Hemorrhagic disorders Flashcards
Coagulation pathway
What helps to balance coagulation out?
Antithrombin, Protein C, Protein S -> to balance coagulation out and break clots down (this is as body is at the state of constantly making clots) -> if any of these ‚balancing’ molecules will be impaired = thrombotic problem
What’s Von Willebrand factor? What’s its role?
VWF -> large adhesive glycoprotein that is required from platelet adhesion to endothelium at site of vessel injury, platelet aggregation (to form platelet plug) and stabilisation of factor VIII in a circulation (factor VIIIa is required for factor X activation)
What questions to ask in the Hx in order to identify the possibility of a pt having a bleeding disorder?
- Questions about iron deficiency and blood transfusions -> to what extend they bleed (what treatment was required)
- Ask about tonsillectomy -> if pt had a procedure and did not bleed -> high chance that no bleeding disorder
- Dental extraction -> did they need to stitch it/ go back to dentist (due to heavy bleeding)
- Did they start having bleeding problem after starting anti-coagulant (that may be the cause)
- if bruises come out possibly in the places where we do not expect to hit ourselves/bump onto things
What’s the normal number of platelets? ( range)
Normal number of platelets 150 - 450 (this is considered as more than we need)
At what point (level) do we treat low number of platelets?
We treat platelets that are about 30 or less
Ix in suspected bleeding disorder (and justification)
- Renal function -> uraemia can interfere with platelet function
- Liver function -> coagulation proteins
- Haematinics: folate and B12 -> we need it to make platelets
- Paraprotein -> is there an abnormal protein?
- PT (extrinsic pathway/factor VII)
- APTT (intrinsic pathway; factor XII)
What does PT look at?
Prothrombin Time (PT)
- PT looks at extrinsic pathway (factor VII etc)
- long prothrombin time -> long for the blood to clot
What does APTT look at?
APTT looks at intrinsic pathway (factor XII, kallakerin etc)
Causes of long PT
causes of long APTT
What findings may be suggestive of coagulation problems? (2)
•Factor inhibitors = autoantibodies against coagulation factors
•Lupus anticoagulant = autoantibodies directed against phospholipid -> can cause artificially prolonged APTT (due to consumption of phospholipids that are put into the tube - so blood
cannot clot properly -> it is a false positive result)
What ‘other’ Ix we perform in a pt with suspected coagulopathy?
- Bleeding time - we lancet somebody arm and see how long it takes to bleed
- Mixing studies- patient’s plasma and somebody else’ plasma mixed together; if there is a deficiency of coagulation factor -> patient sample will get better (as normal stuff are put with it); if anti-body against factors causes the problem - it will not get better as it will destroy somebody else’s factors
- D-dimer - breakdown product of fibrin
- Factor assays - we can see how the factors behave in terms of their activity levels
- Genetics -> to directly look for mutations
• Global coagulations assays -> used in trauma and surgical setting; how long does it take for
the blood to clot
What factors deficiencies are there in:
Haemophilia A
Haemophilia B
- Haemophilia A -> factor VIII deficient
- Haemophilia B -> factor XI deficient
What is (a simple) genetic mechanism of hemophilia?
X linked
What abnormality is seen on Ix of Haemophilia?
As factors VIII and IX belong to intrinsic cascade -> prolonged APTT (as intrinsic cascade is affected)
Complications/consequences of haemophilia
- Haemarthrosis - bleeding into joint spaces
- Haemophilic Arthropathy -> result of haemarthrosis
- Intramuscular bleeds
- Intracranial bleeds
- Haematuria
- ‘hidden bleeds’
Pathology of Haemophilic Arthropathy
recurrent bleed into joint space -> inflammation is activated -> destruction of the joint -> changes in the joint -> functional problems
Treatment of haemophilia
To replace what’s missing - clotting factors:
- So for patient with haemophilia A -> we give factor VIII -> to bring missing factors levels up to normal
- DDAVP -> desmopressin injection -> to release endogenous stores of factor VIII and vWF (as vWF will be released so more factor VIII too as it is bound to vWF) -> for people with mild disorders we can push up the factor levels to normal) *only effective for Haemophilia A treatment
- Tranexamic acid -> stops bbreakdown of clots (anti- thrombolytic)
Possible complications of Haemophilia treatment
•Person with severe haemophilia is not used to high levels of missing factors -> so if they are administrated -> antibody against them can be developed*
*more common in haemophilia A
- immune modulation -> someone is given immuno-active protein
- Thrombosis -> perhaps over-treated -> too much coagulation -> clot
- anaphylaxis
- infections (e.g. Hep B, HIV, Hep C, etc - before the screening was introduced)
Genetics behind Von Willebrand Disease
- Type 1 and 2 vWD are autosomal dominant
*sometimes type 2 may be recessive
- Type 3 autosomal recessive
Pathophysiology of Von Willebrand Disease
- Deficiency in quality or quantity of vWF
- Deficiency of vWF will show primarily in organs with extensive small vessels (e.g. skin, GI, uterus)
What type of Von Willebrand Disease is most common + features
Type 1 is most common
- mild bleeding symptoms (e.g. nosebleeds)
- occasional more severe symptoms
*blood type may affect the presentation of vWD and severity of its symptoms
What severity of symptoms type 2 vWD has?
Type 2: second most common type
- mild to moderate symptoms
Clinical presentation/ features of Von Willebrand Disease
Clinical features: bleeding tendency, easy bruising, nosebleeds, bleeding gums (specific to women: heavy menstrual periods and blood loss during child birth)
*depend on severity and type of vWD
Diagnosis (Ix) of Von Willebrand Disease
- blood plasma of patient is investigated for qualitative and quantitative deficiencies of vWF
- factor VIII levels -> as factor VIII is bound to vWF (deficiency of vWF can lead therefore to
reduction in factor VIII) -> elevation of PTT (takes longer to clot as factor is reduced)
- coagulation studies (not routinely performed, for type 2) -> to look at platelet interaction with sub endothelium
- other specialised tests
Detection of vWD is complicated as vWF is an acute phase reactant -> levels may be raised in infection, pregnancy and stress
Other tests: FBC, APTT with INR, thrombin time (TT) and fibrinogen level; test for factor IX if haemophilia B is suspected
Desmopressin in management of Von Willebrand Disease
- use
- MoA
- routes of administration
- contraindications
Desmopressin (analogue of vasopressin; natural anti-diuretic) -> use in cases of minor trauma, preparation for dental or minor surgical procedures
MoA: Desmopressin -> release of vWF stimulated from endothelial cells -> level of vWF and VIII is increased
Available as: intra-nasal preparation or IV
Contraindication: type 2b of vWD (risk of thrombotic complication and increased thrombocytopenia)
Management of Von Willebrand Factor
- Desmopressin
- Oestrogen - containing medication - for women with heavy menstrual bleeding
- Human - derived medium - purity factor VIII (containing vWF)-> for patient undergoing scheduled surgery or having clinically significant haemorrhage
- Contraceptive pill -> if someone has problem with menorrhagia
- Plans before the surgery
- combination of vWF and factor VIII -> to replace what’s missing
Two types of platelets disorders. What do they mean?
A. Quantitative - a body is not producing enough platelets, or destruction is increased (e.g. destroyed in the spleen, hereditary disorders) etc.
B. Qualitative - proteins being missed, platelet proteins abnormalities, drugs reducing/inhibiting platelets’ activity, systemic disorders, haematological disorders etc
Causes of reduced platelet production
- Bone marrow could be suppressed by drugs, alcohol
- Viral infections - can transiently cause low platelets
- Hereditary bone marrow disorders -> either all cell line or just platelet
What’s the name of the condition?
Thrombocytopenia with absent
radius
- no radius (happen as part of the syndrome)
What happens in Immune Thrombocytopaenia? (pathology)
Isolated thrombocytopenia -> only platelet count goes down
Pathology: Body recognises platelets as foreign body and gets rid of them
Potential causes of Immune Thrombocytopenia
- happens on its own
- happens in association with infections e.g. HIV, malaria etc.
- drugs: heparin, gold, quinine
- Post-transfusion purpura -> delayed adverse reaction to a blood transfusion -> alloantibodies to foreign platlets (usually 5-12 days post-transfusion) -> rapid decline in platelet count
- NAIT (neonatal alloimmune thrombocytopenia) -> passed through the placenta from mum to foetus (inherited platelet antigens)
Diagnosis of Immune Thrombocytopenia
- no diagnostic tests
- exclusion (to investigate for other potential causes)
When do we start to treat Immune Thrombocytopenia?
whether we start to treat or not - depends on platelet levels
if it is 80 that’s fine as should not cause any problems; if it is 20 - we do treat
Drugs used in treatment of Immune Thrombocytopenia
- steroids -> to induce immunosuppression -> so to reduce production of alloantibodies
- IVIg -> immunoglobulin -> donor antibody given and saturates all the receptors on the spleen - > so platelets with antibodies attached to them not able to bind (for destruction)
- Rituximab -> anti CD20 antibody -> stops from producing antibodies
- Splenectomy -> so platelets with antibodies attached cannot be destroyed
- TPO-receptor agonist -> new approach, drug stimulating bone marrow to produce new platelets (thrombopoietin is platelet equivalent of erythropoietin EPO) -> producing more of platelets by putting bone marrow into overdrive to produce lots of platelets and to outnumber the antibodies that were produced
What (other than autoimmune) conditions may lead to platelet destruction?
- DIC - consumption of coagulation factors
- TTP/HUS - rare hematological endothelial disorders -> platelet aggregation within vessels
- Heart Bypass
- Cardiopulmonary Bypass
- Spleen is overactive -> getting rid of platelets
What is defective/abnormal in ‘qualitative’ platelet disorder?
- defective glycoproteins
- abnormalities of platelet granules
- drugs
- haematological disorders
What is deficient in vitamin K deficiency?
Vitamin K deficiency -> reduced production of: II, VII, IX, X, C and S
What group of patients is at increased risk of vitamin K deficiency?
*may happen in hospitalised/ICU patients due to lack of adequate nutrient
What may vitamin K cause in the newborn?
Vitamin K may cause hemorrhagic disease of a newborn (HDN) *therefore babies get vitamin K at birth to reduce their risk of bleeding
HDN - coagulation disturbance caused by vitamin K deficiency
Management of vitamin K deficiency
- vitamin K
- in active bleeding -> vitamin K and fresh frozen plasma (ready coagulation factors)
What is seen on Ix in vitamin K deficiency?
What is Scurvy?
Scurvy -> Vitamin C deficiency -> problems with collagen (vessels affected) -> bleeding from them
DIC
- what happens?
- causes
Pathophysiology of Acquired Haemophilia
-it is not inherited
Pathology: Autoantibody (IgG) produced against factor VIII -> body gets rid of their own factor VIII
*it is spontaneous development of autoantibodies in someone who normally used to produce factor VIII
Diagnosis of Acquired Haemophilia
- very long aPTT
- no correction in aPTT with mixing studies (so does not get better if somebody else’s plasma is put there -> as antibodies will destroy someone else’s factors)
What to do if we see long aPTT?
If long aPTT is seen and we cannot see obvious explanation -> ask specialist (do not ignore
someone sitting on the ward with big bruises and massive aPTT)
Treatment of Acquired Haemophilia
- Factor VIII Inhibitor Bypassing Activity
- Novo-Seven -> recombinant factor VIIa
- steroids
- Rituximab
- DDAVP - desmopressin
