Related synonyms: bleeding diathesis, clotting disorder, coagulation disorder, coagulopathy, haemostatic disorder
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. Bleeding disorders may result from faults at many different levels in the coagulation cascade. They can range from severe and life-threatening conditions, such as haemophilia A, to much more mild variants. Some bleeding symptoms (eg bruising without obvious cause, nosebleeds and heavy menstrual bleeding) are quite common in the general population and there is phenotypic variation even among individuals with defined bleeding problems. Investigation of mild bleeding problems often fails to provide a diagnosis.
The coagulation cascade
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.
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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. 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.
- 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
- 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).
- 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.
- 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.
- 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
- 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.
Systemically look for:
- Haemodynamic status
- Lymphadenopathy or hepatosplenomegaly
- Skin, palate and gums for:
- 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.
|Comparing coagulation factor and platelet defects|
|Coagulation factor defects||Platelet disorders and von Willebrand's disease|
|Bruising on trunk and limbs||Large bruises||Small bruises|
|Bleeding from cuts||Relatively slight||Profuse|
|Nosebleeds||Uncommon||Common, frequently profuse and of long duration|
|Haemarthrosis||In severe haemophilia||Very rare|
|Bleeding after surgery or dental extraction||Up to a day's delay before bleeding occurs||Immediate bleeding|
- FBC, blood film and platelet count - may detect leukaemia, lymphoma or thrombocytopenia or abnormal platelets.
- 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. 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.
- 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.
- A new investigation - the platelet function analyser - is currently under development and may replace the in vivo bleeding time test.
- 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.
- 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.
- Activated partial thromboplastin time (APTT):
|Haemostasis tests in bleeding disorders|
|Platelet count||Prothrombin time||Activated partial thromboplastin time||Bleeding time||Thrombin time||Additional tests|
|Haemophilia A||Normal||Normal||Prolonged||Normal||Factor VIII low|
|Haemophilia B||Normal||Normal||Prolonged||Normal||Factor IX low|
|Von Willebrand's disease||Normal||Normal||Prolonged or normal||Prolonged||VWF and Factor VIII activity low and
impaired ristocetin-induced platelet aggregation
|Liver disease||Low||Prolonged||Prolonged||Normal (rarely prolonged)|
|Disseminated intravascular coagulopathy||Low||Prolonged||Prolonged||Grossly prolonged|
|Oral anticoagulants||Normal||Grossly prolonged||Prolonged||Normal|
|Heparin||Normal (rarely low)||Mildly prolonged||Prolonged||Prolonged|
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.
Further reading & references
- Geil JD; Pediatric Von Willebrand Disease, Medscape, Apr 2012
- The Haemophilia Society
- UK haemophilia centre doctors' organisation; UK haemophilia centre doctors' organisation (UKHCDO); access to current haemophilia guidelines
- Leung AK, Chan KW; Evaluating the child with purpura. Am Fam Physician. 2001 Aug 1;64(3):419-28.
- Hayward CP; Diagnosis and management of mild bleeding disorders. Hematology Am Soc Hematol Educ Program. 2005:423-8.
- Stvrtinová V, Jakubovsk² J, Hulin I; Pathophysiology Principles of Diseases 1995.
- Bolton-Maggs PH, Pasi KJ; Haemophilias A and B. Lancet. 2003 May 24;361(9371):1801-9.
- Mannucci PM, Duga S, Peyvandi F; Recessively inherited coagulation disorders. Blood. 2004 Sep 1;104(5):1243-52. Epub 2004 May 11.
- Hampton KK, Preston FE; ABC of clinical haematology. Bleeding disorders, thrombosis, and anticoagulation. BMJ. 1997 Apr 5;314(7086):1026-9.
- Chalmers EA; Neonatal coagulation problems. Arch Dis Child Fetal Neonatal Ed. 2004 Nov;89(6):F475-8.
- Schafer AI; Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia. Blood. 2006 Jun 1;107(11):4214-22. Epub 2006 Feb 16.
- Liesner RJ, Machin SJ; ABC of clinical haematology. Platelet disorders. BMJ. 1997 Mar 15;314(7083):809-12.
- Carville D, Guvyer K; Coagulation testing Part 1: Current methods and challenges IVD Technology Magazine 1998.
- Bontempo F; Use and Misuse of the Bleeding Time Transfusion Medicine Update 1994.
- Franchini M; The platelet function analyzer (PFA-100): an update on its clinical use. Clin Lab. 2005;51(7-8):367-72.
- Israels S; Inherited Abnormalities of Fibrinogen emedicine, Feb 2009.
- Rodeghiero F; Management of menorrhagia in women with inherited bleeding disorders: general Haemophilia. 2008 Jan;14 Suppl 1:21-30.
- Oyesiku JO, Turner CF; Reproductive choices for couples with haemophilia. Haemophilia. 2002 May;8(3):348-52.
|Original Author: Dr Chloe Borton||Current Version: Dr Chloe Borton|
|Last Checked: 11/12/2009||Document ID: 1872 Version: 21||© EMIS|
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