Sudden death due to massive bone marrow sequestration crisis in a patient with sickle cell disease
Authors: Jose Archuleta, Marcella van der Graaf, Fleur H. J. Kaptein, Lars Althaus, Nina Kooij, John‐John Schnog
Journal: American Journal of Hematology (2021)

Sickle cell disease (SCD) is a severe hemoglobinopathy characterized by an increased susceptibility to infections, chronic hemolytic anemia and continuous micro-vascular occlusion with acute exacerbations leading to accumulating organ damage and a decreased life expectancy.1 One of the most acutely life-threatening complications is the splenic sequestration crisis. Sluggish blood flow through splenic sinusoids with low oxygen tension and low pH favor the sickling process. Acute splenic pooling of blood can lead to hypovolemic shock and death. This occurs mostly in children with sickle cell anemia (HbSS) prior to the occurrence of splenic infarction with ensuing atrophy. In sickle cell patients with compound heterozygous states or hereditary persistence of fetal hemoglobin (HPFH) (or drug induced elevated fetal hemoglobin [HbF]%) the spleen remains anatomically intact and thus these patients remain at risk for this complication. Chronic sequestration of sickle erythrocytes can occur in the liver, leading to hepatomegaly which can also, in severe forms, lead to rapid liver enlargement, extreme jaundice and circulatory collapse. Here we present, to our knowledge, the first case of sudden death in a sickle cell patient due to massive sequestration of blood in the bone marrow. A 19-year-old female with sickle cell anemia was admitted to our hospital with a painful crisis. Her high-performance liquid chromatography result was compatible with HPFH (HbF of 29.2%, a normal HbA2 and the remaining hemoglobin constituting HbS). She rarely suffered painful crises and experienced no other specific complications. Several weeks earlier she was diagnosed with IgG4-related hepatitis. She had persistently elevated ALAT and ASAT levels with normal liver function tests. Viral serology, ANA screen, anti-mitochondrial antibodies were all negative, with normal serum ceruloplasmin and antitrypsin concentrations. Ultrasound revealed a normal sized liver and spleen (respective length, width and height being 6.3 x 3.9 x 6.7 in and 2.3 x 3.2 x 3.7 in). Serum IgG4 levels were increased (7.16 g/L, ULN 1.40). A liver biopsy revealed marked chronic inflammation and fibrosis grade 2. She started oral corticosteroids (1 mg/kg) with rapid normalization of ALAT and ASAT concentrations. At admission she was on folic acid and a tapering dose of prednisone (40 mg daily) which were continued. She had pain in both upper arms and lower back, recognizable as that of a painful crisis. Vital signs were normal (BP 118/65 mmHg, pulse rate 88/minute, oxygen saturation on room air 99%, temperature 98.1 °F) and there was no organomegaly. Her weight, length and BMI were 128 lb, 5.1 ft and 24 kg/m2, respectively. Laboratory studies at admission (day 1) are shown in the Supplementary table 1. Kidney function and electrolytes were normal. She received parenteral hydration with 3 liters of saline (0.45%) per 24 hours, acetaminophen and morphine. On the 3rd day she was almost free of pain, blood work revealed no unexpected findings (Supplementary Table 1), and discharge was planned for the next day. In the morning of day 4 she felt nauseated and went to the bathroom where she vomited once. She was hypotensive (BP 77/56 mmHg, pulse rate 102/minute, respiration rate 16/minute, oxygen saturation on room air 99%, temperature 97.5 °F), erroneously interpreted by the attending nurse as a vagal reaction to vomiting and she was guided back to her bed. She was found unresponsive shortly thereafter and immediate cardiopulmonary resuscitation (CPR) was started. She was in asystole. There was no indication of pneumothorax, no organomegaly, capillary blood glucose excluded hypoglycemia. Despite absence of right heart strain on cardiac ultrasound the thrombolytic agent, alteplase was administered with a working diagnosis of pulmonary embolism. After several attempts finally blood could be drawn via the femoral artery and arterial blood gas analysis revealed severe lactic acidosis and severe anemia (Supplementary Table 1). CPR was stopped after 74 minutes, and she was pronounced dead. Permission for autopsy was granted. Macroscopic examination ruled out acute myocardial infarction, pulmonary thromboembolism and stroke. The most striking feature was that during the organ dissection there was hardly any blood within the blood vessels, as seen in cases of complete exsanguination. There was no blood in the gastro-intestinal tract. For this reason, forensic pathology was consulted. There were no findings suggesting external or internal blood vessel trauma or puncture or hematoma. The respective weights of liver and spleen were 3.35 and 0.49 lb, ruling out massive acute splenic and/or hepatic sequestration of blood as the cause of the almost empty vascular bed. The weight of the lungs was normal. Microscopic findings of the liver and spleen revealed red cell entrapment (Figure 1A,B) without red cell entrapment in the lungs (Figure 1C). Examination of a lumbar vertebra revealed massive entrapment of sickled red blood cells (Figure 1D). Based on these findings it seems that circulatory arrest occurred largely due to acute blood sequestration in the bone marrow. A bone marrow sequestration crisis has not, to our knowledge, been previously described. Normal bone marrow histology shows at least 95% hematological precursor cells, with a few mature red cells occurring in transit to or in the microvascular space. In our patient, the marrow was massively engorged with mature red cells, comparable to findings as described in pathology studies of splenic sequestration crises.2 The acute circulatory collapse, absence of blood in the vessels and massive red cell sequestration in the marrow indicate that a mechanism similar to splenic and hepatic sequestration had occurred in the marrow. Based on the lowest normal weight estimates of liver and spleen in females with a BMI 18.5–25 kg/m2 (normal ranges 1.71–4.29 and 0.11–0.57 lb respectively),3 the maximal weight gain of liver and spleen in our patient is 1.64 and 0.38 lb (total 2.02 lb corresponding to 916 ml). To classify as class IV circulatory shock, at least 1085 mL (2000–916 mL) of blood must have been sequestered in the marrow space. However, given the normal hepatic and splenic size on ultrasound and their respective weights at autopsy, it is likely that an even larger blood volume was entrapped in the marrow space leading to her fatal circulatory collapse. Vaso-occlusion of the microvasculature leading to ischemia and bone marrow infarction with ensuing pain is the hallmark complication of SCD.1 In sickle cell patients, magnetic resonance imaging and pathology studies have shown that fatty marrow of the appendicular skeleton is replaced by hematopoietic marrow in especially metaphyseal and diaphyseal space, and that infarction in SCD readily occurs in such areas of active hematopoiesis.4 The anatomy of the bone marrow vascularization carries some similarities with the splenic circulation with sluggish flow in a low pO2 environment in deeper sinusoidal regions5 and lower pH 6 favoring the sickling process. The bone marrow constitutes one of the largest organs in the body and the marrow space allows rapid intraosseous infusion (IOI) of fluids in for example circulatory shock,7 even though volume administered via IOI exits the marrow space to the intravascular compartment rapidly. Outflow obstruction due to large scale vaso-occlusion of microvasculature in bone marrow by sickled cells could therefore lead to large volume blood sequestration of in the marrow. In mice, it is estimated that up to 30% of marrow tissue volume can encompass blood, which, in an average human with a marrow mass of 6.61 lb would, correspond to a volume of 900 mL.7 Massive marrow sequestration such as described here is likely a very rare event. For acute splenic sequestration crises, a clear trigger is often not recognized. It is not clear what triggered the massive marrow sequestration in our patient. There is no association in literature of IgG4 disease with SCD, rendering the IgG4 related hepatitis unlikely to harbor a causal relation to the marrow sequestration crisis. Corticosteroids may actually abate acute vaso-occlusive painful events,8 which were continued during admission in our patient. Accumulating marrow fibrosis due to continuous silent and acute vaso-occlusion is probably protective against a massive bone marrow sequestration crisis in analogy to protection against acute splenic sequestration crisis due to splenic fibrosis. However, in patients with for example HPFH, lack of fibrotic marrow changes may actually render them more susceptible to this rare event. In conclusion, we present, to our knowledge, a first case of a sickle sequestration crisis with the main organ of blood entrapment being the bone marrow. This is very likely an extremely rare event. Prompt recognition of a sequestration crisis is paramount in order to institute timely intervention, and therefore clinician awareness of this newly described complication is of importance. A bone marrow sequestration crisis should be considered in sickle cell patients with circulatory compromise without another explanation. Treatment should be in analogy to the management of splenic or hepatic sequestration crisis with immediate volume and red cell repletion. Importantly, with potential subsequent release of red cells from the bone marrow into the circulation, as can occur during resolution of a splenic or hepatic sequestration crisis, bloodletting may be indicated in order to keep the hematocrit below 30% in order to prevent hyper-viscosity with ensuing vaso-occlusive complications.9 All authors contributed to design and writing of the manuscript. The authors declare no conflict of interest. The authors received no specific funding for this work. Data sharing not applicable - no new data generated. Supplementary Table 1: Laboratory studies Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.