.
Causes shock, kidney failure and death
When does a non-haemolytic febrile reaction occur in relation to the transfusion? [1]
How serious is this? [1]
What are the features? [1]
- Occurs during or soon after the transfusion
- Unpleasant but not life-threatening
Features:
- Fever
- +/- tachycardia
- +/- inflammatory symptoms (rigors / myalgia / breathlessness / naseau)
How do you treat a febrile non-haemolytic transfusion reactions? [2]
Slow / stop transfusion
Give paracetamol (antipyretic) & monitor
Allergic reactions in blood transfusions are more common in? [3]
In components with more platelets as thought to be caused by foreign plasma proteins
- Platelets
- Plasma
- FFP
- Cryoprecipitate
Blood transfusion reaction
Describe how you would treat a:
- Minor allergic reaction [3]
- Anaphylaxis reaction [2]
Minor allergic reaction:
- Temporarily stop transfusion
- Antihistamine
- Montior
Anaphylaxis reaction
- Stop transfusion
- IM adrenaline
- ABC supprt (w/ oxygen & fluids)
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
Which of the following occurs due to white blood cell HLA antibodies
Non-haemolytic febrile reaction
Allergic/anaphylaxis reaction
Acute haemolytic transfusion reaction
Transfusion-associated circulatory overload (TACO)
Transfusion-related acute lung injury (TRALI)
Non-haemolytic febrile reaction
Which of the following has complications that include disseminated intravascular coagulation, and renal failure
Non-haemolytic febrile reaction
Allergic/anaphylaxis reaction
Acute haemolytic transfusion reaction
Transfusion-associated circulatory overload (TACO)
Transfusion-related acute lung injury (TRALI)
Acute haemolytic transfusion reaction
What is the management of a minor allergic reaction during a blood product transfusion? [1]
Temporarily stop the transfusion, give antihistamine, monitor
Slow or stop the transfusion, paracetamol, monitor is the treatment for which reaction type? [1]
a non-haemolytic febrile reaction
Describe what is meant by post-transfusion purpura (PTP) [2]
PTP is an adverse reaction to a blood transfusion or platelet transfusion that occurs when the body produces alloantibodies to the introduced platelets’ antigens.
These alloantibodies destroy the patient’s platelets leading to thrombocytopenia.
PTP usually presents 5–12 days after transfusion.
The typical clinical features of [] include fever during blood transfusion with no associated haemolysis.
The typical clinical features of Febrile non-haemolytic transfusion reaction (FNHTR)
include fever during blood transfusion with no associated haemolysis.
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.
