Bleeding Disorders

Synonyms: bleeding diatheses

Bleeding disorders are usually taken to mean coagulopathies with reduced clotting of the blood but also encompass disorders characterised by abnormal platelet function or blood vessel walls that result in increased bleeding.

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.¹ 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.²
• Von Willebrand's disease is the most common inherited bleeding disorder. Usually the condition is mild without spontaneous bleeding. It occurs in 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's disease) affecting platelet membrane glycoproteins and causing abnormal platelet binding and aggregation

Acquired disorders³

• Liver disease and cirrhosis cause reduced synthesis of clotting proteins and thrombocytopenia.
• Vitamin K deficiency due to dietary deficiency, GI malabsorption or absence of gut bacteria in infancy (Haemorrhagic disease of the newborn⁴).
• 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 SLE) or to platelets (as in immune thrombocytopenic purpura or ITP).
• 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.

• Haemophilia A occurs at a rate of 1 per 5000 male births. About a third will have no previous family history of the disease. Haemophilia B is more rare and occurs at a rate of about 1 per 30,000 male births. Both are sex-linked recessive disorders, occurring almost entirely in male patients.
• Von Willebrand's Disease is an autosomal dominant disorder and is present in about 1% of the general population.¹
• ITP is one of the most common autoimmune disorders. It occurs either as an acute self-limiting disease of childhood (incidence of 15/100,000 children pa) or as a chronic condition seen most often in adult females.

Symptoms

• Abnormal bruising after minimal trauma
• Prolonged bleeding from minor cuts and scratches
• Bleeding from gums without gingival disease and unrelated to brushing.
• Repeated nosebleeds lasting more than 10 minutes despite compression (especially in children)
• Persistent menorrhagia sufficient to cause iron deficiency anaemia with normal uterus
• Post-partum haemorrhage
• History of excessive or recurrent bleeding after dental extraction or minor surgery

Signs

• Unexplained anaemia
• GI bleeding without obvious cause
• Haemarthrosis
• Bruising and petechia (non-blanching haemorrhagic spot <2 mm diameter), purpura (2-10 mm diameter), ecchymosis (>10mm diameter). Petechia associated with bleeding conditions are usually non-tender, whilst those associated with vasculitis are tender.

Differentiation of main types of bleeding disorders³:

Ensure history covers:

• Surgical/Obstetric and Gynaecological history including need for transfusion.
• Medication(particularly aspirin, NSAIDs, corticosteroids, heparin)
• Concurrent liver or renal disease
• Family history of bleeding disorders
• Alcohol use

• Blood count and film
• Platelet count
• Activated partial thromboplastin time- prolonged with factor VIII and IX deficiency
• Prothrombin time - prolonged with deficiency of factors I, II, V, VII and X
• Thrombin time or fibrinogen- hypo- or dys-fibrinogenaemia; fibrin degradation products
• Bleeding time - assesses platelet-vessel wall interaction
• Specific factor assays - factors VIII or IX to determine severity of haemophilia; factor VIII and vWF in von Willebrand's disease
• Gene analysis

Depends on condition:

• Haemophilia
  • All haemophiliacs should receive long term follow-up and specialist care via a regional haemophilia centre.
  • 'On-demand' treatment with replacement clotting factors. When a haemophiliac starts bleeding, factor VIII or IX needs to be transfused as soon as possible. Many are able to administer this themselves at home. (Normophilic patients with trauma have also had recombinant clotting factors used to treat massive bleeding.⁶)
  • Symptomatic relief - analgesia, rest, physiotherapy etc - may also be needed for bleeds into muscles and joints.
  • Prophylactic treatment can be used to prevent bleeds and their debilitating consequences. Tranexamic acid is sometimes used to prevent bleeding after minor ops in those with mild haemophilia and desmopressin can be used to prevent bleeding in those with mild or moderate haemophilia A only. Some argue for the use of factor VIII or IX prophylactically and this approach has been used over many years in Sweden but not universally adopted due medical, psychosocial and cost implications. Inadequate trials exist to back or refute the use of clotting factors in this way.⁷
  • Haemophilia has long been a target for gene therapy. Ultimately, it is hoped, direct correction of the gene mutation might be possible and enable 'cure' of the condition. Some success with animal models and one human patient with haemophilia B who achieved 10% normal factor IX activity after liver-directed gene therapy using adenovirus as vector. However, therapy became ineffective after a month, probably due to immune response to the modified cells.⁸ Clearly gene therapy is still some way off.
• Von Willebrand's disease
  • Cases should be referred to haematology for assessment and advice
  • Mild cases are treated with desmopressin, tranexamic acid and combined pill for menorrhagia.
  • Severe cases may need treatment with vWF. As yet, there is no recombinant form of vWF
  • Patients should be advised to avoid NSAIDs and aspirin, to reveal their condition and plan ahead for surgical or dental procedures and to wear a medic alert tag in case of emergencies.
• Acute ITP - rarely needs treating but steroids may be useful. Refer to paediatrics/haematology depending on age.

Those with serious inherited bleeding disorders may wish for genetic counselling and prenatal diagnosis.⁹