Flashcards in Week 7. Disorders of haemostasis Deck (39):
What can defective haemostasis with abnormal bleeding be caused by?
1. Abnormalities of the vessel wall (vascular system)
3. Disordered platelet function (thrombocytopathy)
4. Defective blood coagulation.
(severity increases as you go down this list, vascular wont affect as much as coagulation)
Vascular bleeding disorders
Characteristics: Easy and spontaneous bruising
Spontaneous bleeding from small vessels.
Pathology: Abnormality in blood vessels- lost in elasticity.
Bleeding and other haemostasis tests usually give normal results, wont pick up a different.
Most common inheristed vascular disorder= Hereditary haemorrhagic telangiectasia
What are vessel wall abnormalities characterized by?
Easy bruising and purpura (bleeding into skin or mucous membrane. Purple dots on old people.
1.Vascular and platelet bleeding disorders are associated with what?
2. Coagulation disorders?
1. Bleeding from mucous membrane into skin
2. Bleeding into joins or soft tissues
Hereditary Haemorrhagic Telangiectasia
Cause and symptoms
Uncommon, approz 1.2 million worldwide.
Autosomal dominant- not sex linked.
Defects in at least 3 genes but only one gene is the cause in any one family.
Abnormally formed blood vessels- thin walled capillaries.
Telangiectases: dilated microvascular swellings, easy to rupture.-> can see this in tongue and lips.
Nose bleeds and gastrointestinal blood loss.
Chronic iron deficiency is frequent
Hereditary Haemorrhagic Telangiectasia- treatments
Embolization:artifically produce clot to stem bleeding.
Laser treatment: stop blood flow
Tranxemic acid: inhibits breakdown of fibrin in clots to treat haemorrhage.
What are the categories of Vascula purpura?
1. Purpura simplex
Common benign disorder, women of child bearing age. Causes unknown. Not dangerous.
2. Senile purpura
Old age, due to loss of skin elasticity and atrophy of vascular collagen. Mainly on forearms and hands.
3. Infectin associated purpura
Bacterial and viral infections, e.g. measles, meningitis cause damage to blood vessel wall.
Deficiency in platelet numbers. Defined as low platelet count with numbers less than 150 x 10^9/L.
Causes of thrombocytopenia
1. failure of platelet production
2. increased platelet destruction
3. sequestration (abnormal distribution) of platelets
Failure of platelet production
what does it cause?
what's it part of?
Most common cause of thrombocytopenia.
Usually part of bone marrow failure:
-aplastic anaemia or leukaemia(overproduction of WBC. bone marrow can't cope, cant make platelets)
-drug/viral induced toxicity
Diagnosis: clinical history, peripheral blood count, blood fiilm and bone marrow examination-> see what's happening with precursor cells.
Increased destruction of platelets.
What causes it?
What disease does it lead to?
Primary cause: autoantibodies attaching onto platelet surface
Autoimmune (idiopathic) thrombocytopenia purpura (ITP).
Two disease categories-chronic ITP and acute ITP.
young women 15-50 yrs old.
Asymptomatic or insidious(no trigger) onset of bleeding
Autonatnibodies on their plasma and platelets.
Platelets sensitized with autoantibodies (mostly IgG): destroyed by macrophages in spleen and liver.
Antibodies: glycoproteins IIb/IIIa or Ib.
Platelet lifespan reduced to as little as a few hours.
general features: children under 10
usually sudden onset after vaccine or viral episode.
Post viral cases: likely IgG antibody attaches to viral antigen absorbed onto platelet surface.
Dramatic fall in platelet count to less than 20 x 10^9/L
Spontaneous remissions usual
Minority of cases develop chronic ITP
Sequestration of platelets
Normal situation: spleen contains approx 30% of all platelets.
Splenomegaly- up to 90% of platelets may be sequestered in the spleen. Leading to thrombocyopenia.
Means they aren't available for clotting when they're needed.
Disorders of platelet function.
considered when clinical signs and symptoms of thrombocytopenia but in the presence of a normal platelet count.
What kind of thrombocytopathy are there?
Inherited and acquired disorders
Inherited: rare but capable of producing defects at each of the different phases of platelet rxn (activation, adhesion, secretion, aggregation)
-Acquired: much more common
Giev 2 examples of acquired disorders of platelet function (thrombocytopathy)
1. Antiplatelet drugs (aspirin)
inactivates COX, stops production of thromboxane A2 from arachidonic acid.
Result: inhibition of platelet aggregation. Extends bleeding time significantly. Haemorrhage in patients with thrombocytopenia. (thromboxane a2 allows platelets to change shape and swell)
2. Haematological malignancy
e.e. actue myeloid leukaemia
any myeloproliferative disorders and myeloma
Diagnosis of platelet disorders
-Initial blood count and blood film examination
-Bone marrow biopsy: thrombocytopenic patients- ascertain failure of platelet production.
-Blood count: within normal limits
-Prolonged bleeding time detected: defect usually acquired and should be evident on clinical investigation.
-Patients with hereditary defects require further testing to define the specific abnormality.
What are 3 inherited coagulation disorders?
Haemeophilia A- deficiency in factor VIII: mutations lead to under-production of it. X-linked recessive.
Haemophilia B (christmas disease)- X linked recessive.
von Willebrand's disease (vW)- Usually autosomal dominant. Mutation in vWF gene.
Most common hereditary clotting factor deficiency.
Deficiency in factor 8: mutations lead to under production of F8 and clinical symptoms of haemophilia.
X-linked recessive disorder.
-All males with defective gene have haemophilia
-All sons of haemophilic men are normal
-All daughters are carriers.
Can be spontaneous mutation with no family history
Clinical features of haemophilia A?
Severity of bleeding is related to the factor 8 level.
Severe haemophilia features:
Bleeding into joints and sometimes muscles
Knees, elbow and ankles most commonly affected
Pain in effected areas
Intracranial bleeding: main cause of death from the disease
Diagnosis of haemophilia A
Prolonged APTT (activated partial thromboplastin time)
Confirmed by a factor 8 clotting assay
Carrier detection and antenatal diagnosis uses dna technology
Chronic biopsies at 8-10 weeks of gestation provide DNA for analysis
Treatment of haemophilia A
Factor 8 replacement when bleed occurs
Usually recombinant factor 8
1-amino-8-D-arginine vasopressin (DDAVP)
Mobilize factor 8 from endothelial cells. Replacing the F8.
Haemophilia B (christmas disease)
Deficiency of factor IX: mutations
Clinically indistuishable from Haemophilia A (but less common)
Clinical features: like A, recurrent joint bleeds.
Diagnosis: APTT prolonged. Diagnosis confirmed by factor IX clotting assay.
Treatment: use of factor IX replacement.
von Willebrand's disease (vwd)
1. Prevalence of 1 in 100 (no symptoms)
Clinically significant 1 in 10,000
2. Usually autosomal dominant.
Most patients are heterozygous for VWF gene.
3. Mutations in the von Willebrand factor (vWF) gene.
vWF synthesized as a large protein, exists in the plasma.
promotes platelet adhesion to damaged endothelium and other platelets; carrier for factor 8.
Von Willebrand's Factor
3 types depending on the electrophoretic analysis of vWF multimers
types 1 and 3: partial reduction or nearly complete absence of vWF molecules.
type 2: abnormal form of the protein-functional abnormality.
Diagnosis: prolonged APTT, reduced factor 8 clotting activity. Imparied platelet aggregation.
reduced levels of vwf.
vWD clinical features?
Extent of bleeding variable
Spontaneous bleeding usually confined to mucous membranes and skin
Severe haemorrhage may occur following surgical procedures
mild or moderately affected
increases both vWF and factor 8
most effective in type 1 vwd patients
-Tranexamic acis: mild bleeding
Acquired coagulation disorders
More common than inherited disorders
usually to do with vit k deficiency and disseminated intravascular coagulation
Platelet and fibrin form basis
form clot in circulation
(involved in MI, deep vein occlusion, cerebrovascular disease)
Arterial or venous
Incidence increases with age
1. occlusion of vessel by a foreign material/blood clot
2. Occlusion of a vessel by a blood clot which has moved from its starting position
3. INherited or acquired disorders predispose to thrombosis
Virchow's triad outlines the factors that predispose to thrombus formation. What are they?
1. Changes in blood flow: slowing down of blood flow, for example when sitting down for ages at a desk.
2. Changes in blood constituents:
hypercoagulability of the blood, for example caused by genetic deficiencies
3. Changes within the walls of blood vessels:
Vessel wall damage, for example caused by trauma, infection
Thrombus in an artery- rupture of atheroma.
Two diseases can be classified under this category;
Stroke- thrombotic stroke-> thrombus forms around atherosclerotic plaque with gradual blockage of artery.
M.I: obstruction of the coronary artery. If diagnosed within 12 hours then thrombolytic therapy can be done. /tpa, streptokinase
INcreased systemic coagulability and stasis: most important.
Deep vein thrombosis- most common in legs.
Signs and symptoms- swelling, pain, erythema, if part of DUT forms embolus can cause pulmonary embolism (PE)
Pulmonary embolism symptoms:
Dyspnoea-shorntess of breath
Factor V leiden (activated protein C resistance)
Hereditary coagulation abnormality that is a risk factor for venous thrombosis.
5% of caucasions in UK
Single point mutation in factor V gene in 90% of cases. Arginine-> glutamine.
Factor V is less susceptible (x10) to cleavage by activated protein C.
Heterozygous: 7 fold increase thrombosis risk.
Homozygotes: 50 fold increase!
Give some aquired thrombophilia risk factors?
Disseminated cancer: secretion of tumour substances activate FX.
Endothelial injury- smoking, infection
Alteration to blood flow: atrial fibrillation.
What drugs are used for antithrombotic therapy?
Two main classes:
1. Anticoagulents- prevent thrombosis and stabilise an established clot. (heparin and warfarin)
2. Thrombolytic agents- dissolve thrombus