The coagulation cascade^[2]

When a blood vessel is injured, a series of biochemical reactions is brought into play, called the coagulation cascade. The result of this series of reactions is to achieve haemostasis by developing a clot, stopping its formation at the right time, and eventually facilitating clot dissolution when the vessel has healed. Most of the proteins required for the cascade are produced by the liver as inactive precursors (zymogens) which are then modified into clotting factors. The implication of the term 'cascade' is that a small stimulus can produce a reaction which is sufficiently widespread to produce a significant clot.

There are two routes for activation of the coagulation system. The intrinsic pathway is activated by contact with collagen from damaged blood vessels (or indeed any negatively-charged surface). Platelet activation is normally involved. The extrinsic pathway is activated by contact with tissue factor from the surface of extravascular cells.

Both routes end in a final common pathway - the proteolytic activation of thrombin and the cleaving of fibrinogen to form a fibrin clot. The intrinsic pathway is the main 'player' in this scenario, with the extrinsic pathway acting as an enhancer.

Classification

Congenital bleeding disorders

• Haemophilia A (factor VIII deficiency) and B (factor IX deficiency or Christmas' disease) are the most well known congenital bleeding disorders as well as celebrated examples of X-linked genetic disease.^[3] A spectrum of severity exists, from severe (less than 2% coagulation factor) with spontaneous bleeding into muscles and joints leading to crippling joint disease, to moderate (2-5%) and mild where bleeding only occurs after trauma or surgery. Other inherited bleeding disorders affecting the coagulation pathway are much rarer and inherited in an autosomal recessive fashion; for example, prothrombin (factor II) deficiency is found in about 1 in 2 million individuals.^[4]
• Von Willebrand's disease (vWD) is the most common inherited bleeding disorder. Usually the condition is mild without spontaneous bleeding. It occurs equally in men and women and is caused by reduced production or abnormality of Von Willebrand's factor (vWF) that both promotes normal platelet function and stabilises factor VIII.
• Rare autosomal recessive disorders (Glanzmann's thrombasthenia and Bernard-Soulier syndrome) affecting platelet membrane glycoproteins and causing abnormal platelet binding and aggregation

Acquired disorders^[5]

• Liver disease and cirrhosis cause reduced synthesis of clotting proteins and thrombocytopenia.
• Vitamin K deficiency due to dietary deficiency, gastrointestinal malabsorption or absence of gut bacteria in infancy (haemorrhagic disease of the newborn).^[6]
• Shock, sepsis or malignancy can all cause an increased bleeding tendency, often through the final common pathway of disseminated intravascular coagulopathy (DIC) where simultaneous microvascular thrombosis and generalised bleeding occur due to massive consumption of coagulation factors or damage to vessel walls (for example in meningococcal septicaemia).
• Renal disease causes platelet dysfunction and reduced aggregation.
• Circulating autoantibodies to coagulation factors (eg in lymphoma and systemic lupus erythematosus) or to platelets (as in immune thrombocytopenic purpura).
• Amyloidosis where factor X deficiency occurs as well as local infiltration of blood vessels.
• Advanced age, prolonged steroid use and vitamin C deficiency all reduce the integrity of the blood vessel wall.

Remember that some diseases can be associated with both bleeding and thrombosis, eg polycythaemia rubra vera and essential thrombocythaemia.^[7]

Presentation^[5]

Symptoms

• Bruising may be spontaneous or recurrent:
  • Large bruises on sun-exposed areas of limbs in the elderly are usually due to cumulative ultraviolet vessel damage and are rarely significant.^[5]
  • Large bruises on the trunk are more indicative of a bleeding disorder.
• Prolonged bleeding:
  • After minor cuts or abrasions.
  • Nosebleeds lasting >10 minutes despite compression (especially in children).
  • Severe menorrhagia causing anaemia, with normal uterus.
  • Bleeding from gums without gingival disease and unrelated to brushing.
  • Following dental extraction.
  • Postpartum haemorrhage.
  • After injections or surgical procedures.

Also enquire regarding:

• Current medication
  • Including aspirin, non-steroidal anti-inflammatory drugs, warfarin and complementary/alternative preparations.
  • Remember drug interactions between warfarin and other medications that prolong the international normalised ratio (INR).
• Family history of bleeding tendency.
• Alcohol intake.
• Other constitutional symptoms, eg malaise, weight loss.
• Past history or thrombosis (can be suggestive of thrombophilia).
• Previous blood transfusions.
• Renal or hepatic impairment.

Signs

Systemically look for:

• Pallor
• Sepsis
• Haemodynamic status
• Lymphadenopathy or hepatosplenomegaly

Check:

• Skin, palate and gums for:
  • Bruising
  • Petechia (non-blanching haemorrhagic spot <2 mm diameter)
  • Purpura (2-10 mm diameter)
  • Ecchymosis (>10 mm diameter)
• Fundi for retinal haemorrhages
• Joints for haemarthrosis
• Rectal or vaginal examinations where appropriate.

Investigations^[5]

• FBC, blood film and platelet count - may detect leukaemia, lymphoma or thrombocytopenia or abnormal platelets.^[8]
• Consider checking U&Es to exclude uraemia causing a platelet disorder.
• Consider LFTs to detect hepatic cause of acquired coagulation factor deficiency and alcohol-related damage.
• Bone marrow biopsy.
• A coagulation screen usually involves taking blood in a mixture of citrate, EDTA and clotted sample bottles.^[9] It includes:
  • Activated partial thromboplastin time (APTT):
    • This measures the intrinsic pathway (which includes factors I, II, V, VIII, IX, X, XI, and XII) and the common pathway.
    • A plasma sample is used and the intrinsic pathway is activated by adding phospholipid, an activator such as kaolin (which acts as a negatively-charged surface), and calcium ions. The formation of prothrombinase complexes on the surface of the phospholipid enables the formation of thrombin and a subsequent clot. The result is reported as the time in seconds for this reaction.
    • The test is a used to assess the overall competence of the coagulation system, as a routine test to monitor heparin therapy, and as a preoperative screen for bleeding tendencies. It will also reveal possible coagulation factor deficiencies, as in haemophilia A and B.
  • Prothrombin time (PT):
    • This assesses the extrinsic and final common pathway of the coagulation cascade, thus can detect factor I, II, V, VII or X deficiency or the effects of warfarin.
    • It is performed by adding thromboplastin and calcium ions to a plasma sample. The time for clot formation is measured.
    • Prolonged time suggests the presence of an inhibitor to, or a deficiency of, one or more coagulation factors, the presence of warfarin, the existence of vitamin K deficiency or liver dysfunction.
    • The INR, used to monitor warfarin, is derived by comparing the patient's clotting time to that of a standardised sample.
  • Thrombin clotting time test:
    • This measures the rate of a patient's clot formation compared with a normal plasma control. The plasma is first depleted of platelets, and a standard amount of thrombin added.
    • The test is used in the diagnosis of DIC, and other conditions that can affect fibrinogen level, such as liver disease.
  If the above tests are all normal, the vast majority of common haemostatic disorders will have been excluded. However, if symptoms persist and/or there is a suggestion of family history, patients should be referred to a haematologist for further tests which may include:
  • Bleeding time - this tests the interaction between the platelets and the vessel walls. A standardised spring-loaded lancet is used to make a small cut in the patient's forearm and the time for the bleeding to stop is then measured. The test is not useful as a screening test, as it has a high false positive result, but is sometimes useful in certain clinical situations, eg the investigation of vWD and the effect of drugs on the coagulation system.^[10]
  • A new investigation - the platelet function analyser - is currently under development and may replace the in vivo bleeding time test.^[11]
  • Fibrinogen - the level can be determined by immunological or functional assay. It is usually performed when APTT or PT screening tests are prolonged. The main disorders detected are afibrinogenaemia or hypofibrinogenaemia (due to absence or a low level of fibrinogen production) and dysfibrinogenaemia (due to a molecular alteration of fibrinogen, causing poor function). Differences in the level of fibrinogen measured by the two methods is suggestive of dysfibrinogenaemia.^[12]
  • Specific factor assays - factors VIII or IX to determine severity of haemophilia; factor VIII and vWF in vWD.
  • Gene analysis looking for specific gene defects.

Management

Management is dependent on the underlying condition - see separate articles on Haemophilia A (Factor VIII Deficiency) and Haemophilia B (Factor IX Deficiency) and the separate article Von Willebrand's Disease.

Whilst the sex-linked nature of haemophilia results in mostly male sufferers, women are much more likely to present with mild bleeding disorders due to the demands of menstruation and childbirth. Menorrhagia can be tackled by standard means (tranexamic acid, combined oral contraceptives, levonorgestrel intrauterine system) or where these fail, or are contra-indicated, treatment with desmopressin (where patients are known to be responsive) may be tried prior to surgical treatments.^[13]

Prevention

Those with serious inherited bleeding disorders may wish for genetic counselling and prenatal diagnosis.^[14]