British Journal of Haematologg, 1986,64,419-424

Annotation
POST-TRANSFUSION PURPURA

In 1959, van Loghem et al described a 51-year-old woman, Zw, who developed severe
thrombocytopenia and purpura 7 d after elective myomectomy, did not respond to repeated
blood transfusions and recovered spontaneouslyafter about 3 weeks. Her serum contained a
strong antibody which enabled the definition of the 6rst platelet-specific antigen Zwa.
However, the patient's thrombocytopenia was not attributed to platelet alloimmunization,
and it was Shulman and associates (Shulman & Jordan, 1982) who 6rst established their
causal relationshipand coined the term post-transfusion purpura (PTP).New immunological
data and therapeutic achievements warrant a review of this rare, but serious iatrogenic
complication of transfusion therapy.

Definition and incidence

TRe syndrome of PTP, characterized by a sudden onset of thrombocytopenic purpura
approximately 1 week after transfusion of blood containing platelet material, is rare. Until
1980 approximately 30 cases had been published mostly as anecdotal reports (Mueller-
Eckhardt et al, 1980). The latest review by Shulman & Jordan (1982) compiled 34 well-
documented patients and five others that were not fully substantiated serologically. Since
then a considerable number of additional cases have been mentioned in the literature now
comprising a total of about 150 patients (Abramson et al, 1985; Aster, 1984: Berney et al,
1985;Boizard & Wautier, 1984; von dem Borne & van der Plas-van Dalen, 1985; Bross et al,
1979; Dunstan&Rosse, 1985: Gludetal, 1983;Hamblinetal, 1985; Keimowitzetd, 1986;
K i a n i et al, 1983; Lau et al, 1980; Le Row et al, 1981: Lillicrap et al, 1986; Mueller-
Eckhardt et al, 1986; Pegels et al, 1981; Phadke & Isbister, 1980; Rank et al, 1980; Slichter.
1982: Taaning et al, 1985; Vogelsang et al, 1986; Weinberg & Linker, 1984). Only four
larger series have so far been studied by the groups of Aster, von dem Borne, Shulman and
ourselves. The exact incidence of PTP is not known.

Clinicalfeatures
Eighty-five out of 89 patients (where sufficient information was available)were women, four
weremalesaged 51,52,53 (seeShulman&Jordan,1982)and 73 (Taaningetal, 1985).The
mean age of women was 56.6 years (range 2 1-80 years, N = 68). There is a preponderance
in the sixth and seventh decade. With regard to racial prevalence, most patients were white.
At least one black (Dunstan & Rosse, 1985), but no oriental patient, has been reported.
Correspondence: Professor C. Mueller-Eckhardt, Institute of Clinical Immunology and Blood Trans-
fusion, Justus-Liebig-University,LanghanssQ. 7,P6300 Giessen. P.R.G.
419
420 Annotation
Practically all patients had been pre-exposed to platelet antigens by pregnancies and/or
blood transfusion. Of the 62 women for whom information on previous pregnancies is
available, 58 had been pregnant. Three of the four nonpregnant women had previously
received blood transfusions, one had had an operation, but did not know of having been
transfused (case2, Mueller-Eckhardtet d,1986).Likewise three out of four male patients had
been transfused,one was not (Taaninget d,1985) and he had an exceptionallylong time lag
between transfusions and onset of purpura (24 d) (see below).
Without exception, the thrombocytopenia developed after blood transfusions consisting
either of whole blood or of packed red cells. One patient (Cimo& Aster, 1972) received only
plasma, but this was obtained by expressing the supernatant from whole blood after storage
for 2 weeks, thus containing soluble platelet antigensafter decay of cells. Indicationsfor blood
transfusion were variable, most often because of operations or acute haemorrhage. One of
our patients (no. 10) had autoimmune, another drug-dependent immune haemolytic
anaemia (no. 11, Mueller-Eckhardt et al, 1986).
The first bleeding symptoms usually occurred 5-10 d after the blood transfusions: shorter
or longer intervals were rare. One of our patients (no. 1, Mueller-Eckhardt et d,1986)
showed purpura on day 2. Haemorrhagic symptoms were usually quite severe, but
subclinical cases have been reported (Kmaniet d,1983; Soulier et d,1979). Haematuria
and melaena were frequent. The platelet count was usually quite low with a nadir below
10 x 109/l.Megakaryocyteswere regularly present in normal or increased numbers, but also
failure of megakaryocyte maturation was noted (Soulier et d,1979; Svejgaard et d,1967;
Vaughan-Neil et d,1975). In untreated cases, the thrombocytopenic state lasted between 1
and 4 weeks, sometimes as long as 60 (case 1, Mueller-Eckhardt et d,1986) or even 120 d
(Soulier et d,1979).

Diflerentid diagnosis
The occurrence of an unprecedented thrombocytopenic episode in a woman over 40 years of
age following approximately 1 week after a blood tranfusion is indicative of PTP. However, in
our experience PTP was suspected merely on clinical grounds in only three out of 1 3 cases
(Mueller-Eckhardtet d,1986). A frequent misdiagnosiswas heparin-induced thrombocyto-
penia supposedly because these patients had received heparin prophylactically after
operations. Other conditions such as disseminated intravascular coagulation, drug-
dependent immune thrombocytopenia,toxic thrombocytopeniaand thrombotic thrombocy-
topenic purpura must be ruled out, but this was not always possible (Lillicrap et al, 1986).

Treatment and prognosis

Almost all patients had received prednisone, but its efflcacy has not been adequately
evaluated. In one case, a relapse occurred after tapering of prednisone followed by a second,
complete response upon reinstitution (Weinberg& Linker, 1984).Platelet transfusions, even
with Zw" negative platelets, were also ineffective and often accompanied by severe adverse
reactions. Exchange transfusions with whole blood or plasma have been Med in at least 20
 Annotation 42 1
patients. While it has been reported to be effective in most instances, recurrence of
thrombocytopenia may occur requiriig repeated exchanges (Dunstan & Rosse, 1985; Lau et
al, 1980;Mueller-Eckhardtet al, 1986;Shulman & Jordan, 1982).Exchange transfusion was
unsuccessful in at least four cases (Berney et d,1985; Erichson et d,1978; Hamblin et d,
1985; Mueller-Eckhardt et d, 1986). Recently, highdose immunoglobulin has been
advocated for PTP (Mueller-Eckhardtet ul, 1983),and of the eight cases so far treated (Becker
et al, 1985; Berney et al, 1985: Glud et d,1983; Hamblin et ul, 1985) seven have responded
favourably including two patients who showed no response to plasmapheresis (Berney et d,
1985;Hambli et d,1985).Thus, highdose IgG is probably the treatment of choice for PTP.
The prognosis of PTP is undeterminable. Of the 71 patients for whom clinical data were
available, at least five died from cerebral haemorrhage within the first 10 d (Boizard &
Wautier, 1984; Gerstner et al, 1979; Gockerman & Shulman, 1973; Shulman & Jordan,
1982; Vogelsang et al, 1986). Since fatal haemorrhage usually occurs early in the course of
PTP, immediate treatment is mandatory.

Pathophysiology and platelet immunology

In nearly all cases in which appropriate serological tests have been done antibodies against
the platelet-specific antigen Zw" (=PIN) were detected. Shulman &Jordan (1982) in their
survey of the literature noted 34 out of 39 cases to be associated with anti-Zw". Von dem
Borne and associates (von dem Borne & van der Plas-Van Dalen, 1985; Pegels et d,1981)
found antibodies in all of their 19 cases. Kunicki & Aster (1983) state that in 43 of their 56
cases (77%)in which antibody was detected specificity for the Zw" (Pl") antigen was present.
Twelve out of 13 of our cases had this specificity (Mueller-Eckhardtet al, 1986). Two cases of
PTP due to antibodies against the allelic determinant, Zwb (Taaning et ul, 1985), one case
associated with antibodies against Lek" (Boizard & Wautier, 1984) and another against Bak"
(Keimowitzet al, 1986) have recently been documented. It is likely that the specificity of the
latter two antibodies is identical (von dem Borne & van der Plas-van Dalen. 1986; Keimowitz
et al, 1986).In a number of other cases the specificity of the antibodies has not been definable.
Since most of the sera of PTP patients are heavily contaminated with HLA antibodies,
serological antibody dissection is a difficult task. Nevertheless, there is as yet no proof that
HLA antibodies by themselves have any role in PTP.
The pathogenetic mechanism by which destruction of autologous platelets is brought
about by an alloantibody directed against antigens of the transfused platelets is as yet
obscure. Morrison & Mollison (1966) have suggested that a second antibody, arising with
anti-Zwa,crossreacts with Zwa-negativeplatelets to cause thrombocytopenia. This hypothe-
sis has not yet been substantiated. Shulman and associates (see Shulman & Jordan, 1982)
have promoted the idea that the antibody stimulated by transfused ZWa antigen combines
with that antigen to form soluble immune complexeswhich then destroy autologous platelets
by an 'innocent bystander' mechanism. We favour a third mechanism for which evidence
has recently come from observationsin a very similar condition in the red blood cell system,
i.e. delayed haemolytic transfusion reactions. We have shown (Salama & Mueller-Eckhardt,
1984, 1985) that in these patients alloantibodies with limited specificity can be formed
42 2 Annotation
against transfused antigens which not only bind to allogeneic, but also to autologous red
cells. Upon binding they activate complement and may cause the transitory destruction of
allogeneic as well as autologous RBC reflected in the delayed haemolytic episode. We have
postulated (Salama & Mueller-Eckhardt, 1984) that in PTP initial Zw" antibodies may be
produced in the early anamnestic phase that combine with autologous platelets (pseudo-anti-
Zwa)and elicit transitory complement activation. Indeed thii notion is supported by recent
data of von dem Borne & van der Plas-van Dalen (1985) who found anti-Zwa antibodies in all
three ether eluates prepared from platelets of PTP patients between days 9 and 2 1.

Irnrnunogenetic risk factors

Reznikoff-Etievantetd(l981,1983)6rst haveshownthatHLA-B8 and, evenmore, DR3 are
strongly associated with an immune response to ZWa in mothers giving birth to children with
neonatal alloimmune thrombocytopenia. Since most PTP patients are women with Zw"
antibodies and pregnancies in their past history,these HLA determinants may constitute risk
factors for PTP. Indeed, five out of six of our DR-typed PTP patients were DR3 positive
(Mueller-Eckhardtet d,1986). More recently, de Waal et d (1986) found DR3 in 11out of 12
and DRw52 in all cases studied. Thus, there is no doubt that ZWa negative, HLA-DR3 and,
possibly, DRw52 positive women with previous pregnancies are at risk to develop PTP. This
does not, however, seem to be the case for Zwb-assocfated PTP: neither patient had DR3
(Taaning et d , 1985).

ACKNOWLEDGMENT

These studies were supported by the Deutsche Forschungsgemeinschaft (Mu 277/9-5).

Znstitute of Clinical Zmmunologg and Blood Transfusion, C. MUELLER-ECKHARDT
just us-Liebig-Universi tg,
Giessen. F.R.G.

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