American Journal of Hematology 56:183–186 (1997)

Severe Thrombocytopenia Suggesting Immunological

Mechanisms in Two Cases of Vivax Malaria
Sayuri Yamaguchi,1 Tatsumi Kubota,1 Takahiro Yamagishi,1 Kiyoshi Okamoto,1
Tomoyuki Izumi,1 Masashi Takada,1 Shigeyuki Kanou,2 Mamoru Suzuki2, Jun Tsuchiya,3
and Takuji Naruse4
1
Department of Internal Medicine, Fukaya Red Cross Hospital, Saitama, Japan
2
Department of Parasitology, Gunma University School of Medicine, Tokyo, Japan
3
Gunma University School of Health Sciences, Tokyo, Japan
4
Department of Third Internal Medicine, Gunma University School of Medicine, Tokyo, Japan

Case 1: A 27-year-old woman, referred to our hospital because of relapsing fever after
travel to Thailand, was given a diagnosis of vivax malaria. Clinical investigation revealed
thrombocytopenia, elevated platelet-associated IgG (PAIgG), and negative antibody
against Plasmodium vivax antigen. After antimalarial treatment, the levels of both the
platelets and PAIgG returned to normal. Case 2: A 28-year-old Sri Lankan man was
admitted to our hospital with a complaint of fever. The patient had thrombocytopenia,
elevated PAIgG, and positive antibody against Plasmodium vivax antigen. He contracted
malaria in Sri Lanka about 6 months prior to this admission. After treatment, the platelet
count and PAIgG level returned to normal. In these two cases, high levels of PAIgG may
have been involved in the development of the thrombocytopenia. In the first patient, in
particular, the thrombocytopenia was thought to be induced by some immunological
mechanism prior to the detection of antimaralial antibodies in serum. Am. J. Hematol.
56:183–186, 1997. © 1997 Wiley-Liss, Inc.

Key words: vivax malaria; platelet-associated IgG (PAIgG); thrombocytopenia; antima-

larial antibody

INTRODUCTION a 40°C fever, which vanished the next day. On the third
The number of malaria patients in Japan has been in- day, the fever occurred again, and the patient was admit-
creasing recently, because more travelers are going ted to our hospital. Her physical examination was unre-
abroad to destinations such as Southeast Asia, South markable except for the presence of fever. Laboratory
America, and Africa, and more foreigners are entering investigations were performed: white blood cell count
Japan from countries where the incidence of malaria is 56.0 × 109/l, with 38% neutrophils, 52% lymphocytes,
high [1]. Thrombocytopenia is a common findings in 6% monocytes, and 4% atypical lymphocytes; hemoglo-
both Plasmodium (P.) vivax and P. falciparum malaria bin 11.5 g/dl and platelet count 22 × 109/l. Blood chem-
[2,3], but the mechanism of thrombocytopenia in malaria istries disclosed elevated LDH (307 IU/l (normal 60–22
remains unknown. We report here two cases with malaria IU/l)), total bilirubin 1.2 mg/dl, direct bilirubin 0.2 mg/
vivax who showed thrombocytopenia suggesting an im- dl, CRP 16.35 mg/ml, haptoglobin <10 mg/100 ml,
munological mechanism and increased level of platelet- Coombs test (direct, indirect) negative, complement 37.3
associated IgG (PAIgG). CH50U/ml and immune complexes (C1q) <1.5 mg/ml.
Blood coagulation test revealed no abnormality for dis-
seminated intravascular coagulation (DIC). The PAIgG
CASE REPORTS

Case 1 *Correspondence to: Dr. Sayuri Motomura, Department of Hematol-

ogy, Tokyo Women’s Medical College, 8-1 Kawada-cho, Shinjyuku-
A 27-year-old Japanese woman was admitted to our ku, Tokyo, Japan.
hospital because of a fever after an 11-day trip to Thai-
land. Ten days after she returned to Japan, she developed Received for publication 4 April 1997; Accepted 11 June 1997
© 1997 Wiley-Liss, Inc.
184 Case Report: Yamaguchi et al.

Fig. 1. Trophozite (a), shiz-

ont (b), and gametocytes (c)
of P. vivax in case 1 (Wight-
Giemsa stain, ×1,000).

level was elevated to 308 ng/107 cells (normal 9.0–25.0 were performed: white blood cell count 36.0 × 109/l, with
ng/107 cells). The bone marrow aspiration disclosed nor- 44% neutrophils, 34% lymphocytes, 16% monocytes, 1%
mocellular bone marrow with normal numbers of mega- eosinophiles, and 5% atypical lymphocytes; hemoglobin
karyocytes. Ultrasonography of the abdomen revealed 10.8 g/dl and platelet count 53 × 109/l, LDH 334 IU/l,
mild splenomegaly. Peripheral blood smear revealed en- total bilirubin 1.6 mg/dl, direct bilirubin 0.4 mg/dl, CRP
larged red blood cells (RBC) including the gametocytes, 16.33 mg/ml, haptoglobin 39 mg/100 ml, Coombs test
shizont and trophozoite of Plasmodium vivax in 0.6% of (direct, indirect) negative, complement 41.5 CH50U/ml,
the RBC (Fig. 1). Antibody titers against P. vivax and P. and immune complexes (C1q) <1.5 mg/ml. The blood
falciparum were negative, although after 3 days those coagulation test result was normal, and the PAIgG level
against P. vivax were found to be positive at 1:4 by was 431.7 ng/107 cells. The bone marrow contained nor-
indirect fluorescent antibody test [4,5]. The patient was mal numbers of cells and megakaryocytes. Ultrasonog-
treated with sulfadoxine (25 mg)-pyrimethamine (500 raphy of the abdomen revealed mild splenomegaly. Pe-
mg) (Fansidar) 3 tablets, followed by primaquine at 15 ripheral blood smear revealed enlarged RBC including P.
mg per day for 14 days (Fig. 2A). On the fourth day of vivax in 2% of the RBC. Antibody titers against P. vivas
treatment, the fever vanished and P. vivax was not seen and P. falciparum were shown at 1:256 and 1:64, respec-
in the blood smear. The thrombocytopenia and increase tively. The patient received chloroquine 150 mg per day
of PAIgG were no longer present by the eighth and for 3 days, followed by primaquine at 15 mg per day for
twelfth day, respectively. 14 days (Fig. 2B). The fever and P. vivax in blood smear
vanished on the third day. The thrombocytopenia was no
Case 2 longer present on the seventh day, and the PAIgG level
was decreased to 111.5 ng/107 cells on the seventh day.
A 28-year-old Sri Lankan man was admitted to our
This case was considered to be a recurrence of the ma-
hospital because of a fever. He had come to Japan 4 years
laria contracted in Sri Lanka.
earlier, and had gone to Sri Lanka 8 month prior to this
admission; he was infected with malaria during that trip
to Sri Lanka. He had a 39°C fever in January, February, DISCUSSION
and March for 3 to 7 days each time. He did not seek
treatment at the time, because the fever was subsided Thrombocytopenia is a common pathological feature
within one week. The patient had a 39°C intermittent of malaria [2,3]. It is reported that 22 of 26 (85%) pa-
fever (3–5 days) again in April, at which time he was tients with falciparum malaria and 30 of 39 (72%) pa-
admitted. His physical examination was normal except tients with vivax malaria had depressed platelet counts
for mild icterus and fever. Laboratory investigations below 150 × 109/l [6]. The mechanism of thrombocyto-
 Case Report: Immune Thrombocytopenia in Vivax Malaria 185
firmed that specific IgG bind directly to malaria antigen
on platelets through the Fab terminus, and that the non-
specific binding of IgG to platelet and immune com-
plexes binding to Fc receptor of platelets are unlikely to
be responsible for the thrombocytopenia in malaria.
CD4+ T-cells are also considered to be associated with
the thrombocytopenia of a mouse malaria model [14].
In our two patients, laboratory investigations indicated
no evidence of DIC, the numbers of megakaryocyte in
their bone marrow were within normal range, and only
mild splenomegaly was observed by ultrasonography. No
phagocytosis of platelets was observed in the blood
smear, the lymphocyte numbers were not increased, and
immune complexes (C1q) were within normal range. The
PAIgG levels were increased and showed a close inverse
relationship with the thrombocytopenia. The PAIgG in-
crease may be based on an increase in total platelet IgG,
which reflects the a-granule IgG content of platelets, or
platelet surface IgG, which reflect greater binding of im-
munoglobulin [15] such as antiplatelet antibody, immune
complexes, non-specific IgG, or antimalarial antibody.
Although there is no data about platelet surface IgG in
present study, antiplatelet IgG is not a likely factor, be-
cause the PAIgG decreased without immunosuppressive
therapy such as steroid hormone. Immune complexes and
non-specific IgG are not likely because the patients im-
mune complex levels were normal, and because of the
above-described data of Kelton et al. [13]. Thus, antima-
larial antibody is the most likely causal factor, because
malaria antigen is present on the platelets [9]. The de-
tailed mechanisms of the thrombocytopenia in our pa-
Fig. 2. Clinical course of case 1 (A) and case 2 (B). tients are unclear, but immunological mechanisms are
suspected.
Furthermore, in Case 1, before the antimalarial anti-
penia in acute malaria remains unknown. It was sug- body became positve in her serum, the PAIgG level in-
gested that DIC was responsible for thrombocytopenia creased and severe thrombocytopenia occurred. It is re-
[7], but it was later shown that most patients with malaria ported that antimalarial antibodies are first detected a few
do not have DIC [8]. A direct interaction between plas- days after infection of the blood, and the antibody levels
modium and platelets has also been suggested, because rise quickly to a plateau and are then maintained in serum
P. vivax has been demonstrated by electron microscopy for a long period of time [4]. Thus, it is likely that anti-
to exist inside the platelet of patients with vivax malaria malarial antibody is not detected in serum because of its
[9]. The phagocytosis of platelets has also been reported binding to platelets. The present finding that the throm-
in patients infected with malaria [10]. bocytopenia and PAIgG increase occurred before the de-
Immune mechanisms are considered to underlie the tection of antimalarial antibody is of note for the eluci-
thrombocytopenia seen in malaria patients. Immune dation of thrombocytopenia in malaria infection.
complexes that are present in the circulation of malaria-
infected patients may play a role in the peripheral de-
struction of platelets as well as RBC [11,12]. Kelton et al. CONCLUSION
[13] reported that thrombocytopenia was present in 17 of
28 malaria patients, and the PAIgG level was increased We report here two cases of vivax malaria in which
in 16 cases, and they also demonstrated that the PAIgG thrombocytopenia and an increase of PAIgG were
level and platelet count returned to normal as the para- closely associated and present before the detection of
sites were cleared from the circulation. They also con- antimalarial antibody.
186 Case Report: Yamaguchi et al.
REFERENCES thrombocytopenia in malignant tertian malaria. Br Med J 2:515,
1973.
1. Takeuchi T: Imported parasitic disease-recent epidemiology and prog- 9. Fajardo LF, Tallent C: Malarial parasites within human platelets.
ress in the chemotherapy. Jpn J Clin Med 40:2824, 1992. JAMA 229:1205, 1974.
2. Looareesuwan S, Davis JG, Allen DL, Lee SH, Bunnag D, White NJ: 10. Jaff MS, Mckenna D, Mccann SR: Platelet phagocytosis: A probable
Thrombocytopenia in malaria. Southeast Asian J Trop Med Public mechanism of thrombocytopenia in Plasmodium falciparum infection.
Health 23:44, 1992. J Clin Pathol 38:1318, 1985.
3. World Health Organization. Malaria Action Programme: Severe and 11. Contreras C, June CH, Perrin LH, Lambert PH: Immunopathological
complicated malaria. Trans R Soc Trop Med Hyg 80(Suppl 1):1, 1986. aspects of Plasmodium berhei infection in five strains of mice. Clin
4. Voller A, Draper CC: Immunodiagnosis and seroepidermiology of Exp Immunol 42:403, 1980.
malaria. Br Med Bull 38:173, 1982. 12. Perrin LH, Mackey LJ, Miescher PA: The hematology of malaria in
5. Kanou S, Waki S, Igarashi I, Nakazawa S, Masuda G, Suzuki M: man. Semin Hematol 19:70, 1982.
Retrospective malaria diagnosis by indirect fluorescent antibody titra- 13. Kelton JG, Keystone J, Moore J, Denomme G: Immune-mediated
tion on Japanese patients. Jpn J Parasitol 39:475, 1990. thrombocytopenia of malaria. J Clin Invest 71:832, 1983.
6. Horstman RD, Dietrich M, Bienzle U, Rasche H: Malaria-induced 14. Grau GE, Piguet PF, Gretener D, Vesin C, Lambert PH: Immunopa-
thrombocytopenia. Blut 42:157, 1981. thology of thrombocytopenia in experimental malaria. Immunology
7. Dennis LH, Eichelberger JW, Inman MM, Conrad ME: Depletion of 65:501, 1988.
coagulation factors in drug-resistant Plasmodium falciparum malaria. 15. George JN: Platelet immunoglobulin G: Its significance for the evalu-
Blood 29:713, 1967. ation of thrombocytopenia and for understanding the origin for a-
8. Shudowitzs RB, Karz J, Lurie A, Levin J, Metz J: Mechanisms of granule proteins. Blood 76:859, 1990.