History Of Hemolysis Research Articles

Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria: Multicenter Analysis by the Polish Adult Leukemia Group.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole potential cure for paroxysmal nocturnal hemoglobinuria (PNH); however, the data on its utility in PNH are limited. This retrospective analysis of patients with PNH who underwent allo-HSCT in 11 Polish centers between 2002 and 2016 comprised 78 patients with PHN, including 27 with classic PNH (cPNH) and 51 with bone marrow failure-associated PNH (BMF/PNH). The cohort was 59% male, with a median age of 29 years (range, 12 to 65 years). There was a history of thrombosis in 12% and a history of hemolysis in 81%, and 92% required erythrocyte transfusions before undergoing allo-HSCT. No patient received eculizumab, and 26% received immunosuppressive treatment. The median time from diagnosis to allo-HSCT was 12 months (range, 1 to 127 months). Almost all patients (94%) received reduced-toxicity conditioning, 66% with treosulfan. The stem cell source was peripheral blood in 72% and an identical sibling donor in 24%. Engraftment occurred in 96% of the patients. With a median follow-up of 5.1 years in patients with cPNH and 3.2 years in patients with BMF/PNH, 3-year overall survival (OS) was 88.9% in the former and 85.1% in the latter (P=not significant [NS]). The 3-year OS for patients with/without thrombosis was 50%/92% (P=NS) in the cPNH group and 83.3%/85.3% (P=NS) in the BMF/PNH group. The 3-year OS for in the BMF/PNH patients with/without hemolysis was 93.9%/62.9% (hazard ratio, .13; P=.016). No other factors impacted OS. After allo-HSCT, the frequency of the PNH clone was reduced to 0%, <1%, and <2.4% in 48%, 48%, and 4% of cPNH patients and in 84%, 11%, and 5% of BMF/PNH patients, respectively. The frequency of acute graft-versus-host disease (GVHD) grade II-IV was 23%, and the cumulative 1-year incidence of extensive chronic GVHD was 10.8% in the BMF/PNH group and 3.7% in the cPNH group. Allo-HSCT is a valid option for PNH patients, effectively eliminating the PNH clone with satisfactory overall survival and acceptable toxicity. Reduced-toxicity conditioning with treosulfan is effective and safe in patients with cPNH and BMF/PNH.

An Unusual Type of Lymphomatoid Papulosis Presenting in Pregnancy: Risk-Benefit Analysis of Antepartum Treatment [18H

INTRODUCTION: Lymphomatoid papulosis (LyP) has an incidence of 2 per 1,000,000 and is associated with lymphoproliferative disorders. Type E, characterized by angioinvasion, is the rarest subtype and is associated with CD30 and CD8 expression. LyP is associated with immune compromising disorders, making pregnancy a potential setting for presentation. We present one of the first cases of LyP type E in pregnancy. METHODS: Case: 30-year-old G5P3, with a pregnancy complicated by a history of hemolysis, elevated liver enzymes and low platelet count syndrome in a previous pregnancy, presented in early pregnancy with a two month history of diffuse painful skin lesions. As the pregnancy progressed, the lesions spread and would blister and ulcerate before resolving. Biopsy returned with CD30+ angioinvasive LyP type E. Prednisone and topical steroids provided minimal symptomatic improvement. Peginterferon alfa-2a was offered as an alternative therapy; however, was deferred until after delivery. CONCLUSION: Appropriate diagnosis of LyP and subtype as well as multi-disciplinary follow-up is essential given possible associated lymphoproliferative disorders. Treatment may involve more risk than benefit and has not been proven to prevent associated malignancy necessitating individualized risk-benefit analysis. Conservative treatment is preferred, even in significantly symptomatic pregnant patients. In some severely symptomatic patients, peginterferon alfa-2a may be considered with a better safety profile compared to other agents in pregnancy. The angiodestructive nature of type E may be associated with pregnancy complications including those on the preeclampsia spectrum. These pregnancies may require closer monitoring and the consideration of aspirin prophylaxis. Early diagnostic biopsy will allow for timely intervention.

Decreased INR on LVAD Support: To Bridge or Not to Bridge?

In volume 6, issue 2 of The VAD Journal, we published a paper by Rainess et al. who reported their experience with managing subtherapeutic INRs, mostly in patients with HeartMate II (Thoratec, Pleasanton, CA). Although, the cohort did include some HeartMate 3-supported patients. In their program (Wake Forest University), pharmacists manage anticoagulation according to the institutional protocol, which allows bridging with low molecular weight heparin when INR decreases to less than 1.8. The study is unique because the patients did NOT require interruption of anticoagulation for any purpose. In all instances, the INR decreased because of dietary variations, recent dose changes, skipped doses, medication interactions, etc. Almost half of their patients had a history of hemolysis or pump thrombosis. After analyzing 155 bridging episodes, the authors reported systemic bleeding events in 9% of the patients and localized bleeding in 10%. Importantly, no event resulted in hospitalization or blood transfusion; this rate seems to be excessive considering a relatively minor deviation of INR from the therapeutic range, and it raises a question about an appropriate threshold for bridging initiation. Studies such as Rainess et al. fill an important knowledge gap. From our standpoint, a 20% risk in bleeding, which includes a 9% risk of systemic bleeding, is a too high price to pay for such a minor decrease in INR. Perhaps tolerating a subtherapeutic INR for a few days would be a safer approach. A specific cutoff of the INR value triggering bridging should be a subject of a randomized study, but setting the bar at 1.8 may represent an excessively aggressive strategy.

Diagnostic and Therapeutic Implications of Cholelithiasis in Children

Introduction: Cholecystitis, for a long time considered as a disease of adults, has had an increased documented incidence of non-haemolitic cholelithiasis in the Pediatric Surgery practice in the last 20 years. Even though diseases of the gall bladder are rare in children, pediatric patients account for 4% of all cases with cholecystectomy. Cholecystitis and other diseases of the gall bladder should be considered in differential diagnosis in every patient with abdominal pain in the right upper quadrant, followed by jaundice, especially in children with history of hemolysis. Aim: The aim is to discuss the diagnostic and therapeutic modalities in 6 children with acute cholecystitis and cholelithiasis diagnosed and treated at the clinic of the authors. Patients and Methods: In the last 5 years, at UCCK, 6 patients under 12 years of age were operated, cholecystectomy was performed. The disease was more prevalent in female patients (66.66%—4 patients) than in male patients (33.33%—2 patients). Mean age was 8.6. Clinical manifestations presented: increased body temperature, abdominal pain and abdominal tenderness during examination. Other clinical manifestations included: vomiting in 4 patients (66.66%), jaundice in 2 patients (33.33%). Lab results showed leucosytosis in 3 patients (50%), disorders of the liver in 2 patients (33%). 2 patients were diagnosed with spherocytosis and splenomegaly, 1 patient had empyema of gall bladder (wall thickness of the gall bladder > 3.7 mm). Clinical diagnosis was confirmed with ultrasound. Ultrasound criteria are: gall bladder thickness (3.5 mm), stones ose sludge with acoustic shadow, and collection of liquid around gall bladder (pericholecystitis). Results: All patients were initially treated with naso-gastric tube (suction), fluids and antibiotics. Cholecystectomy was performed in 4 patients and cholecys-tectomy with splenectomy in 2 patients due to spherocytosis. Discussion and conclusion: Choleli-thiasis in children is most commonly associated with haemolitic and haemoglobin diseases (Hereditary Spherocytosis, Sideropenic Anaemia, Thalasemia etc.). The incidence of cholesterol stones is higher than pigment stones. Cholecystitis and cholelithiasis in children are more common than previously thought. Ultrasound confirms with great accuracy the presence of stones and acalculous cholesytitis. Treatment is usually surgical, laparoscopic or open surgery, depending on the stage of the disease and the experience of the surgeon.

G6PD Deficiency in an HIV Clinic Setting in the Dominican Republic.

Because human immunodeficiency virus (HIV)-infected patients receive prophylaxis with oxidative drugs, those with glucose-6-phosphate dehydrogenase (G6PD) deficiency may experience hemolysis. However, G6PD deficiency has not been studied in the Dominican Republic, where many individuals have African ancestry. Our objective was to determine the prevalence of G6PD deficiency in Dominican HIV-infected patients and to attempt to develop a cost-effective algorithm for identifying such individuals. To this end, histories, chart reviews, and G6PD testing were performed for 238 consecutive HIV-infected adult clinic patients. The overall prevalence of G6PD deficiency (8.8%) was similar in males (9.3%) and females (8.5%), and higher in Haitians (18%) than Dominicans (6.4%; P = 0.01). By logistic regression, three clinical variables predicted G6PD status: maternal country of birth (P = 0.01) and a history of hemolysis (P = 0.01) or severe anemia (P = 0.03). Using these criteria, an algorithm was developed, in which a patient subset was identified that would benefit most from G6PD screening, yielding a sensitivity of 94.7% and a specificity of 97.2%, increasing the pretest probability (8.8-15.1%), and halving the number of patients needing testing. This algorithm may provide a cost-effective strategy for improving care in resource-limited settings.

G6PD Deficiency In An HIV Clinic Setting In The Dominican Republic

G6PD deficiency is the most common human enzymopathy, particularly in individuals of African descent. Its epidemiology has not been studied in the Dominican Republic, where many individuals have African ancestry. HIV-infected patients are at risk for adverse effects from G6PD deficiency due to receiving prophylaxis with oxidative drugs, which can induce hemolysis in G6PD-deficient patients. We determined the prevalence of G6PD deficiency, as well as the spectrum of variants, in HIV-infected patients at the Clínica de Familia La Romana, a free HIV clinic in the Dominican Republic.A medical history, chart review, and G6PD testing were performed for 238 consenting HIV-positive adults. A qualitative assay (Trinity Biotech), performed at the clinic, was assessed for color change at 30 and 60 minutes. All blood samples were also shipped to our home institution for quantifying enzyme activity (Trinity Biotech) and molecular testing by Sanger sequencing. The threshold for G6PD deficiency was 5.42 U/g hemoglobin (Hb; i.e. <60% of the mean normal activity level, by WHO criteria). Severe anemia was defined as Hb <8 g/dL. A history of hemolysis was defined as a report of dark urine or jaundice. Statistical analysis was performed using SAS 9.3.The overall prevalence of G6PD deficiency was 8.8% and was similar in males (9.3% [9/97]) and females (8.5% [12/141]), but higher in Haitians (18% [9/50]) as compared to Dominicans (6.4% [12/187]; p=0.01), determined by maternal country of birth. All G6PD-deficient subjects carried the “African” variant (G6PD A-). ∼60% of patients had received and ∼15% were currently on trimethoprim-sulfamethoxazole (TMP-SMX), regardless of G6PD status. Two G6PD-normal patients received Dapsone after TMP-SMX was stopped for allergy or anemia. Univariate analysis identified variables associated with G6PD deficiency in this cohort. A multivariable logistic regression model identified three variables that predicted G6PD status (p<0.05): maternal country of birth (p=0.01), a history of hemolysis (p=0.01), and a history of severe anemia (p=0.03). Using these criteria for screening the cohort, we identified a subset of patients who would benefit most from qualitative G6PD testing. A stepwise screening strategy using clinical history and biochemical testing yielded a diagnostic sensitivity of 94.7% and specificity of 97.2%. In addition, using the combined approach, rather than biochemical testing alone, increased the pretest probability from 8.8% to 15.1% and halved the number of patients needing testing. This algorithm for diagnosing G6PD deficiency may be a cost-effective strategy for improving the quality of care for HIV-infected patients in resource-limited settings.Screening for G6PD deficiency in the developing world is further complicated by lack of access to confirmatory testing. Detecting heterozygous females with intermediate, or even normal, G6PD activity is a diagnostic challenge for enzyme assays. To diagnose heterozygotes definitively, all G6PD exons were sequenced for all subjects with G6PD activity near or below the threshold, with discordant qualitative and quantitative Results, and for selected controls. Of 55 subjects sequenced, 29 had at least one G6PD A- allele. The G6PD A+ allele, also associated with African ancestry, was the only other variant detected. Overall, the 3 Methods agreed well when subjects had low or high G6PD activity, with uncertainty near the quantitative threshold for G6PD deficiency. The sequencing assay detected the G6PD A- allele in all subjects found to be G6PD-deficient by the quantitative assay, but also identified 8 heterozygous females with normal enzyme activity. The qualitative assay, whose sensitivity was increased by assessing color change at 30 minutes, was able to detect the majority (12/19) of heterozygous females, but 6 were heterozygotes with normal enzyme activity. Nonetheless, because genotype does not directly correlate with clinical severity, low activity remains the gold standard for diagnosing G6PD deficiency. Therefore, optimizing qualitative enzyme assays to detect biochemically deficient patients in conjunction with using clinical screening to increase pretest probability may together improve the diagnosis of clinically relevant G6PD deficiency in resource-limited settings. Disclosures:No relevant conflicts of interest to declare.

Spontaneous Rectus Sheath Hematoma Pregnancy: Case Report and Review of the Literature

Rectus sheath hematoma (RSH) is a rare, but important potential cause of acute upper abdominal pain in pregnancy. We report a patient with history of hemolysis, elevated liver enzymes, low platelets syndrome who presented with upper abdominal pain, hypotension, elevated hepatic transaminase levels, and a visibly enlarging right costal margin mass at 33 weeks' gestation. She underwent emergent cesarean delivery and upper abdominal exploration with findings of a large hematoma involving the entire right rectus sheath. The current case illustrates that the diagnosis of an RSH in pregnancy can be difficult as its presentation can mimic many common causes of abdominal pain seen outside of pregnancy, as well as many specific to pregnancy. Review of the published cases from the past 20 years shows that correct diagnosis remains difficult in pregnancy despite advances in diagnostic imaging. Although management of an RSH outside of pregnancy is frequently conservative, it is very often treated surgically in pregnant patients and often leads to preterm delivery.

Dominantly Inherited β-Thalassemia

Dominantly inherited β-thalassemia (thal) or “inclusion body β-thalassemias” are heterogeneous at the molecular level and are due to mutations at or near the β-globin gene locus. Many of these involve mutations of exon 3 of the β-globin gene. They include frameshifts, premature chain termination (nonsense) mutations, and complex rearrangements that lead to the synthesis of truncated or elongated and highly unstable β-globin gene products. The resulting β chain variants are very unstable, and in many cases, the products of the dominantly inherited β-thal are not detectable. Hematological and clinical observations made in several families with comparable forms of β-thal and with certain highly unstable hemoglobin (Hb) variants, have indicated a striking overlap; many subjects with detectable unstable Hb variants and with a dominant type of β-thal without a detectable abnormal Hb, have similar phenotypes. Here, a review of dominantly inherited β-thal is given, and new examples of hyperunstable Hbs (Hb Stara Zagora and Hb Jambol) are presented.The first example is a hyperunstable variant named Hb Stara Zagora that was found in a 2-year-old Bulgarian boy. The abnormal Hb is associated with severe hemolytic anemia as a consequence of its hyper instability. The anemia was noticed at the age of 2 months and since then he has been on a regular monthly blood transfusion regimen. Hemoglobin analysis revealed no abnormalities, except the presence of inclusion bodies. Sequencing of the β-globin gene revealed a heterozygosity for a 6 bp deletion (−TGGCTA) at codons 137 (the second and third bp), 138 and 139 (the first bp), thus forming a new codon at position 139 (GAT). This event eliminates three amino acids (Val-Ala-Asn) and introduces a new residue (Asp). It creates a new restriction site for HphI. The parents and his twin brother had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.The second example is a new hyperunstable variant named Hb Jambol, found as a de novo mutation in a 2-year-old Bulgarian girl with severe hemolytic anemia. The mutation was detected through RNA/DNA analysis. It represents a complex genomic rearrangement involving an insertion of 23 nucleotides (nts) after IVS-II-535, a deletion of 310 nts extending from IVS-II-550 to the first nt of codon 108, and an insertion of 28 nts at the deletion junctions (derived from inverted sequence between nts +3707 and +3734 3′ to the β-globin gene termination codon). At the protein level, this mutation leads to a deletion of four amino acid residues (Leu-Leu-Glu-Asn) at positions 105, 106, 107 and 108, and an insertion of nine residues (Val-Pro-Ser-Val-Thr-Leu-Phe-Phe-Asp) at the same location, creating an abnormal elongated β chain of 151 amino acid residues. The parents had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.

Hb Stara Zagora: A New Hyper-Unstable Hemoglobin Causing Severe Hemolytic Anemia

We describe a new hyper-unstable β chain variant (codons 137–139, − 6 bp) in a 2-year-old Bulgarian boy. The abnormal hemoglobin (Hb) is associated with severe hemolytic anemia as a consequence of its hyper instability. The child was admitted to the Pediatric Clinic (Faculty of Medicine, Stara Zagora, Bulgaria) at the age of 2 months. Because of anemia (Hb 6.9 g/dL) and high serum iron level (58 μM/L) the child was transfused. However, a month later his Hb level had dropped to 7.5 g/dL, and since then he has been on a regular monthly blood transfusion regimen. Hemoglobin analysis of a blood sample collected 2 months after the last transfusion at the age of 2 years, revealed no abnormalities except for the presence of inclusion bodies after incubation of peripheral blood with brilliant cresyl blue. Sequencing of the β-globin gene revealed heterozygosity for a 6 bp deletion (–TGGCTA) at codons 137 [the second and third base pair (bp)], 138 and 139 (the first bp), forming a new codon at position 137 (GAT). This event eliminates three amino acids (Val-Ala-Asn) and introduces a new residue (Asp). It creates a new restriction site for HphI. The parents and his dizygotic twin brother had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.

Subsequent pregnancy outcome in women with a history of HELLP syndrome at ≤ 28 weeks of gestation

Objective: The purpose of this study was to describe subsequent pregnancy outcome in women with a history of hemolysis, elevated liver enzymes, and low platelet count syndrome for which delivery occurred at ≤ 28 weeks of gestation during the index pregnancy. Study Design: A descriptive report of women with previous hemolysis, elevated liver enzymes, and low platelet count syndrome who were delivered between August 1984 and July 1998 at the E.H. Crump Women's Hospital (Memphis, Tenn) and between March 1994 and July 1998 at the Central Baptist Hospital (Lexington, Ky). To have adequate time to study subsequent pregnancy outcome, only patients who were delivered >2 years before the analysis were included. Medical records of the index pregnancy and subsequent outcomes were available for review. Results: Adequate follow-up data were available in 69 patients; the median duration of follow-up was 5 years (range: 2-14 years). There were 76 subsequent pregnancies among 48 women, of which 62 pregnancies (82%) progressed beyond 20 weeks of gestation. Preeclampsia developed in 34 of 62 subsequent pregnancies (55%). Recurrent hemolysis, elevated liver enzymes, and low platelet count syndrome developed in 4 of these pregnancies (6%), and abruptio placentae developed in 3 of these pregnancies (5%). There were no cases of eclampsia in our population. Delivery before 37 weeks of gestation occurred in 33 of the cases (53%), and 17 of the newborn infants (27%) were small for gestational age (<10th percentile). The perinatal mortality rate was 11%. Conclusion: Patients with a history of hemolysis, elevated liver enzymes, and low platelet count syndrome at ≤ 28 weeks of gestation during the index pregnancy are at increased risk for obstetric complications in subsequent pregnancies. Overall, however, the rate of recurrent hemolysis, elevated liver enzymes, and low platelet count syndrome is only 6%. (Am J Obstet Gynecol 2003;188:1504-8.)

Long-term follow-up in patients with a history of (H)ELLP syndrome.

To provide long-term follow-up data on women with a history of hemolysis, elevated liver enzymes, and low platelets [(H)ELLP] syndrome regarding the risk of recurrence in subsequent pregnancies and disease in later life. All women admitted to the Academic Medical Centre between January 1984 and January 1996 with (H)ELLP syndrome and a living singleton fetus in utero were included. Women with known preexisting diseases were excluded. The (H)ELLP syndrome was defined as elevated liver enzymes (serum aspartate aminotransferase or serum alanine aminotransferase >or= 50 U/L) and low platelet count (< 100 x 10(9)/L). Those patients with hemolysis (LDH >or= 600 U/L) were classified as HELLP, the remaining ones were classified as ELLP. The participants were asked to fill out a questionnaire regarding their general health and their own obstetric and medical history and that of their first-and second-degree relatives. One hundred sixteen (94%) of 123 women responded; 4 women had died. The median age of the group was 36.0 years at completion of the questionnaire; the median interval after the index pregnancy was 5.7 years (3-12.9). The incidence of hypertension requiring medical treatment was three times higher than in a reference population of Dutch women between 20 and 40 years old. The need for psychological support was frequent. Thirty-nine patients (34%) refrained from further pregnancies. Twenty-nine percent of the first subsequent pregnancies were complicated by gestational hypertension (GH), but only 2% had (H)ELLP syndrome. Birth weight was, on average, 1385 g higher and gestational age at delivery 5 weeks later in the first subsequent pregnancy irrespective of a recurrence of GH. A family history of cardiovascular disease or preeclampsia was common in the total group; however, this did not influence the recurrence rate. Multiparity, gestational age at delivery <30 weeks, and birth weight <1000 g in the index pregnancy increased the risk of recurrence of GH in the first subsequent pregnancy significantly. (H)ELLP syndrome is a severe complication of pregnancy that has not only short-term but also long-term sequelae.

Long-Term Follow-up in Patients with a History of (H)Ellp Syndrome

Objective. To provide long-term follow-up data on women with a history of hemolysis, elevated liver enzymes, and low platelets [(H)ELLP] syndrome regarding the risk of recurrence in subsequent pregnancies and disease in later life.Methods. All women admitted to the Academic Medical Centre between January 1984 and January 1996 with (H)ELLP syndrome and a living singleton fetus in utero were included. Women with known preexisting diseases were excluded. The (H)ELLP syndrome was defined as elevated liver enzymes (serum aspartate aminotransferase or serum alanine aminotransferase ≥ 50 U/L) and low platelet count (<100 × 109/L). Those patients with hemolysis (LDH ≥ 600 U/L) were classified as HELLP, the remaining ones were classified as ELLP. The participants were asked to fill out a questionnaire regarding their general health and their own obstetric and medical history and that of their first- and second-degree relatives.Results. One hundred sixteen (94%) of 123 women responded; 4 women had died. The median age of the group was 36.0 years at completion of the questionnaire; the median interval after the index pregnancy was 5.7 years (3–12.9). The incidence of hypertension requiring medical treatment was three times higher than in a reference population of Dutch women between 20 and 40 years old. The need for psychological support was frequent. Thirty-nine patients (34%) refrained from further pregnancies. Twenty-nine percent of the first subsequent pregnancies were complicated by gestational hypertension (GH), but only 2% had (H)ELLP syndrome. Birth weight was, on average, 1385 g higher and gestational age at delivery 5 weeks later in the first subsequent pregnancy irrespective of a recurrence of GH. A family history of cardiovascular disease or preeclampsia was common in the total group; however, this did not influence the recurrence rate. Multiparity, gestational age at delivery <30 weeks, and birth weight <1000 g in the index pregnancy increased the risk of recurrence of GH in the first subsequent pregnancy significantly.Conclusions. (H)ELLP syndrome is a severe complication of pregnancy that has not only short-term but also long-term sequelae.

Hb nijkerk: A new mutation at codons 138/139 of the β-giobin gene inducing severe hemolytic anemia in a dutch girl

We describe a new structural mutant of the β-globin chain in a 17-year-old Dutch Caucasian girl. The mutant is associated with a severe pathology as a consequence of hyper-instability of the hemoglobin tetramer. The proband, whose parents had no history of hemolysis, was admitted to the hospital at 5 months of age with hemolytic anemia and splenomegaly. No indications for autoimmune defects or enzymopathies were found. Repeated hemoglobin electrophoresis on cellulose acetate revealed no abnormalities. At the age of 17 years, a minor abnormal band of less than 1% was detected on starch gel electrophoresis, migrating slightly faster than Hb A2. Sequencing of the β-globin gene revealed heterozygosity for a 4 bp deletion (GCTA) in combination with a 1 bp insertion (T) at codons 138/139. This event eliminates two amino acids (Ala-Asn) and introduces a new residue (Tyr). We discuss the hematological and the pathophysiological consequences of this mutant, which is fully expressed as a gene product, and apparently assembled into unstable tetramers that precipitate shortly after.

Genetic factors in relation to drugs.

In this review, recent developments in the area of pharmacogenetics will be emphasized that, according to the author's view, are especially important. References prior to 1964, the time covered by the previous review for this series by Kalow (79), have been excluded except where it seemed essential for clarity. Since the last general review appeared, numerous authors (38, 39, 80-82, 88, 89, 110, 112, 127, 128) have either surveyed the general field of pharmacogenetics or considered certain aspects of the area. Each has em­ phasized certain disciplines. In the following, consideration will be limited to those areas wherein there is a clear link between genetic factors and drug effects in man. Animal studies have been excluded except when they provide better understanding of studies in man. Also omitted from consideration here is the large area of resistance of microorganisms to the action of drugs, studies of which have provided so much basic information on the mechanisms of antibacterial chemotherapy. Similarly, the resistance of insects to in­ secticides has also been excluded. The history of hemolysis of erythrocytes by drugs began more than a century ago, and the number of hemolytic agents known today approxi­ mately parallels the development of pharmaceutical chemistry. Dausset & Contu (25) listed more than 50 drugs reported to have induced hemolysis of red blood cells under certain circumstances. These conditions include hemo­ lysis in normal erythrocytes, in red blood cells deficient in certain enzymes or co factors, in the newborn, and in individuals with various hemoglobinop­ athies. Although normal individuals may show hemolysis of red blood cells when exposed to a sufficiently high concentration of the hemolytic drugs, we are concerned here with those subjects in whom hemolysis occurs following a dose that ordinarily would have no effect in normal individuals. In sensitive individuals, the response, in numerous instances, results from some heredi­ tary deficiency or abnormality in metabolism of the red blood cell or in hemoglobin structure. The normal duration of active function and survival of the mature red cell is remarkahle since it has no nucleus, mitochondria, endoplastic reticulum,