Lecture 9/10 - Disorders of haemostasis Flashcards
Four causes of defective haemostasis with abnormal bleeding
- Abnormalities of the vessel wall (vascular system)
- Thrombocytopenia
- Disordered platelet function (thrombocytopathy)
- Defective blood coagulation
How are vessel wall abnormalities characterised?
Characterized by easy bruising and purpura (bleeding into the skin or mucous membranes)
What are vascular and platelet bleeding disorders associated with?
Associated with bleeding from the mucous membranes and into the skin
Where is bleeding often located in Coagulation disorders?
Bleeding is often into joints or soft tissues
Vascular building disorders: what are the characteristics and what is the pathology?
Characteristics:
* Easy bruising
* Spontaneous bleeding from small vessels
Pathology:
* Abnormality in blood vessels
* Bleeding and other haemostasis tests usually normal
Hereditary haemorrhagic Telangiectasia: how many people are affected, is it a dominant or recessive illness, where are the defects in the genome, what are they symptoms, and what are the treatments?
Uncommon - approx. 1.2 million worldwide (equally between men and women)
Autosomal dominant
Defects in at least 3 genes but only 1 gene is the cause in any one family
Abnormally formed blood vessels: Arteriovenous malformations
Symptoms mild - severe:
* Telangiectases - dilated microvascular swellings, easy to rupture (90-95%: at least a few telangiectasias on the skin of the face and/or hands by middle age)
* nose, tongue and lips (90-95% nosebleeds by adulthood at varying frequencies)
* Nosebleeds and gastrointestinal blood loss.
* Chronic iron deficiency is frequent
* 20-25%: bleeding in the stomach or intestines, but rarely before 50 y.old.
Treatment: embolization, laser treatment and tranexamic acid (prevents fibrinolysis)
Acquired vascular defects: what causes them, and what can they be characterised as?
Wide variety of causes: incl. infections, drug reactions, trauma, old age and steroid use.
Vascular purpura can be categorized as such:
- Purpura simplex - common benign disorder, in women of childbearing age.
- Senile purpura - old age, due to the loss of skin elasticity and atrophy of vascular collagen, mainly on the forearms and hands
- Infection-associated purpura - bacterial and viral infections, e.g. measles can cause purpura from vascular damage by the organism.
Thrombocytopenia: what is it and what are the three main causes of it?
Deficiency in platelet numbers (defined as a low platelet count with values less than 150 x 109/L)
3 main causes of thrombocytopenias:
* Failure of platelet production
* Increased destruction of platelets
* Sequestration (abnormal distribution) of platelets
Platelet production failure: what is it the most common cause of, what is it usually caused by, and how do we diagnose it?
Most common cause of thrombocytopenia
- Usually part of bone marrow failure - aplastic anaemia/leukaemia (deficiency in blood cells produced)
- drug/viral-induced toxicity
Clinical history, peripheral blood count, blood film, and bone marrow examination
Increased destruction of platelets: what is it usually caused by and what does it result in?
Autoimmune response - autoantibodies attach to platelet surface
Autoimmune (idiopathic) thrombocytopenia purpura (ITP) in two disease categories: chronic ITP and acute ITP
Chronic ITP: what are the general features, what causes it, and what happens to platelet lifespan?
Relatively common in young women 15-60 years old, often asymptomatic or have an insidious onset of bleeding?
Autoantibodies (mostly IgG) in plasma and on platelets which make them get destroyed by macrophages in the spleen and liver.
((((Antibodies: glycoprotein IIb/IIIa or Ib)))
Platelet lifespan considerably reduced: as little as a few hours
Acute ITP: general features, what causes it, and what two ways does it usually lead to?
Children under 10
The majority is abrupt following vaccination or viral episode as the IgG antibody attaches to the viral antigen and is absorbed onto the platelet surface, causing a dramatic fall in platelet count (may be less than 20 x 109/L)
- Spontaneous remissions usual
- The minority of cases develop chronic ITP
Sequestrian of platelets: how many platelets are in the spleen normal and how many platelets are in the spleen when splenomegaly occurs?
Normally, the spleen contains ~30% of all platelets
Splenomegaly: up to 90% of platelets sequestered in the spleen - thrombocytopenia
Thrombocytopathy: what is it, when is it diagnosed, and what is it caused by?
Disorders of Platelet Function
Considered when clinical signs and symptoms of thrombocytopenia but in the presence of a normal platelet count
Inherited and Acquired disorders:
* Inherited disorders - rare but capable of producing defects at each of the different phases of the platelet reaction (activation, adhesion, secretion, aggregations).
* Acquired disorders - much more common
Antiplatelet drugs (Aspirin): what do they do, what do they result in, and what is their effect of them?
Irreversibly inactivates the enzyme cyclooxygenase (COX), preventing the production of thromboxane A2 from arachidonic acid
Result: inhibition of platelet aggregation
Significantly extends the bleeding time which may cause haemorrhage in patients with thrombocytopenia
Haematological malignancy: what does it do and what may it be caused by?
Causes platelets to function incorrectly
- acute myeloid leukaemia
- any myeloproliferative disorders and myeloma
Platelet disorder diagnosis
- Initial blood count and blood film examination
- Bone marrow biopsy - thrombocytopenic patients, ascertain failure of platelet production
- Blood count: within normal limits - other tests performed to detect abnormal platelet function
- Prolonged bleeding time detected - defect usually acquired and should be evident in clinical investigation
- Patients with hereditary defects require further testing to define the specific abnormality
Haemophilia a
The most common hereditary clotting factor deficiency
Factor VIII deficiency
30-100 per million of a population
X-linked recessive disorder - all males with the defective gene suffer, sons of haemophiliac men are (usually) non-sufferers but their daughters will be carriers (or sufferers)
Can be spontaneously mutated
Clinical features of factor VIII level in bleeding severity: what are the symptoms and what are deaths mainly caused by?
Severity of bleeding is related to the factor VIII level
Clinical features of severe haemophilia:
* Bleeding into joints and less frequently muscles
* Knees, elbows and ankles are most commonly affected by bleeding
* The majority of bleeds require treatment
* Presenting symptoms: pain in affected areas
Intracranial bleeding: the main cause of death from the disease
High death rate: HIV-contaminating factor VIII observed in the USA and Europe in the last two decades
Haemophilia b: what is it, what is it caused by, how many people suffer from it, how related is it to haemophilia a clinically, and how is it treated?
X-linked recessive bleeding disorder
Factor IX deficiency
Not as common as haemophilia a (15-20 per million of the population)
Clinically indistinguishable from haemophilia a
APTT prolonged, confirmed by factor IX clotting assay
Use of factor IX as a replacement
Haemarthrosis
Bleed into elbow
Diagnosis of haemophilia a
- APTT (prolonged activated partial thromboplastin time)
- Confirmed by a factor VIII clotting assay
- Carrier detection and antenatal diagnosis by using DNA technology
- Chorionic biopsies at 8-10 weeks of gestation provide DNA for analysis.
The concentration of coagulation factor (%of normal) and its relation to bleeding episodes in haemophilia a sufferers
50-100% - none, same as healthy
25-50% - bleeding after severe trauma
5-25% - severe bleeding episodes after surgery, slight bleeding episodes after minor trauma
1-5% - Severe bleeding after slight trauma
<1% - Severe, frequent spontaneous bleeding episodes predominantly in joints and muscles
Haemophilia a treatment
Factor VIII replacement after bleeding, usually recombinant factor VIII
When the disease is mild - 1-amino-8-D-arginine vasopressin (DDAVP) is used to mobilize factor VIII from endothelial cells
VWD: what is it, how prevalent is it, and what is it caused by?
Von Willebrand’s disease
1 in 100 have it but have no symptoms
1 in 10,000 is clinically significant
Autosomal dominant gene - mutations in the VWF gene cause reduced platelet adhesion to damaged endothelium
VWD: classification
Classification:
- Three types which depend on the electrophoretic analysis of VWF multimers:
* Types 1 and 3: partial reduction or nearly complete absence of VWF molecules and
* Type 2: abnormal form of the protein – functional abnormality
VWD: diagnosis
Diagnosis:
* Prolonged APTT
* Reduced factor VIII clotting activity
* Reduced levels of VWF
* Impaired platelet aggregation
VWD: clinical features and treatment
- Variable bleeding extent, spontaneous bleeding usually confined to mucous membranes and skin
- Surgery may result in severe bleeding
Treatment:
* DDVAP (Desmopressin):
- For those mild or moderately affected
- Increases both VWF and factor VIII
- most effective in type 1 VWD patients
- Tranexamic acid: mild bleeding
Acquired coagulation disorders
Usually multifactorial
Associated with varying assortments of platelet dysfunction and coagulation abnormalities including:
* Vitamin K deficiency
* Disseminated intravascular coagulation
* Liver disorders
Thrombus
Platelets and fibrin forming colts in circulation, can develop in arteries or veins, with the incidence increasing in age
Embolism
Cuased by the occlusion of a vessel by foreign material/blood cliot
This may cause a thrombus to occur
Thromboembolism
Occlusion of a vessel by a blood clot which has moved from its starting position
When movement is to the lungs - pulmonary thromboembolism
Thrombosis causes
Risk factors - differ for arterial and venous thrombosis
Thrombophilia - inherited or acquired disorders (genetically predisposed to thrombosis)
Virchow’s triad
Outlines factors predisposing one to thrombus formation:
* Changes in blood flow (plane journey, sitting down etc)
* Changes in blood constituents (Hypercoagulability of the blood, i.e. caused by genetic deficiencies)
- Changes within the walls of blood vessels - (vessel wall damage, i.e. caused by trauma, infection)
Arterial thrombosis
Thrombus within an artery - rupture of atheroma
Two diseases can be classified under this category:
* Stroke
* Myocardial infarction
Stroke
- Disturbance in blood supply to the brain
- Thrombotic stroke - thrombosis forms around atherosclerotic plaque with a gradual artery blockage
Myocardial infarction
- Caused by an infarct (tissue death to ischemia)
- Often due to coronary artery obstruction
- If diagnosed within 12 hours of the initial attack, thrombolytic therapy initiated
Arterial thrombosis risk factors
- Positive family history
- Male
- Cigarette smoking
- Diabetes mellitus
- Hypertension
- Collagen vascular disease
- ECG abnormalities
- Elevated fibrinogen
- Elevated factor VII
Venous thrombosis/thromboembolism
Increased systemic coagulability and stasis
Deep vein thrombosis - most common in lower limbs
- Swelling (often asymmetrical)
- Pain, erythema
- If part of DVT dislodges and forms an embolus, it can lodge itself in lung vasculature - PE
Pulmonary embolism symptoms
- Dyspnoea - not being able to breathe fast/deep enough
- Tachypnoea - Rapid and shallow breathing
- Pleuritic chest pain - sharp chest pain when inhaling deeply
Venous thrombosis hereditary risk factors
Factor V Leiden
Antithrombin III deficiency
Prothrombin G20210A variant
Protein/ protein S deficiency
Venous thrombosis hereditary/acquired risk factors
Raised plasma levels of FVII, VIII, IX, XI, or fibrinogen
Lupus anticoagulant
Oral contraceptive / HRT
Malignancy
Venous thrombosis stasis risk factors
Stroke
Cardiac failure
Prolonged immobility
Venous thrombosis risk factors - unknown factors
Age, Obesity, Sepsis
Factor V Leiden: what does it cause, what is it, what difference do heterozygote and homozygote sufferers have, what is the incidence in those with venous thrombosis, and what does the mutation act as?
Inherited thrombophilia
Activated protein C resistance (x10 resistance to cleavage)
Autosomal dominant, the most common cause of increased venous thrombosis
5% incidence rate in Caucasians in the UK
A single point mutation (R-Q) causes 90% of cases
Heterozygotes: 7-fold increased risk of thrombosis
Homozygotes: 50-fold increased risk
Incidence of FV Leiden in patients with venous thrombosis is ~20-40%
Mutation acts as a co-factor in some hypercoagulable states: e.g. oral contraceptive pill and pregnancy, surgery and immobility
Acquired thrombophilia - risk factors
- Prolonged immobilisation of patient - venous stasis
- Disseminated cancer - secretion of tumour substances that activate FX
- Endothelial injury - smoking, hypercholesterolaemia, hypertension, infection
- Alterations to blood flow: Atrial fibrillation
Antithrombotic therapy
Two main classes of drug used:
Anticoagulants (heparin/warfarin) - prevent thrombosis
Thrombolytic agents - dissolve thrombus
Thrombolytic agents
Must be used before anticoagulant
Mechanism of action - acts as plasminogen activators, converting plasminogen into plasmin which will then dissolve the fibrin of a blood clot
Commonly used agents are:
* Streptokinase (SK): activates free and fibrin-bound plasminogen to release plasmin
* Tissue plasminogen activator (tPA): has a high affinity for fibrin with specific lysis of thrombin
