Disorders of Haemostasis Flashcards
What causes bleeding?
Abnormalities of vasculature (could be due to connective tissue disorders or structural disorders)
Defects of primary haemostasis (platelet disorders)
Defects of secondary haemostasis (procoagulant protein deficiency)
Accelerated breakdown of clot (aka hyperfibrinolysis)
What does it mean to say quantitatiive defects of hamoestasis?
Not enough platelelets produced to produce platelet plug
What are some possible abnormalities in haemostasis?
Quantitative (not enough platelets to form platelet plug)
Qualitative defects
Both
What is the normal concentration of platelets in the blood?
150 - 400 x 10^9/L
When do issues arise with low platelet count?
20 - 50 x 10^9/L (bruising and surgical bleeding)
10 - 20 x 10^9 (nosebleeds and petechial rash)
<10 x 10^9/L (spontaneous serious bleeding)
What should be noted regarding platelet count?
Some people could be taking anti-platelet drugs due to their excessive coagulation ability.
What causes thrombocytopenia?
Congenital (inherited)
Acquired (impaired production at the bone marrow, hypersplenism, increased platelet destruction, and drug-induced)
What conditions can cause impaired bone marrow production of thromboyctes?
Myelodysplasia
Leukemia
Bone Marrow infiltration
What can cause increased platelet destruction?
Severe sepsis/DIC
TTP/HUS syndrome (fragmentation of blood cells and thrombocytes)
Immune thrombocytopenic purpura
Autoimmune conditions
Viral infections (HIV, hepatitis, H.pylori)
Pre-eclampsia
What drugs can reduce platelet count?
Heparin
Gold
Quinine
What is hypersplenism and how does it cause low platelet count?
Larger spleen resulting in more storage of thrombocytes at the spleen
What must be ensured with isolated thrombocytopenia conditions?
That the low platelet count is not caused by something else
What causes immune (idiopathic) thrombocytopenic purpura?
It is spontaneous and results in increased platelet destruction due to B cells producing IgG antibodies targeting the megakaryocytes
What do the IgG antibodies do to platelet production at the bone marrow?
They cause it to be stopped
How does immune thrombocytopenic purpura (ITP) present itself?
Children present with severe thrombocytopenia a few weeks after viral infection.
Adults present with more gradual onset and recovery. They can be treated with steroids, intravenous immunoglobulins, splenectomy, etc
What can activated GPIIb/IIIa bind?
fibrinogen
How can NSAIDs or other drugs like aspirin cause disorders in haemostasis?
They can reduce the action of cyclooxygenase which results in TXA2 deficiency and in turn inhibits platelet aggregation response
Name some inherited bleeding disorders:
Von-Willebrand’s disease
Haemophilia
Name some acquired bleeding disorders:
Liver disease
Vitamin K deficiency
Renal disease
Warfarin
What factors are deficient in haemophilia?
factor 8 and factor 9
When and how is haemmophilia typically diagnosed?
As infants diagnosed with severe bleeding under the skin.
Spontaneous haemarthrosis (bleeding into joints), muscle haematomas (due to bleeding into muscles), intracranial haemorrhage and internal bleeding
What is haemophilia A caused by?
Factor 8 (FVIII) deficiency
What is haemophilia B caused by?
Factor 9 (FIX) deficiency
What is another name for haemophilia B?
Christmas disease
Is bleeding in haemophilia A and B the same?
Yes, very similar
What kind of genetic inheritance does haemophilia follow?
X-linked recessive making it more likely in males
How is haemophilia diagnosed?
Most important clinical test is clinical history (i.e personal bleeding history, family history, and drugs)
Lab screening test (APTT would be extra long in haemophilia patients because factor 8 and 9 are in the intrinsic pathway)
An 18 month old boy with a short history of a painful swollen left knee. His blood was found to have a normal prothrombin time (PT) but an abnormally long APTT (93 seconds) and his factor VIII levels were <1% what is the diagnosis?
Haemophilia A
How is haemophilia managed?
Recombinant FVIII for procedures or treatment of bleeds. This is administered prior to procedures which can cause bleeding and as prophylaxis for newly diagnosed childred.
In the past they used blood donors to get FVIII which resulted in many people acquiring HIV and HepC.
In Australia all patients given the recombinant treatment.
What do patients with haemophilia have which details their diagnosis?
A haemophiliac card
What are the common differences between platelet defects and clotting factor deficiencies?
In platelet defects:
There is excessive bleeding after minor cuts which is not usual in clotting factor deficiencies
Petechiae are common (very uncommon in clotting factor deficiencies)
Ecchymoses are small and superficial in platelet defects and may be large and in soft tissues in clotting factor deficiencies
Haemarthroses are uncommon in platelet defects and common in clotting factor deficiencies
Bleeding with invasive procedures is immediate in platelet deficiencies and is delayed in clotting factor defects
Platelet conditions cause mucocutaneous bleeding whereas clotting factor deficiencies cause deep tissue bleeding
Do people with platelet defects bleed severely after minor cuts?
Yes
Do people with clotting factor deficiencies bleed severely after minor cuts?
Not usual
Which patients have petechiae typically; platelet defect patients or clotting factor deficient patients?
Platelet defect patients
Which factor is a carrying factor of factor 8?
Von-Willebrand factor
How is Von-Willebrand’s disease inherited?
Autosomal dominant condition found in 1% of the population
What are the types of VWD?
Type 1 (decreased quantity of VWF)
Type 2 (Decreased function of VWF)
Type 3 (rare, severe deficiency of VWF due to inheriting 2 mutated genes 1 from each parent)
How is VWD diagnosed in the lab?
May or may not have prolonged APTT (VWF carrier protein for FVIII)
von-willebrand screen can be done (VWF antigen level and VWF function tests such as collagen binding ability)
Factor VIII levels
Normal >50%, abnormal <30% and people with 30-50% are not diagnosed in this category but clinical history moves them one way or another.
How is VWD treated?
DDAVP which causes release of VWF from storage granules in platelets and endothelium.
Tranexamic acid tablets (or mouthwash) which stabilizes fibrin clot which may be taken for first 4 - 5 days after the procedure.
Biostate which is taken for severe deficiency (Type 3 VWD) or in people who don’t respond to DDAVP. Plasma-derived product comes from blood donors that contains FVIII and VWF. It must be given on the same day as the procedure.
What is DDAVP?
Desmopressin is a drug which is infused IV which increases VWF release from storage granules in platelets and endothelium.
It has a duration of effect of 4 - 6 hours so it must be given on the same day as procedure.
What is Tranexemic acid?
Stabilizes fibrin clot which may be taken for first 4 - 5 days after the procedure.
What is biostate? How is it made?
taken for severe deficiency (Type 3 VWD) or in people who don’t respond to DDAVP.
Plasma-derived product comes from blood donors that contains FVIII and VWF. It must be given on the same day as the procedure.
A 7-day old baby at home is found unconscious and bleeding from his nose and mouth. Clotting tests show a PT of 98s, APTT of 102s. Fibrinogen 2.9g/L and platelets 288x10^9/L. What is a possible cause and why?
Vitamin K deficiency
What is the role of Vitamin K?
Essential for several carboxylase enzymes within hepatic cells which are necessary for activation of factors 2,7,9,and 10.
Where is vitamin K1 produced?
In green leaft veggies and broccoli
Where is vitamin K2 produced?
Gut flora
What can vitamin K deficiency cause?
Neonatal haemorrhagic disease.
What causes VitK in babies typically?
All neonate vit K deficient are deficient because it wasn’t infused post-delivery (IntraMuscularly)
Very little VitK in breast milk.
What causes VitK deficiency in adults?
Any cause of malnutrition or malabsorption
Why are babies prone to vitamin K deficiency?
No transplacental passage of Vitamin K
Immature liver
Sterile Gut
Very little vitamin K in breast milk
A 54 year old publican is admitted with major haematemesis (vomitting blood). Clotting test show 32x PT, 56 second APTT, 1.2g/L fibrinogen, and 56x10^9/L platelets. What is a possible cause?
Patient has liver disease and so there is low synthetic function, low vitamin K absorption, low clearance of activated clotting factors.
Hyperfibrinolysis, thrombocytopenia, and acquired platelet dysfunction
What is massive transfusion?
Replacement of >50% of blood volume in 12-24 hours.
In adults >10 units of packed RBCs and this results in dilution of clotting factors and platelets.
What causes coagulopathy to become worse in patients of massive transfusions?
Acidosis and hypothermia, calcium deficiency
What is Disseminated Intravascular Coagulation?
Death Is Coming (DIC has bad prognosis)
Systemic process where blood is exposed to procoagulant factor such as tissue factor.
Massive thrombin generation and widespread coagulation followed by fibrinolysis and depletion of clotting factors.
What are some causes for Disseminated Intravascular Coagulation (DIC)?
Acute can be caused by sepsis, severe trauma, and complications of pregnancy, as well as snake bite and acute leukemia
Chronically can be caused by cancer
What do RBCs look like in DIC?
fragmented and damaged
How does DIC present in clinic?
Bleeding (64%) including spontaneous bleeding from cannula sites
Renal dysfunction (25%)
Hepatic dysfunction (19%)
Respiratory dysfunction (16%)
Shock (14%)
Thrombo embolism (7%)
CNS involvement (2%)
What are risk factors for venous thromboembolism?
Virchow’s triad:
Endothelial injury
Hypercoagulability
Abnormal blood flow
These 3 result in thrombosis
What are the clinical features of deep vein thrombosis?
Swelling
Redness
Tenderness
Pitting Oedema (enlargement and swelling of leg where pushing into it leaves a pit there)
What is the probability that someone has DVT if they present with the symptoms?
1 in 5 people suspected to have DVT actually have it
Can DVT be safely diagnosed based on history/exam alone?
No
What must be done for diagnosis of DVT?
Assessment of pre-test probability of DVT
Testing D-dimer
Testing through ultrasound of legs
What are D-dimer?
When fibrin cross links are broken apart the resulting subunits are called D-dimers
What breaks down fibrin into D-dimers?
Plasmin
Where are D-dimers typically seen?
In conditions like DVT, DIC, Infection, malignancy, trauma
They are not enough for DVT diagnosis
Why are D-dimers measured?
If the D-dimer is negative then it is unlikely to be a DVT
What are the clinical features of PE?
Chest pain
Shortness of breath
Cough/haemoptysis
Palpitations
Syncope
Non-specific symptomsand objective testing to confirm are required
What are some PE differential diagnoses?
Chest infection
Cardiac failure
Malignancy
Other
How is PE diagnosed?
Clinical history/exam
Chest X-Ray/ECG/Full Blood Picture
Pulse oxymetry
D-dimer negative excludes PE
Calculate pre-test probability
Imaging studies (ventilation and perfusion lung scan, CT pulmonary angiogram)
What is the natural history of venous thromboembolism (VTE)?
Usually starts in calf veins
Majority of symptomatic DVT are proximal
PE usually arise from proximal DVT
What is the prognosis of VTE?
about 50% of proximal DVT cause PE
10% of symptomatic PE are rapidly fatal
30% of untreated symptomatic non-fatal PE will have a fatal recurrence
What is treatment of VTE?
Relieve symptoms
Prevent PE
Prevent death
Prevent recurrence
Prevent complications of clotting
Anticoagulation is the mainstay of treatment
How long is DVT treated for?
3 months is usually enough for most people after surgery
What is the risk of DVT coming back after the first occurrence if it was spontaneous?
1 - 4% in first year
10% at 5 years
30% at 10 years
These people need to given continuous anticoagulant therapies
What are the risk factors for acquired VTE conditions?
Previous VTE
Major trauma
Major surgery
Cancer
Nephrotic syndrome
Immobility
Major medical illness with hospitalisation
Central Venous line
Some drugs (tamoxifen)
Pregnancy
Oestrogen
Antophospholipid antibodies
Obesity
Age
What are some inherited risk factors for VTE?
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden mutation
Prothrombin gene mutation
Dysfibrinogenemias
What does antithrombin do?
Inhibits thrombin and factor X
What does protein C and protein S do?
Inhibits factor V and factor VIII. If this pathway is inhibited coagulation cascade will keep going unchecked.
What does antithrombin do?
In absence of heparin it slowly inactivates thrombin. In presence of heparin conformation is changed and thus it rapidly inactivates thrombin
How is antithrombin deficiency inherited?
Autosomal dominant with variable clinical penetrance
How is antithrombin deficiency acquired?
liver disease, warfarin therapy, protein loss, and DIC
What is protein C?
Vitamin K dependent protein dependent on vitamin K.
How is protein C deficiency inherited?
Autosomal dominant inheritance
What form must protein C be in to function?
Active protein C form (aPC)
What does aPC do?
Inactivates Va and VIIIa
What enhances protein C function?
Protein S
What is the inheritance of protein S deficiency?
Autosomal dominant
What is protein S action dependent on?
Vitamin K
What are the acquired causes of protein S deficiency?
Acquired causes include:
Pregnancy
OCP
Liver disease
Certain drugs
HIV
What is the incidence of inherited thrombophilic syndromes in Caucasian populations?
antithrombin deficiency: <1%
Protein C deficiency: 1%
Protein S deficiency: 1%
Factor V Leiden: 5%
Prothrombin gene mutation: 3%
What is factor V leiden?
Point mutation in factor V so protein C can’t inactivate factor V. This condition is also called activated protein C resistance
How common is factor V leiden?
5%
How do risk factor effects combine for VTE?
Combination of risk factors is very powerful in combination with each other.
