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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Bol Asoc Med P R. Author manuscript; available in PMC 2017 March 9.
Published in final edited form as:
Bol Asoc Med P R. 2015 Jul-Sep; 107(3): 9–12.
PMCID: PMC5344193
NIHMSID: NIHMS842944

A Hispanic female patient with heartburn: A rare presentation of Paroxysmal Nocturnal Hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant, acquired clonal hematopoietic stem cell disease that can present with bone marrow failure, hemolytic anemia, smooth muscle dystonias, and thrombosis.

We present a case of a 32 year-old-female, G2P2A0 with no past medical history of any systemic illnesses who refers approximately 2 months of progressively worsening constant heartburn with associated abdominal discomfort. CBC showed leukopenia (WBC 2.9 × 103 /μL) with neutropenia (segmented neutrophils 48%), macrocytic anemia (Hgb 6.1 g/dL, hematocrit 20%, MCV 113 fL) and thrombocytopenia (platelet count 59 × 109/L). Abdomino-pelvic CT scan revealed a superior mesenteric vein thrombosis, which was treated initially with low-molecular-weight heparin for full anticoagulation. Peripheral blood flow cytometry assays revealed diminished expression of CD55 and CD59 on the erythrocytes, granulocytes and monocytes.

Paroxysmal nocturnal hemoglobinuria is a rare, clonal, hematopoietic stem-cell disorder whose manifestations are almost entirely explained by complement-mediated intravascular hemolysis. The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10 to 15 years, but with a wide range. Thrombosis is the leading cause of death, but others may die of complications of bone marrow failure, renal failure, myelodysplastic syndrome, and leukemia. Anticoagulation is only partially effective in preventing thrombosis in PNH; thus, thrombosis is an absolute indication for initiating treatment with Eculizumab. Nevertheless, bone marrow transplantation (BMT) is still the only curative therapy for PNH but is associated with significant morbidity and mortality.

Index words: Paroxysmal nocturnal hemoglobinuria, PIG-A gene, glycosyl phosphatidylinositol (GPI)–anchored proteins, complement, eculizumab

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant, acquired clonal hematopoietic stem cell disease that can present with bone marrow failure, hemolytic anemia, smooth muscle dystonias, and thrombosis.1 The disease arises from chronic and uncontrolled complement activation causing dysfunction in all 3 blood cell lines: red blood cells, white blood cells (both granulocytes and monocytes), and platelets.3 It is a rare disease, with a worldwide prevalence estimated in the range of 1–5 cases per million regardless of ethnicity; an increased prevalence is reported in some regions which also harbor higher incidence of aplastic anemia.5 The median age of presentation is 40 years, but the disease occurs in all age groups.2

We present the case of a 32 year-old-female with no past medical history of any systemic illnesses who presents with heartburn, abdominal discomfort and fatigue with associated occasional dizziness.

Case history

This is the case of a 32 year-old-female, G2P2A0with no past medical history of any systemic illnesses who refers approximately 2 months of progressively worsening constant heartburn with associated abdominal discomfort. Patient visited the emergency room on multiple occasions where she was treated for heartburn and gastritis with proton pump inhibitors and IV hydration without resolution of her symptoms. She says changing her diet and avoiding precipitating foods did not help. Abdominal symptoms progressed to a point of being intolerable. She reports associated nausea and fatigue as well as an orange-colored morning urine which later progressed to Coca-Cola colored urine. Denies vomiting, fever, chills, melena, hematochezia or any other constitutional symptoms. Family history is non-contributory. Social history is only pertinent for occasional alcohol use and surgical history relevant for two cesarean delivery which required patient to receive blood transfusions, and cholecystectomy. Upon physical examination patient is noted to be hypotensive (BP: 100/63 mmHg) with no orthostatic changes and heart rate within normal range (HR: 83 bpm). Abdominal examination is remarkable for positive bowel sounds, soft and depressible, no tenderness, no guarding or rebound but slight abdominal discomfort on deep palpation diffusely. CBC showed leukopenia (WBC 2.9 × 103/μL) with neutropenia (segmented neutrophils 48%), macrocytic anemia (Hgb 6.1 g/dL, hematocrit 20%, MCV 113fL) and thrombocytopenia (platelet count 59 × 109/L). Patient was transfused 2 units of packed red blood cells. Other laboratories revealed elevated LDH levels 850 units/L, total bilirubin of 1.8 mg/dL and a reticulocyte count 15.4% consistent with hemolysis. Folate, Iron, Vitamin B12 levels were under normal limitis. Direct Coomb's test resulted negative. Disseminated intravascular coagulation (DIC) panel was unremarkable with normal PT, PTT, INR, fibrinogen, fibrin split products and D-dimer.

In view of history of persistent gastrointestinal symptoms an abdominopelvic CT-scan was performed. Abdominopelvic CT-scan revealed a superior mesenteric vein thrombosis (Fig. 3) which was treated initially with low-molecular-weight heparin for full anticoagulation and later changed to warfarin to maintain a therapeutic INR between 2.0 and 3.0. In order to assess etiology of pancytopenia a bone marrow aspirate and biopsy was done showing hypocellularity of 20% (Fig. 4).

Figure 3
Abdomino-pelvic CTscan; revealed a superior mesenteric vein thrombosis
Figure 4
Bone marrow biopsy and aspiration, remarkable for hypocellularity of 20%.

This is a young, healthy female with an interesting constellation of idiopathic thrombosis associated with pancytopenia and highly suspicious for paroxysmal nocturnal hemoglobinuria.

Flow cytometry assays of peripheral blood revealed diminished expression of CD55 and CD59. A fluorescein-labeled proaerolysin variant (FLAER) identified a population with deficient levels of expression of glycosylphosphaditdylinositol linked antigens and anchor proteins on 81% erythrocytes, 80% granulocytes, and 75% monocytes. (Fig. 1--22)

Figure 1
Flow cytometry report: Populations with deficient GPI-Anchored proteins are identified (approximately 81%).
Figure 2
Flow cytometry identifies a population with deficient levels of expression of glycosylphosphaditdylinositol linked antigens and anchor proteins on 81% erythrocytes, 80% granulocytes, and 75% monocytes.

Discussion

Paroxysmal nocturnal hemoglobinuria is a rare, clonal, hematopoietic stem-cell disorder whose manifestations are almost entirely explained by complement-mediated intravascular hemolysis.2 The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10 to 15 years, but with a wide range.1 Thrombosis is the leading cause of death, but others may die of complications of bone marrow failure, renal failure, myelodysplastic syndrome, and leukemia.1

PNH is divided into three categories for a more focused approach: 1- Classical PNH, these patients have the characteristic symptoms of PNH with intravascular hemolysis, a cellular bone marrow and have no evidence of any other bone marrow pathology.2- PNH in the setting of another specified bone marrow disorder; these patients have symptoms of intravascular hemolysis but also have, or have previously had, an underlying bone marrow abnormality such as aplastic anemia (AA) or myelodysplasia (MDS). 3- Subclinical PNH, these patients have no evidence of ongoing hemolysis.6

The disease originates from a multipotent hematopoietic stem cell that acquires a mutation of the PIG-A gene.1 Clinical manifestations of the disease arise secondary to the expansion and differentiation of the PIG-A mutant stem cell. The PIG-A gene product is required for the biosynthesis of glycophosphatidylinositol anchors, a glycolipid moiety that attaches dozens of proteins to the plasma membrane of cells.1 Consequently, the PNH stem cell and all of its progeny have a reduction or absence of glycosyl phosphatidylinositol (GPI)– anchored proteins.1 CD55 and CD59, are two of these proteins which are also complement regulatory proteins and fundamental to the pathophysiology of the disease when absent. CD55 inhibits C3 convertases and CD59 blocks formation of the membrane attack complex (MAC) by inhibiting incorporation of C9 into the MAC.1 The loss of complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis, but it is the intravascular hemolysis that contributes to much of the morbidity and mortality from the disease.1 Free hemoglobin is released to the plasma due to intravascular hemolysis. This free plasma hemoglobin searches nitric oxide leading to depletion of nitric oxide at the tissue level which contributes to various PNH manifestations including esophageal spasm, male erectile dysfunction, severe fatigue, renal insufficiency, and thrombosis.

The combination of nitrous oxide depletion, complement-mediated platelet activation, and exposure of the procoagulant interior of the red cell membranes makes PNH an extremely hypercoagulable state.3 In fact, thrombosis accounts for 40% to 67% of the mortality from the disease.3 Venous thrombosis in PNH can occur anywhere, with the abdominal veins (hepatic, portal, splenic, and mesenteric) and the cerebral veins being the most common sites2. Patients with a large PNH cell population (60% of granulocytes) seem to be at greatest risk for thrombosis.2 Our patient had a PNH cell population of 80% of granulocytes. A history of even one thrombotic event is associated with a 5-fold to 10-fold higher risk of death for PNH patients.3 Therefore, it should be treated promptly with anticoagulation and depending on the location of the thrombus with thrombolytic therapy.

Anticoagulation is only partially effective in preventing thrombosis in PNH; thus, thrombosis is an absolute indication for initiating treatment with eculizumab.1 Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement–mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH).7 Eculizumab is highly effective in reducing intravascular hemolysis in PNH; it decreases or eliminates the need for blood transfusion, improves quality of life, and reduces the risk of thrombosis among both patients with classic PNH and those in whom PNH develops secondary to aplastic anemia.7 Treatment with Eculizumab was initiated in our patient and has been well tolerated, showing significant clinical improvement, with gradual decrease in LDH levels with no reported complications and no more transfusions required. Nevertheless, bone marrow transplantation (BMT) is still the only curative therapy for PNH but is associated with significant morbidity and mortality.1

In conclusion, PNH is an unusual hematological disease that is easy to miss but impossible to ignore. To the best of our knowledge this is the first PNH case reported in the medical literature with initial presentation of heartburn.

Footnotes

Conflict of Interest: The authors declare that there is no conflict of interest.

References

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