Direct Hematopoietic Injury

The most common cause of BM hypoplasia is iatrogenic; transient BM failure routinely follows treatment with cytotoxic chemotherapeutic drugs or irradiation. Certain chemical or physical agents directly injure proliferating and quiescent hematopoietic cells. However, patients with community-acquired AA rarely have a history of exposure to such physicochemical agents. Even benzene, which can act as a particularly inefficient cytotoxic chemical, is an infrequent cause of AA in developed countries. Drugs are associated with acquired AA, and in some instances, they can directly cause BM dam age. Compared with chemotherapeutic agents, which are delivered in high doses, relatively low total quantities of ingested drug apparently cause idiosyncratic hematologic reactions. In addition to their direct toxic effects, chemicals and viruses may induce complex and not well understood immune reactions leading to BM failure.

Immune-Mediated Bone Marrow Failure

 In the 1970s, Mathé and colleagues observed an unexpected improvement of pancytopenia due to AA after failed BM transplantation. They speculated that the immunosuppressive conditioning regimen, intended to allow engraftment of the donor BM, might instead have promoted the recovery of host BM function. The effectiveness of diverse treatments that reduce lymphocyte number or block T-cell function, and the superior results obtained when agents are combined strongly suggest that such therapeutic success is caused by the immunosuppressive effects of the drugs used. AA shares clinical and pathophysiologic features with other autoimmune or immune-mediated human diseases that are also characterized by T-cell–mediated, tissue-specific organ destruction (inflammatory bowel disease, type 1 diabetes, multiple sclerosis, uveitis, and others).

Immune system destruction of BM occurs in animal models of graft-versus-host disease (GVHD) and in humans with transfusion associated GVHD, in which AA is the cause of death. Very small numbers of effector cells, which have been conveyed by residual lymphocytes contained within the transfusion product or with solid organ transplants, are sufficient to mediate GVHD under these conditions. AA is associated with rheumatologic syndromes, such as eosinophilic fasciitis, and with systemic lupus erythematosus. AA occasionally occurs in individuals with hypogammaglobulinemia or congenital immunodeficiency syndrome, thymoma, thymic hyperplasia, and thymic carcinoma. AA is a rare complication of immunotherapy of cancers, both checkpoint inhibitors and chimeric antigens receptor T cells (CAR-T cells).

Laboratory support for the immune hypothesis first came from coculture experiments in which mononuclear cells from AA patient’s blood or BM were shown to suppress in vitro colony formation by hematopoietic progenitor cells. T-cell depletion sometimes improved colony formation in vitro. Patient’s blood and BM cells were shown to produce a soluble factor that inhibited hematopoiesis, ultimately identified as interferon (IFN)-γ. Patient’s cells overproduce IFN-γ and tumor necrosis factor (TNF), two cytokines that inhibit hematopoietic proliferation. The T-box transcription factor, Tbet, which is critical to Th1 polarization, is constitutionally expressed in a majority of AA patients. AA blood and BM also contain elevated numbers of activated cytotoxic lymphocytes, and activity and levels of these cytotoxic cells are decreased with antithymocyte globulin (ATG) therapy. T regulatory cells, as in other human immune-mediated diseases, are decreased in AA. IFN-γ and TNF negative effects on the proliferation of early and late hematopoietic progenitor, and stem cells are far more potent when these cytokines are secreted into the BM micro environment than when they were simply added to in vitro cultures. IFN-γ and TNF can suppress hematopoiesis by inhibiting cell proliferation, inducing Fas-mediated apoptosis, and blocking hematopoietic growth factor intracellular signals. The early immune system events that must precede the global destruction of hematopoietic cells are not clear. Involvement of CD4 lymphocytes has been suggested based on the overrepresentation of HLA-DR15 among patients with immune-mediated AA. Clones of HLA-DR–restricted T cells derived from a few patients have been shown to proliferate in response to BM cells.

Many features of human AA can be reproduced in mouse models of GVHD, in which the donor inoculum lacks stem cells. Major and minor histocompatibility mismatches demonstrate the potency and specificity of small numbers of T cells, the role of cytokines, efficacy of immunosuppressive therapies, an “innocent bystander effect,” and roles for specific lymphocyte regulatory and effector T-cell subsets.

Radiation

BM aplasia is a major acute toxic effect of radiation (Fig. 1); a dose-related pancytopenia occurs 2 to 4 weeks after exposure to radiation. Mortality from hematologic toxicity is a function of the ability of BM to tolerate damage to stem cells. The capacity for hematopoietic recovery after even massive single irradiation exposures is considerable, reflecting the resistance of the quiescent stem cell damage and enormous BM repopulating potential. At intermediate radiation doses around the median lethal dose (LD50 ), at which BM toxicity limits survival, supportive efforts can dramatically alter outcomes. Autopsies of atomic bomb victims in Japan showed acellular BMs in the first weeks of the explosion, but later regenerating BM was frequently present. The histologic picture of radiation-mediated aplasia includes necrosis, nuclear pyknosis and karyorrhexis, nuclear lysis, and ultimately cytolysis; the associated phagocytosis, marked congestion, and hemorrhage are rapidly followed by fatty replacement. BM hypoplasia occurs with radiation doses higher than 1.5 to 2 Gy to the whole body. Precise LD50 figures for humans do not exist, and estimates are based on limited direct human data and extrapolation from animal experiments. The LD50 is highly dependent on the quality of medical care, and improved support may double the tolerated radiation dose. From assessment of the outcome of radiation accidents and high-dose therapeutic irradiation, the LD50 has been estimated at approximately 4.5 Gy (see Fig. 1).

Fig1. SCALE OF WHOLE-BODY RADIATION DOSES. A Gray (Gy) is a measure of absorbed dose equivalent to 1 J/kg unit mass, and 1 Gy equals 100 rads. Radiation represents radiant energy. When absorbed by biologic tissue, radiant energy causes release of electrons and molecular ionization, which result in further energy release. Radiant energy can directly break chemical bonds and indirectly damage macromolecules through generation of high-energy free radical forms. The relationship between increased mutation rate and radiation dose is very approximate (hatched bars). Measurement of the phenotype of an autosomal recessive gene such as for glycophorin would be expected to be a very sensitive indicator. Because malignant transformation is almost certainly a two-step process, increased leukemogenesis is probably an underestimation of the effect of radiation on a single gene. Even the extensive data on the atomic bomb survivors of Hiroshima are subject to statistical errors because of the small number of cases; a linear or exponential curve fit gives various results, and very high doses of radiation may not be associated with as high a risk of leukemia because of stem cell death. Other data that can bear on mutation frequency lie outside the range shown. In a patient with ankylosing spondylitis who underwent irradiation of the spine, leukemogenesis was observed at relatively low doses (doubling of the leukemia rate can be extrapolated to approximately 7 Gy), but such individuals can be predisposed to leukemia. An increased risk of thyroid cancer after irradiation of the mediastinum in childhood occurred at approximately 4 Gy. BMT, Bone marrow transplantation; CT, computed tomography; LD50 , median lethal dose; RBC, red blood cell.

Although the immediate management of pancytopenia after a single large dose of irradiation is similar to that for treating AA, some unique points should be made concerning immediate evaluation and long-term prognosis. The type and intensity of the source of radiation, and the distance and shielding of the subject are the major determinants of radiation injury. However, these factors are often difficult to assess. Early recognition of the nature of the accident pro vides the best opportunity for dosimetry by accident reconstruction and use of blocking, displacement, or chelation agents. Exposure correlates well with the degree of pancytopenia. Because lymphocytes are particularly sensitive to radiation, their rate of decline can be used to estimate the dose of total body exposure to a level of approximately 3 Gy. At higher doses, the fall in the numbers of granulocytes and the severity of thrombocytopenia and reticulocytopenia can be used as gauges. The survival of some patients who received doses higher than 9 Gy suggests that autologous BM reconstitution may occur in most persons who survive the immediate consequences of accidental radiation exposure.

AA is not well documented as a delayed event after radiation exposure. A variety of hematologic abnormalities are associated with chronic low-level radiation exposure, most commonly lymphocytosis, neutropenia, dysmorphic leukocytes, and giant platelets (see Fig. 1). Cytogenetic abnormalities accumulate with time after chronic exposure, but they may not be reliably related to dose. AA does not appear to be more frequent among nuclear power plant or thorium processing factory workers. The excessive risk of death from AA previously reported after therapeutic irradiation of the spine for ankylosing spondylitis may have been overestimated. Cancer patients who had received therapeutic irradiation or higher exposure to natural background radiation were not found to have an increased risk of AA.

Drugs and Chemicals

 AA is frequently associated with medical drug use (Table 1). At the end of the 19th century, chemicals were linked to BM function through observations of benzene effects on workers. Establishment of a relationship between amidopyrine analgesics and agranulocytosis in the early 20th century and an apparent epidemic of AA after the intro duction of chloramphenicol in the 1960s also supported this concept. Initially suggested by the accumulation of case reports, drug associations have been established in formal case-control population-based epidemiologic studies. In the IAAAS, relative risks were estimated for individual drugs and large classes of pharmaceutical agents, including nonsteroidal antiinflammatory drugs (NSAIDs), drugs affecting thy roid function, certain cardiovascular agents, some psychotropics, and sulfa-based antibiotics (Table 2). Approximately 25% of the cases of AA identified in the IAAAS could be attributed to drug use. Drug use as a risk factor was also assessed by similar methods in Thailand, where the incidence of AA is higher than in the West. Surprisingly, chloramphenicol was not shown to be a risk factor; the etiologic fraction for drugs was only 15%.

Table1. Classification of Drugs and Chemicals Associated With Aplastic Anemia

Table2. Drugs Associated With Aplastic Anemia in the International Aplastic Anemia and Agranulocytosis Study ^a

Associations between drug exposure and AA can be divided into two classes. Drugs used in cancer chemotherapy are selected for their cytotoxicity, and their regular, dose-dependent induction of BM aplasia is an expected effect. Most AA associated with medical drug use in the community is described as idiosyncratic, meaning that its occurrences are unexpected and rare. Many of the drugs implicated in AA also appear to cause other, milder forms of BM suppression such as neutropenia. Although difficult to prove, some dose relationship probably does exist even for idiosyncratic reactions. In most case reports, patients received normal or high doses of the agent, usually for a period of weeks to months. Drug-induced aplasia cannot be distinguished by history from idiopathic forms of the disease; the clinical course, including the favorable response to immunosuppressive therapy, is the same as in idiopathic disease.

The low probability of developing AA after a course of drugs may be a reflection of the gene variant frequency for metabolic enzymes (for direct chemical effects) or immune response genes. The rarity of idiosyncratic drug reactions could then arise from the infrequent combination of unusual circumstances: exposure, genetic variations in drug metabolism, the physical properties of the agent, enzymatic pathways that chemically alter the drug, and the susceptibility of the host to the action of a toxic compound. Examples of detoxifying enzyme systems directly applicable to BM failure that also demonstrate genetic variability include arylhydrocarbon hydroxylase (e.g., benzene toxicity), epoxide hydrolases (e.g., phenytoin toxicity), S-methylation (e.g., 6-mercaptopurine, 6-thioguanine, azathioprine) and N-acetylation (e.g., sulfa drugs). Genomic approaches have revealed the complex role of genetic variation in metabolic pathways that process arylhydrocarbons and even links to immune function.

Benzene

Benzene exposure is linked to AA. Benzene myelotoxicity can be placed between the predictable effects of chemotherapeutic agents and idiosyncratic drug reactions. Industrial emissions add greatly to the biologic sources of ambient benzene. Significant benzene expo sure can also occur outside of industry. Although the concentrations of benzene to which consumers are exposed are orders of magnitude lower than those observed in industrial workers, the effect of low-dose chronic exposure is uncertain, but genetic variations in metabolizing enzymes may influence susceptibility to BM suppression at these levels. Benzene metabolites are also generated from the diet. Water soluble products of benzene metabolism such as phenols, hydro quinones, and catechols mediate toxicity to the BM. Benzene and its intermediate metabolites covalently and irreversibly bind to BM DNA, inhibit DNA synthesis, and introduce DNA strand breaks. Benzene acts as a “mitotic poison” and as a mutagen. Acutely, the more mature, actively cycling BM precursor cells are preferentially damaged over more primitive progenitors. Intermittent exposure may be more damaging to the stem cell compartment than is continuous exposure. BM stroma can also be damaged by benzene.

The range of hematologic disease attributable to benzene is broad, from relatively frequent mild alterations in blood counts to AA or leukemia. Studies of exposed North American workers earlier in the 20th century suggested that the risk of AA was 3% to 4% in men exposed to concentrations higher than 300 ppm and that 50% of individuals exposed to 100 ppm developed some blood cell count depression. Leukopenia, anemia, thrombocytopenia, and lymphocytopenia are common consequences of benzene; other manifestations include macrocytosis, an acquired Pelger-Huet anomaly, eosinophilia, basophilia, and less often, polycythemia, leukocytosis, thrombocytosis, or splenomegaly. The BM is usually normocellular but can show hypocellularity or hypercellularity; a hypercellular phase can precede complete aplasia.

Aromatic Hydrocarbons

The common perception that other molecules resembling benzene or containing a benzene ring can also cause AA is not well supported by evidence. Neither the closely related alkylbenzenes nor pure toluene or xylene are established BM toxins. Often, an aromatic hydrocarbon has been implicated as causative by a clinician only for lack of another apparent etiology. For some substances, toxicity might result from the presence of benzene as a contaminant of the synthesis of the molecule or in the petroleum distillates used to dissolve the compound. However, the total number of AA cases reported with aromatic hydro carbon exposures is small when the large populations exposed to this heterogeneous group of chemicals are considered. For example, the significance of a handful of case reports associated with insecticide exposure in the context of the vast use of these compounds is questionable. However, the very high prevalence of aromatic hydrocar bons in daily life would greatly amplify even a small individual risk. Pesticides and insecticides have been associated with AA for decades, with almost 300 medical case reports appearing in the medical literature. The most frequently cited insecticides are chlordane, lindane, and dichlorodiphenyltrichloroethane.

Chloramphenicol

 The structural similarity of chloramphenicol to amidopyrine, a drug known to cause agranulocytosis, led to early prediction of possible hematotoxicity associated with the administration of this antibiotic. During the period of its unrestrained use, chloramphenicol was considered the most common cause of AA in the United States, accounting for 20% to 30% of total cases and 50% of drug-associated cases. Estimates of the risk of AA after a course of chloramphenicol ranged from 1 case per 20,000 to 1 case per 800,000 people. Based on these figures, a course of chloramphenicol was estimated to increase the risk of AA 13-fold. Although the introduction of chloramphenicol into the US market was perceived as having increased the total number of cases of AA, this assumption was only weakly supported by epidemiologic data, and the mortality from AA remained essentially constant during the period of chloramphenicol’s introduction, extensive use, and after the withdrawal of chloramphenicol from the market. Chloramphenicol has not been associated with AA in Thailand, despite its high rate of use there. In Hong Kong, where the use of chloramphenicol is almost 100 times higher than in the West, drug associated AA occurs infrequently.

Nonsteroidal Antiinflammatory Drugs

Compared with chloramphenicol, it took far longer to associate phenylbutazone with AA. Mortality estimates have ranged from 1 case per 100,000 to 1 case per 1 million treatment courses. The use of other NSAIDs is associated with case reports of AA. A large case-control led investigation in Europe confirmed the risk of AA with phenylbutazone use and identified even higher probabilities with other NSAIDs. There was a suggestion of increased risk with drugs taken regularly for a prolonged period at very high doses, and in some cases, hematologic reactions were reproduced on repeat exposure.

Neuroleptics and Psychotropic Drugs

A variety of drugs used to treat disorders of the central nervous system have been associated with AA: the hydantoins and carbamazepine, antidepressants, tranquilizers, and the anticonvulsant felbamate. The marketing of felbamate was severely affected by the occurrence of AA in more than 30 patients. Monitoring of drug blood levels and peripheral blood counts in patients receiving carbamazepine was recommended despite fewer than two dozen AA cases reported by 1982. There was doubt about the validity of the many cases reported, as well as several large series of patients who did not develop hematologic toxicity and an estimated AA case rate of approximately 1 in 200,000 treated patients, having led to questions concerning the relationship between carbamazepine and AA.

اخر الاخبار

اخبار العتبة العباسية المقدسة

المجمع العلمي يقيم مهرجانًا بذكرى الولادات الشعبانية في بغداد

معهد القرآن الكريم النسوي يباشر استعداداته لإقامة مهرجان السقاء القرآني السنوي الخامس

بالتعاون مع جامعة ستانفورد.. جامعة الكفيل تعتمد منهجًا متطورًا لطب الطوارئ

سماحة السيد الصافي يستقبل وفد شركة (سيتي فارما) الباكستانية المختصة في الأدوية

المزيد

الآخبار الصحية

اللحظات الأخيرة قبل الموت.. هذا هو تسلسل "فقدان الحواس"

وخز الأطراف وضعف الذاكرة.. علامات على نقص فيتامين هام

عادة صباحية بسيطة.. تأثيرها قد يحسن ضغط الدم

عادات يومية تدمر قلبك بصمت.. خبراء يطلقون التحذير

المزيد

الآخبار التكنلوجية

الذكاء الاصطناعي يفك لغز آثار أقدام الديناصورات

القمر أولا.."سبيس إكس" تؤجل خططها الخاصة بالرحلات إلى المريخ

الذكور أم الإناث؟ دراسة "تنسف الشائع" بشأن التوحد

خبير يكشف عن اقتراب العلماء من فك شفرات "لغات الحيوانات" !

المزيد

مواضيع ذات صلة

Hyperthyroidism: Etiology and Treatment

Clinical Features of Hyper- and Hypothyroidism

Clinical Associations of Aplastic Anemia

Typical and Atypical Presentations of Aplastic Anemia

Epidemiology of Aplastic anemia

Pneumonia

Bronchitis

Pathogenesis of the respiratory tract: Microorganism Factors

Pathogenesis of the respiratory tract: Host Factors

Clinical Manifestations of Bloodstream Infections

Definition of Sepsis

Types of Bloodstream Infections