Joe C. Files

Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant.

pregnancy Complicated by Preeclampsia-eclampsia With the Syndrome of Hemolysis, Elevated Liver Enzymes, and Low Platelet Count : how Rapid is Postpartum Recovery?

The rapidity of postpartum disease recovery for severe preeclampsia associated with hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) has not been well studied. Between January 1980 and March 1989, 158 pregnancies with preeclampsia-eclampsia complicated by HELLP syndrome were managed at the University of Mississippi Medical Center. The 70 patients with platelet nadir below 50,000/microL (class 1 HELLP syndrome) required as long as 11 days for all members to achieve a platelet recovery concentration of more than 100,000/microL, whereas all 88 gravidas with platelet nadir between 50,000-100,000/microL (class 2 HELLP syndrome) exceeded this platelet concentration by the sixth postpartum day, a statistically significant difference (P less than .0001). The interval between delivery and the onset of diuresis (mean +/- SD) was significantly longer in class 1 than in class 2 patients with milder disease (22.7 +/- 18.9 compared with 15.9 +/- 11.1 hours). Significantly more postpartum days were required in class 1 than in class 2 HELLP parturients for the lactic dehydrogenase (LDH) concentration to decrease below 500 IU/L (4.2 +/- 4.9 compared with 3.2 +/- 2.7 days). No women in the class 2 group required plasma exchange therapy to effect disease arrest and reversal, but 11 of 58 severely ill women in class 1 were treated with this modality. We conclude that the platelet count and LDH serum concentration, as indicators of HELLP severity and recovery, are clinically useful tools and that a more protracted postpartum recovery period should be expected for progressively severe expressions of HELLP syndrome.

Admixture Mapping of White Cell Count: Genetic Locus Responsible for Lower White Blood Cell Count in the Health ABC and Jackson Heart Studies

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped across >or= 1322 single nucleotide polymorphisms that were pre-selected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p < 10(-12)). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained approximately 20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications.

Postpartum plasma exchange for atypical preeclampsia-eclampsia as HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome

OBJECTIVE Our purpose was to investigate the postpartum use of plasma exchange in patients considered to have atypical preeclampsia-eclampsia manifested as persistent HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome with or without evidence of other organ injury. STUDY DESIGN During a 10-year period, 18 patients with HELLP syndrome were treated post partum with single or multiple plasma exchange with fresh-frozen plasma. Each patient was entered into the clinical trial either because of persistent evidence of atypical preeclampsia-eclampsia as HELLP syndrome > 72 hours after delivery (group 1) or with evidence of worsening HELLP syndrome at any time post partum in association with single- or multiple-organ injury (group 2). All procedures were performed with the IBM 2997 Cell Separator (IBM, Cobe Laboratories, Inc., Lakewood, Colo.) system. Maternal and perinatal outcomes were the main outcomes studied. RESULTS In the absence of other disease conditions, the 9 patients in group 1 with persistent postpartum HELLP syndrome complicated only by severe clinical expressions of preeclampsia-eclampsia responded rapidly to one or two plasma exchange procedures with few complications and no maternal deaths. In contrast, in the 9 patients of group 2 with HELLP syndrome presentations complicated by other organ disease, the response to plasma exchange was variable and there were two deaths in this group. CONCLUSION The current series of patients details the successful postpartum application of plasma exchange therapy for unremitting HELLP syndrome but reveals that a uniformly positive response to this therapy will not always be observed when there is additional single or multiple organ injury.

The intrapartum platelet count in patients with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome: is it predictive of later hemorrhagic complications?

OBJECTIVE We wished to determine in patients with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) whether (1) there is an intrapartum threshold platelet count that is predictive of immediate or delayed hemorrhagic complications and (2) whether prophylactic platelet transfusion at delivery prevents these outcomes. STUDY DESIGN In this retrospective, descriptive study, the peripartal courses of 132 patients with class 1 (< or = 50,000/microliters platelet nadir) and 160 patients with class 2 (> 50,000 but < or = 100,000/microliters platelet nadir) HELLP syndrome were reviewed with special attention to laboratory data, evidence of hemorrhage, and details of platelet transfusion therapy. RESULTS A higher incidence of postpartum hemorrhagic complications (p < 0.001) occurred in class 1 versus class 2 HELLP pregnancies. The tendency to have postpartum incisional bleeding after abdominal or vaginal delivery was related to the degree of thrombocytopenia (p = 0.006). The antepartum threshold platelet count most predictive of subsequent postpartum hemorrhagic complications was < or = 40,000/microliters. The prophylactic administration of platelets does not appear to have either significantly decreased the incidence of postpartum hemorrhagic complications or significantly hastened normalization of the postpartum platelet count. CONCLUSIONS Although bleeding in the gravid patient is related to more factors than platelet count alone, patients with HELLP syndrome in whom an intrapartum platelet count above 40,000/microliters maintained are unlikely to have clinically significant postpartum bleeding. Patients with intrapartum platelet counts < or = 40,000/microliters, however, are at significant risk for postpartum bleeding, but prophylactic platelet transfusion at delivery does not ensure a significantly lower incidence of postpartum hemorrhagic complications.

Postpartum plasma exchange as adjunctive therapy for severe acute fatty liver of pregnancy

Acute fatty liver of pregnancy (AFLP) is a rare disease of progressive hepatic insufficiency and secondary systemic compromise that poses significant fetal‐maternal risk. Plasma exchange (PEX) is an effective bridge therapy to sustain liver function and enable hepatocellular regeneration to occur in nonpregnant patients following acute decompensation of a chronic liver disease or while awaiting liver transplantation. The application of PEX for patients with AFLP is a novel concept; since 1988 we have utilized postpartum PEX (PPEX) as adjunctive medical therapy for six patients with severe AFLP. Before PPEX initiation, four patients had signs and symptoms of encephalopathy, three required ventilatory support, five had advanced liver insufficiency, and all six were developing renal failure. PPEX was initiated 2–8 days following delivery and repeated (two to four times, mean = 3) at 24–48‐h intervals thereafter. All patients responded with composite clinical (symptoms/signs) and laboratory improvement; the average length of hospitalization following final PPEX for five of six patients was 7 days. No significant PPEX‐related complications occurred. PPEX utilization in patients with severe AFLP may enhance maternal recovery by preventing secondary sequelae from hepatic insufficiency until spontaneous healing can occur. Further study appears to be indicated to validate a role for PPEX as supportive therapy for puerperal patients with AFLP suffering multiorgan failure. J. Clin. Apheresis, 2008.

Autoimmune thrombocytopenic purpura: current concepts and recommended practices.

Autoimmune thrombocytopenic purpura is the most common autoimmune disorder encountered in the pregnant patient. It is potentially fatal for the mother and fetus yet treatable and potentially curable. Analysis of current perinatal literature reveals not only a great deal of interest and activity in the study of this syndrome and its special problems during pregnancy but also significant controversy. The disease can be acute or chronic and vary in time of onset and severity of manifestations. If not forewarned with an awareness of this disorders pathogenesis and potential fetal effects particularly in the pregnant woman who has undergone splenectomy, the obstetrician cannot respond appropriately. The usefulness of platelet antibody determinations to facilitate obstetric management decisions is discussed. The importance of cooperative care among the obstetrician, hematologist, and neonatologist is emphasized. Recommendations for management of autoimmune thrombocytopenic purpura in pregnancy are derived from a review of current concepts of the disorders pathogenesis, pathophysiology, criteria for diagnosis, and modes of therapy as well as special maternal/fetal considerations of antepartum, intrapartum, and postpartum care.

Automated erythrocyte exchange in fulminant falciparum malaria.

Excerpt With increasing travel to endemic areas and negligent prophylaxis, the number of gravely ill patients with malaria in this country is increasing (1). Prompt, effective treatment is essentia...

Thrombotic thrombocytopenic purpura : Evolution across 15 years

Thrombotic thrombocytopenic purpura (TTP) was originally described 70 years ago. It is considered an uncommon disorder with a reported occurrence rate of one case per 1 million patients. Mortality has decreased from almost 100% early on to 30–50% with the advent of newer treatment methods. We reviewed 41 patients with a diagnosis of TTP spanning the years 1980 to mid 1994. We found a much higher case rate, one per 6000 hosptial admissions, and an overall death rate of 40%. However, isolating 5 year periods we noted a marked fall in mortality from 54% (1980–1984), 44% (1985–1989), to 18% (1990–1994). Previous reports describe relapsing TTP and report an incidence of 7–15% although very recent data suggests a higher incidence. In our study, we found an overall relapse rate of 25% and by 5 year periods 23% (1980–1984), 13% (1985–1989), and 46% (1990–1994). We suggest that the improvement in survival and the increase in relapse rate are related and reflect more effective therapy for this once almost always fatal disease. Patients now survive their initial episode and thus are at risk for recurrence. Identification of risk factors for relapse will require further study.

Systemic treatment of cancer in the elderly

The goal of this review is to provide a readable and exhaustive reference in three major areas of geriatric oncology: complications of chemotherapy and radiotherapy, responsiveness of cancer to systemic treatment, social issues in the care of elderly patients with terminal illnesses. The conclusions of this study are: 1. Progressive deterioration of renal function is the most consistent change of aging. Adjustment of doses of renally excreted drugs to individual creatinine clearance may prevent life-threatening myelotoxicity in the elderly. 2. Intensive chemotherapy regimens (acute leukemia, non Hodgkins lymphoma) cause more serious and prolonged myelotoxicity in the elderly. Elderly are more susceptible than younger patients to cardiotoxicity and central and peripheral neurotoxicity. Age is a poor predictor of complications in other organs or systems. 3. The prognosis of patients with Hodgkins disease worsens with aging, possibly due to increased prevalence of mixed cellularity histology. It is controversial whether the prognosis of other neoplasias is poorer. Prognosis is not age-related in multiple myeloma. In general, elderly in good performance status may benefit from systemic cancer treatment to the same extent as younger patients, except for Hodgkins disease. 4. The Informal Support Network, epitomized by the family, appears the most suitable environment to care for the elderly with cancer.