Cerebrovascular disease associated with sickle cell pulmonary hypertension

In patients with sickle cell disease, anemia is a recognized risk factor for stroke, death, and the development of pulmonary hypertension. We have proposed that hemolytic anemia results in endothelial dysfunction and vascular instability and can ultimately lead to a proliferative vasculopathy leading to pulmonary hypertension. Consistent with this mechanism of disease, we now report a case series of six patients with obliterative central nervous system vasculopathy who also have pulmonary hypertension and high hemolytic rate. These patients, identified in the course of a prospective screening study for pulmonary hypertension, presented with neurological symptoms prompting neuroimaging studies. Compared to 164 other patients of similar age in the screened population, those with newly diagnosed or clinically active cerebrovascular disease have significantly lower hemoglobin levels and higher levels of lactate dehydrogenase. A review of the literature suggests that many clinical, epidemiological, and physiological features of the arteriopathy of pulmonary hypertension closely overlap with those of stroke in sickle cell disease, both known to involve proliferative vascular intimal and smooth muscle hypertrophy and thrombosis. These cases suggest that cerebrovascular disease and pulmonary hypertension in sickle cell disease share common mechanisms, in particular, reduced nitric oxide bioactivity associated with particularly high-grade hemolysis. Clinicians should suspect occult cerebrovascular disease in sickle cell patients with pulmonary hypertension.     

Staged single-ventricle palliation in an infant with hemoglobin SC disease

Staged single-ventricle palliation is used to treat many cyanotic congenital heart diseases. Hemoglobin sickle cell disease is associated with anemia and significant vascular sickling sequelae, which increase the risk associated with single-ventricle palliation. To our knowledge, there are no reports in the English-language medical literature of single-ventricle palliation having been performed on a patient who had either sickle cell anemia or sickle cell-hemoglobin C disease. Herein, we discuss our clinical and surgical management of an infant with tricuspid atresia type IA and hemoglobin sickle cell disease who survived single-ventricle palliative procedures through the 2nd stage of a bidirectional Glenn anastomosis.     

The pathophysiology, prevention, and treatment of stroke in sickle cell disease

PURPOSE OF REVIEW: Stroke is one of the most devastating complications of sickle cell disease, but current research has led to improved understanding of its pathogenesis and to new approaches in the prevention of both primary and secondary stroke. This review focuses on advances reported in the past 2 years. RECENT FINDINGS: New concepts in the pathophysiology of central nervous system events in sickle cell disease have centered around hemolytic anemia and nitric oxide metabolism. Genetic risk factors are now being explored. Major improvement in primary stroke prevention has occurred through transcranial Doppler ultrasonography screening, but utilization of this technique is far from optimal. Hydroxyurea is now being tested as an alternative approach to chronic transfusion for secondary stroke prevention through a multicenter trial. Other studies are addressing the management of silent infarcts and nocturnal hypoxemia. SUMMARY: Increased understanding of the etiology and pathogenesis of stroke in sickle cell disease should eventually lead to improved management of all central nervous system complications. Alternative secondary stroke prevention with hydroxyurea may allow patients to avoid dependence on life-long chronic transfusion. Primary stroke prevention through transcranial Doppler ultrasonography screening may ultimately yield a dramatic reduction in the incidence of stroke in sickle cell disease.     

Perinatal Maternal Mortality in Sickle Cell Anemia: Two Case Reports and Review of the Literature

As outcomes of patients with sickle cell anemia improve and survival into adulthood with good quality of life and expectation of long-term survival becomes more common, challenges have developed, including issues related to reproduction. Pregnancy is frequently complicated in patients with sickle cell anemia with mortality up to 4.0%. Here we report maternal perinatal mortality in two women with sickle cell anemia who died post-partum due to acute chest syndrome (ACS), caused by bone marrow fat embolism and review the literature pertinent to this subject. Patient A was a 28-year-old woman with sickle cell anemia with multiple complications. At 30 weeks’ gestation she developed hemolysis associated with poor placental function necessitating delivery by C-section. The fetus was delivered successfully but she died due to multi organ failure after delivery. Autopsy showed pulmonary and amniotic fluid embolization. Patient B was a 37-year-old woman with uncomplicated sickle cell anemia who presented with pre term labor and crisis, then ACS and fetal distress. The infant was delivered successfully but the patient died after cardiovascular collapse. Autopsy results showed fat and bone marrow embolization as the cause of death. Pregnancy continues to be high risk for patients with sickle cell anemia including those with mild disease. Maternal perinatal mortality could be unpredictable due to serious complications of sickle cell disease. More studies to assess maternal perinatal mortality are needed.     

Acute pancreatitis during sickle cell vaso-occlusive painful crisis

Sickle cell disease is characterized by chronic hemolytic anemia and vaso-occlusive painful crisis. The vascular occlusion in sickle cell disease is a complex process and accounts for the majority of the clinical manifestations of the disease. Abdominal pain is an important component of vaso-occlusive painful crisis and may mimic diseases such as acute appendicitis and cholecystitis. Acute pancreatitis is rarely included as a cause of abdominal pain in patients with sickle cell disease. When it occurs it may result form biliary obstruction, but in other instances it might be a consequence of microvessel occlusion causing ischemia. In this series we describe four cases of acute pancreatitis in patients with sickle cell disease apparently due to microvascular occlusion and ischemic injury to the pancreas. All patients responded to conservative management. Acute pancreatitis should be considered in the differential diagnosis of abdominal pain in patients with sickle cell disease.     

Hypothyroidism in adults with sickle cell anemia.

Persons with sickle cell anemia have several indications for transfusion of red blood cells. One of the complications of transfusion of red blood cells is iron overload. Iron overload has been associated with multiple endocrine abnormalities. We report herein three cases of hypothyroidism in adult individuals with sickle cell disease. All three patients were over the age of 45 years at the time of the diagnosis and had received multiple units of transfused red blood cells and had serum ferritin levels of greater than 6,000 ng/mL. All patients were diagnosed during times when they were critically ill. Replacement therapy was instituted in all cases; however, all three patients died shortly after the diagnosis of hypothyroidism was made. Congestive heart failure appeared to be a primary cause of death in all three patients. In the one patient in whom a postmortem examination was done, there was evident extensive fibrosis of the thyroid gland as well as extensive deposition of iron in the cells lining the thyroid follicles. We believe that this represents the first report of clinical hypothyroidism in patients with sickle cell anemia who have received multiple transfusions. Awareness of this condition is especially important given that congestive heart failure is common in sickle cell disease.     

Prevention and management of strokes in patients with sickle cell disease

Overt strokes occur in about 11% of children with sickle cell disease, and many more develop silent infarcts. Until recently, the only available management intervention was the use of chronic transfusions to prevent stroke recurrence. The stroke prevention trial in sickle cell anemia (STOP) demonstrated that children at risk for strokes can be identified by transcranial Doppler (TCD) ultrasonography. In high-risk patients, the risk of first stroke can be decreased by 90% if patients are placed on chronic transfusion regimens. However, transfusing all patients with abnormal TCD is also problematic; as many as 60% do not seem to develop a stroke. At this time, a more precise stratification of stroke risk based on imaging studies, genetic studies, and neuropsychological testing is needed. Moreover, the development of alternatives to chronic transfusions, such as hydroxyurea and other pharmacologic therapies, may also improve the outlook for patients at high risk for stroke.     

Defective regulation of complement by the sickle erythrocyte: evidence for a defect in control of membrane attack complex formation

A prominent clinical manifestation of sickle cell disease (SCD) is hemolytic anemia. Although complement activation can lead to intravascular hemolysis, its role in the hemolysis of SCD is not known. Because normal red blood cells induced to vesiculate by treatment with calcium and ionophore become sensitive to damage by activated complement and because sickle cells release microvesicles as they circulate, we postulated that sickle cells might also be unusually sensitive to complement-dependent hemolysis. Complement activation is tightly regulated on the membrane of the normal erythrocyte; therefore, defective complement regulation by the sickle cell would be necessary for complement-dependent hemolysis to occur. These studies show a defect in the regulation of membrane attack complex (C5b-9) formation in sickle erythrocytes, particularly in the most dense cells. The defect is characterized by increased binding of C5b-7 and of C9 to denser sickle cells and results in increased susceptibility of sickle cells to C5b-9-mediated (reactive) lysis initiated by either C5b6 or activated cobra venom factor. Among the densest sickle cells, irreversibly sickled cells are especially sensitive to reactive lysis. The similarity of this defect to that previously described in a patient with paroxysmal nocturnal hemoglobinuria suggests that complement- mediated hemolysis could play a role in the anemia of SCD.     

How I manage sickle cell patients with high transcranial doppler results

Stroke is one of the most severe complications to affect children with sickle cell anaemia (SCA). Transcranial doppler (TCD) is an accurate and non‐invasive method to determine stroke risk. Randomised controlled trials have demonstrated the efficacy of chronic transfusion therapy in stroke prevention based on risk stratification determined by TCD velocities. This has led to the regular use of TCD monitoring for children with SCA in order to determine stroke risk. Significant resource allocation is necessary to facilitate training, quality assurance and failsafe arrangements for non‐attenders. In a subgroup of patients, chronic transfusions for primary stroke prevention can be replaced by hydroxycarbamide therapy, provided careful monitoring is undertaken; including repeat TCD studies at frequent intervals. The authors propose an evidence‐based algorithm for the management of abnormal TCD velocities and discuss the role of this test in other clinical contexts, such as in Haemoglobin SC disease.     

Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia

Seven young adults with uric acid overproduction due to sickle cell anemia were normouricemic with a mean serum uric acid level of 4.9 mg/100 ml. Urate clearance was greater in these patients than in normal subjects or in patients with primary hyper-uricemia due to uric acid overproduction. The increase in urate clearance was entirely accounted for by increased pyrazinamide suppressible urate clearance. Pyrarinamide administration abolished the uricosuric response to ribonucleic acid (RNA) feeding in these patients with sickle cell anemia, and maximal uricosuric response to the administration of probenecid was similar in the patients with sickle cell anemia and in normal subjects suggesting that reabsorption of both filtered and secreted urate was not impaired in sickle cell disease. Pyrazlnamide suppressible urate clearance at maximal uricosuric response to probenecid was increased in patients with sickle cell disease suggesting increased tubular secretion of urate. This increase in urate secretion permits most young adults with urate overproduction due to sickle cell anemia to remain normouricemic and may account for the low frequency of secondary gout in this disease.     

Factor V Leiden is not responsible for stroke in patients with sickling disorders and is uncommon in African Americans with sickle cell disease

Cerebrovascular accidents in patients with sickle cell anemia are among the most devastating complications of the disease. It has recently been demonstrated that some patients have a hypercoagulable state on the basis of the presence of an abnormal factor V molecule, factor V Leiden. We undertook this study to evaluate the presence of factor V Leiden in sickle cell patients with stroke. Eighty-two patients with either Hgb SS, Hgb SC, or Hgb Sβ⁺-thalassemia comprised the study population. Of the 82 patients in the study, 19 of them had a history of stroke. In our study population, none of the stroke patients possessed the factor V Leiden mutation. One of the non-stroke patients was a heterozygote for the mutation (P = 1.00). The overall frequency of the factor V Leiden allele in our population is 0.6%. The estimated prevalence for this mutation is reportedly between 3 and 7% in Caucasian populations. We conclude that the gene frequency for factor V Leiden is less common in Africa Americans with sickle cell disease. Furthermore, factor V Leiden does not appear to be responsible for the development of stroke in sickle cell patients. Am. J. Hematol. 54:12–15, 1997. © 1997 Wiley-Liss, Inc.     

Unusual causes of abdominal pain: sickle cell anemia

Sickle cell disease is characterized by chronic hemolytic anemia and vaso-occlusive painful crises. The vascular occlusion in sickle cell disease is a complex process and accounts for the majority of the clinical manifestation of the disease. Abdominal pain is an important component of vaso-occlusive painful crises. It often represents a substantial diagnostic challenge in this population of patients. These episodes are often attributed to micro-vessel occlusion and infarcts of mesentery and abdominal viscera. Abdominal pain due to sickle cell vaso-occlusive crisis is often indistinguishable from an acute intra-abdominal disease process such as acute cholecystitis, acute pancreatitis, hepatic infarction, ischemic colitis and acute appendicitis. In the majority of cases, however, no specific cause is identified and spontaneous resolution occurs. This chapter will focus on etiologies, pathophysiology and management of abdominal pain in patients with sickle cell disease.     

Clinical presentation of severe anemia in pediatric patients with sickle cell anemia seen in Enugu,Nigeria

Anemia is a major cause of morbidity and mortality among patients with sickle cell anemia. In this study, 108 episodes of severe anemia were prospectively evaluated in 108 patients with hemoglobin SS disease attending the pediatric sickle cell clinic of the University of Nigeria Teaching Hospital, Enugu, Nigeria. Young children between the ages of 2 and 4 years were found to be at the greatest risk of developing anemic crises (severe anemia). There was a gradual but progressive decline in the incidence of severe anemia in the age range 8-16 years old. Upper respiratory tract infections are the most commonly associated infections in patients with severe anemia. Others included malaria, septicemia, urinary tract infection, acute chest syndrome, and osteomyelitis. Their role in precipitating episodes of severe anemia among the patients studied could not be fully evaluated. Pallor, jaundice, and fever were the most commonly encountered symptoms in patients with severe anemia on admission. About half of the parents/guardians failed to notice severe anemia among the patients studied, perhaps due to the dark color of the African skin. Caregivers need to be educated on how to recognize anemia among patients with sickle cell anemia when they develop febrile episodes.     

Chronic liver disease in a patient with sickle cell anemia.

Various disorders of the hepatobiliary system can occur due to sickling in patients with sickle cell anemia. Pathology and frequency of these disorders are not clearly known. Liver biopsies of these patients show erythrocytosis, erythrophagocytosis, sinusoidal dilatation and hyperplasia in Kupffer cells. We present a 21-year-old male patient diagnosed with sickle cell anemia who developed chronic liver disease, together with a review of the literature.     

Chronic liver disease in a patient with sickle cell anemia.

Various disorders of the hepatobiliary system can occur due to sickling in patients with sickle cell anemia. Pathology and frequency of these disorders are not clearly known. Liver biopsies of these patients show erythrocytosis, erythrophagocytosis, sinusoidal dilatation and hyperplasia in Kupffer cells. We present a 21-year-old male patient diagnosed with sickle cell anemia who developed chronic liver disease, together with a review of the literature.     

Kidney abnormalities in sickle cell disease

Patients with sickle cell disease exhibits numerous kidney structural and functional abnormalities, changes that are seen along the entire length of the nephron. Changes are most marked in patients with homozygous sickle cell anemia, but are also seen in those with compound heterozygous states and the sickle cell trait. The renal features of sickle cell disease include some of the most common reasons for referral to nephrologists, such as hematuria, proteinuria, tubular disturbances and chronic kidney disease. Therapy of these conditions requires specialized knowledge of their distinct pathogenic mechanisms. Spanish Haemathology and Hemotherapy Association has recently publicated their Clinical Practice Guidelines of SCD management. Renal chapter is reproduced in this article for Nefrología difussion.     

Leg ulcers in patients with sickle cell disease [see comments]

During the entry examination, leg ulcers were present in 2.5% of 2,075 patients 10 years of age and older with sickle cell disease who entered into the Cooperative Study of Sickle Cell Disease (CSSCD) between 1979 and 1986. Prevalence rates were highest among patients with sickle cell anemia and sickle cell anemia with thalassemia genotypes. Among sickle cell anemia patients free of ulcers at entry, the overall incidence was 5.73 per 100 person years in those having associated alpha-thalassemia and 9.97 for those without. Among sickle cell anemia patients with two alpha genes, the estimated incidence of leg ulcers is 2.38 per 100 person years and 6.12 per 100 person years among sickle cell anemia patients with three alpha genes (P less than .05). In both groups, the incidence was highest among those patients over 20 years of age and considerably higher among males than females (P less than .001). Leg ulcers were nonexistent in patients with sickle beta plus thalassemia and sickle hemoglobin C disease. Low steady-state hemoglobin is associated with a higher incidence of ulcer formation (P less than .0001) in sickle cell anemia patients. The protective effect of hemoglobin F is apparent at all levels of total hemoglobin among sickle cell anemia patients and those with associated alpha-thalassemia.     

Hydroxyurea-induced splenic regrowth in an adult patient with severe hemoglobin SC disease

Hydroxyurea has been extensively used in patients with sickle cell anemia and severe sickle cell-hemoglobin C (SC) disease to reduce the severity of their diseases. We report here our experience with an adult patient with severe SC disease who developed symptomatic splenomegaly requiring splenectomy while being treated with hydroxyurea. This case suggests that hydroxyurea might restore some splenic function in functionally asplenic patients with sickle cell anemia or SC disease, but also raises the clinical concern that hydroxyurea may induce splenic regrowth, resulting in symptomatic splenomegaly. With the increasing use of hydroxyurea in the management of SS disease or other hemoglobinopathies, the importance of spleen monitoring must be further emphasized in these patients.     

Mitral valve replacement in sickle cell disease

Cardiac dysfunction, including mitral valve regurgitation and congestive heart failure, can occur in patients with sickle cell disease. However, major surgery poses a greater risk in this population. This paper reports on the management of a patient with sickle cell disease who underwent successful replacement of the mitral valve.     

Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality

OBJECTIVE: To determine the incidence, clinical course, and risk factors associated with the onset of chronic renal failure in sickle cell anemia and sickle C disease. DESIGN: A prospective, 25-year longitudinal demographic and clinical cohort study. A matched case-control study was conducted to determine risk factors. PATIENTS: A total of 725 patients with sickle cell anemia and 209 patients with sickle C disease who received medical care from the hematology service in a large municipal hospital. Most were observed from birth or early childhood. MEASUREMENTS: Thirty-six patients developed sickle renal failure: 4.2% of patients with sickle cell anemia and 2.4% of patients with sickle C disease. The median age of disease onset for these patients was 23.1 and 49.9 years, respectively. Survival time for patients with sickle cell anemia after the diagnosis of sickle renal failure, despite dialysis, was 4 years, and the median age at the time of death was 27 years. Relative risk for mortality was 1.42 (95% Cl, 1.12 to 1.81; P = 0.02) compared with patients who did not develop renal insufficiency. MAIN RESULTS: Histopathologic studies showed characteristic lesions of glomerular "drop out" and glomerulosclerosis. Case-control analysis showed that ineffective erythropoiesis with increasingly severe anemia, hypertension, proteinuria, the nephrotic syndrome, and microscopic hematuria were significant pre-azotemic predictors of chronic renal failure. The risk for sickle renal failure was increased in patients who had inherited the Central African Republic beta s-gene cluster haplotype. CONCLUSIONS: The pre-azotemic manifestations of hypertension, proteinuria, and increasingly severe anemia predict end-stage renal failure in patients with sickle cell disease. The rate of progression of renal insufficiency is genetically determined. Treatment of the uremic phase has been dismal, underscoring the need for the development of useful pre-azotemic therapeutic modalities.