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Retrospective Survey on the Outcome of 36 Diverse Cases of Anemia

Anemia is clinical common event. In this study,a retrospective study of 36 different types of anemias was place in proper interpretative review for their therapeutical outcome. By using comprehensive treatment regimen according to patients’ condition, 23 patients obtained cure or complete remission (CR), with the exception of refractory cancers and uremic anemia. Iron supplement was provided in 5 iron deficiency anemia. One megaloblastic anemia required the prescription of the supplement of vitamin B12 or folate deficiency. 2 aplastic anemia obtained complete remission with the integrated protocol of methyltestosterone,adenine,leucogen,and levamisol. Steroid hormone (e.g. prednisone) mixed traditional medicine were occasionally promising benefit in a nephrotic syndrome and renal insufficiency. Among 2 cases with duginduced immune hemolytic anemia (DIIHA), laboratory studies a patient's serum contained paracetamol -dependent antibody that in the presence of paracetamol, agglutinated in vitro with "O" red cells with or without complement. Drug antibody titer was 1:4 positive. The reactive mechanism was attributed to both immune complex type and drug-adsorption, whereas another herba origanum vulgareinduced hemolysis secondary to drug adsorption only. In addition, regarding anemia caused by malignant tumours, the molecular genetic regulation of retinoic acid in acute promyelocytic leukemia (APL) has been further illustrated (see figure in full text). Therefore,to strengthen the active prevention and/or early interceptive treatment of anemia is our care.


Introduction
Anemia is the common blood condition in clinical. Anemia define the condition in which there is a reduced number of circulating erythrocytes and a smaller than normal hematocrit or a reduced concentration of hemoglobin in peripheral blood. Many hormones,in addition to erythropoietin,participate in the regulation of erythropoiesis. Hormones that affect enzyme and protein synthesis also affect synthesis of hemoglobin and production of red cells. The characteristic anemia of hypothyroidism is normochromic-normocytic,mild to moderate anemia.
There are many types of anemia. Condition associated with the causes of anemia include: bone marrow and stem cell problems (e.g. aplastic anemia,thalassemia),iron-deficiency anemia(IDA),Vitamin deficiency anemia specifically vitamin B12 or folate. Anemia also linked to other chronic diseases,such as advanced kidney failure or cancer. One of the most remarkable reports is in the field of drug antibody-induced immune hemolytic anemia. This paper will attempt to place in a retrospective survey of 36 anemias outcome in my group.

Material and Methods
36 animas were included in the study during 1989-2019. All patients were in progressive when they were hospitalization. The sex ratio of male:female was 23:13 respectively. Among age distribution, it was ranging from 4 to 75 years. The clinical diagnosis in a broad variety of anemias included: Iron deficiency anemia(IDA) 1 case,gastric ulcer hemorrhage complicated with iron deficiency anemia 4 cases; megaloblastic anemia(MA) 1;aplastic anemia(AA) 2;Idiopathic thrombocytopenic purpura(ITP) complicated with severe anemia 1;Malarial anemia 1; Drug-induced immune hemolytic anemia (DIIHA) 2 [ 1 case following paracetamol-induced,another case following herbs Origanum vulgare(wild mint) -induced]; uremic anemia(UA) 2; 22 anemias caused by various tumors: hematologic malignancies(ALL 1,AML 3,APL 1, CML 2, CML with blast crisis 1, CLL 1,multiple myeloma 1);metastatic lymph node adenocarcinoma 1;myelodysplasia(MDS) 2;nasophyaryngeal carcinoma 2;gastric cancer 4;colon cancer 1;bladder cancer 1;and advanced liver cirrhosis complicated with gastric hemorrhage 1 case. The treatment regimen varied among different types of anemias. The criteria of complete remission (CR) and/or partial remission (PR) in cancers is according to the rules where physicians have in common with in clinics. Complete remission (CR): there was no tumor or tumor complete regressed in patients for at least 1 month; Partial remission (PR): the tumor decreased by more than 50% in patients for at least 1 month. Disease progression: the tumor increased by more than 25% in patients,or new lesions emerged. The efficacy was evaluated according to the survival time from the day when patients were at onset. The clinical data for 2 cases of DIIHA were previously described.

Results
Anemia treatment will depend on the different types of anemias. The remaining patients achieved 9 cases with complete remission or 14 cured through different regimen of integrated western and traditional medicine, with the exception of refractory cancers, uremic anemia and one patient with ITP and liver cirrhosis complicated with hemorrhage transferred to another hosiptal.
During the schedule of drug administration (see table 1), many preparation of oral iron are available in 5 patients with iron deficiency anemia (IDA) or IDA following gastric ulcer hemorrhage. A significant increase in hemoglobin can be gained by observing the response to iron therapy. One patient with megaloblastic anemia often required the supplement of vitamin B12 and folic acid,which produced an excellent response. Steroid hormones (e.g. prednisone) and especially traditional medicine produced complete remission in one nephrotic syndrome and renal insufficiency.

Sex
Age   ),and origanum vulgare(wild mint). After 4 days,an episode of 4 days of significant hemoglobinuria(soy urine) was noted. On September 2, 1985, he developed icteric skin and sclera,and his temperature reached to 38℃. His initial hemoglobin level was 50g/l. He was the suspect of "hepatitis" in a local country hospital,and subsequently as anemia cause,transferred to our hospital. He had no past history of tuberculosis. Upon physical evaluation: T 38.2℃, P 96/min,R 32/min,BP 120/60mmHg. Icteric skin,sclera and mucous membranes. There was no abnormal in his heart and lung. The liver edge could be palpable 1.5cm below the right costal margin and no spleenomegaly. Laboratory evaluation: Hb 51g/l,WBC 14.7 x109/l,leukocyte differential count:segmented neutrophils 81%,lymphocytes 16%,monocytes 2%,eosinophils 1%. Platelets 208 x 109/l. Urine samples were negative for proteins. Serum BUN 9.7mg/dl. The serum albumin (ALB) 3.56g/dl,and globulin(GLB) 3  There was no useful following various combination regimen of conventional western and traditional medicine. At that time,the patient occasionally passed out,and he catched a persistent fever over 39℃. After grinding and drink with rhinoceros horn solution daily,the processed plan was considered the combination of methyltestosterone(30mg/day),leucogen,vitamin B4(adenine) and Batil,and levamisole. Remission was obtained following 4 months treatment duration. An induction of breast tumours was unexpectively uncovered by the use of 6+ months of methyltestosterone treatment,and tumour was progressive regressed after stopping this drug for four months. The patient had a health child. He is a well survivor now. Case 4. On August 21, 1996, a 34-year-old woman was admitted to the hospital due to her nephrotic syndrome and renal insufficiency for 3 years. On admission,she was chief complaint of severe pallor,fatigue,and facial edema. At physical examination,she had a percussion of bilateral flank pain. Ascites +++. BP 120/80 mmHg. Urine analysis: protein 4+; sediment: 1-2 RBC/HP and 4-6 WBC/HP. Blood chemistry showed BUN 7.7 mmol/l(control:2.9-7.1 mmol/l). She was given penicillin G sodium and dexamethasone intravenously,with traditional medicine and adjuvant intramuscular testosterone. The drugs vitamin C and Ferrous sulfate tablets were also given orally. On August 29, 1996, proteinuria was declined to 1+. The traditional medicine and testosterone were continued to be taken later. On September 8 and October 24,1996 respectively, repeat urinalysis showed protein negative.Traditional medicine consisted of Codonopsis pilosula, astragalus membranaceus(30-60g), radices rehmanniae, angelica sinensis, ophiopogon japonicus, daizheshi(processed Haematite), lycium barbarum(wolfberry), poria cocos, polyporus umbellata, rhizoma anemarrhenae, orange peel. She died of severe renal failure,and she was a 8 years survivor.
Case 5. On June 27, 1997, a 75-year-old woman was the chief presentation of her anemia following melena,fatigue and progressive weakness one year ago. After careful inquiry,the patient suffered from metastatic nasopharynx cancer. She had a past history of stomach bleeding,which considered its metastatic origin. On admission,a thumb lymph node behind her right ear was palpable. CR was obtained through a main regimen of traditional medicine and small dosage of chemotherapy (cyclophosphamide and 5-Fu),and enlarged metastatic lymph node was progressive regression. The detail processed method mixed cyclophosphamide or 5-Fu solution into the decoction of traditional medicine, oral use, twice daily. Traditional medicine consisted of Prunella vulgaris, astragalus membranaceus, rehmannnia glutinosa, ophiopogon japonicus, lycium chinensis(wolfberry), red date, spatholobi caulis, scutellaria barbata d. don, oldenlandin diffusa roxb. She was a 4years survivor. Case 6. On December 26, 1997, a 35-year-old woman was admitted to the hospital because of her relapsed gastric cancer,with anemia and recurrent fever for one month duration. On admission, her temperature was 36.9℃ (in the morning) and 40.5℃ (at night), and blood pressure 100/70mmHg. Hemogram: Hb 95g/l, WBC 10.3 x109/l, platelets 263 x109/l. In March, 1996 she was undergoing surgery in a local country hospital due to her tarry stools. At post-operatively,a rodent ulcer(5 x4 x0.8cm) with harden margin was detected in lesser curvature of the stomach, accompanied with adjacent metastatic lymph nodes. NHL was diagnosed according to her stomach tissue specimens. She had a past history of tuberculosis. CR was obtained after small dosage of FMC (5-Fu, MMC, CYT) in conjunction with cinobufacini intravenously,oral daily demethylcantharidin and traditional medicine. As an outpatient,she had continued to traditional herbs Scutellaria barbata d. don. On June 4, 1998, she was consulted as an outpatient due to her fever reached to 38℃. After an injection of penicillin G and small doses of 5mg of dexamethasone,fever regressed to normal(T 36.2℃). On March 5, 2000, she had a fever 39℃, and she was at the third hospitalization. Chest X-ray disclosed her dual lung tuberculosis with bullous formation. Her OT test: positive (+). Gastroscope at that time showed a normal image. Her high fever declined to 36.2-36.8℃ by the combined use of ampicillin,intramuscular streptomycin 0.75g, bupleuri injection and additional herba houttuyniae(cordata) injection. On June 6, 2002, the patient was at fourth hospitalization due to an episode of her temperature ranging from 37.8℃ to 38℃. Treatment consisted of ampicillin 1g intramuscularly, bupleuri injection,with adjuvant subcutaneous BCG injection. The fever fell ranging from 36.2℃(morning) to 37.4℃(night). She was a long-term survivor for 6 years and died of severe tuberculosis (type IV). Case 7. On April 14,1999, a 50-year-old woman was admitted to hospital due to her chronic anemia and recurrent abdominal pain for more than half a year. In september,1998,the patient presented a unexplained dull pain in the epigastrium,accompanied with acid regurgitation and belching. No nausea and vomiting were noted. Physical examination revealed anemia. The was no obvious tenderness around the umbilicus. A 10x 8cm2 harden mass was palpable in the abdomen,with a unsmooth surface and an indistinct surrounding. Gastroscope showed an advanced gastric adenocarcinoma,complicated with hepatic metastasis. Treatment consisted of the combination regimen of daily 250mg 5-Fu and 1-3mg/day of homoharringtonine for 10 days, in conjunction with intravenous cinobufacine and oral demethylcantharidin. Afterwards, a combination chemotherapy was intermittent to be given according to patient condition. On May 18,1999,she obtained a short CR. She was continued to the prescription of traditional medicine,or 5-Fu solution mixed the decoction of traditional medicine. Case 8. On May 3,2000, a 19-year-old man was admitted to hospital because of dizziness and progressive fatigue for more than half a year,and a recent episode of epistaxis for 10 days. Physical data on admission disclosed anemia. The temperature was 38.5℃. Ear,throat and occular examination were normal. There were no obvious abnormality as to heart and both lungs. His heart rate was 105 beats per minute. There was no lymphadenopathy,hepatomegaly,or splenomegaly. He had a past history of hepatitis B. Laboratory data: on admission,blood findings were Hb 90g/l, decreased WBC, platelets 20 x109/l. Bone marrow showed a marked hypoplasia. Bone marrow differential count: 29.6% myeloid, of which band and segmented neutrophils accounting for 27.7%, 5.5% orthochromatic normoblasts, 38.8% lymphocytes,and 7.4% plasmacytes. An almost complete marrow depression was apparent. The diagnosis of aplastic anemia was made. Treatments consisted of a combination regimen of methyltestosterone, stanozol, levamisole and prednisone tablets,and adjuvant with traditional medicine. An additional use concluded intravenous phytohaemagglutinin for 1 week in order to accelerating the number recovery of CFU-S and initiating DNA synthesis of cells. After a 4 months of oral methyltestosterone, he was forced to discontinuing this drug due to his breat swelling and pain and suspected breast tumour. The patient was once receiving subcutaneous erythropoietin. On October 26,2000, complete remission in peripheral blood was obtained following the combination treatment for near 6 months. Becuse of without undergoing continuous treatment, on April 2002, the patient was transferred to another hematological hospital following the recurrence of aplastic anemia. After the follow up of 18 years, he is a survivor now. Case 9. On october 16,2003, a 31-year-old man was the chief of his pallor and fever for 15 days. On admission,physical examination showed a marked anemia and hepatomegaly. Persistent fever reached to 39℃. Chest X-ray showed small amount of hydrothorax. Liver CT scan demonstrated a 7.0 x 4.5 cm2 mass which was considered as secondary hepatic tumor. AFP was negative. Laboratory data: hemoglobin concentration(Hb) was 53g/l, white blood cells(WBC) count was 3.4 x109/l,leukocyte differential count in blood smear:20% promyelocytes. The platelet count was 2.4 x109/l. Bone marrow aspiration revealed normal cellularity. Bone marrow differential count showed 77% promyelocytes. The patient was diagnosed as acute promyelocyte leukemia(APL) complicated with secondary hepatoma. Treatment consisted of 80mg/day of retinoic acid(RA) and 1mg/day of homoharringtonine(H) intraveously for 5 days. His high fever was declined to normal following small dose of dexamethasone and traditional medicine. On November 20,2003, repeated bone marrow smear showed only 3.5% myeloid blast and promyelocytes. On the routine peripheral blood smear uncovered no immature myeloid cells. Hemogram:Hb 102-108g/l, WBC 7.7-5.0 x109/l, platelets 229 x109/l. CR was obtained after 1 month period of RA,chemotherapy and traditional medicine. On June 5,2005,he died of APL relapse(94% blasts and promyelocytes in peripheral blood and in bone marrow). The repeated liver scan found the complete regression of his liver tumor albeit the recurrence of his leukemia.

Discussion
In this study,a series of the long follow up of 30 different types of anemias were reported. Uptil now,about 130 drugs in DIIHA has been incriminated. Regarding drug-dependent antibody formation,the most accepted idea involves covalent binding of the drug to erythrocyte membrane,creating a neoantigen composed of membrane and drug. An antibody(usually IgG) can be created against the drug,which then binds to the drug-coated erythrocytes and is subsequently activate complement,and cause acute hemolysis. Drug-dependent antibody formation is most commonly caused by penicillin,peracillin,along with cefotetan and ceftriaxone(1-6). We reported 2 patients with penicillininduced DIIHA previously (Lin zhusan, Zhu yuejun, Zhang guangsheng,etal, 1984, data not shown). One 16-year-old boy was identified his penicillin antibody -dependent hemolysis,which was mediated by immune complex type and drug adsorption,and autoantibody multiple mechanisms. In immune complex type detection, the drug antibody titer reached to 1:512. Another 40-year-old woman with DIIHA was mediated by the drug-adsorption only. The penicillin antibody titer: 1:16. Two additional paracetamol -dependent and herbs wild mintinduced DIIHA were presented here.
As a novel retinoic acid(RA) to APL treatment,this specific APL harboring oncogenic pml/RARa fusion. This oncogenic receptor derivative pml/RARa fusion act as a constitutive repressor of RAR and retinoic acid signaling, inducing differentiation blockade at promyelocytic stage, whereas pharmacologic retinoic acid(ATRA or cis RA) can bind to oncogenic pml/RARa, then relieve the blockage of pml/RARA repression(also derepression), and subsequently oncogenic pml/RARa degradation via autophagy or UPS proteosome system, immature promyelocytes toward maturation. Finally,APL patients obtained complete remission(CR)(see the following figure)(9-18) Therefore,we cannot say that the drug retinoic acids stimulate(bind to) a pml/RARa oncogene. This model is first described in eukaryotes.