Haem 8 - Abnormalities of haemostasis Flashcards
List some factors that would constitute as abnormal bleeding?
- Epistaxis not stopped by 10 minutes compression or requiring medical attention/transfusion
- Cutaneous haemorrhage or bruising without apparent trauma (esp. multiple/large).
- Prolonged (>15 mins) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in 7 days after wound. Spontaneous GI bleeding leading to anaemia.
- Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions of the uterus.
- Heavy, prolonged or recurrent bleeding after surgery or dental extractions.
Summarise haemostatic plug formation
See slide 9 - same as haem 7
What is the cause of abnormal haemostasis?
Lack of a specific factor: “Quantitative defect”
- Failure of production: congenital and acquired
- Increased consumption/clearance
Defective function of a specific factor: “Qualitative defect”
- Genetic defect
- Acquired defect – drugs, synthetic defect, inhibition
Problem with primary haemostasis:
1) Platelet
2) VWF
3) Vessel wall
What are the two methods of platelet adhesion?
1) Platelet to VWF - Gp1b
2) Platelet to collagen - Gp1a
How are platelets activated?
Thromboxane and ADP
Describe the disorder of primary haemostasis in terms of platelets
Low numbers (quantitative): Thrombocytopenia
- Bone marrow failure eg: leukaemia (the monoclonal cells fill the bone marrow pushing out the healthy normal megakaryocytes), B12 deficiency.
- Accelerated clearance eg: immune (ITP - common cause of thrombocytopenia), DIC - disseminated intravascular coaguation.
Impaired function (qualitative):
- Hereditary absence of glycoproteins or storage granules
- Acquired due to drugs: aspirin, NSAIDs, clopidogrel. This is way more common.
Describe auto-ITP
1) antiplatelet autoantibodies
2) sensitises the platelet - it binds to the platelet marking it for phagocytosis
3) the sensitised platelets are phagocytosed by macrophages - cleared more quickly.
What are the mechanisms and causes of thrombocytopenia?
- Failure of platelet production by megakaryocytes
- Shortened half life of platelets
- Increased pooling of platelets in an enlarged spleen
(hypersplenism) + shortened half life
What are the different hereditary loss of glycoproteins?
Loss of GpIIb/IIIa - Glanzmann’s thrombasthenia, autosomal recessive = rare. No platelet aggregation
Loss of GpIb - Bernard Soulier syndrome, not a severe as Glanzmann’s
Loss of of granules - storage pool disease. Loss of ADP
Describe the disorder of primary haemostasis in terms of VWF
Von Willebrand disease
- Hereditary decrease of quantity +/ function (common)
Type 1 (AD) - partial quantitative deficiency of VWF
Type 3 (AR) - No VWF (rare: autosomal recessive)
Type 2 (AD) - abnormal function
- Acquired due to antibody (rare)
What is the function of VWF?
It acts as the bridge between the subendothelial layer and the platelets - binds to collagen + captures platelets
It acts as the carrier for FVIII - if VWF is low then FVIII may also be low (stabilising factor)
Describe the disorder of primary haemostasis in terms of the vessel wall.
Inherited (rare) Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disorders
Acquired: Scurvy, Steroid therapy, Ageing (senile purpura), Vasculitis
See slides
What is specifically seen with thrombocytopenia?
Petechiae
What is seen in severe VWD?
Haemophilia-like bleeding
How do you test for disorders of primary haemostasis?
Platelet count, platelet morphology
Bleeding time (PFA100 in lab - same thing but in the lab)
Assays of von Willebrand Factor (measure VWF)
Clinical observation
What is a thrombogram?
See slide
We can visualise the process of coagulation by measuring thrombin generation over time.
What is the role of the coagulation cascade in terms of thrombin?
Generate a burst of thrombin which will convert fibrinogen to fibrin.
Deficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formation
What happens in haemophilia?
Failure to generate fibrin to stabilise platelet plug.
The primary platelet plug is sufficient for small vessel injury. In larger vessels it will fall apart. Fibrin formation stabilises the platelet plug.
What are the different disorders of coagulation?
Deficiency of coagulation factor production
- Hereditary
1) Factor VIII/IX: haemophilia A/B - Acquired
1) Liver disease
2) Dilution - blood transfusions with not enough plasma with the coagulation factors.
3) Anticoagulant drugs - warfarin
Increases consumption
- Acquired
1) Disseminated intravascular coagulation (DIC)
Describe the different coagulation factor deficiencies?
Factor VIII and IX (Haemophilia)
- Severe but compatible with life
- Spontaneous joint and muscle bleeding
Prothrombin (Factor II)
- Lethal (don’t survive beyond embryonic stage)
Factor XI
- Bleed after trauma but not spontaneously
Factor XII
- No excess bleeding at all
What are the more common acquired coagulation disorders seen in hospital practice?
Liver failure – decreased production
- Most coagulation factors are synthesised in the liver
Dilution
- Red cell transfusions no longer contain plasma
- Major transfusions require plasma as well as rbc and platelets
What is DIC?
Generalised activation of coagulation – Tissue factor
Associated with sepsis, major tissue damage, inflammation
Consumes and depletes coagulation factors
Platelets consumed
Activation of fibrinolysis depletes fibrinogen
Deposition of fibrin in vessels causes organ failure
What is the difference in the bleeding patterns of people with primary haemostatic disorders and coagulation disorders?
This describes haemophiliacs: coagulation disorders
- superficial cuts do not bleed (platelets)
- bruising is common, nosebleeds are rare
- spontaneous bleeding is deep, into muscles
and joints - bleeding after trauma may be delayed and is prolonged
- frequently restarts after stopping
What are the clinical distinction between bleeding due to platelet and coagulation defects?
Platelet/Vascular
- Superficial bleeding into skin, mucosal
membranes
- Bleeding immediate after injury
Coagulation
- Bleeding into deep tissues, muscles, joints
- Delayed, but severe bleeding after
injury. Bleeding often prolonged
What are the tests for coagulation disorders?
Screening tests (‘clotting screen’)
- Prothrombin time (PT) (extrinsic pathway)
- Activated partial thromboplastin time (APTT) (intrinsic pathway)
Pick up deficiency in clotting factors - see old skool diagram
- Full blood count (platelets)
Factor assays (for Factor VIII etc)
Tests for inhibitors
See slides
What bleeding disorders are not detected by routine clotting tests?
Mild factor deficiencies von Willebrand disease Factor XIII deficiency (cross linking) Platelet disorders Excessive fibrinolysis Vessel wall disorders Metabolic disorders (e.g. uraemia) (Thrombotic disorders)
Best thing to do is to look at bleeding history
What are the different disorders of fibrinolysis?
Disorders of fibrinolysis can cause abnormal bleeding but are rare
Hereditary
- antiplasmin deficiency
Acquired
- drugs such as tPA
- Disseminated intravascular coagulation - everything i being consumed.
Describe the genetics of haemophilia
Sex linked recessive disorders
X-linked = mainly affects the boys
With carriers (females) They can varying levels of FVIII/FIX depending on random activation - lionization.
All the other factor deficiencies are autosomal recessive.
Describe the genetics of VW disease
Autosomal dominant
What are the treatment methods of abnormal haemostasis?
Failure of production/function
- Replace missing factor/platelets
1) Prophylactic
2) Therapeutic - Stop drugs
Immune destruction
- Immunosuppression (eg prednisolone)
- Splenectomy for ITP
Increased consumption
- Treat cause
- Replace as necessary
What are the principles of Treatment of Haemostatic
Disorders Causing Bleeding?
See slide 61
List some additional haemostatic treatments
DDAVP (desmopressin) - Increases endothelial cells release of VWF
Tranexamic acid - tPa binds to this preventing of its activation. Inhibits fibrinolysis
Fibrin glue/spray -
