Formation of thrombi is discussed with special reference to the fibrin-matrix derived from fibrinogen and its related substances including α₂-plasmin inhibitor (α₂-PI), fibronectin (FN), plasminogen (Plg) and its activators.
An overview of fibrinogen to fibrin transition is presented by introducing recently elucidated structural data reported from our own as well as other laboratories on the evolution of fibrin strands. These include mechanisms and its physiological implications of fibrinopeptide releases by thrombin, polymerization of fibrin monomers and cross-linkings of fibrin to itself and other relevant plasma proteins. Since various types of amino acid substitution have recently been clarified in the fibrinopeptide A domain in relation to its impaired release from abnormal fibrinogens, our knowledges on the first step of fibrinogen to fibrin transition have substantially improved.
We verified the presence of a newly hypothesized polymerization site which functions abnormally in a congenital dysfibrinogenemia designated as “Fibrinogen Tokyo II”. Based on the data, we proposed a model depicting the polymerization sites in fibrin molecules (Matsuda, M et al.: J Clin Invest 72: 1034∼1041, 1983).
At the last step of fibrin formation, fibrin is stabilized by cross-link formation to itself and α₂-PI mediated by activated factor XIII (Sakata, Y and Aoki, N: J Clin Invest 65: 290∼297, 1980). α₂-PI may thus protect the α-chain of fibrin and prevents fibrin clots from resolution by plasmin at least at the initial stage of fibrin formation.
FN, a recently characterized multifunctional glycoprotein is also cross-linked to the α-chain of fibrin indifferently from α₂-PI (Tamaki, T and Aoki, N: J Biol Chem 258: 7168∼7174, 1983). This protein has also been shown to cross-link to collagen via a Gln residue as amine receptor (Mosher, DF: J Biol Chem 255: 1181∼1188, 1980). Since FN has two cross-linking sites, one each in its two possibly identical subunits, FN-bound fibrin could be associated with collagen exposed to blood upon endothelial damages. Thus fibrin clots composed of fibrin, α₂-PI and FN may be closely associated with the subendothelial layer at the nidus of thrombus formation.
Besides these proteins, Plg and its physiological activators are also shown to bind to fibrin via the lysine binding sites, thus enabling efficient Plg to plasmin conversion and clot lysis when fibrin clots are evacuated at the stage of convalescence.

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Recent studies on arachidonate metabolites demonstrated the roles of TXA₂ and PGI₂ on platelet aggregation and suggested some ways for the development of anti-aggregating drugs. Possible methods by drugs are as follows. (1) Psychotropic drugs, chlorpromazine and imipramine, suppress the aggregation in vitro through the inhibition of arachidonic acid release but platelets of patients treated with chlorpromazine for a long period were changed their aggregability susceptible. (2) Some non-steroidal anti-inflammatory drugs, aspirin and indomethacin, inhibit PGs and TXA₂ production in platelets to suppress the aggregation but also may inhibit PGI₂ production in endothelial cells. Then, the dose for the treatment is delicate. (3) Recently specific TX synthase inhibitors were developed. Some drugs showed strnog anti-aggregating activity in vitro only when the drug was in PRP together with an aortic ring which converts PGH₂ to PGI₂ though PGH₂ accumulated after the inhibition of TX synthase made platelets aggregate. TX synthase inhibitors may be usefull in vivo because platelets in plasma were always surrounded by endothelial cells and plasma may convert PGH₂ to PGD₂ which has anti-aggregating activity as well as PGI₂. (4) The combination of adenylate cyclase activator with c-AMP phosphodiesterase inhibitor potentiated accumulation of c-AMP in platelets and inhibited the aggregation in small dose of each drug. (5) Enhancement of endogeneous PGI₂ production may lead platelets to unsusceptible state. Some drugs which act as a co-factor of PG hydroperoxidase like tryptophan accelerated rat aortae to form PGI₂ endogenously in vitro and prevented the formation of the aggregate of platelets in the microcirculation of hamster cheek pouch in vivo.
As prostaglandins and c-AMP have general physiological roles in tissues and cells, it is difficult to find a drug acting only on platelet. It is suggested that the combination of drugs acting the different steps of the platelet metabolism may be effective for inhibition of the aggregation at the small doses and lower any adverse effect.

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Prostacyclin (PGI₂) is the most potent known endogenous inhibitor of platelet aggregation, and it is also capable of disaggregating platelet aggregates. The effects of thrombin inhibitors (heparin, MD-805 and FUT-175) and a fibrinolytic agent (urokinase) on the platelet aggregation and the disaggregatory property of PGI₂ were investigated. MD-805 (10 μM-1 mM) had no direct effect on the platelet aggregation induced by ADP, collagen and arachidonate. FUT-175 inhibited these aggregations at 1 μM or more, and reversed the aggregation at concentrations higher than 10 μM. Urokinase showed mild inhibition of platelet aggregation induced by ADP and collagen. Heparin or MD-805 did not enhance the disaggregation by PGI₂. However, these agents potentiated the disaggregatory activity of PGI₂ when added with additional calcium before the addition of ADP. Simultaneous addition of FUT-175 with PGI₂ resulted in additive disaggregation of platelet aggregates induced by ADP. Urokinase, when added before the addition of ADP, augmented the disaggregation by PGI₂, probably due to the inhibition of aggregation. From these results, it was assumed that platelet aggregates can be dispersed easily by PGI₂ if the intercellular and/or intracellular process during and after platelet aggregation is confined to some extent.

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The tissue plasminogen activator (T-PA) was highly purified from the culture fluid of a human melanoma cell line, and its thrombolytic property was compared with that of human urokinase (UK). In purified systems composed of fibrinogen or fibrin, plasminogen and α₂-antiplasmin as well as in whold plasma, T-PA digested fibrin without degrading fibrinogen significantly. On the other hand, UK digested fibrinogen mainly. In the circulating plasma system, where fibrinogen and fibrin (thrombus) existed, T-PA showed about 10 times more efficient fibrinolytic action than UK, without any systemic fibrinolytic activation. In the experimental pulmonary embolus, T-PA had a much higher thrombus-lysing efficiency (fibrinolytic to fibrinogenolytic ratio) than UK. In dog femoral vein thrombosis model, T-PA showed higher thrombus-lysing efficiency than UK; that is, T-PA digested fibrin (thrombus) without systemic activation of blood fibrinolysis, but UK digested fibrinogen (systemic fibrinolytic activation) first, followed by fibrinolysis. In the experiments on the circular dichroism, T-PA showed positive band near 230 mμ, which was not oberved in that of UK. Thus, T-PA has efficient thrombolytic properties than UK and thrombolytic therapy near future may be occupied by T-PA.

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We studied the functional parameters of platelets in thrombotic diseases. In postoperative states where massive hemostatic thrombi were being formed, platelet aggregation was decreased and platelet electrophoretic mobility (surface negative charge) was increased. In the acute stage of various thrombotic diseases, both platelet volume and adenine nucleotide contents were significantly smaller than normal platelets or those from the recovery stage of the diseases. Thromboxan A₂ (TXA₂) synthesizing activity of platelets was significantly decreased in the acute stage of myocardial infarction than in normal controls or in the recovery stage of the disease. Platelet electrophoretic mobility was increased in the patients with prostatic carcinoma under estrogen therapy.
Studies on density subpopulation of normal platelets revealed that dense platelets were larger in volume, smaller in surface negative charge, higher in aggregability and TXA₂ synthesizing activity than less dense platelets.
These findings suggested that those dense and larger platelet which were also higher in adenine nucleotide contents and TXA₂ synthesizing activity and less in surface negative charge made a hyperreactive group as a subpopulation and were selectively consumed into the formation of thrombus. This may result in the alteration of the population of circulating platelets.

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Hemorrhagic infarction following cerebral arterial occlusion has been discussed from the viewpoint of thrombolytic therapy for many years. It was demonstrated that on CT findings, hemorrhagic infarction may be classified into two groups, massive hemorrhages which are of grave prognostic sign, and petechial hemorrhages which indicate good prognoses. Massive hemorrhages are not observed even after recanalization of the occluded artery or migration of the thrombus, except for cases with some defects in hemostasis or coagulation system such as thrombocytopenia, hypofibrinogenemia, or marked decreases in vitamin K-dependent coagulation factors, due to chronic liver diseases.
There were no differences in recanalization rate of the occluded artery between cases in which high dosage of urokinase (700,000 IU) was administered in the early stages and cases administered moderate dosage (180,000 IU per day) for 5 days. However, it became apparent that the administration of high dosage of urokinase in the early stages shortened the time required for recanalization to occur. Also it became evident that in occlusion of the middle cerebral artery prognosis was better in cases with recanalization than in cases with non-recanalization. Though the prognosis was poor in both groups with occlusion of the internal carotid artery, the mortality rate was obviously higher in cases with non-recanalization than in cases with recanalization.
To estimate the effectiveness of thrombolytic treatment for the viewpoint of coagulation-fibrinolysis in vessel walls, changes of blood-coagulation-fibrinolysis were studied after the intravenous administration of 8 μg of DDAVP. Maked increases in factor VIII: C were observed in cases with non-recanalization. Whereas, levels of plasminogen activator were higher in most of the recanalized cases before and after the administration of DDAVP. These findings suggest the presence of hypercoagulable and hypofibrinolytic state in the vessel walls of cases with non-recanalization.
Intraarterial infusion of urokinase via a polyvinyl catheter proximal to the site of occlusion, and intravenous infusion of lysyl-plasminogen were performed simultaneously in 3 cases in order to resolve the thrombus as soon as possible and consequently, to prevent the extension of areas of fresh infarction and the perifocal edema in cases of cerebral arterial occlusion, refractory to urokinase therapy alone. Two cases with occlusion of middle cerebral artery recovered without any development of infarction on CT. One case with occlusion of internal carotid artery showed recanalization immediately after the concurrent administration of urokinase and lysyl-plasminogen.

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For the purpose of improving the thrombolytic therapy for cerebral thrombosis we are investigating oral application of Urokinase (UK) and clinical use of a new thrombolytic agent, Lysyl-plasminogen (Lys-PLg) prepared from human placenta. In this report recent results of these studies are presented.
On the basis of our previous confirmation that UK given by oral route increases fibrinolytic activity in the blood and, furthermore, it maintains the effect much longer than the intravenous administration, a double blind test of the oral UK was performed in collaboration with 27 institutions.
One hundred and one patients with cerebral thrombosis were involved in the test who received a daily dose of 120,000 units for 7 days, and the overall clinical improvement was estimated at the end of the treatment and at 3 weeks after it. In the moderately severe patients the oral UK-treated group showed a significantly higher improvement than the placebo group. no noticeable side effects were present.
Subsequently to the finding that Lys-PLg, given intravenously, caused prolonged fibrinolytic potentiation, as revealed by shortening of ELT for more than several hours, without subtsantial changes in the levels of α₂-AP, α₂-M and α₁-AT, a therapeutic trial of the agent was performed for 71 patients with cerebral thrombosis in a dose of 60mg every 24 hours for successive 7 days. Of them, 29 per cent at the end of the treatment and 52 per cent at 3 weeks after it showed remarkable and moderate grade of overall improvement.
The improvement was apparently higher in earlier thrombosis, within two weeks after stroke, and even in old thrombosis that more than one month had elapsed faire improvement was observed in some cases. Slight side effects were noted in seven cases, consisting of 1 fever, 1 skin eruption and 5 slight elevation of serum transaminases. Hemorrhagic infarction was not accompanied by this therapy.

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1) We have examined clinical results of urokinase (UK) therapy for arterial or venous thrombosis of the extremities. The intravenous drip infusion of UK (240.000∼960.000 U/day) was performed in 29 patients. Symptoms were improved in 67 per cent and angiographic dissolution of thrombus was observed in 80 per cent of patients with arterial thrombosis. In venous thrombosis, symptoms were improved in 93 per cent but angiographical improvement was observed only in 18 per cent. The final assesment for the effect of UK was obtained from both symptomatic and angiographic improvements. In both arterial and venous thrombosis, the final assesment was about 66 per cent on analog scale from 0% to 100%.
2) We have studied the effects of UK on concentration changes of α₂-antiplasmin (α₂-AP) and on fibrinogenolysis. Medium dose (480.000 U) or large dose (960.000 U) of UK was given to normal volunteers by intravenous drip infusion within six hours, and blood analysis was carried out. Total α₂-AP, which includes free α₂-AP-plasmin complex, decreased to 50 per cent of total α₂-AP at the end of UK infusion. Bβ 1-42, which is liberated from fibrinogen (fbg) at the very early stage of fibrinogenolysis, increased significantly with UK infusion and was 65 times as much as the normal range at the end of UK infusion. On the other hand, fibrinogen degradation products (FgDP) measured with enzyme immunoassay (EIA) increased only slightly, and moreover, plasma fibrinogen level did not decrease. In conclusion, we consider that 960.000 U of UK is enough to neutralyze α₂-AP and will cause only very early stage of fibrinogenolysis without advanced fibrinogenolysis which may result in bleeding tendency.
3) UK of 960.000 U was given to patients with thrombosis and same blood analysis was performed. In contrast to normal volunteers, FDP level increased significantly, which shows that fibrinolysis occurred in patients with thrombosis.

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Acute graft-versus-host disease (GVHD) was studied in 25 patients with acute leukemia who received allogeneic bone marrow from their HLA identical sibling donors. Acute GVHD developed in 10 of 21 patients who survived more than 30 days after transplantation. Compared with results reported by other centers, the incidence of moderate to severe acute GVHD was markedly low (4 of 21 patients) while the overall incidence of acute GVHD (48%) was similar to those reported. Skin biopsy was routinely performed for the histological diagnosis of GVHD-like skin lesions. Two patients lacked consistent or diagnostic lesions of the cutaneous GVHD in histological findings of the biopsied skin. It was difficult in some patients to determine the severity of acute GVHD according to the clinical grading criteria. This might be due to the discrepancy in scoring the severity of involved organs. Factors associated with acute GVHD were investigated. The age of the patient was found to influence the occurrence of acute GVHD. Compared with older patients, the incidence of acute GVHD decreased in patients younger than 20 years. Additional finding was that patients with acute GVHD were highly susceptible to interstitial pneumonia.

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Fifty-seven adult patients with relapsing acute non-lymphocytic leukemia (ANLL) who underwent reinduction chemotherapy during 1971∼1983 were analysed with special referance to comparative effectiveness of two treatment shedules.
Twenty-seven patients received reinduction chemotherapy after the first relapse with regimen A in which administration of DCMP, ACMP or BH-AC·DMP was continued until the reduction of leukemic cells to a certain target level was achieved. Twenty-five patients were evaluable (Group A). The remaining thirty patients were treated with regimen B (repeated 4 consecutive day therapy of DCMP or AVCP) after their first relapse. Twenty-six patients were evaluable (Group B).
Complete remission (CR) rate was 16/25 (64%) in Group A, whereas it was 3/26 (12%) in Group B. Thus CR rate in Group A was significantly superior to that in Group B (p<0.01). The CR rate of Group A patients was close to the figure attained by the previousely untreated patients (73%). Fifty percent remission duration and survival time from diagnosis in Group A were 363 and 560 days, while those were 90 and 169 days in Group B, respectively. Significant difference (p<0.01) was observed in median duration of survival between the two groups.
These observations indicate that regimen A is as effective for the reinduction of relapsing ANLL as for the first remission induction.

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Casuses of failures in remission induction in adult acute leukemia were analyzed. Thirty-four patients who were initially treated and failed to enter a complete remission were classified according to a criterion proposed by Preisler. Sixteen patients failed to attain marrow hypocellularity and in 11 patients an early regrowth of leukemia cells occurred after a short period of hypoplasia. Two patients expired due to a lack of the recovery of normal bone marrow cells. Two patients expired during the marrow hypoplasia. Three patients expired before enough time had passed to evaluate the antileukemic effect of the drugs administered.
These results suggested that the major cause of induction failures in our center was leukemic cell resistance to the drugs employed. In fact, rate of the induction failure of ANLL could be reduced after doses of antileukemic drugs were increased, accompanied with an improvement of the supportive care. Rate of the induction failure of ALL, however, could not be reduced inspite of various induction regimens.

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The causes of death in 125 patients with severe hematologic disorders, admitted to the Second Department of Internal Medicine of Kumamoto University Medical School during the period from 1973 to 1981, were analyzed with the following results.
1) Two major causes of death in patients with severe hematologic disorders were bleeding (43.4%) and infection (36.8%).
2) Infection (49.2%) and bleeding (38.0%) were two major causes of death in acute leukemia, while tumor death was the most frequent cause of death in malignant lymphoma and chronic myeloid leukemia in blast crisis.
3) Postmortem examinations showed that the most common etiologic agents of infection were fungi, including candida, aspergillus, mucor and cryptococcus.
Forty-six percent of the patients with acute leukemia had fungal infection. Particularly, mucormycosis was frequent (14.5%) in acute leukemia patients and its fatality rate was 89%.

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Anemia is often an outstanding feature of chronic myelocytic leukemia (CML). Decrease in the number of marrow erythroblasts due to the myeloid overgrowth has been regarded to be a major cause of the anemia in CML.
Circulating red cell volume was measured by ⁵¹Cr-tagged autologous red cells in 19 cases of CML with hemoglobin less than 12 g/100 ml. Normal or increased red cell volume was calculated in 8 cases (42%). Inverse relationship, i.e., an increase in red cell volume and decrease in hemoglobin with an increase in spleen volume, was pointed out. On the other hand, plasma volume correlated positively with splenic volume and negatively with hemoglobin.
These results suggeted a dilution of circulating peripheral blood due to an increase in red cell volume, plasma volume and red cell mass in the spleen with an enlargement of the spleen.
Multiple factors other than low hemoglobin concentration should be considered in evaluating the anemia in CML.

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A method was described for normal human peripherial B-lymphocyte colony formation in vitro. After a day of preincubation with 30 μg of phytohemagglutinin-P (PHA-P), irradiated T lymphocyte, and non-T cell population, these cells were cultured in methylcellulose gel. Colonies with more than 50 cells were counted under a dissecting microscope.
As a result, a linear relationship between the number of seeded cells and the growth colonies was seen in methylcellulose gel. 570±333 colonies per 5×10⁵ seeded cells were detected at 4 days of culture. Cells in colonies had surface immunoglobulin demonstrated by using FITC-labeled anti human F (ab)₂ rabbit serum under a fluorescent microscope and characteristic and differentiated to plasma cells or lymphocytes in Giemsa stain, but no E rosetteforming ability.
The patients with rheumatoid arthritis had significantly fewer B colonies than normal subjects.

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A 65-year-old man with CML treated with busulfan for three years was admitted to our hospital in February, 1981 because of marked basophilia (22.5%). Predominance of mature basophils and presence of Ph¹ chromosome led the diagnosis of Ph¹ positive CML in the accelerated phase. As basophils decreased markedly after radiation to the spleen, he was discharged in April, 1981.
He was readmitted in July, 1981 complaining of the increasing tumor on the head. The WBC was 60,200/mm³ with 30.5% basophils, RBC 298×10⁴/mm³ and Platelet 19.6×10⁴/mm³. Peripheral basophils increased to levels as high as 90% and marked basophilia was persistent. Immature basophils were occasionally predominant. Chromosome analysis demonstrated double Ph¹ and aneuploidy. A diagnosis of basophilic (blastic) crisis of CML was made.
In September, 1981, another tumor due to a infiltrate of immature basophils developed in the right axillary region.
Histamine levels were extremely high aut “Hyperhistaminic syndromes” did not occur.
The patient did not respond to chemotherapy and died of pneumonia on October 28, 1981. Basophilic crisis of CML associated with tumor of basophils has not been reported.

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A case of macroglobulinemia Waldenström (MW) associated with prostatic cancer is reported.
A 77-year-old man was found to have prostatic cancer and IgM paraprotein on health screening, which were improved by the Honvan therapy with gradual decreases of serum acid phosphatase and IgM. He was admitted to our hospital with complaints of a sudden increase of IgM paraprotein, right axillary lymphadenopathy and hepatosplenomegaly occurring after interruption of the Honvan therapy because of hepatic damage.
Pathological findings of lymph node were characterized by scattered proliferation of immunoblasts, plasmacytoid lymphocytes and plasma cells, and paracortical histiocytosis. Immunological examinations revealed monoclonal proliferation of B cells with surface IgM and cytoplasmic IgM. Serum IgM was rapidly increased up to 12 g/dl after discontinuance of the VP (vincristine plus prednisolone) therapy because of severe hepatic damage. He died of acute pneumonia in spite of the treatment with ACNU and cyclophosphamide.
This patient was considered to have MW, which became manifest after interruption of the therapy against prostatic cancer. It was suggested that the immune response to prostic cancer would be related to the development of MW because pathological findings of resected lymph node were mainly those of reactive changes.

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A 70-years old woman with lumbago, pathological fractures, hypergammaglobulinemia and high serum level of IgA was diagnosed as multiple myeloma of IgA-K type.
The myeloma protein in the serum of patient showed double precipitin lines on immunoelectrophoresis when assessed with commercial anti-human IgA antisera as well as a homemade anti-IgA that was prepared by immunization with IgA₁ myeloma protein into rabbit and subsequently absorbed with L chains. One of the double precipitin lines (major band) was defined to be due to myeloma protein of IgA₂ subclass by double immunodiffusion test and by molecular weight determination of its heavy chain.
Allotype of the myeloma protein was characterized as IgA₂m(2) by the fact that the protein had disulfide bonds between heavy and light chains.
It was determined that the myeloma protein in the patient's serum was mainly of trimeric IgA.
The other minor component of the double precipitin lines was considered to be normal residue of IgA₁ of monomer and polymer type.

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A case of helper T cell lymphoma of diffuse type arising from so-called T-zone lymphoma with polycythemia and eosinophil infiltration is reported.
A 22-year-old man born in Yokohama was admitted with complaints of generalized lymphadenopathy.
At first, the pathological diagnosis of resected lymph nodes was considered to be a reactive lymphadenitis based on the findings of follicle remnants with germinal center and proliferation of medium-sized cells, numerous post-capillary venules, eosinophil infiltration in the paracortex.
However, because the pathological picture has undoubtedly changed to malignant lymphoma of diffuse and medium-sized cell type after 7 months, first lesion might be retrospectively thought to have been Lennert's T-zone lymphoma.
Furthermore T-zone lymphoma was suggested to arise from helper T cell because this case was terminally identified as helper T cell malignancy (OKT 4⁺) by analysis with monoclonal antibodies (OKT series) at the time of the exact diagnosis of malignant lymphoma.
Besides the co-existence of polycythemia and eosinophilia with eosinophil infiltration suggested the character of the functioning tumor.

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Three cases of adult type Gaucher's disease in two Japanese families were described. All cases were clinically characterized by splenomegaly and hypersplenism. Bone lesions were found in one case. Importance of measurement of β-glucosidase activity in a granulocyte-rich leukocyte fraction in the diagnosis of Gaucher's disease and its carrier was stressed. Gaucher cells were positive for Fcr and C₃b receptors, and Ia-like antigens. They also reacted positively with monoclonal antibodies, OKIal and OKM1. These findings, together with their cytochemical characteristics, clearly indicated their origin from bone marrow mononuclear phagocyte system.
A huge intrasplenic mass consisting of conglomerates of Gaucher cells of various maturity observed in one splenectomized case might suggest their ability of local proliferation.
Fifty eight cases of Gaucher's disease in Jananese reported during 1970∼81 were reviewed, and relative predominance of infantile type was confirmed.

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Two males with primary acquired sideroblastic anemia terminated in blastic transformation are reported. Hematological studies disclosed bicytopenia in one patient and pancytopenia in the other, and an appearance of a few blast cells, low rate of ringed sideroblasts, and abnormal karyotypes of mitotic cells in the bone marrow. Morphological findings showed an appearance of nucleated red cells, pseudo-Pelger nuclear anomaly and giant platelets in the peripheral blood, and hypermegakaryopoiesis with micromega-karyocytes and maturation arrest of erythroid and myeloid series in the bone marrow. Neither androgen nor pyridoxin was beneficial, so repeated blood transfusions were required through the clinical course. Marked proliferation of blast cells was noted 12 months or 24 months later (M2 and M5), and the combination chemotherapy was done, but failed to induce remission. They died of infection and leukemic proliferation. Autopsy of both cases revealed leukemic infiltration and hemosiderosis in multiple organs.

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Adult T-cell leukemia-lymphoma (ATL) has been characterized as a T cell neoplasm. The pathogenesis has been attributed to the C-type retro-virus named as ATL-virus. The association of ATL with monoclonal gammopathy is very rare. Yet the etiological significance of M-component in the T-lymphocytic proliferation remains still in controversial.
We now report two patients with ATL which were found three and seven years after the discovery of a monoclonal gammopathy respectively. The antibodies for the ATL-associated antigen were positive in their sera. These results suggest that; 1) these patients had been previously infected by ATL-virus and 2) a monoclonal gammopathy found in these patients was a part of the result of ATL-virus infection which led the malfunction of the immune surveillance system in these patients.
Further studies are warranted to disclose which factor play an important role to make such patients overt ATL.

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