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The term 'purpura' is used to describe small cutaneous extravasations of blood. More extensive cutaneous bleeding, which is often associated with purpura, is called 'ecchymosis', or bruising. Purpura is caused by thrombocytopenia, platelet dysfunction, or a primary cutaneous or vascular disease that may produce or mimic purpuric lesions. The causes of thrombocytopenia are numerous but can be broadly classified into decreased platelet production, diminished platelet survival, or abnormal distribution of the peripheral platelet mass due to hypersplenism. A pathogenic classification of thrombocytopenia is summarized in Table 1. Very often, several causes may be operative in the same patient. Defective platelet production is readily detected by a bone marrow aspirate. It is also possible to identify associated bone marrow disorders such as a haematological neoplasm, secondary carcinoma, alcoholism, or megaloblastic anaemia. These various conditions causing a primary bone marrow defect in platelet production are discussed in detail elsewhere.
| A. Defective bone marrow production |
| 1. Megakaryocyte aplasia |
| 2. Dysthrombopoiesis (a) infiltration (b) metabolic |
| B. Diminished platelet survival |
| 1. Immune mediated |
| 2. Excess platelet consumption |
| 3. Structural platelet defects |
| C. Loss from the systemic circulation |
| 1. Splenomegaly |
| 2. Loss from the body-extracorporeal circulation |
Immune-mediated thrombocytopenia
Immune-mediated thrombocytopenia is one of the most commonly encountered haemostatic disorders. The different types are summarized in Table 2. In all these conditions thrombocytopenia is caused by circulating antibody binding to platelet-membrane surface antigen causing increased platelet destruction in the reticuloendothelial system, mainly in the spleen and liver. Antibody binding may also inhibit platelet function, particularly if this blocks the specific receptors of the platelet-activation pathway, usually glycoprotein (Gp)-Ib or the -IIb/IIIa complex.
| By autoimmunity |
| Autoimmune thrombocytopenia |
| Pseudothrombocytopenia |
| By alloimmunity |
| Neonatal alloimmune thrombocytopenia |
| Post-transfusion purpura |
| Refractoriness to platelet transfusion therapy |
| By drug-induced immune mechanisms |
| Drug-induced thrombocytopenia |
Autoimmune thrombocytopenia, or immune thrombocytopenia, usually presents without any obvious precipitating cause, and hence it is also referred to as 'idiopathic thrombocytopenic purpura', or ITP. In children, the disease is often preceded or accompanied by an acute viral infection and occurs equally between the sexes, whereas in adults it occurs more frequently in females and is rarely preceded by an infective illness.
The main objectives of the management of immune thrombocytopenia are to control the bleeding and, at the same time, determine whether the thrombocytopenia is secondary to a remedial cause.
Immune thrombocytopenia may present with a few purpuric spots or bruises, or much more acutely with extensive purpura and bleeding from the mucous membranes. The skin lesions are widespread, although they tend to be more marked over pressure areas or below the site of a venous tourniquet. Oral lesions present typically as a dark 'blood blister' that bursts and leaves a small, pale, ulcerated region. The major danger is bleeding into the brain. Apart from the haemorrhagic findings there are no other characteristic physical signs; splenomegaly is not usually found and if present suggests that the thrombocytopenia is secondary to another disorder.
Particularly in children, ITP is usually a short, self-limiting illness that lasts up to 1 to 2 weeks and then resolves. A similar pattern may be seen in adults. However, in later life the disorder may follow a much more chronic, relapsing course, when it is referred to as chronic ITP. Chronic ITP may follow an acute episode or may be characterized by relapsing bouts of purpura, with or without bleeding, which may last for many years.
The presenting platelet count is generally below 50×109/l and serious bleeding is unlikely unless the count is below 10×109/l. In acute ITP the platelets are larger than normal. Bone marrow aspirate shows increased numbers of megakaryocytes with immature cytoplasm, with evidence that they are producing platelets at an earlier stage of nuclear and cytoplasmic differentiation. Occasionally, normal or reduced numbers of megakaryocytes may be found. This is presumably because the antibody responsible for the thrombocytopenia is also recognizing an antigen expressed on the immature megakaryocyte surface. A bleeding-time test is not routinely done, although occasionally it may be significantly more prolonged than expected from the platelet count. Over the years several different tests have been developed to detect and quantitate the presence of platelet-associated immunoglobulin, but overall these tests have been disappointing and their significance remains uncertain.
In a typical case the diagnosis is straightforward. However, in adults an associated disorder or drug-induced thrombocytopenia (see below) must be excluded.
The main disorders to be excluded are systemic lupus erythematosus (SLE), other autoimmune diseases, and lymphoproliferative disorders. Immune thrombocytopenia occurs in approximately 10 per cent of patients with SLE, and in some cases a diagnosis of ITP may precede the development of SLE by several years. The primary antiphospholipid syndrome, diagnosed by a positive lupus anticoagulant test and/or raised anticardiolipin antibodies, may also be associated with an immune thrombocytopenia. About 5 to 8 per cent of patients with immune thrombocytopenia also have a positive direct Coombs' test, which in some cases may be associated with an autoimmune haemolytic anaemia. This is known as Evans' syndrome.
Maternal ITP in pregnancy must be distinguished from incidental thrombocytopenia of pregnancy. This occurs in approximately 5 per cent of healthy women, with mild to moderate thrombocytopenia (usually a platelet count between 80 and 120×109/l). These women and their infants all remain well and no specific precautions or further investigations are necessary. Thrombocytopenia occurs frequently with human immunodeficiency virus (HIV) infections, with approximately 10 per cent of patients having platelet counts of less than 100×109/l due to an immune mechanism at some time during their disease.
The treatment for immune thrombocytopenia depends on the degree of thrombocytopenia and the severity or risk of a major bleeding event. In the acute phase, with a platelet count of below 20×109/l, corticosteroids are still the mainstay of therapy. The results of several clinical trials have given rise to conflicting data. There would seem to be no difference between a high- or low-dosage regimen, and a dosage of between 0.25 to 0.5 mg/kg per day for 3 weeks in adults seems to be as effective as any higher dosage regimen. High doses of intravenous immunoglobulin (0.4 g/kg per day for 3 to 5 days) have also been shown to be effective. This response is usually transient and relapse usually occurs 10 to 20 days later. No superior response rates or efficacy have been demonstrated for the use of intravenous human gammaglobulin infusions, and because of the potential risks of viral transmission and high cost they should not be routinely used in the initial management of acute ITP. With a low-dose regimen of oral steroids approximately 60 to 70 per cent of patients achieve a response in their platelet count within 2 to 3 weeks, which in many adults may only be short term. In children, particularly for episodes following an acute viral illness, the acute phase is self-limiting and treatment is only required if the platelet count is dangerously low, or if there is bleeding.
Chronicity is defined as severe thrombocytopenia with platelet counts of less than 20 to 30 × 109/l for more than 6 months in adults and 12 months in children. For these patients splenectomy is the initial treatment of choice. A positive long-term response has been observed after splenectomy in 60 to 70 per cent of patients. There is a long-term risk after splenectomy of acute and chronic bacterial infections, particularly with pneumococcal and meningococcal organisms. As these infections may occasionally be fatal, patients should routinely be vaccinated against pneumococcal infections, preferably 2-3 weeks before splenectomy, and postoperatively they should receive long-term oral penicillin therapy. The 30 per cent or so of patients in whom splenectomy is ineffective pose a difficult long-term therapeutic problem. If the platelet count is above 40 to 50 × 109/l and the patient is asymptomatic, careful follow-up with no therapy is all that is required. Long-term, low-dose oral steroids may be necessary when spontaneous purpura or excessive bleeding occurs. If this is ineffective, or side-effects cause problems, a variety of secondary therapeutic options are available. These include long-term immunosuppression with cyclophosphamide or azathioprine, or the use of vincristine, vinblastine, vitamin C, anti-D infusions, and interferon-a therapy. The success rate with these agents is low.
Alloimmunization against platelet-specific antigens occurs extremely rarely in neonates and after blood transfusion. Most cases are caused by immunization to the platelet antigen PLA1, part of the Gp-IIb/IIIa complex. Between 5 and 10 days after transfusion of a platelet-containing product there is a sudden fall in the platelet count associated with severe bleeding. The patient's own platelets are negative for the antigen involved but are also destroyed by the alloantibody.
Neonatal alloimmune thrombocytopenia results when the mother develops an antibody against a specific antigen on the fetal platelets. These alloantibodies cross the placenta and destroy the fetal platelets, which can result in severe intracerebral haemorrhage, either during fetal life or at the time of delivery. Usually these cases are unsuspected and about 50 per cent occur during the first pregnancy.
Thrombocytopenia due to excessive platelet consumption
Excessive peripheral platelet consumption occurs in acute and chronic disseminated intravascular coagulation (DIC) or in the thrombotic microangiopathic syndromes, thrombotic thrombocytopenic purpura, and the haemolytic-uraemic syndrome.
The thrombotic microangiopathies are a range of clinical syndromes characterized by microangiopathic haemolytic anaemia, thrombocytopenia, microvascular thrombosis, and multiple organ dysfunction and failure. Thrombotic thrombocytopenic purpura (TTP) is a rare, multiple system disease that occurs in approximately one per million of the population per year. TTP typically presents with fever, non-immune intravascular haemolytic anaemia associated with fragmented red cells, consumptive thrombocytopenia, renal failure, and various neurological deficits. Widespread microvascular thromboses consist of platelet aggregates and fibrin in capillaries and precapillary arterioles, predominantly involving the kidney, pancreas, adrenal, brain, and heart. The TTP syndrome has been associated with SLE, other connective tissue disorders, pregnancy, and oral contraceptive use. Rarely, there seems to be a familial association. In approximately 10 per cent of patients, multiple, recurrent relapses over prolonged periods have also been reported. However, in the majority of cases there is no known causal event or associated disease process. TTP is found in both sexes of all ages, with a slight predominance in females and a peak incidence between 30 and 40 years of age. It appears that the pathogenesis is the lack of a von Willebrand factor (vWF)-cleaving protease that results in unusually large vWF multimers in the circulation.
The haemolytic-uraemic syndrome (HUS) is usually defined as the association of thrombocytopenia and haemolytic anaemia with renal dysfunction, although occasional non-renal manifestations may also occur. HUS is more likely to occur in young children after a recent viral or acute gastrointestinal infection. The typical histological microvascular lesions are precipitated by vascular endothelial injury, which can be induced by a variety of infections and in particular those associated with endotoxin or verotoxin production. Occasionally childhood gastroenteritis caused by a verotoxin-producing serotype of Escherichia coli or shigellae has been reported to cause epidemic clustering of cases.
This is suggested by the presence of a microangiopathic haemolytic anaemia, with fragmented red cells and thrombocytopenia, after excluding alternative diagnoses, particularly DIC. A clotting screen, including a thrombin time and fibrinogen level, is almost always within the normal range. There is often a mild increase in the reticulocyte count but the serum lactate dehydrogenase (LDH) level is often greatly elevated. Serial measurements of LDH along with haemoglobin levels and reticulocyte and platelet counts are the most valuable laboratory tests for assessing disease severity and response to therapy.
The mainstay of treatment for acute TTP is plasma infusion or exchange with fresh frozen plasma. Recent multicentre clinical trials have shown that plasma exchange with approximately 3 litres of fresh frozen plasma daily gives a response rate of approximately 80 per cent, compared to approximately 60 per cent with fresh frozen plasma infusions alone. Although not as effective as plasma exchange, plasma infusion alone may be effective in mild cases and may also be useful as regular prophylaxis in patients with relapsing TTP. The unusually large multimers of vWF can be removed by plasma exchange, and the vWF cleaving protease is a component of normal fresh frozen plasma.
Unfortunately, despite an initial response to plasma exchange, some patients have an incomplete resolution and a prompt relapse. For refractory cases, high-dose steroids, vincristine, splenectomy, antiplatelet agents, or immunosuppressive therapy with a variety of drugs such as cyclophosphamide or azathioprine have occasionally been reported to be successful. Cases unresponsive to fresh frozen plasma infusions may respond to cryosupernatant. Cryosupernatant has processing activity for the unusually large multimers of vWF, but it lacks any actual vWF. Platelet transfusions are contraindicated because infusion of platelet concentrates may exacerbate the process and cause rapidly fatal, widespread microvascular thrombosis.
Excessive loss of platelets from the systemic circulation
Normally, approximately one-third of the total circulating platelet mass is in the spleen. Splenomegaly from any cause, particularly if the spleen is more than 4 cm enlarged, is often accompanied by thrombocytopenia. The principal cause is intrasplenic pooling of platelets, but occasionally accelerated destruction may also occur.
Acquired qualitative platelet defects
Abnormalities in platelet function with a normal or raised platelet count causing purpura and episodes of bleeding have been reported in a large number of acquired disorders. Frequently the specific biochemical defect in platelet function causing the abnormality is poorly understood. The conditions in which qualitative platelet disorders are recognized are listed in Table 3.
| Uraemia | Dysproteinaemias |
| Myeloproliferative disorders | Amyloid |
| Essential thrombocythaemia | Acquired von Willebrand syndrome |
| Polycythaemia rubra vera | Acquired storage-pool disease |
| Chronic myeloid leukaemia | Liver disease |
| Myelofibrosis | Autoimmune platelet disorders |
| Acute leukaemia | Drugs |
| Myelodysplasia | Extracorporeal circulation |
Many qualitative platelet defects have been
recorded in renal failure, but the most
important determinant of uraemic bleeding is low
haematocrit, below 0.20, that frequently
accompanies long-standing renal failure. The
prolonged bleeding time in these patients is
corrected by blood transfusion or the
administration of recombinant erythropoietin to
correct the anaemia. In addition, platelets show
defective aggregation to
adrenaline, collagen, and ADP; ristocetin-induced
agglutination may also be impaired. An infusion
of
desmopressin (deamino-
The precise uraemic retention product responsible for these platelet functional defects has not been identified, although it is believed to be the so-called middle molecules with molecular weights of between 500 and 5000.
Platelet defects associated with bleeding episodes as well as thromboembolic complications have been recognized in association with all the myeloproliferative disorders. Unfortunately, laboratory evidence of platelet dysfunction does not always correlate with bleeding. The most consistent defect of platelet aggregation is an impaired response to adrenaline.
Any cause of a raised paraprotein concentration may lead to a quantitative platelet defect. Paraproteins may bind to the platelet membrane and interfere with the normal function of specific receptors on the membrane surface. As platelets possess Fc receptors it has been proposed that paraproteins may specifically bind to them, and that inhibition of other activation receptors is merely mechanical. There is a high frequency of bleeding in IgA multiple myeloma and Waldenström's macroglobulinaemia in particular. Acute bleeding episodes can be controlled by plasma exchange and chronic bleeding by specific chemotherapy to reduce the paraprotein level.
There are now several reports of von Willebrand's disease appearing in older people with no previous manifestations of a bleeding problem. The reported underlying mechanisms include an inhibitor, usually a paraprotein, against vWF, or accelerated clearance of that factor from the circulation by binding to abnormal lymphoid cells. Treatment of bleeding episodes with steroids, plasma exchange, and replacement with factor VIII concentrate containing significant quantities of vWF have been successful. Long-term immunosuppression and treatment of the primary underlying condition may lead to remission in the von Willebrand syndrome.
Deficiencies in both dense- and a-granule content, or a defect in their secretion, have been reported in several disorders as an acquired defect. These conditions include autoimmune disorders, particularly chronic idiopathic thrombocytopenia, DIC, TTP, chronic alcoholism, and various haematological malignancies. The depletion of platelet-granule contents has also been reported in patients with severe valvular disease, Dacron aortic grafts, and after cardiac-pulmonary bypass procedures.
Chronic liver disease is usually associated with excessive bleeding due to multiple deficiencies of blood coagulation factors, their inhibitors, and fibrinolysis. However, a variety of platelet functional abnormalities may significantly contribute to the increased bleeding tendency.
Many drugs have been shown to affect platelet function and these may occasionally precipitate bleeding. The most important are listed in OTM3, p.3629, Table 4 (and see also Further reading).
Non-thrombocytopenic vascular purpura
A variety of general medical conditions can result in widespread clinical purpura and must be distinguished from thrombocytopenia or platelet functional disorders. These include congenital or acquired primary disorders of blood vessels, connective tissue disorders, metabolic diseases, allergic diseases, or psychogenic bleeding disorders. The vascular defects that cause purpura are listed in Table 4.
| Simple easy bruising |
| Senile purpura |
| Hereditary haemorrhagic telangiectasia |
| Giant cavernous haemangioma |
| Hereditary connective tissue disorders |
| Ehlers-Danlos syndrome |
| Pseudoxanthoma elasticum |
| Osteogenesis imperfecta |
| Marfan's syndrome |
| Scurvy |
| Amyloid |
| Dysproteinaemias |
| Steroid therapy |
| Infections |
| Streptococcal |
| Viral |
| Allergic vasculitis |
| Psychogenic |
Purpuric lesions frequently occur in normal people, usually women. Single or multiple bruises appear spontaneously, mainly on the arms or legs, which rapidly resolve without any specific treatment. Those patients who consult physicians are usually exceedingly anxious or concerned for cosmetic reasons. No changes are found in the haemostatic screening tests and the patients should be reassured.
Senile purpura is often found in older people, usually on areas exposed to mild but recurrent trauma such as the backs of the hands, the forearms, and the face. The purpura is caused by atrophy of the subcutaneous tissue with progressive loss of collagen and elastin fibres in the skin, which leads to inadequate support of the subcutaneous blood vessels. Mild shearing forces lead to rupture, and subcutaneous extravasation and spread of blood. There are no abnormalities in the haemostatic screening tests, although the skin bleeding time may be prolonged. The lesions retain their dark colour, often for several weeks, and unfortunately there is no specific therapy.
This is a rare condition that is transmitted as an autosomal dominant trait. It presents with typical telangiectasiae that are found in the mucous membranes of the nose, lips, mouth, the whole of the gastrointestinal tract, urinary tract, vagina, and skin. The most common presentations are recurrent epistaxis or prolonged and progressive gastrointestinal bleeding from multiple sites, which lead to refractory chronic iron-deficiency anaemia. The standard coagulation screening tests are within normal limits. Repeated episodes of internal bleeding may have to be controlled by endoscopy or local cautery. Some patients respond to oral oestrogen therapy, which has been shown to convert columnar epithelium to stratified squamous epithelium.
There are several rare but readily recognized connective tissue disorders, including the Ehlers-Danlos syndrome, pseudoxanthoma elasticum, osteogenesis imperfecta, and Marfan's syndrome. All these can be present or be associated with recurrent purpura or skin bruising.
Severe scurvy, or vitamin C deficiency, typically presents with excessive bleeding from multiple sites including the gums, alimentary tract, joints, and brain. Perifollicular skin bleeding is also common. Although the bleeding time may be prolonged, the results of studies of platelet function are within normal limits. The diagnosis is confirmed by measuring leucocyte vitamin C concentrations and the bleeding rapidly responds to vitamin C supplements in the diet.
Primary and secondary amyloid can both cause skin purpura. Amyloid may be found infiltrating the small blood vessels and has also been shown to cause platelet functional abnormalities due to membrane coating by the amyloid fibrils.
Long-term administration of corticosteroids over several months causes atrophy of the collagen fibres that support the blood vessels in the skin. This causes widespread purpura and bruises, usually on the extensor surfaces on the hands, arms, and thighs. The purpura is similar in aetiology to the senile type. A similar distribution may also be seen in Cushing's syndrome.
Various allergic vasculitic purpuras are caused by inflammation and infiltration of the blood-vessel wall as an anaphylactic reaction to a variety of agents including chemicals, toxins, infections, and physical stimuli. Henoch-Schönlein purpura is probably the most common and involves the skin, joints, alimentary tract, kidneys, heart, and central nervous system. There is often a preceding upper respiratory tract infection caused by a b-haemolytic streptococcus producing a rising antistreptolysin-O titre. Epidemics may occur in young children, with a fever followed by a purpuric rash that is often raised to the touch and classically affects the fronts of the legs, thighs, and buttocks. In addition, the patient may develop acute arthritis, gastrointestinal pain, and nephritis associated with proteinuria. The disease is usually self-limiting.
Most of these patients have a disturbed or overanxious personality. Very often the diagnosis is only suspected after numerous investigations have been made with all the results being within the normal range, despite continuing worrying and sometimes bizarre bleeding symptoms.