Contents
Introduction
Various diseases that affect haemostasis exist. These can result in either a tendency to bleed (a failure of coagulation) or a predisposition to inappropriate clotting (hypercoaguability). A few diseases can produce either effect or both.
Bleeding Disorders
Haemophilia A
Haemophilia A is the best known disorder of bleeding. Affected patients are deficient in factor VIII. The gene for factor VIII is located on the X chromosome and because the disease is a recessive condition the vast majority of sufferers are male. Patients bruise easily and those who have a severe deficiency suffer spontaneous haemorrhage due to their inability to deal with the very minor blood vessel damage that occurs during everyday normal life. Bleeding into joints is a particular problem in severe haemophilia A and can lead to secondary osteoarthritis and deformity.
Haemophilia B
This is also an X-linked recessive condition and is due to a deficiency of factor IX. It is sometimes known as Christmas disease. The clinical features are the same as haemophilia A.
Von Willebrand Disease
This is caused by a deficiency of von Willebrand factor. Like haemophilia A and B it is an inherited condition, but is autosomal recessive (chromosome 12) so males and females are affected. Its severity is usually less than haemophilia.
Idiopathic Thrombocytopenic Purpura
Almost always abbreivated to ITP, this disease is caused by autoimmune destruction of platelets. Like most autoimmune diseases it is more common in females and not infrequently comes to attention by producing menorrhagia.
Thrombocytopenia
Other causes of thrombocytopenia exist and like ITP can result in bleeding under minimal provocation, as well as delayed cessation of the bleeding. Many diseases of the bone marrow can produce thrombocytopenia and drugs may also cause a reduction in the platelet count.
Platelet Dysfunction Syndromes
Various disease exist in which one or other aspect of platelet function is defective. In Glanzmann's disease a lack of the surface glycoproteins IIb and IIIa prevents platelets from aggregating. Bernard-Soulier syndrome features a lack of glycoprotein Ib, so platelets cannot recognise and make use of vWF. Deficiencies of alpha granules and dense granules may also occur.
Blood Vessel Diseases
Blood vessels can also contribute to the panopoly of bleeding disorders, although their involvement is often forgotten. Assorted infections, such as measles, dengue fever and ebola, can damage blood vessels and cause bleeding. Vasculitis also injures blood vessels and may feature haemorrhage. Hereditary haemorrhagic telangiectasia is an autosomal dominant condition in which patients have multiple small swellings of their small blood vessels. These swellings are prone to rupture.
Hypercoaguable states
Protein C and protein S deficiencies
Both of these inherited diseases display an increased tendency of affected patients to develop venous thrombosis and consequent embolism.
Factor V Leiden
Factor V Leiden disease is one of the commonest inherited hypercoaguable / thrombophilic conditions. Factor V Leiden is a variant form of standard factor V that is resistant to deactivation by protein C. Like protein C deficiency, the clotting occurs almost exclusively in veins. It is suggested that around 5% of the population are heterozygous for factor V Leiden.
Homocysteine
Homocysteine is an amino acid that is obtained by adding a CH2 group to cysteine. It increases the tendency to thrombosis and also injures blood vessels through its ability to damage proteins. Homocystinuria is a rare disease that demonstrates elevated levels of homocysteine.
Antiphospholid Syndromes
This group of diseases exhibits an autoimmune response to membrane phospholipids and related proteins. Assorted primary forms exist but the autoimmune response can also be encountered in association with systemic lupus erythematosus. The autoantibodies may react against protein C to inhibit it, or bind to prothrombin and facilitate its conversion to thrombin. Both venous and arterial thrombotic events can happen.
Hyperviscosity
The blood is more sludgy and flows less well in hyperviscosity syndromes, so the risk of thrombophilia is not surprising (haemorrhage can also occur). Hyperviscosity can be caused either by an increase in the protein content of the blood (myeloma, Waldenstrom's macroglobulinaemia) or an increase in the cellular content (polycythaemia; essential thrombocytosis may cause thrombophilia but the platelets that are formed in this disease can be functionally defective so the effect of the elevation of their number is outweighed by the fact that they do not work).
Dehydration can also increase plasma viscosity.
Paroxysmal Nocturnal Haemoglobinuria
PNH is an acquired disease of bone marrow stem cells in which the cells lose the ability to express a cell surface molecule (glucosylphosphatidylinositol) that anchors other molecules which protect the cells against damage mediated by complement. The resulting myeloid, erythroid and megakaryocytic cells produced by the stem cells are therefore susceptible to destruction by complement. Thrombosis occurs because the platelets in PNH bind complement too readily; the binding of complement by platelets can stimulate them.
Nephrotic Syndrome
Healthy kidneys do not lose any protein in the urine. In nephrotic syndrome there is marked protein loss (at least 3g per day). The lost proteins include antithrombin III. The liver may also respond by pumping out proteins, including fibrinogen, to try to maintain the total plasma protein level.
Elevated oestrogen levels
Oestrogen increases the blood levels of factors II, VII, IX and X, promotes platelet aggregation and reduces levels of antithrombin III; plasminogen levels are also raised so at least the clot busting ability of the body is enhanced to deal with any extra clots that arise. This may explain the tendency to hypercoaguability that can occur with some oral contraceptive preparations.
Smoking
Amongst its myriad of other harmful effects, smoking promotes a hypercoaguable tendency. When combined with factor V Leiden deficiency and oestrogen-containing oral contraception, the total increase in risk can be very significant.
Disseminated Intravascular Coagulation
Disseminated intravascular coagulation (DIC) is a disorder in which there is widespread activation of the clotting system at the microvascular level throughout the circulation. The clots are very small and readily broken down by fibrinolysis. However, this huge flurry of activity consumes clotting factors and platelets and exhausts their reserves so that a marked tendency to bleeding results (rarely, the anticoagulant factors are depleted first and the patient suffers from thrombophilia).
DIC can be induced by numerous conditions that include infection, malignant tumours, leukaemia (particularly AML M3), eclampsia, acute pancreatitis, snake and other venom, burns, trauma, liver failure, hyperthermia, hypothermia and amniotic fluid embolism.
Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura is a rare disease in which damage to blood vessels at the microvascular level results in haemolytic anemia and thrombocytopenia. The initial process is inappropriate platelet activation in small blood vessels. This leads to thrombi in these small vessels and the associated clinical features that can be associated with tiny zones of infarction. The widespread activation of platelets that occurs depletes the circulating pool of platelets, yielding thrombocytopenia, at which point a bleeding tendency can develop. As erythrocytes try to force their way through small blood vessels that are narrow by thrombi they become damaged and destroyed by haemolysis.
Some forms of TTP are due to defective function of the enzyme ADAMTS313, which is involved in the metabolism of vWF. The impairment is often autoimmune in origin. Other cases of TTP have intact ADAMTS313 and the pathogenesis remains obscure.