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Keywords:

  • idiopathic thrombocytopenic purpura;
  • bleeding;
  • autoimmune pathogenesis;
  • platelet-associated antibodies;
  • intravenous immunoglobulin therapy

Today's idiopathic thrombocytopenic purpura

  1. Top of page
  2. Today's idiopathic thrombocytopenic purpura
  3. Historical attempts to differentiate bleeding signs
  4. Comment
  5. History of the pathogenesis
  6. History of management of itp
  7. Comment
  8. Recent research in itp: opinion vs evidence-based data
  9. REFERENCES

Today idiopathic thrombocytopenic purpura (ITP) is recognized as a bleeding disorder that occurs either as an acute post-infectious, self-limited condition preferentially in children or as a recurrent or chronic disorder mostly in adults. Individuals present with bruising, petechiae and/or mucosal bleeding (epistaxis, haematuria, rarely central nervous system haemorrhagia). Pathophysiologically, the clinical signs of ITP are caused by severe thrombocytopenic bleeding, which is the consequence of a premature platelet destruction. The severity of disease reflects the balance between platelet production by megakaryocytes and the accelerated clearance of sensitized (by antibodies) platelets, mainly in the spleen. Although known for more than 250 years as a distinct form of purpura, many aspects of this disorder are not well understood.

Historical attempts to differentiate bleeding signs

  1. Top of page
  2. Today's idiopathic thrombocytopenic purpura
  3. Historical attempts to differentiate bleeding signs
  4. Comment
  5. History of the pathogenesis
  6. History of management of itp
  7. Comment
  8. Recent research in itp: opinion vs evidence-based data
  9. REFERENCES

Since the time of Hippocrates, multiple cutaneous bleeding signs have been described as purpura. The Latin word purpur (from Greek porphyra) signifies the precious purple dye, secreted by the purple snail, used as a status symbol during antiquity and the Middle Ages. Without knowledge of the different blood components and functions of course, no differentiation of bleeding signs was possible. In 1557, Amatus Lusitanus mentioned a condition ‘Morbus pulicaris absque febre’ (without fever). Lusitanus was born in Portugal, studied medicine at the University of Salamanca and had to flee from one country to another because of religious persecution. In his work ‘Curationum medicinalum’(Fig 1), he describes ‘a boy with dark macules, resembling flea bites, had no fever and for several days had bloody discharges, eventually recovering’. Lusitanus further speculated ‘whether the rash was due to nervous anxiety or an exudation of detrimental humors’. What Lusitanus described could have been thrombocytopenic purpura. There is of course no proof for it.

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Figure 1. Curationum medicinalum (1557): Amatus Lusitanus (1557) describing ‘a boy with dark macules, resembling flea bites’ what he terms ‘Morbus Pulicaris Absque Febre’ (Jones & Tocantins, 1933).

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In the early seventeenth century, Riverius (Lazarus de la Rivière) attempted to distinguish purpura from ‘pestilential fever or from a vitious quality of the blood or humors joined with malignity’. In his ‘Praxis medica’, he described ‘the spots arisen from the over thinness of the blood … does sprout forth of the capillary veins into the skin … where being retained, it looseth its own colour, and becomes either blewish or black, or light red, and causes great variety of spots …’ (Riverius, 1658).

In Jena, Hornung (1734) subdivided purpura into simplex, febrile and scorbutica, and 1 year later Paul Werlhof (Fig 2), poet, composer, linguist and physician, described the disorder under the name of ‘Morbus Maculosus Haemorrhagicus’ (Werlhof, 1735). Werlhof was a highly respected physician of his time. He studied in Helmstadt, Germany, practised in Peine and later became physician to the King George II of England, at the same time elector of Hannover. Werlhof died in Hannover in 1767.

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Figure 2. Portrait: P.G. Werlhof (1699–1767) (from: ‘Medical Scripts’, Complete Edition, Wichmann 1775/76) (with acknowledgement to Professor G. Gaedicke, Berlin, Gaedicke, 1990).

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In his book ‘De Variolis et Anthracibus’ (Werlhof, 1735) (Fig 3), he described in a footnote a 16-year-old girl with cutaneous and mucosal bleeding which occurred after an infectious disease and recovered with Elixirium acidum halleri (citric acid). The name of the elixir refers to Albrecht von Haller (1708–1777), famous Swiss physician, botanist and poet, who was professor at the University of Göttingen from 1736 to 1753, where he also contacted Werlhof. The term M. maculosus reappeared in the dissertation of Willan as ‘M. maculosus Werlhofii’ in 1801. Willan was acquainted with a variety of different purpuras, among them the purpura haemorrhagica later described by Henoch (1882) as skin bleeding together with the presence of pain, swelling of the joints and intestinal symptoms.

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Figure 3. Cover of the first edition ‘De Variolis et Anthracibus’ by Werlhof (1735) (with acknowledgement to Professor G. Gaedicke, Berlin, Gaedicke, 1990).

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Throughout the nineteenth century many reports on purpura and its varieties were published with little progress, until in 1873 Dohrn described a similar disorder in a neonate and his mother. Krauss (1883) and Denys (1887) stated that platelets were diminished during the height of the purpura and increased when the haemorrhages ceased. These findings were confirmed by Hayem in (1895) who was able to perform more accurate platelet counts. Later, Henoch (1899), at that time Professor of Paediatrics in Berlin, differentiated purpura simplex with bleeding signs of the skin only (today known as ‘dry purpura’) from purpura haemorrhagica with mucosal bleeding (today known as ‘wet purpura’).

Comment

  1. Top of page
  2. Today's idiopathic thrombocytopenic purpura
  3. Historical attempts to differentiate bleeding signs
  4. Comment
  5. History of the pathogenesis
  6. History of management of itp
  7. Comment
  8. Recent research in itp: opinion vs evidence-based data
  9. REFERENCES
  • • Historically, before the platelet and the platelet count were recognized, bleeding signs of ITP and its differentiation into ‘purpura simplex’, today known as ‘dry ITP’, and ‘purpura haemorrhagica’, today known as ‘wet ITP’, were noted.

  • • At present, the patient/child and his/her parents are burdened by and fixed to the thrombocyte number of the platelet count. Considering the decision of intervention by the physician, the platelet count should again become less relevant than bleeding signs. The patient's bleeding, not the platelet count, should be treated!

History of the pathogenesis

  1. Top of page
  2. Today's idiopathic thrombocytopenic purpura
  3. Historical attempts to differentiate bleeding signs
  4. Comment
  5. History of the pathogenesis
  6. History of management of itp
  7. Comment
  8. Recent research in itp: opinion vs evidence-based data
  9. REFERENCES

The pathophysiological role of the spleen in ITP remained unknown even after the first splenectomy in 1916 (see below). In 1938, Troland & Lee (1938) described a substance extracted from spleens of patients with chronic ITP and named it ‘thrombocytopen’, which produced transient thrombocytopenia when injected into rabbits. In St Louis, USA, Harrington et al (1951) observed a child with purpura born to a mother with chronic ITP, a condition already described by Dohrn 1873 (see above). The child's purpura resolved spontaneously within 3 weeks while the mother remained thrombocytopenic. Harrington argued that transfer of a humoral antiplatelet factor from the mother to her baby occurred. He then administered to himself and to nine volunteers with a normal platelet count, plasma from patients with chronic ITP (Fig 4). Eight of the recipients immediately developed transient thrombocytopenia and some of them purpura as well. One of the volunteers, in spite of an earlier splenectomy, also responded with thrombocytopenia, indicating a secondary role of the spleen.

image

Figure 4. Platelet counts of volunteers after infusion of plasma from patients with chronic ITP (Harrington, 1951).

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Harrington's historical experiment clearly suggested an antiplatelet factor in the plasma as the cause of ITP. Later, in Boston, Shulman et al (1965) showed that the causative factor in the plasma of patients with ITP is associated with the 7S IgG fraction and that this factor binds to autologous as well as homologous platelets. The measurement of platelet-associated IgG, first performed by Dixon et al (1975), supported the idea of an immunopathogenic component of ITP. Van Leeuwen et al (1982) provided the first evidence for autoantibodies in chronic ITP. They reported that 32 of 42 eluates from ITP platelets bind to normal but not to thrombasthenic (Glanzmann) platelets. As the latter platelets are deficient in glycoproteins GP IIb and IIIa, they postulated that ITP patients have autoantibodies to one of these glycoproteins. In 1987, two new assays were described simultaneously in the USA (McMillan et al, 1987) and in Germany (Kiefel et al, 1987) that can detect both platelet-associated and free plasmic autoantibodies, i.e. the immunobead assay and the monoclonal antibody-specific immobilization of platelets antigen (MAIPA). The estimated sensitivity of the assays is 49–66%, the specificity 78–92% (Warner et al, 1999).

Recently, new insights into the pathogenesis of ITP have provided evidence of dysregulation of the immune response. Qualitative changes of T-cell activation of natural killer cell populations as well as of different cytokines have been described (Semple et al, 1996) and disturbance of the Th0/Th1 ratio supports the underlying immune mechanism of ITP. Inherited polymorphisms within platelet membrane glycoprotein genes may alter their antigenicity, regulate their expression levels and modulate their functional expression (Forster et al, 2001). Thus, the pathophysiological findings of ITP also become a model for other immune-related disorders with similar autoimmune pathogenesis.

History of management of itp

  1. Top of page
  2. Today's idiopathic thrombocytopenic purpura
  3. Historical attempts to differentiate bleeding signs
  4. Comment
  5. History of the pathogenesis
  6. History of management of itp
  7. Comment
  8. Recent research in itp: opinion vs evidence-based data
  9. REFERENCES

In his posthumously printed ‘Opera Omnia’, Werlhof (1775) commented that phlebotomy for blood-letting in haemorrhagic disorders, the common treatment of his time, was inappropriate in this disease. Robert Willan, in his book ‘On Cutaneous Diseases' (Willan, 1808), prescribed for Morbus Maculosus Haemorrhagicus ‘moderate exercise in the open air, a generous diet, and the free use of wine’.

A hallmark in the treatment of adult ITP occurred in 1916 in Prague. The medical student Kaznelson hypothesized analogy with haemolytic anaemia that excessive destruction of the platelets occurs in the spleen (Kaznelson, 1916). He persuaded one of his tutors, Professor Schloffer, to perform a splenectomy on a woman with chronic ITP. Surgery was followed by a dramatic platelet increase from a preoperative count of 0·2 × 109/l up to 500 × 109/l and clearance of the purpura. Since then, splenectomy has become the mainstay of management in adult patients with refractory, severe ITP.

The increase of platelets by corticosteroids, adrenocorticotropic hormone (ACTH) or other immunosuppressive agents has been described since 1951. The time needed for the increase of platelets to occur and the side-effects associated with long-term treatment prevented them becoming the medication of first choice. The first controlled multicentre study, a randomized double-blind study on corticosteroids versus placebo for 21 d in children with newly diagnosed acute ITP was carried out by the Swiss Joerg Sartorius when he returned from Detroit, USA, to Basel in 1972. At that time, Detroit was a known centre for ITP in children under the leadership of W. W. Zuelzer (see Lusher & Zuelzer, 1966). Owing to the early death of Sartorius, the study was only published posthumously (Sartorius, 1984). The results showed a faster increase of the platelet count in the corticosteroid randomized children compared with those in the placebo arm (Fig 5). Side-effects of 21 d corticosteroid treatment were clearly evident. Forty days later, however, significant differences between the groups were no longer evident.

image

Figure 5. The first controlled multicentre study, a randomized double-blind study in newly diagnosed childhood ITP: corticosteroid versus placebo treatment during 21 d and follow-up (Sartorius, 1972, published posthumously in 1984, Sartorius, 1984).

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After 1980, the treatment of ITP became a model for a new biological and immuno-modulating approach when intravenous application of human IgG concentrate, produced from healthy blood donors, was available. The basis was the successful development of a safe human intravenous immunoglobulin (IVIg) product. Silvio Barandun and colleagues at the Institute for Clinical and Experimental Cancer Research of the University of Berne identified anticomplementary IgG aggregates as the main cause of the untoward side-effects of intravenously administered gammaglobulin in patients with hypogammaglobulinaemia (Barandun et al, 1962). The chance observation of acidification by pH 4 during IVIg production eliminated the anticomplementarity without impairing its function (Haessig, 1991a,b).

The key observation of the efficacy of IVIg in ITP was made at the University Children's Hospital in Berne, Switzerland in a 12-year-old boy with severe haemorrhagic chronic ITP who, as a result of long-term treatment with vincristine and steroids, became lymphocytopenic and, therefore, developed secondary hypogammaglobulinaemia. Considering the disturbed immune response and attempting to correct this child's secondary hypogammaglobulinaemia, the child received the new IVIg and showed a dramatic increase in the thrombocyte count within 24 h, which continued with the administration of an additional four doses of 0·4 g IVIg/kg body weight. Immediately following that observation, a pilot study in 12 consecutive children with acute or chronic ITP and without hypogammaglobulinaemia showed similar dramatic effects in response to IVIg (Fig 6) (Imbach et al, 1981). Consequently, a controlled randomized multicentre study comparing corticosteroid administration (same regimen as in the study by Sartorius, see above) confirmed the new treatment possibility (Imbach et al, 1985).

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Figure 6. (A) Patients with chronic or intermittent ITP. (B) Patients with acute ITP. Upward pointing arrows indicate Ig-SRK, 0·4 g/kg body weight/d; previous treatment Pred, prednisone; Cyclo, cyclophosphamide; VCR, vincristine, *serum IgG (mg/dl) before next infusion (Imbach et al, 1981).

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The mechanism of action of IVIg treatment still remains unclear but clearly is multifactorial. One early concept of mode of action proposed by Fehr et al (1982) was a blockade of Fc-receptors on the monocyte/macrophage system by the patient's red blood cells covered with specific ABO–, rh D-antibodies present in the transferred IVIg preparation. This theory was the basis of the Anti-D IgG treatment of ITP, first published by Salama et al (1984). The application of Anti-D IgG in ITP, however, is not without problems such as intravascular haemolysis (Gaines, 2000).

Comment

  1. Top of page
  2. Today's idiopathic thrombocytopenic purpura
  3. Historical attempts to differentiate bleeding signs
  4. Comment
  5. History of the pathogenesis
  6. History of management of itp
  7. Comment
  8. Recent research in itp: opinion vs evidence-based data
  9. REFERENCES
  • • The ‘I’ in ITP may signify idiopathic or immune thrombocytopenic purpura. Incomplete knowledge of the pathogenesis of the acute post-infectious form of ITP and recent work on the cross-reactive nature of antibodies in virus-associated ITP, e.g. varicella or HIV, as well as problems with the methods for detection of antibodies on platelets all speak for keeping the definition of ‘idiopathic’ rather than ‘immune’ thrombocytopenic purpura.

  • • The management of the bleeding disorder ITP is still controversial. The risk of life-threatening bleeding, although low, is a burden of psychosocial and behavioural discomfort to the patient and his/her environment, and influences the decision for intervention by the physician. A rapid resolution of bleeding signs and platelet increase is welcome, but at what economical price? There still remains the question: to treat or not to treat?

  • • Since 1916, splenectomy in ITP remains controversial, especially in children. Indeed, there is an immediate platelet increase after splenectomy lasting for months and years at a rate of over 70% of patients. Long-term follow-up after splenectomy, however, shows a quite high rate of reappearance of ITP (Fabris et al, 2001). The important adverse effect of splenectomy is the risk of fatal bacterial infections, particularly in children below 5 years of age (Schilling, 1995). The decision has to take into account the potential benefits versus the risks as spontaneous recovery from severe ITP has been observed many years after diagnosis (Tamary et al, 1994). Splenectomy therefore is exclusively indicated in patients with severe bleedings and refractoriness to treatment.

  • • The various mechanisms of action of IVIg led to the use of IVIg in numerous other immune-related disorders such as Kawasaki syndrome, post-transplantation hypogammaglobulinaemia, Guillain–Barré syndrome and other neurological disorders, Hashimoto thyreoiditis and others: ITP was just the can opener! Published papers related to the IVIg-ITP treatment have been quoted more than 3000 times since 1981. In 1982, 300 kg of IVIg was produced; in 1999, 18 tons of IVIg was used worldwide; now there is even shortage of good quality IVIg!

  • • The use of the biological, human product of IVIg is astonishing, owing to the parallel negative experiences of the medical community with plasma-derived proteins in the past. There is still a reluctance to believe in the safety of such human-derived proteins although modern virus reduction procedures fulfil high standards of virus safety (e.g. HIV, hepatitis C and others).

Recent research in itp: opinion vs evidence-based data

  1. Top of page
  2. Today's idiopathic thrombocytopenic purpura
  3. Historical attempts to differentiate bleeding signs
  4. Comment
  5. History of the pathogenesis
  6. History of management of itp
  7. Comment
  8. Recent research in itp: opinion vs evidence-based data
  9. REFERENCES

Recent recommendations for management of ITP are based on group opinion according to practical guidelines of the American Society of Haematology (George et al, 1996), but compliance with these guidelines seems to be poor.

A new approach is based on evidence assembled electronically in a co-operative prospective data register, through the Intercontinental Childhood ITP Study Group (http://www.unibas.ch/itpbasel). The aims are (a) to establish an international network for obtaining evidence-based data; (b) to perform prospective surveys; (c) to perform clinical and laboratory studies.

Currently, 216 physicians from 42 worldwide centres are working together. Within 3 years, 2073 children with newly diagnosed ITP have been correctly registered. The ITP registry I is a prospective world wide survey for investigation of the natural history of ITP. The results of the survey have confirmed some issues of childhood ITP (i.e. demographic data) and revealed unexpected findings (sex prevalence: 54·8% boys vs 45·2% girls, outcome: chronic ITP at 6 months was seen in 31% of children in equal numbers of girls and boys, etc.) (Kühne et al, 2001). The same group has started new studies (e.g. splenectomy registry, registry II on bleeding symptoms).

In this way, the knowledge of ITP will change step by step, from opinion-based to evidence-based discussion of destructive thrombocytopenia.

REFERENCES

  1. Top of page
  2. Today's idiopathic thrombocytopenic purpura
  3. Historical attempts to differentiate bleeding signs
  4. Comment
  5. History of the pathogenesis
  6. History of management of itp
  7. Comment
  8. Recent research in itp: opinion vs evidence-based data
  9. REFERENCES
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