Keeping it in the family: Three relatives with HbSC disease and simultaneous acute pulmonary emboli
Authors: Finn Hawkins, Noelle Ebel, George P. Sorescu, Lillian McMahon, Philippa Sprinz, Elizabeth S. Klings
Journal: American Journal of Hematology (2011)

A 30-year-old African American female (Patient #1) with Hemoglobin SC (HbSC) disease presented with a 1 week history of progressive left flank and lower extremity pain with diffuse myalgias. She had a history of multiple prior vasoocclusive episodes requiring simple and exchange transfusions. At the time of admission on physical examination, she was afebrile and hemodynamically stable with an oxygen saturation of 100% in ambient air. The only pertinent finding was mild diffuse abdominal tenderness. Laboratory studies are summarized in Table 1 and were significant for leukocytosis with a left shift, anemia worse than baseline, a depressed reticulocyte count, a normal bilirubin but a mild elevation in transaminases. Chest radiography was normal. HbSC disease is a compound heterozygous condition characterized by inheritance of one gene for “S” hemoglobin (Glu-Val substitution in the 6th position of the β-globin chain) and one gene for “C” hemoglobin (Glu-Lys substitution in the 6th position of the β-globin chain), with subsequent formation of similar levels of HbS and HbC within the erythrocyte. HbCC disease is a non-sickling disorder which results in a mild hemolytic anemia. The combination of HbS and HbC is much more clinically significant suggesting that HbS has major disease modifying effect. Population studies suggest that while patients with HbSC have less frequent complications occurring later in life than those with HbSS disease, when complications occur they can be equally severe. In contrast, there is generally milder anemia and hemolytic complications, including aplastic episodes and cholelithiasis are less severe compared to HbSS disease [1]. In our first patient, the presence of diffuse pain was suggestive of a vasoocclusive episode (VOE). There were no abnormalities on history, physical exam, or chest radiography suggestive of acute chest syndrome (ACS). In terms of anemia, this patient was noted to have approximately a 3.5 g decrease in Hb concentration with an inappropriately low reticulocyte response. This suggested a VOE complicated by an aplastic crisis. Patient #1 was admitted to the medical service and commenced on treatment for a vasoocclusive epsiode with intravenous fluids and analgesics. She was commenced on low molecular weight heparin (LMWH) for deep venous thrombosis (DVT) prophylaxis. A red blood cell transfusion was administered for treatment of symptomatic anemia. The next day, the 24-year-old brother of Patient #1 (Patient #2), was admitted to the medical service. He also had HbSC disease and lived in same household as Patient #1. He had a history of cough productive of green sputum, fever, chills, myalgia and lower back pain for one week prior to admission. On physical examination, he was afebrile and had an oxygen saturation of 100% in ambient air. The rest of his exam was unremarkable other than pain with limb and spine motion. Laboratory studies are summarized in Table 1 and were significant for a leukocytosis with a left shift, worse anemia from baseline, an abnormally reduced reticulocyte response and mild hyperbilirubinemia. Chest radiography was normal. He was treated with intravenous fluids, analgesics and was administered LMWH for DVT prophylaxis. One of the recognized complications of sickle cell disease (SCD) is a reticulocytopenic anemia, referred to as an aplastic crisis or episode. This condition can be associated with a decrease in any peripheral blood cell lines, but most commonly, there are decreased mature erythrocytes and reticulocytes, and this is referred to as transient red cell aplasia (TRCA) [2]. A number of infectious agents have been implicated as either being causative or temporally related to such an episode. The best detailed of these is Parvovirus B19 (HPV B19), the causative agent of fifth disease. This virus is the only member of the Parvoviridae family known to be pathogenic in humans, occurring world-wide endemically [3]. Most infections occur in children and young adults and are highly contagious. The association between parvovirus infection and hypoplastic episodes in sickle cell anemia was first identified in 1981, when sera from 600 children in a London hospital were analyzed for HPV B19. Six children were identified with either the presence of the B19 antigen or its acute phase antibody [4]. All six were originally from Jamaica, had SCD with worsening anemia and evidence of bone marrow erythroid hypoplasia [4]. Other viruses recognized to be associated with red cell aplasia, although not specifically in SCD, include Epstein Barr, mumps, hepatitis, and Human Herpes virus 6 [5, 6]. On hospital day 2, Patient #1 became acutely hypoxemic with oxygen saturations ranging between 60 and 75% in ambient air. She was tachycardic with heart rates approximating 150 beats per minute (bpm) associated with increasing somnolence. She was transferred to the Medical Intensive Care Unit for further management. There are a number of potential causes of acute hypoxemia in a SCD patient experiencing a vasoocclusive episode. These include ACS, pneumonia, pulmonary embolism (PE), transfusion-related acute lung injury, pulmonary edema and hypoventilation-related atelectasis secondary to pain or the neuro-sedating effects of analgesics with ACS being the most common etiology. ACS is the most frequently reported cause of death in SCD adults [7, 8], the second most common reason for hospital admission and the most common reason for intensive care unit admission among SCD patients [7]. ACS describes a clinical syndrome defined by the presence of a new infiltrate with symptoms including chest pain, dyspnea, cough, wheezing and fever. There are multiple known inciting triggers for ACS and each of the potential causes of hypoxemia in this patient has been linked to ACS previously. Pulmonary infections such as pneumonia are an important cause of morbidity and mortality in SCD patients and are the most common trigger for ACS. SCD patients are at increased infectious risk because of impaired host defenses, loss of antibody protection via auto-splenectomy and impaired neutrophil opsonization [9, 10]. Common pulmonary pathogens in SCD include Mycoplasma pneumoniae, Chlamydia pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae and a number of viruses [11]. There is an increased incidence of PE amongst hospitalized patients with sickle cell disease compared to age-matched patients without SCD making this a possibility in this case [12]. Less common causes for hypoxemia in this scenario include complications related to the treatment of a vaso-occlusive crisis. There is an increased incidence of diastolic dysfunction in SCD patients [13] and these patients may be less tolerant of large fluid infusions. Erythrocyte transfusion commonly prescribed in SCD can lead to transfusion related acute lung injury, a condition difficult to distinguish clinically from ACS [14]. The acute pain of a VOE can produce hypoventilation and sub-segmental atelectasis, particularly in the setting of rib infarctions. Appropriate pain control and incentive spirometry [15] may help prevent the respiratory complications of pain but physicians need to be aware that opioid narcosis can also produce somnolence with consequent hypoventilation and hypoxemia. Patient #1 was deemed to be too medically unstable to leave the floor for a diagnostic CT pulmonary angiogram (CT/PA gram) or ventilation-perfusion scan. Instead, she underwent a bedside echocardiogram which revealed normal left ventricular function with an ejection fraction of 50%. The right ventricle was moderately dilated with severely reduced systolic function. There was flattening of the interventricular septum during systole and diastole with sparing of the apex. The pulmonary artery systolic pressure (PASP) was estimated to be at least 49 mmHg. This echocardiogram is consistent with elevated pulmonary pressures and normal left-sided cardiac function. Echocardiography can be used to screen for abnormalities of cardiac structure, function and hemodynamics. The right ventricular systolic pressure (RVSP) or PASP can be estimated from the peak velocity of regurgitant flow across the tricuspid valve (TRV) using the Bernoulli equation which includes the addition of the estimated right atrial pressure to 4 (TRV)2. Additional echocardiographic findings suggestive of elevated pulmonary pressures include right ventricular dilation and/or hypertrophy, right atrial enlargement and flattening of the interventricular septum with systole and diastole suggestive of a right ventricular pressure that is equal to or greater than the left ventricular pressure. The presence of elevated right-sided pressures by echocardiography is a non-specific finding in SCD. Although suggestive of pulmonary hypertension (PH) when present in a clinically stable outpatient, acute increases in PA pressures can be observed during a VOE, ACS, or an acute PE [16]. Echocardiography can be used to aid in the diagnosis of a pulmonary embolism, however, many of the findings by this modality are non-specific. Generally, in patients without co-existent cardiopulmonary disease, obstruction of at least 50% of the pulmonary vascular bed must occur for elevations in right-sided pressures to be observed. As such, only 30–40% of patients with an acute PE will have an abnormal echocardiogram. Echocardiographic features suggestive of a PE include RV dilation and decreased systolic function, tricuspid valve regurgitation, regional wall motion abnormalities that spare the apex of the right ventricle (McConnell's sign) and rarely, a thrombus within the right ventricle [17]. The link between an acute PE and the long-term development of PH in SCD is unknown at this time. Patient #1 underwent a CT/PA gram the following day, when she was deemed more clinically stable, which revealed multiple, bilateral filling defects within segmental and sub-segmental pulmonary arteries consistent with multiple pulmonary emboli and the dose of LMWH was increased to treatment-level dosing. On the day following admission, Patient #2 developed increased dyspnea, fatigue and headache associated with worsening hypoxemia. He now required supplemental oxygen at a rate of 6 l/min via nasal cannula. A CT/PA gram was performed which revealed pulmonary emboli within the left lower lobe and right middle lobe sub-segmental pulmonary arteries. Bibasilar opacities were present at both lung bases suggestive of atelectasis. The patient was commenced on treatment dose anti-coagulant therapy with low molecular weight heparin. Sickle cell disease is a hypercoagulable state. This appears to be due to increased activation of both platelets and the coagulation system [18-20]. Within the pulmonary vasculature, both venous thromboembolism (VTE) and in situ thromboses occur [18, 21]. A cross-sectional study of hospitalized SCD adults under the age of 40 revealed a prevalence of PE of 0.44% compared to 0.12% in African American controls of a similar age group [12]. Although, anecdotally, there appears to be an inter-relationship between pulmonary emboli and the presence of pulmonary hypertension, this has not been borne out thus far in the clinical literature [21-24]. However, the presence of unexplained hypoxemia in a SCD patient, regardless of their PH history, should prompt an evaluation for acute PE consisting of a CT pulmonary angiogram or radionuclide scanning. Three days following the admission of patient #1, her 7-year-old son (Patient #3) who also had HbSC disease and lived in the same household, was admitted to the Pediatric service, with a 2-day history of increased lethargy, back and right lower extremity pain. On admission, the patient's physical examination revealed a temperature of 97.8° F, heart rate of 114 bpm, BP of 100/73 and respiratory rate of 28 with an O2 saturation of 99% in ambient air. There were no significant findings on physical exam. His laboratory data is shown in Table 1. He was admitted for a vasoocclusive episode and worsening anemia. He did not receive DVT prophylaxis. On hospital day 2, despite hydration and adequate pain control he became tachycardic with heart rates in the 130–140 bpm range. His hemoglobin and reticulocyte counts did not worsen from admission and an increase in reticulocyte count to 6.1% was noted. Electrocardiography as well as chest and abdominal radiographs were within normal limits. No further changes in management occurred. On hospital day 4, he became acutely tachypneic with a respiratory rate up to 60/min and a decrease in his oxygen saturation to 86–88% in room air. His physical examination now revealed a new 2/6 systolic ejection murmur and diminished breath sounds at both lung bases. A repeat chest x-ray showed new focal, parenchymal opacities in the right lower and left lower lobes with bilateral pleural effusions. He was transferred to the Pediatric ICU for worsening hypoxemia. He became febrile to 103.1° F and following cultures, was commenced on Ceftriaxone and Azithromycin. In children and adolescents with SCD, ACS is the most common cause of death [11]. The etiology of ACS is multi-factorial and in some cases, may be due to pulmonary infections, fat and bone marrow embolization or increased adherence of sickled erythrocytes, leukocytes and platelets to the pulmonary vascular endothelium producing lung injury and infarction [25]. The peak incidence of ACS occurs in children between two and four years. In most of these young children, there is an infectious etiology identified. Nearly half of the cases of ACS occur in patients initially admitted to hospital for a different reason, usually a VOE [11]. A change in the patient's cardiopulmonary status after admission should prompt the physician to perform a more comprehensive workup. In this case, this patient's worsening hypoxemia, tachypnea and tachycardia could be due to ACS, however, because of the acuity and serious nature of his deterioration, other diagnoses were considered including pulmonary embolism, pneumonia, pneumothorax or pulmonary edema. Pulmonary edema and pulmonary embolism are both unusual diagnoses to occur in the general pediatric population. Pediatric patients with SCD however are at increased risk for both. With concern for a PE, patient #3 underwent a CTPA gram which revealed bilateral pulmonary emboli (Fig. 1). A work up was unrevealing for a primary hypercoagulable state. He was commenced on treatment dose low molecular weight heparin. Parvovirus titers confirmed a current infection with an IgM of 8.23 IV (normal < 1.1 IV). Parvovirus titers from patients #1 and 2 were 8.33 IV and 7.88 IV respectively. All of these titers returned to normal approximately 4 weeks after hospitalization confirming acute Parvovirus B19 infection in all three patients. CT pulmonary angiogram (coronal section) from patient #3 demonstrating pulmonary embolism in the right pulmonary artery (white arrow). CT scan also demonstrates right middle and lower lobe atelectasis and consolidation. These cases illustrate pulmonary emboli in the setting of an acute Parvovirus B19 infection in HbSC patients. One of the major questions raised by this case is whether these emboli were thrombotic or due to fat emboli. SCD is a hypercoagulable state and even patients with sickle cell trait appear to be at increased risk for VTE [18, 26]. Increased platelet activation, abnormal interactions between platelets and the vascular endothelium, platelet genetic heterogeneity and dysregulation of the coagulation cascade are amongst the implicated mechanisms for this pathology [18-20, 27]; it is not clear, however, the exact role that each of these play in thrombosis generation. Embolic disease has long been an associated cause of ACS. Most classically, this is due to fat embolism, identified in 8.8% of 671 cases of ACS enrolled as part of the multi-center National Acute Chest Syndrome Study Group. However, in 16% of cases, a pulmonary infarction was implicated but, in nearly 46%, no clear cause was identified [11]. Unfortunately, no diagnostic studies are perfect for differentiating between emboli which are primarily thrombotic as compared to those that are comprised of fat. Typically, patients with fat embolism syndrome will have cutaneous and cerebral manifestations but, in up to 25%, only pulmonary symptoms occur [28]. The lack of systemic findings in these cases makes the presence of fat embolism syndrome less likely but in no way is this definitive. One major question to arise from these cases surrounds the optimal diagnostic strategy to differentiate between thrombotic and fat emboli in SCD. The current state of the literature does not provide a clear diagnostic strategy and because of this, management between centers can be quite divergent. The link between acute Parvovirus B19 infection and increased thrombotic risk is provocative. Case reports have identified a potential causal link between HPV 19 infection and the catastrophic systemic fat embolism syndrome in SCD [29-31]. The link between HPV B19 infection and a variety of auto-immune disorders has been described. Two case series in non-SCD patients describe the transient induction of antiphospholipid antibodies with resultant pulmonary emboli in the setting of acute HPV 19 infection [32, 33]. One case report describes parvovirus infection followed by thromboembolic stroke and transient antiphospholipid antibodies in a pediatric SCD patient [34]. This is thought to occur as a result of Parvovirus B19 induced phospholipase A2-like activity leading to an increased inflammatory response and induction of auto-antibodies [18]. Despite this association and the link between HPV 19 infection and ACS, very little is known about the association of parvovirus illnesses and hypercoagulability in SCD patients. This is an interesting question that may lead to further insights into the pathogenesis of SCD related vascular disease. In summary, many unanswered questions remain concerning these interesting cases. Much is not known about the inter-relationship between thromboembolic disease and the two primary pulmonary complications of SCD, the acute chest syndrome and pulmonary hypertension and we believe that this is an important avenue for future research interest. We present these cases to stimulate future research efforts in studying this interesting potential disease modulator.