haemostasis Flashcards
What is primary haemostasis?
Primary Haemostasis
• This stage occurs within seconds
• 1. Vasospasm: Vasoconstriction of the blood vessel by
Prostacyclin (PI2), Thromboxane A2 (TXA2) and serotonin
(5-HT). Slows down the bleeding.
• 2. Platelet Plug: Adherence of platelets to collagen of
damaged endothelial cells. Platelet aggregation: Role of
thrombin, adenosine diphosphate (ADP), PI2, TXA2, 5-HT
and prostaglandins.
What is secondary haemostasis?
Secondary Haemostasis
• This stage takes several minutes. Stabilizes the soft clot
and maintains vasoconstriction.
• 3. Fibrin Clot: Conversion of prothrombin to thrombin.
Thrombin stimulates the conversion of fibrinogen (Blood
protein) to polymerized fibrin (mesh).
• 4. Dissolution of the clot by fibrinolysis: Plasminogen
is converted to plasmin, the enzyme that dissolves the
fibrin.
What is the role of thrombin in coagulation?
Tissue factor provides stimulus for initial thrombin production
Thrombin activates platelets and clotting factors required for its own production
The conversion of fibrinogen to fibrin by thrombin is the critical step in clot formation
What are the steps in thrombus formation?
- stimulus
- initiation(platelet activation) and thrombin initiation(activation of coagulation factors): thrombin is the most potent platelet activator
- thrombin amplification (takes place on surface of activated platelets)
- thrombus formation(large quantities of thrombin are needed for converting fibrinogen to fibrin)
What is the process of blood coagulation?
• Initiated by the Extrinsic Pathway
– VII binds TF exposed by vascular injury
– VIIa can also activate IX in the presence of TF
– Activation of XII not required for hemostasis
• Each step of the cascades involves:
– Protease (from previous step)
– Zymogen
– Non-enzymatic cofactors
• V (Xa)
• VIII (IXa)
• TF (VIIa)
– Ca2+
– Organizing surface (platelets)
• Thrombin cleaves peptides from fibrinogen to produce fibrin monomers(gel)
• XIIIa crosslinks fibrin monomers with transglutamination
What is the normal range for Activated Partial Thromboplastin Time (aPTT)?
• aPPT normal range: 25-37 seconds
What causes pathophysiologic variability when testing aPTT?
• Age, Stress, Physical exercise, Surgery (post-op) can mask other hemostatic defects!
• Prolonged : Acquired conditions (DIC, drugs - heparin), lupus anticoagulant antobodies, VIII or iX inhibitors, Inherited: intrisic Factors deficiency
(FVIIi, FIX, FXII, prekallicrein, HWWK), vWD
• Shortened in Pregnancy/post-partum, during oral contraceptives (due to increased FVIII), after Physical exercise and stress.
• normal APTT does not exclude mild hemophilia A or B or weak inhibitors
How is Prothrombin Time; Prothrombin Ratio (PR) and Internationalized Ratio (INR) tested?
– Measures of the extrinsic/common pathway
• PT reference range: 12-15 sec; measures factors II, V, VII, X and fibrinogen.;
Used in conjunction with aPTT
• INR (International Standardize Ratio) normal range: 0.8-1.2
What causes pathological variability in PT and INR?
Pathophysiologic variability
• Circardial rythms
• Vitamin K deficiency and malabsorption (leading to vitamin K deficiency)
• Liver disease
• Afibrinogenaemia and dysfibrinogenemia
• Dilutional coagulopathy e.g. massive blood transfusion
• Multiple clotting factor deficiencies e.g. FV and FVIII deficiency including DIC
What is the interpretation for isolated prolonged PT?
Factor VII deficiency
What is the interpretation for Prolonged PT in
association with other coagulation abnormalities?
• Vitamin K deficiency
• Vitamin K antagonists e.g. warfarin, phenindione, rodenticides
• Liver disease
• Malabsorption (leading to vitamin K deficiency)
• High concentrations of unfractionated heparin
• Direct thrombin inhibitors e.g. Lepirudin, argatroban,
dabigatran
• Afibrinogenaemia and dysfibrinogenemia
• Dilutional coagulopathy e.g. massive blood transfusion
• Multiple clotting factor deficiencies e.g. FV and FVIII
deficiency
• Abnormalities of the vitamin K cycle e.g. mutations within the VKORC1 gene
• Chromosomal aberrations - the F7 and F10 genes are located on the long arm of chromosome 13 - deletions of which are associated with reduced FVII and FX levels.
What is the interpretation for a shortened PT?
Following treatment with rVIIa
What do problems associated with PT, aPTT and TT imply?
• PT Prothrombin Time
=> Exogenous coagulation (extrinsic system)
• APTT Activated Partial Thromboplastin Time
=> Endogenous coagulation (intrinsic system)
• TT Thrombin Time
=> Fibrinogen / fibrin conversion
What is the reference range for fibrinogen?
1.5-4.0 g/L
In which instances would the fibrinogen level be decreased?
• DIC due the consumption of clotting factors
• Liver disease due to decreased synthesis
• Massive transfusion leading to a dilutional coagulopathy
Inherited deficiencies e.g. hypofibrinogenaemia,
afibrinogenaemia and dysfibrinogenaemia
• Following thrombolytic therapy
In some patients following treatment with asparaginase
In which instances would the fibrinogen level be increased?
- Increasing age
- Female sex, pregnancy, oral contraception
- In post-menopausal women
- Acute phase reaction
- Disseminated malignancy
What is hemophilia A?
Factor VIII deficiency
X linked recessive
occurs in 1/10 000 males
What is hemophilia B?
Factor IX deficiency
X linked recessive
occurs in 1/50 000 males
What is the severity of bleeding in hemophilia?
Related to factor level
<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild injury
5-30% - Mild - bleeding with surgery or trauma
What are D-dimers indicative of?
end product of fibrinolysis
reference value of <500 ug/ml
In which situations can D-dimers be raised?
Pregnancy; Burns Malignancy; Liver disease Infection; Snake bites DIC; Atrial fibrillation Vaso-occlusive sickle; Renal failure Cell crisis; Cardiac failure, Surgery; Venous thromboembolic disease [VTED] Pulmonary embolism; Aortic dissection
What are common clinical conditions associate with DIC? Activation of both coagulation and fibrinolysis triggered by these initiating events
• Sepsis • Trauma – Head injury – Fat embolism • Malignancy • Obstetrical complications – Amniotic fluid embolism – Abruptio placentae • Vascular disorders • Reaction to toxin (e.g. snake venom, drugs) • Immunologic disorders – Severe allergic reaction – Transplant rejection
What is von willebrand factor?
Synthesized in endothelial cells & megakaryocytes Functions: 1) Stabilizes Factor VIII 2) Essential for platelet adhesion deficiency causes mucosal bleeding
How does liver disease affect hemostasis?
- Decreased synthesis of II, VII, IX, X, XI, and fibrinogen
- Dietary Vitamin K deficiency (Inadequate intake or
malabsortion) - Dysfibrinogenemia
- Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)
- DIC
- Thrombocytoepnia due to hypersplenism
