Disorders of Haemostatsis Flashcards
Normal haemostasis
Clotting mechanisms
Clotting mechanisms = interchangeable = Clot lysis
thus:
- Internal and external bleeding controlled
- Pathological thrombosis prevented
What are the factors that maintain the clotting equilibrium
- Blood vessel– vasoconstriction
- Platelets– initial haemostatic plug
- Blood coagulation – fibrin; permanent haemostatic plugs
- Fibrinolysis– plasmin to remove fibrin thrombi
Role of platelets
Early phase of haemostasis via
- Adhesion
→ Attracted to exposed collagen
→ Activation: release of cytoplasmic granules - Aggregation
→ Accumulation/aggregation of large numbers of platelets to form haemostatic plug
Blood coagulation
- Plasma precursors → fibrin → permanent haemostatic plug
- Activation of a series of clotting factors normally present in an inactive form → need to be activated
- Thrombin - key enzyme → determines over clotting activity
- Some factors are serine proteases
- Many clotting factors are synthesised in the liver Some(II, VII, IX, X)require Vit K for their synthesis
Thrombin
key enzyme in blood coagulation
→ determines over clotting activity
Clinical laboratory testing for haemostasis
- Clinical laboratory testing is a critical and main element in the diagnosis and treatment of haemostatic disorders
- A vast array of laboratory tests can be used to assess haemostasis - normal and specific disorders
Laboratory testing of haemostatsis
- internal control (control) is more reliable than published figures → not rely in normal value and add an internal control due to possible human, system, etc errors
- Routine tests to determine normal haemostasis
- Specialised tests to determine the type of abnormality if an abnormality found in routine testing.
- All tests must have control plasma run with them
→In many cases, the difference between patient and control that is more important than normal ranges
Sample collection of haemostatsis testing
- A clean venous blood sample for coagulation
- Blood should be immediately placed into plastic tubes containing appropriate anticoagulants:
→ potassium EDTA: full blood count
→ sodium citrate: clotting studies - blood should be gently mixed
- blood should be tested ASAP (2-4 h) → if not may undergo abnormal changes
Preparation of PPP(platelet-poor plasma)
- Accurate coagulation testing requires the plasma free of platelets (except platelet function tests)
- Immediately spin the sample (3000rpm, 10 min)
- Keep the sample at room temperature until PPP obtained to prevent platelet activation
- Test immediately or remove the plasma and store (at 4oC for a few hours or - 40oC for several wks)
Pre-analytical & analytical variation
- Common technical “errors” affect coagulation results
- already affects results even before analysis
- Pre-analytical variation−Poor sample collection−Wrong anticoagulant / no anticoagulant−Contamination−Storage / transportation
- Analytical variation−Incorrect temperature for analysis - Out of date or poorly prepared reagents -Out of date or poorly prepared control material
Tests of haemostatic function
Routine tests
- Bleeding time: an index ofplatelet integrity
- Activated partial thromboplastin time (APTT): test for
Intrinsic+ Common(XII, XI, IX, VIII, X, V, II & I) - Prothrombin time (PT): test forExtrinsic+ Common (VII, X, V, II & I)
Special Investigations - test of haemostatic function
- 50:50 Correction Studies (APTT)−With normal plasma−With known deficient plasmas (which factor)
- Factor Assays (level of deficiency of that factor)
- Inhibitor Studies (abnormal inhibitor coagulation)
What are disorders of primary haemostasis?
- Platelet abnormalities
- Defects of small blood vessels
Skin and mucous membrane especially involved
What are disorders of blood coagulation?
- Congenital clotting factor deficiency
- Acquired disorders of coagulation
Typically: haemarthroses, muscle haematomas, bleeding after injury or surgery
Thrombocytopenia
reduction of platelet numbers
Causes of thrombocytopenia
- Failure of production
- Increased destruction
- Sequestration
Where there is abnormalities of blood platelets, what is bleeding due to?
−Thrombocytopenia
−Abnormal platelet function
What is abnormalities of blood platelets characterised by?
Characterised bypurpuraandbleeding from mucous membranes
> 80 x109/L platelet count meaning
no clinical defect
< 50 x109/L platelet count meaning
bleeding after trauma
< 20x109/L platelet count meaning
spontaneous bleeding
Causes of thrombocytopenia
Failure of production
Increased destruction/use of platelets
Sequestration
Idiopathic thrombocytopenic purpura (ITP)
Causes of thrombocytopenia
-Failure of production
- Megaloblastic anaemia
- Haematological malignancy
- Solid tumour infiltration
- Aplastic anaemia/bone marrow failure
Causes of thrombocytopenia
-Increased destruction/use of platelets
- Autoimmune(ITP Idiopathic thrombocytopenic purpura )
- Secondary immune(SLE, viruses, drugs)
- Alloimmune(neonatal & post-transfusion purpura)
- DIC(disseminated intravascular coagulation) → consume a lot of clotting factors
- Thrombotic thrombocytopenic purpura
Causes of thrombocytopenia
- Sequestration
Hypersplenism
Idiopathic thrombocytopenic purpura (ITP)
Bleeding disorder due to immune destruction of platelets
Idiopathic thrombocytopenic purpura (ITP) - Causes & pathogenesis
Immune system produces platelet Ab→ Ab attach to platelets→spleen destruction
ITP in children
usually acute but self-limiting; bone marrow examination not usual
ITP in adult
less acute than in children; characteristically in women; associated with other autoimmune disorders (e.g. SLE); platelets Ab in 60-70% patients
Clinical features of ITP
- Major haemorrhage rare, seen only with severe thrombocytopenia
- Easy bruising, purpura, epistaxis, menorrhagia−Physical examination: normal except evidence of bleeding
Laboratory investigation of ITP
- Thrombocytopenia: the only blood count abnormality
- Anti-platelet auto-antibodies
ITP Treatment
In children, not usually require treatment; if necessary:
- High dose anti-inflammatory steroid → inhibit the immune responses
- i.v. immunoglobin (very serious bleeding, urgent surgery)
What level does platelets need to be for an adult patient to require no treatment?
Platelets ≥30x109/L - no treatment
What is the first line of treatment in adults for ITP?
corticosteroids(iv IgG if rapid platelets rise desired)
What is the second line of treatment in adults for ITP?
splenectomy(majority respond),
- if fails other treatments (high dose corticosteroids, immunosuppresion; recombinant thrombopoietin).
Platelet transfusion (intracranial or other extreme haemorrhage)
ITP treatment for adults
First line:
corticosteroids (iv IgG if rapid platelets rise desired)
Second line:
splenectomy(majority respond),
if fails other treatments (high dose corticosteroids,immunosuppresion; recombinant thrombopoietin)
Platelet transfusion (intracranial or other extreme haemorrhage)
Disorders of blood coagulation
- Coagulation/fibrinolytic disorders may cause thrombosis or haemorrhage
- Congenital or acquired
- Majority of these are acquired
Congenital coagulation disorder
- Uncommon and usually involve deficiency of one factor only
- not all factors express bleeding → they are not important
- factor 8 and 9 are important
Congenital coagulation disorder types
−Haemophilia A
−Haemophilia B
−Von Willebrand’s disease
Haemophilia A genetic relation
- inherited as X-linked
- recessive trait
- Occurring mainly in males → show phenotype in men- rare to show in women
What is haemophilia A deficiency of?
factorVIII (FVIII)
Clinical features of Haemophilia A
−Clinical severity depends on residual FVIII activity
- 1-5%, bleeding after minor trauma
- < 1%, bleeding spontaneously
- > 5%, asymptomatic
Coagulation deficiency type bleeding; purpura is not a feature
- spontaneous bleeding into muscle, joints; bleeding after dental surgery typical
Aids is a major complication in some patients (due to treatment with FVIII concentrate)
Laboratory feature go haemophilia A
- Partial thromboplastin time prolonged; FVIII↓ (<20%)
- Prothrombin time & bleeding time: normal
Treatment of haemophilia A
Maintaining plasmaFVIIIactivity activity without bleedingat a level that per
Haemophilia B
- Haemophilia B (Christmas disease) is uncommon (1 in 50,000)
- Deficiency of factorIX
- X-linked recessive inheritance, greater prevalence in males
- Clinical picture identical to haemophilia A
Von Willebrand’s disease
- A moderate to mild bleeding disorder
- Deficiency or abnormality of Von Willebrand Factor
(vWF, a glycoprotein; essential cofactor for platelet adhesion & also stabilising factor VIII)
What does Von Williebrand’s disease cause?
- abnormal platelet adhesion- low factorVIIIclotting activity
- Autosomal gene, numerous mutations identified
Acquired coagulation disorder
Coagulation factor deficiency developed in some diseases or by drug therapies
- Vitamin K deficiency
- Liver disease
- Anticoagulant & fibrinolytic drugs DIC
Vitamin K deficiency
- Some factors(II, VII, IX & X)are Vit K dependent
- Source of Vit K - green vegetables, gut microflora
- Lipid soluble, hence requires bile for absorption
- Therefore Vit K deficiency in obstructive jaundice & liver disease
- Haemorrhagic disease of the newborn– lack of gut flora
Warfarin
- A coumarin, potent Vit K antagonist
- Inhibiting complete synthesis of coagulation factors
How is liver disease related to haemostatic diseases?
Liver disease→ a number of defects in haemostasis
Liver disease as a haemostatic disease
- Vit K deficiency (over disease affects the absorption) due tointra/extra hepatic cholestasis
- Reduced synthesis as a result of severe hepatocellular damage
- Thromocytopenia due to hypersplenism
- Functional abnormalities fibrinogen
- DIC – in acute liver failure in platelets and e
