Michael F. Murphy
University of Oxford and NHS Blood and Transplant and Department of Haematology, John Radcliffe Hospital, Oxford, UK
In 1959, van Loghem and colleagues described a 51-year-old woman who developed severe thrombocytopenia 7 days after elective surgery [1]. The thrombocytopenia did not respond to transfusion of fresh blood, but there was a spontaneous recovery after 3 weeks. The patient's serum contained a strong platelet alloantibody, which enabled the description of the first human platelet antigen (HPA) (Zw, see Chapter 5). However, the relationship of platelet alloimmunization to posttransfusion thrombocytopenia was not recognized until 2 years later when Shulman and colleagues studied a similar case, naming the antibody anti-PlA1 (later shown to be the same as anti-Zw), and coined the term posttransfusion purpura (PTP) [2].
Definition
PTP is an acute episode of severe thrombocytopenia occurring about a week after a blood transfusion. It usually affects HPA-1a-negative women who have previously been alloimmunized by pregnancy. The transfusion precipitating PTP causes a secondary immune response, boosting the HPA-1a antibodies, although the mechanism of destruction of the patient's own HPA-1a-negative platelets remains uncertain.
Incidence
PTP is considered to be a rare complication of transfusion. Over 200 cases had been reported in the literature till 1991 [3]. However, this may not reflect the true incidence of PTP, which is not known except through reporting to haemovigilance schemes. In the first 4 years of the Serious Hazards of Transfusion (SHOT) scheme, during which approximately 13 million blood components were transfused, 37 cases were reported, giving an approximate incidence of 1 case in 350 000 transfusions. In the following 10 years, after the introduction of universal leucocyte reduction of blood components in the UK, only 13 cases were reported to SHOT, giving an approximate incidence of 1 in 2 million blood components transfused [4].
The low incidence of PTP relative to the 2.5% of the population who are HPA-1a negative and at risk of the condition raises the question of individual susceptibility. As in neonatal alloimmune thrombocytopenia (NAIT), the antibody response to HPA-1a is strongly associated with a certain HLA class II type (HLA-DRB3*0101) (Chapter 5).
Clinical features
PTP typically occurs in middle-aged or elderly women (mean 57 years, range 21–80), although it has also been reported in a small number of males [5]. All patients, apart from rare exceptions, have had previous exposure to platelet antigens through pregnancy and/or transfusion. The interval between pregnancy and/or transfusion and PTP is variable, the shortest being 3 years and the longest 52 years. The initial maternal sensitization to platelet antigens during pregnancy in females subsequently developing PTP is rarely of sufficient degree to cause NAIT.
Blood components implicated in causing PTP are:
· whole blood;
· packed red cells; and
· red cell concentrates.
There are occasional case reports of PTP following the transfusion of plasma, presumably due to the presence of platelet particles expressing platelet antigens [5].
Severe thrombocytopenia and bleeding usually occur about 5–12 days after transfusion; shorter or longer intervals are rare. The onset is usually rapid, with the platelet count falling from normal to <10 × 109/L within 12–24 hours. Haemorrhage is very common and sometimes severe. There is typically widespread purpura and bleeding from mucous membranes and the gastrointestinal and urinary tracts. In many cases the precipitating transfusion has been associated with a febrile nonhaemolytic transfusion reaction, probably due to the presence of HLA antibodies stimulated by previous pregnancy and/or transfusion. Megakaryocytes are present in normal or increased numbers in the bone marrow and coagulation screening tests are normal in uncomplicated PTP. In untreated cases the thrombocytopenia usually lasts between 7 and 28 days although it occasionally persists for longer.
Differential diagnosis
The rapid onset of severe thrombocytopenia in a middle-aged or elderly woman should arouse suspicion of PTP and a history of recent blood transfusion should be sought. The differential diagnosis includes other causes of acute immune thrombocytopenia such as:
· autoimmune thrombocytopenia;
· drug-induced thrombocytopenia, e.g. heparin-induced thrombocytopenia (HIT) (see Chapter 30);
· nonimmune platelet consumption, e.g. disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP);
· a less likely possibility is passively transfused platelet-specific alloantibodies from an immunized blood donor when thrombocytopenia occurs within the first 48 hours after the transfusion [6, 7]; and
· pseudothrombocytopenia due to ethylenediamine tetra-acetic acid (EDTA)-dependent antibodies should be excluded in any patient with unexplained thrombocytopenia by examination of the blood film.
Laboratory investigations
A preliminary diagnosis of PTP on clinical grounds needs to be confirmed by the detection of platelet-specific alloantibodies. The majority (80–90%) of cases of PTP are associated with the development of HPA-1a antibodies in HPA-1a-negative patients [5, 8]. Antibodies against HPA-1b, HPA-3a, HPA-3b, HPA-4a, HPA-5a, HPA-5b, HPA-15b and Naka have been associated with PTP, and occasionally multiple antibodies are present, e.g. anti-HPA-1a, anti-HPA-2b and anti-HPA-3a were found in one case.
HLA antibodies are often present in patients with PTP. There is no evidence that they are involved in causing PTP but their presence complicates the detection of platelet-specific antibodies. Modern platelet serological techniques such as the monoclonal antibody immobilization of platelet antigens (MAIPA) assay are useful for resolving mixtures of antibodies in patients with PTP (Chapter 5).
Pathophysiology
The time course of events in PTP is shown in Figure 12.1. A blood transfusion triggers a rapid secondary antibody response against HPA-1a and there is acute thrombocytopenia about a week after the transfusion. It is difficult to understand why the patient's own HPA-1a-negative platelets are destroyed. There remains no generally accepted mechanism to explain this although a number of suggestions have been made as follows.
· Transfused HPA-1a-positive platelets release HPA-1a antigen, which is adsorbed on to the patient's HPA-1a-negative platelets, making them a target for anti-HPA-1a. Support for this hypothesis comes from observations such as the elution of anti-HPA-1a from HPA-1a-negative platelets in some cases of PTP and the demonstration of the adsorption of HPA-1a antigen on to HPA-1a-negative platelets after incubation with plasma from HPA-1a-positive stored blood [9].
· The released HPA-1a antigen forms immune complexes with anti-HPA-1a in the plasma and the immune complexes become bound to the patient's platelets, causing their destruction.
· The transfusion stimulates the production of platelet autoantibodies as well as anti-HPA-1a. Evidence in favour of this mechanism is the detection of positive reactions of some PTP patients' sera from the acute thrombocytopenic phase with autologous platelets.
· In the early phase of the secondary antibody response, anti-HPA-1a may be produced which has the ability to cross-react with autologous as well as allogeneic platelets.
Fig 12.1 A typical time course of posttransfusion purpura. Purpura and severe thrombocytopenia occurred 5–10 days after a blood transfusion. The figure indicates the secondary antibody response of anti-HPA-1a and the postulated transient appearance of free HPA-1a antigen in the plasma, which binds to HPA-1a-negative platelets, HPA-1a/anti-HPA-1a immune complexes, platelet autoantibodies or crossreacting HPA-1a antibodies.
Management
Immediate treatment is essential as the risk of fatal haemorrhage is greatest early in the course of PTP. In a review of 71 cases of PTP, five died within the first 10 days because of intracranial haemorrhage [5]. The main aim of treatment is to prevent severe haemorrhage by shortening the duration of severe thrombocytopenia.
No randomized controlled trials of treatment for PTP have been carried out. Comparison of various therapeutic measures is complicated because it may be difficult to differentiate a response to treatment from a spontaneous remission in individual cases.
High dose intravenous immunoglobulin (IVIgG) (2 g/kg given over 2 or 5 days) is the current treatment of choice, with responses in about 80% of cases [10]; there is often a rapid increase in the platelet count within 48–72 hours [11] (Figure 12.2). Steroids and plasma exchange were the preferred treatments before the availability of IVIgG and plasma exchange, in particular, appeared to be effective in some but not all cases [5].
Fig 12.2 Haematological course of a patient with posttransfusion purpura showing the onset of profound thrombocytopenia 6 days after a blood transfusion. Initial treatment with random platelet concentrates caused rigors and bronchospasm, and there was no platelet increment. There was no response to prednisolone (60 mg/day) or plasma exchange (2.5 L/day for 3 days), but there was a prompt remission following high-dose IVIgG (30 g/day for 3 days). Redrawn with permission from Berney et al. [11].
Platelet transfusions are usually ineffective in raising the platelet count but may be needed in large doses to control severe bleeding in the acute phase, particularly in patients who have recently undergone surgery before there has been a response to high dose IVIgG. There is no evidence that platelet concentrates from HPA-1a-negative platelets are more effective than those from random donors in the acute thrombocytopenic phase. There is no evidence to suggest that further transfusions in the acute phase prolong the duration or severity of thrombocytopenia.
Platelet transfusions have been reported to cause severe febrile and occasionally pulmonary reactions in patients with PTP; these were probably due to HLA antibodies reacting against leucocytes in non-leucocyte-reduced platelet concentrates.
Prevention of recurrence of PTP
Recurrence of PTP has been reported. However, it is unpredictable and has usually occurred following a delay of 3 years or more after the first episode. The patient should be issued with a card to indicate that he/she has previously had PTP and ‘special’ blood is required for future transfusions.
Future transfusion policy should be to use red cell and platelet concentrates from HPA-compatible donors or autologous transfusion. If these are not available, leucocyte-reduced blood components are considered to be safe. There have been occasional reports of recurrence of PTP with leucocyte-reduced red cell concentrates, but the implicated components would not have complied with current standards for leucocyte reduction.
Key points
1. Posttransfusion purpura (PTP) is characterized by an acute episode of severe thrombocytopenia occurring about a week after a transfusion.
2. The pathophysiology remains uncertain.
3. PTP typically occurs in HPA-1a-negative women who have been alloimmunized by pregnancy.
4. Haemorrhage is common and sometimes severe, although the thrombocytopenia resolves spontaneously within a few weeks.
5. High dose intravenous immunoglobulin (IVIgG) (2 g/kg given over 2 or 5 days) is the current treatment of choice to shorten the duration of thrombocytopenia, with responses in about 80% of cases.
6. Universal leucocyte reduction of blood components in the UK has resulted in a marked reduction in the number of reported cases.
References
1. Loghem JJ van, Dorfmeijer H, Hart M van der & Schreuder F. Serological and genetical studies on a platelet antigen (Zw). Vox Sanguinis 1959; 4: 161–169.
2. Shulman NR, Aster RH, Leitner A & Hiller MC. Immunoreactions involving platelets. V. Post-transfusion purpura due to a complement-fixing antibody against a genetically controlled platelet antigen. A proposed mechanism for thrombocytopenia and its relevance in ‘autoimmunity’. J Clin Invest 1961; 40: 1597–1620.
3. Shulman NR. Post-transfusion purpura: clinical features and the mechanism of platelet destruction. In: SJ Nance (ed.), Clinical and Basic Science Aspects of Immunohaematology. Arlington, VA: American Association of Blood Banks; 1991, pp. 137–154.
4. Serious Hazards of Transfusion (SHOT) Steering Group. The 2010 Annual SHOT Report. www.shotuk.org.
5. Mueller-Eckhardt C. Post-transfusion purpura. Br J Haematol 1986; 64: 419–424.
6. Ballem PJ, Buskard NA, Decary F & Doubroff P. Post-transfusion purpura due to secondary transfer of anti-PlA1 by blood transfusion. Br J Haematol 1987; 66: 113–114.
7. Solenthaler M, Krauss JK, Boehlen F, Koller R, Hug M & Lamlle B. Br J Haematol 1999; 6106: 258–259.
8. Kr von dem Borne AEG & van derPlas-van Dalen CM. Further observations on post-transfusion purpura. Br J Haematol 1985; 61: 374–375.
9. Kickler TS, Ness PM, Herman JH & Bell WR. Studies on the pathophysiology of post-transfusion purpura. Blood 1986; 68: 347–350.
10. Becker T, Panzer S, Maas D et al. High-dose intravenous immunoglobulin for post-transfusion purpura. Br J Haematol 1985; 61: 149–155.
11. Berney SI, Metcalfe P, Wathen NC & Waters AH. Post-transfusion purpura responding to high-dose intravenous IgG: further observations on pathogenesis. Br J Haematol 1985; 61: 627–632.
Further reading
Waters AH. Post-transfusion purpura. Blood Rev 1989; 3: 83–87.