2. Bleeding Flashcards
History taking bleeding
Examination bleeding
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Broad categories of why someone may have prolonged bleeding/symptoms of bleeding?
Clotting cascade deficiencies
- congenital eg haemophilia
- acquired eg lymphoma, SLE, amyloidosis
Platelet dysfunction
- VWF disease
- thrombocytopenia (destruction) eg ITP, TTP, HIT, HUS, medications, alcohol
- thrombocytopenia (decreased production) eg leukemia, myelodysplastic, myeloma
Widespread coagulopathy
- DIC
- low vitamin K (newborn, warfarin)
- major haemorrhage
- liver failure
Other
- vasculidities
- scurvy
symptoms that indicate a platelet disorder
Bleeding immediately after trauma
Bleeding of mucus membranes- epistaxis, bleeding gums
Cutaneous and subcutaneous bleeding- petechiae, purpura, easy bruising
Menorrhagia
symptoms that indicate a coagulation disorder
Delayed bleeding after trauma
Deep tissue bleeding- hemarthrosis , hematomas
Large, palpable ecchymoses
Presentation haemophilia
- bleed excessively in response to minor trauma
- spontaenous haemorrhage eg bleeding into joints (haemoathrosis) and muscles are a classic feature of severe haemophilia
intracranial haemorrhage, haematomas and cord bleeding in neonates.
Abnormal bleeding can occur in other areas:
Gums
Gastrointestinal tract
Urinary tract causing haematuria
Retroperitoneal space
Intracranial
Following procedures
investigations haemophilia
Diagnosis is based on bleeding scores, coagulation factor assays and genetic testing.
Prolonged APTT
Low factor VIII/IX coagulant level with normal levels of vWF
Others are normal
Family history
management haemophilia
The affected clotting factors (VIII or IX) can be replaced by intravenous infusions. This can be either prophylactically or in response to bleeding.
management of acute bleeding/ preventing bleeding during surgical procedures haemophilia
Infusions of the affected factor (VIII or IX)
Desmopressin to stimulate the release of von Willebrand Factor
Antifibrinolytics such as tranexamic acid
haemophilia A vs B are which clotting factor deficiencies
Haemophilia A is caused by a deficiency in factor VIII (8).
Haemophilia B (also known as Christmas disease) is caused by a deficiency in factor IX. (9)
which is the most common hemophilia
A
inheritance hemophilia
X linked recessive
risk with what is a complication of hemophilia treatment?
IV clotting factors (VIII or IX)
A complication of this treatment is formation of antibodies against the clotting factor resulting in the treatment becoming ineffective.
acquired coagulation disorders? what can cuase? pathophysiology?
Lymphoma and SLE can lead to acquired clotting factor deficiencies by the creation of antibodies against clotting factors
presentation von willebrand disease
Often asymptomatic
Bleeding from mucosa (epistaxis, menorrhagia, gums)
Easy bruising
Postoperatively
Family history of bleeding
invetsiations von willebrand
Prolonged bleeding time with normal platelet count
APTT may be prolonged or normal
Decreased plasma vWF
Decreased factor VIII activity
management VWF disease
Care when using NSAIDs, antiplatelets (e.g. aspirin, clopidogrel): can cause increased bleeding
Desmopressin-induces vWF release from endothelial cells
Factor VIII concentrates containing vWF-during surgery
what should you not / be cautious when prescribing vwf
NSAIDs, antiplatelets (e.g. aspirin, clopidogrel): can cause increased bleeding
what symptoms are associated with thrombocytopenia below 50x 1089/L
Nosebleeds
Bleeding gums
Heavy periods
Easy bruising
Haematuria (blood in the urine)
Rectal bleeding
what are platelet counts below 10x1089/L at risk of?
high risk for spontaneous bleeding. Particularly concerning are:
Intracranial haemorrhage
Gastrointestinal bleeding
What blood product have the highest risk of bacterial contamination
Platelet transfusions have the highest risk of bacterial contamination compared to other types of blood products
At what platelet level should you give platelets in active bleeding
Offer platelet transfusions to patients with a platelet count of <30 x 10 9 with clinically significant bleeding (World Health organisation bleeding grade 2- e.g. haematemesis, melaena, prolonged epistaxis)
Platelet thresholds for transfusion are higher (maximum < 100 x 10 9) for patients with severe bleeding (World Health organisation bleeding grades 3&4), or bleeding at critical sites, such as the CNS.
It should be noted that platelet transfusions have the highest risk of bacterial contamination compared to other types of blood product.
At what platelet level should you give patients platelets pre-invasive procedure
Platelet transfusion for thrombocytopenia before surgery/ an invasive procedure.
Aim for plt levels of:
> 50×109/L for most patients
50-75×109/L if high risk of bleeding
>100×109/L if surgery at critical site
At what platelet level should you give patients platelets if no active bleeding and no planned invasive procedure
A threshold of 10 x 109 except where platelet transfusion is contradindicated or there are alternative treatments for their condition
For example, do not perform platelet transfusion for any of the following conditions:
Chronic bone marrow failure
Autoimmune thrombocytopenia
Heparin-induced thrombocytopenia, or
Thrombotic thrombocytopenic purpura.
what is ITP
Immune (or idiopathic) thrombocytopenic purpura (ITP) is an immune-mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex. It is an example of a type II hypersensitivity reaction.
what type of hypersensitivity reaction is ITP
type 2
Presentation ITP
usually children
bruising
petechial or purpuric rash
bleeding is less common and typically presents as epistaxis or gingival bleeding
Investigations ITP
full blood count should demonstrate an isolated thrombocytopenia
blood film
bone marrow examinations is only required if there are atypical features e.g.
lymph node enlargement/splenomegaly, high/low white cells
failure to resolve/respond to treatment
management ITP
usually, no treatment is required
ITP resolves in around 80% of children with 6 months, with or without treatment
advice to avoid activities that may result in trauma (e.g. team sports)
other options may be indicated if the platelet count is very low (e.g. < 10 * 109/L) or there is significant bleeding.
Options include:
- oral/IV corticosteroid
- IV immunoglobulins
- platelet transfusions can be used in an emergency (e.g. active bleeding) but are only a temporary measure as they are soon destroyed by the circulating antibodies
education and advice ITP
Avoid contact sports
Avoid intramuscular injections and procedures such as lumbar punctures
Avoid NSAIDs, aspirin and blood thinning medications
Advice on managing nosebleeds
Seek help after any injury that may cause internal bleeding, for example car accidents or head injuries
complications ITP
Chronic ITP
Anaemia
Intracranial and subarachnoid haemorrhage
Gastrointestinal bleeding
what is TTP
Thrombotic thrombocytopenic purpura (TTP) is a condition where tiny thrombi develop throughout the small vessels, using up platelets. As the problem is in the small vessels, it is described as a microangiopathy. microangiopathic haemolytic anaemia
TTP is caused by a deficiency in ADAMTS13, a metalloprotease that cleaves von Willebrand factor multimers. This leads to the accumulation of ultra-large von Willebrand factor multimers, which promote platelet aggregation and thrombus formation.
This may be inherited or acquired (Autoimmune disease, where antibodies are created against the protein (acquired)
Pentad TTP
Microangiopathic haemolytic anaemia
Fever
Disturbed neurological function (Tissue ischaemia and end-organ damage)
Renal failure (Tissue ischaemia and end-organ damage)
Thrombocytopenia
treatment of choice TTP
Plasma exchange
Treatment is guided by a haematologist and may involve plasma exchange, steroids and rituximab.
what does ADAMTS13 usually do?
This protein normally:
Inactivates von Willebrand factor
Reduces platelet adhesion to vessel walls
Reduces clot formation
what is heparin-induced thrombocytopenia?
Heparin-induced thrombocytopenia (HIT) involves the development of antibodies against platelets in response to heparin (usually unfractionated heparin, but it can occur with low-molecular-weight heparin). Heparin-induced antibodies target a protein on platelets called platelet factor 4 (PF4).
presentation and pathophysiology HIT?
The condition typically presents around 5-10 days after starting treatment with heparin. HIT antibodies bind to platelets and activate the clotting system, causing a hypercoagulable state and thrombosis (e.g., deep vein thrombosis). They also break down platelets and cause thrombocytopenia. Therefore, there is a counterintuitive situation where a patient is on heparin, has a low platelet count, and develops abnormal blood clots.
diagnosis HIT
testing for HIT antibodies on a blood sample.
management HIT
- Stop heparin
+ using an alternative anticoagulant guided by a specialist (e.g., fondaparinux or argatroban).
What is HUS? triad?
triggered by a bacterial toxin called shiga toxin –>
thrombosis within small blood vessels throughout the body (THROMBOCYTOPENIA)
blood clots (thrombi) partially obstructing the small blood vessels –> destruction of red blood cells as they travel through the circulation
through the circulation (HAEMOLYTIC ANAEMIA)
red blood cells block the kidneys –> (ACUTE KIDNEY INJURY)
what increases the risk of developing HUS?
The use of antibiotics and anti-motility medications such as loperamide to treat gastroenteritis caused by these pathogens increases the risk of developing HUS.
Presentation HUS?
brief gastroenteritis, often with bloody diarrhoea
The symptoms of haemolytic uraemia syndrome typically start around 5 days after the onset of the diarrhoea.
Reduced urine output
Haematuria or dark brown urine
Abdominal pain
Lethargy and irritability
Confusion
Oedema
Hypertension
Bruising
management HUS
Urgent referral to the paediatric renal unit for renal dialysis if required
Antihypertensives if required
Careful maintenance of fluid balance
Blood transfusions if required
70 to 80% of patients make a full recovery.
what drugs are well-known for causing thrombocytopenia?
Sodium valproate
Methotrexate
how does alcohol affect platelet levels
Drinking alcoholic beverages regularly and in higher than recommended quantity has been shown to cause bone marrow suppression, defective platelet formation, a decrease the lifespan of a platelet leading to premature removal from the body, and impaired platelet function.
what leukemia is the most common in children
acute lymphoblastic leukemia
which leukemia is associated with downs
acute lymphoblastic leukemia
which leukemia is associated with richers transformation and smudge cells
CLL
which leukemia is associated with philedelphia chromosome
CML
which leukenia is assocated with transformation from a myeloproliferative disorder and is associated with auer rods
AML
how does leukemia cuase pancytopenia
Leukaemia is a form of cancer of the cells in the bone marrow. A genetic mutation in one of the precursor cells in the bone marrow leads to excessive production of a single type of abnormal white blood cell.
The excessive production of a single type of cell can lead to suppression of the other cell lines, causing underproduction of other cell types. This results in a pancytopenia, which is a combination of low:
Red blood cells (anaemia),
White blood cells (leukopenia)
Platelets (thrombocytopenia)
what is required urgently when leukemia is a ddx for a presentation
An urgent full blood count
features of leukemia?
anaemia: lethargy/fatigue and pallor
neutropaenia: frequent or severe infections
thrombocytopenia: easy bruising, petechiae
Hepatosplenomegaly: due to leukemic infiltration
Fever: A persistent, recurrent or refractory fever that is most likely a constitutional symptom and may present alongside a history of night sweats, weight loss.
Lymphadenopathy: a build-up of large numbers of cancerous cells which have travelled from the bone marrow
Failure to thrive (children)
why does leukemia cause hepatosplenomegaly
due to leukemic infiltration
why does leukemia cause lymphadenopathy
a build-up of large numbers of cancerous cells which have travelled from the bone marrow
when should ?leukemia be sent for immediate specialist assessment
They recommend children or young people with petechiae or hepatosplenomegaly are sent for immediate specialist assessment.
initial investigation leukemia
FBC
investigation leukemia
- FBC
- lactate
- bone marrow biopsy
- CT and PET scans
- lymph node biopsy
- genetic tests
what are the two cell lines coming from multipotential hematopoeitic cells
- myeloid –> (megakaryocyte (–> thrombocytes), erythrocyte, mast cells, myeloblast ) then myeloblast –> basophil, neutrophil, eosinophil, monocyte (–> macrophage)
- lymphoid –> natural killer cell and small lymphocyte. small lymphocyte –> T lymphocyte, B lymphocyte (–> plasma cell)
presentation CLL
slow proliferation of a single type of well-differentiated lymphocyte, usually B-lymphocytes. It usually affects adults over 60 years of age. It is often asymptomatic but can present with infections, anaemia, bleeding and weight loss. It may cause warm autoimmune haemolytic anaemia.
smudge cellsa ssociated with?
CLL
what is richters transformation
Richter’s transformation refers to the rare transformation of CLL into high-grade B-cell lymphoma.
phases of CML
chronic - years of high WCC
accelerated - blast cells push out other types - anaemia, thrombocytopenia, immunodeficiency
blast phase - over 20% blasts in blood - severe symptoms and is often fatal
CML genetic associtaed
philedelphia chromosome
This refers to an abnormal chromosome 22 caused by a reciprocal translocation (swap) of genetic material between a section of chromosome 9 and chromosome 22.
AML age
from middle age onwards
what may cause AML
myeloprolifertaive disorder such as polycythaemia vera or myelofibrosis
blood film AML
A blood film and bone marrow biopsy will show a high proportion of blast cells. Auer rods in the cytoplasm of blast cells are a characteristic finding in AML.
management leukemia
Leukaemia is mainly treated with chemotherapy and targeted therapies, depending on the type and individual features.
Examples of targleted therapies include (mainly used in CLL):
Tyrosine kinase inhibitors (e.g., ibrutinib)
Monoclonal antibodies (e.g., rituximab, which targets B-cells)
Other treatments options include:
Radiotherapy
Bone marrow transplant
Surgery
complications of chemo
Failure to treat cancer
Stunted growth and development in children
Infections due to immunosuppression
Neurotoxicity
Infertility
Secondary malignancy
Cardiotoxicity (heart damage)
Tumour lysis syndrome
what is tumor lysis syndrome
Tumour lysis syndrome results from chemicals released when cells are destroyed by chemotherapy, resulting in:
High uric acid
High potassium (hyperkalaemia)
High phosphate
Low calcium (as a result of high phosphate)
Uric acid can form crystals in the interstitial space and tubules of the kidneys, causing acute kidney injury. Hyperkalaemia can cause cardiac arrhythmias. The release of cytokines can cause systemic inflammation.
Very good hydration and urine output before chemotherapy is required in patients at risk of tumour lysis syndrome. Allopurinol or rasburicase may be used to suppress the uric acid levels.
what is myelodysplastic syndorme
Precancerous disease of myeloid cells in bone marrow whereby the dysplastic cells may cause abnormal or inadequate blood cell rpoduction
Badly fucntioning → anaemia, thrombocytopenia, leukopenia etc.
Tries to compensate by increasing haematopoeisis
Dysplasia has risk of progressing to acute myeloid leukemia
FBC myelodysplastic syndrome
Myelodysplastic syndrome causes low levels of blood components that originate from the myeloid cell line:
Anaemia (low haemoglobin)
Neutropenia (low neutrophil count)
Thrombocytopenia (low platelets)
risk factors myelodysplasia
older age and previous chemotherapy or radiotherapy.
presentation myelodysplasia
Patients may be asymptomatic. It may be diagnosed after incidental findings on a full blood count.
They may present with symptoms of:
Anaemia (fatigue, pallor or shortness of breath)
Neutropenia (frequent or severe infections)
Thrombocytopenia (bleeding and purpura)
blood film myelodysplasia
Full blood count will be abnormal. There may be blasts on the blood film.
Bone marrow biopsy is required to confirm the diagnosis.
management myelodyspalsia
Watchful waiting
Supportive treatment (e.g., blood or platelet transfusions)
Erythropoietin (stimulates red blood cell production)
Granulocyte colony-stimulating factor (stimulates neutrophil production)
Chemotherapy and targeted therapies (e.g., lenalidomide)
Allogenic stem cell transplantation (risky but potentially curative)
what is myeloma
Myeloma is a cancer of the plasma cells (type of B lymphocytes that produce antibodies). Cancer in a specific type of plasma cell results in large quantities of a single antibody being produced.
what is Monoclonal gammopathy of undetermined significance (MGUS)
is where there is an excess of a single type of antibody or antibody components without other features of myeloma or cancer.
pathophysiology myeloma
B cells in bone marrow producing antibodies → genetic mutation causing one antibody to be produced uncontrollably (50% of the time this is IgG)
Bone marrow infiltration → anaemia, neutropaenia, thrombocytopaenia
Plasma cells releasing cytokines → increased osteoclast activity → myeloma bone disease → skull, spine, long bones affected → bone pain / pathological fractures → releasing lots of calcium from bones → hypercalcaemia
Kidney failure is common in patients with a monoclonal gammopathy, most frequently due to hypercalcemia or myeloma cast nephropathy. Immunoglobulin crystallization is an uncommon phenomenon that also results in kidney injury
hypercalcaemia can ppt kidney stones,
presentation myeloma
PC: anaemia
PC: neutropenia
PC: thrombocytopenia
PC: pathological fractures
PC: bone pain, particularly back pain
PC: myeloma renal disease
PC: hyperviscosity
PC: kidney stones
Initial tests myeloma
FBC: anaemia
Calcium and bone profile: hypercalcaemia
U&Es : renal failure
ESR
Plasma viscosity
If suggetsive –>
then very urgent (within 48hrs)
- protein electrophoresis
- bence-jones urine test
if +ve 2ww
bone marrow biopsy and look at all results
diagnostic criteria multiple myeloma
The diagnostic criteria for multiple myeloma requires one major and one minor criteria or three minor criteria in an individual who has signs or symptoms of multiple myeloma.
Major criteria
Plasmacytoma (as demonstrated on evaluation of biopsy specimen)
30% plasma cells in a bone marrow sample
Elevated levels of M protein in the blood or urine
Minor criteria
10% to 30% plasma cells in a bone marrow sample.
Minor elevations in the level of M protein in the blood or urine.
Osteolytic lesions (as demonstrated on imaging studies).
Low levels of antibodies (not produced by the cancer cells) in the blood.
what is a Autologous hematopoietic cell transplantation
involves the removal of a patient’s own stem cells prior to chemotherapy, which are then replaced after chemotherapy
what is allogenic haematopoeitic stem cell transplant
Allogenic hematopoietic cell transplantation
is not commonly used in myeloma due to high rates of overall mortality and symptoms of graft-ve
stages of myeloma treatment
A combination of drugs is used to treat myeloma - ‘induction therapy
targeted drugs (such as thalidomide, lenalidomide, bortezomib, daratumumab)
chemotherapy (such as cyclophosphamide or melphalan)
steroids (such as prednisolone or dexamethasone)
The particular combination depends on whether a patient may be suitable for autologous hematopoietic cell transplantation or not.
Autologous hematopoietic cell transplantation
involves the removal of a patient’s own stem cells prior to chemotherapy, which are then replaced after chemotherapy
prolong both event-free and overall survival when compared with non-transplant strategies
typically it is younger, healthier patients who are suitable for stem cell transplantation and rigorous chemotherapy regimes.
symptom management and complication avoidance myeloma
pain: treat with analgesia (using the WHO analgesic ladder)
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
treat all possible underlying causes
if symptoms persist consider an erythropoietin analogue.
mechanism of DIC
Sepsis and trauma lead to a release of pro-inflammatory cytokines in a so-called systemic inflammatory response. In other conditions, the expression of certain pro-coagulant factors, such as tissue factor, is upregulated.
→ activate clotting cascade → micro clots → multi-organ failure due to tissue ischaemia. plus clotting factors used up –> bleeding eg petechiae
how does the cause of DIC relate to presentation and blood results
Infection and septic shock tend to cause a more prothrombotic form of DIC, which predominantly causes excess clot formation. Alternatively, DIC due to obstetric catastrophes or leukemia tends to cause depletion of fibrinogen leading to hemorrhage.
Low fibrinogen is more common in predominantly fibrinolytic types of DIC (e.g., patients with acute promyelocytic leukemia or obstetric-related DIC).
Sepsis increases fibrinogen levels, so sepsis-induced DIC may have elevated or normal levels of fibrinogen. Falling fibrinogen may suggest ongoing DIC with consumption of fibrinogen.
Management of DIC
Stopping bleeding
- Platelet transfusions should be considered if the patient is bleeding. The platelet count should be maintained >50 x 109/L in the presence of bleeding.
- In bleeding patients with a prolonged PT and/or APTT, fresh frozen plasma can be considered.
- If there is severely low fibrinogen then transfusions of cryoprecipitate or fibrinogen concentrate should be considered.
Stopping clotting
- If thrombosis is a prominent feature, then therapeutic doses of heparin should be considered. If there is co-existing high risk of bleeding, then unfractionated heparin can be used since this has a significantly shorter half-life and is more readily reversible than low molecular weight heparin.
- In other patients who are non-bleeding, prophylactic doses of heparin are recommended to protect against VTE.
How does liver fialure affect coagualiton
Liver failure impacts all three stages of hemostasis: primary hemostasis, coagulation, and fibrinolysis
Thrombocytopenia
- platelet sequestration due to congetsive splenomegaly as a result of portal HTN
- bone marrow suppression by alcohol/foalte def
- imapired hepatic synthesis of TPO
Coagulation
- reduced synthesis of clotting factors
- also reduction in anticoagualtion factors : Natural anticoagulant protein levels fall progressively with increasing severity of liver disease.6 Antithrombin, protein C and protein S levels
OVerall
“rebalanced hemostasis” According to this model, the hemostatic alterations that occur result in a new balance within and between procoagulant, anticoagulant and fibrinolytic systems (Figure 2).7 Because of the relative deficiency of procoagulant and anticoagulant factors, the hemostatic balance is more precarious and may tip toward bleeding or thrombosis depending on provoking circumstantial risk factors.
which babies are at higher risk of Haemorrhagic disease of the newborn
Breast-fed babies are particularly at risk as breast milk is a poor source of vitamin K. Maternal use of antiepileptics also increases the risk
pathophysiology and presentation scurvy
The condition is caused by a lack of vitamin C in the diet, which is essential for the production of collagen and other important functions in the body. Symptoms of scurvy can include fatigue, weakness, joint pain, and bleeding gums. In severe cases, patients may experience anaemia and skin lesions.
warfarin Major bleeding (e.g. variceal haemorrhage, intracranial haemorrhage)
Stop warfarin
Give intravenous vitamin K 5mg
Prothrombin complex concentrate - if not available then FFP*
warfarin INR > 8.0
Minor bleeding
Stop warfarin
Give intravenous vitamin K 1-3mg
Repeat dose of vitamin K if INR still too high after 24 hours
Restart warfarin when INR < 5.0
INR > 8.0
No bleeding
Stop warfarin
Give vitamin K 1-5mg by mouth, using the intravenous preparation orally
Repeat dose of vitamin K if INR still too high after 24 hours
Restart when INR < 5.0
warfarin INR 5.0-8.0
Minor bleeding
Stop warfarin
Give intravenous vitamin K 1-3mg
Restart when INR < 5.0
warfarin INR 5.0-8.0
No bleeding
Withhold 1 or 2 doses of warfarin (2 days)
Reduce subsequent maintenance dose
