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Haemostasis

Haemostasis is the halting of bleeding by the clotting process. There are two main components of this process. Primary haemostasis concerns the clumping of platelets to a damaged vessel wall. Secondary haemostasis is the involvement of clotting factors to create a clot. This pathway is summarized:

  1. Damage to the vessel wall
  2. Collagen and tissue factor exposed
  3. Von Willebrands factor (vWF) binds collagen in the wall
  4. Primary haemostasis: platelets adhere to the vWF-collagen complex. Platelets are activated to attract more platelets
  5. Secondary haemostasis: Tissue factor and platelets activate the clotting cascade to make thrombin. Thrombin converts finbrinogen in to an insoluble fibrin clot

The clotting cascade is summarized here:

The clotting cascade. "a" indicates activation.

The basics of the clotting cascade should be learnt. This may seem intimidating at first but really it is only neccesary to know the factors in the intrinsic pathway (12, 11, 9, 8), the factors in the extrinsic pathway (there is only one: 7), and the common pathway (10, 5, 2, 1).

The factors activate each other like dominoes, from either the extrinsic pathway or intrinsic pathway. It was previously thought that these two pathways were of equal importance, but now it is realized that the extrinsic pathway is the primary starting mechanism of clotting and this has been renamed the "Tissue Factor" pathway.

Lab investigation of coagulation

Initial Tests

  1. Platelet count (normally 150-400x10 9 ). If this is low it is necessary to perform a blood film to exclude machine error
  2. Prothrombin time, PT (normally 12-14 seconds). This is measures clotting in the extrinsic and common pathways. It is used to measure warfarin, expressed as the International Normalized ratio (INR) which is the the tested value divided by the normal prothrombin time.
  3. Activated partial prothrombin time, aPTT (25-35 seconds). This measures clotting in the intrinsic and common pathways. It is used to measure unfractionated heparin (fractionated heparin has a more reliable blood concentration and so does not normlaly need to be measured)

Prolonged clotting times can be either: a deficiency of single/multiple factors (e.g. Haemophilia A which is low factor 8), or reduced function of factors by an inhibitor (e.g. acquired Haemophilia A). Some bleeding disorders can be associated with normal values for all these tests (for example a disorder of platelet function . Conversely some disorders cause abnormalities of or these values but are not associated with abnormal bleeding.

Just using these three investigations a number of diseases can be diagnosed:

PT aPTT Platelets Diagnosis
Normal Normal Normal Platelet function disorder, 8 deficiency, low molecular weight heparin therapy
Normal Normal 7 deficiency/inhibitor, early warfarin therapy
Normal Normal 11/9/8 deficiency or inhibitor, Von Willebrand's Disease
Normal Warfarin/unfractionated heparin, vitamin K deficiency (may occur in liver disease), 2/5/10/fibrinogen deficiency
"Massive transfusion", Diffuse Intravascular Coagulation, liver disease
Normal Normal Failure of platelet production, peripheral destruction of platelets

This table may be overwhelming at first, but it is quite logical if studied. The interpretation of these investigations is a common exam question.

Further investigations

These are performed to further investigate an abnormality of one of the above

  1. Mixing study: does the PT or aPTT correct when mixed 50:50 with normal plasma? If so then suspect a clotting factor deficiency. If not then suspet a factor inhibitor.
  2. Fibrinogen assay: a measurement of the plasma fibrinogen. Amongst other uses fibrinogen is low in Diffuse Intravascular Coagulation due to clotting factors being used up.
  3. Assays for specific factors
  4. D-Dimer: a fibrin degradation product, it is raised when the coagulation system is activated (e.g. in Diffuse Intravascular Coagulation).
  5. Platelet function tests: assessing the ability of platelets to aggregate in a test tube
  6. Lupus coagulant and inhibitor tests: these are complex tests to for the quantification of inhibitors in plasma. Despite the name, it is nothing to do with Systemic Lupus Erythematosus.

Clinical Features of clotting disorders

The symptoms of diseases of primary and secondary haemostasis differ:

Disorders of primary Haemostasis

These can be divided in to those involving a decrease in platelet number, and those involving a decrease in the function.

Low platelets (Thrombocytopenia)

This can occur due to a decrease in production due to chemotherapy/radiotherapy, leukaemia, B12/folate deficiency. It can also occur due to an increase in destruction of platelets: autoimmune thrombocytopenia, hypersplenism, consumptive coagulopathies (e.g. DIC). 

On investigation of autoimmune thrombocytopenia there is low platelets, marrow changes (an increase in megakaryocytes). Treatment is steroids, IV immunoglobulin and consideration of splenectomy.

Platelet function disorder

This can be due to drugs (aspirin, non-steroidal anti-inflammatories), uraemia, cardiopulmonary bypass, and heritable disorders. On investifation there is often normal platelet number. A platelet aggregation test evaluates the ability of platelets to attach to each other.

The commonest heritable disorder involving platelet function is von Willebrands Disease in which there is a deficiency of von Willebrand's Factor (vWF). This is an autosomal dominant condition giving rise to symptoms of primary haemostasis. VWF is necessary to prevent factor 8 destruction in the blood, and so on investigation there also is a deficiency of this factor. Normally the disease requires no treatment although IV desmopressin may be given, which raises a patient's endogenous levels of von Willebrand's factor.

Disorders of secondary haemostasis

Heritable

The commonest heritable disorder of secondary haemostasis (i.e. clotting) is Haemophilia A , which is factor 8 deficiency. The symptoms depend on the level of factor 8 in the blood. If there is less than 1% then there is severe lifelong bleeding. Treatment is recombinant factor 8. Haemophilia A may also be acquired, when it is often quite severe.

Acquired

Diffuse Intravascular Coagulation is the situation whereby there is consumption of platelets and clotting factors, giving rise to the counterintuitive situation of bleeding and microvascular thrombosis. It can arise as a complication of a number of conditions including sepsis, abruption of the placenta in pregnancy, and liver disease. On investigation there is increased PT and aPTT, decreased platelets, and decreased fibrinogen. Clinically the patient is very ill and treatment is often in intensive care. The underlying cause must be managed. Transfusion or fresh frozen plasma may be administered with protein C concentrate (which is  antithrombotic).

Anticoagulants such as heparin or warfarin may be overadministered causing symptoms of secondary haemostasis. The treatment is to withold further treatment with these drugs. Protamine can be given to reverse the effect of heparin (by binding to it). To reverse overcoagulation with warfarin vitamin K can be given. Acutely if symptoms are severs beriplex can also be delivered. This contains the factors that warfarin inhibits (10, 9, 7, 2).

Multiple clotting factor deficiencies may arise due to liver disease or vitamin K deficiency (as with warfarin). On investigation the PT and aPTT may be raised (depending on which factors are low). Treatment may require fresh frozen plasma, and cryoprecipitate (which is a blood product containing fibrinogen and some clotting factors).

Venous thrombosis and thrombophilia

The physiological anticoagulant mechanisms are:
Risk factors for venous thrombosis. There are many, and the important ones should be learnt:
Acquired
Immobility, trauma, surgery, pregnancy, oestrogen (the pill, hormone replacement therapy), malignancy, inflammation, age, myeloproliferative disorders, antiphospholipid syndrome (presenting as thrombosis, miscarriage, thrombocytopenia. It is antibody mediated)
Heriditary
Increased pro-coagulant factors, decreased anticoagulant factors, decreased effectiveness of anticoagulant factors (e.g. factor 5 Leiden disease)
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