








CMI 2019;13(1)1-5.html


		A Case of Paroxysmal Nocturnal Hemoglobinuria (PNH) in an Obstetric Patient: A South African Perspective

		Garrick Laudin 1, Lizemarie Wium 2

		1	Department of Internal Medicine, Kalafong Tertiary Hospital, University of Pretoria, South Africa

		2	Department of Internal Medicine, Steve Biko Academic Hospital, University of Pretoria, South Africa 

		Abstract

		Paroxysmal Nocturnal Hemoglobinuria (PNH) originates from an acquired genetic defect in a multipotent hematopoietic stem cell that becomes stem-cell-like in its ability to survive, expand, and self-renew. PNH is a rare condition characterized by intravascular hemolysis. PNH can arise anew or in the setting of an underlying bone marrow disorder such as aplastic anemia (AA), myelodysplastic syndrome (MDS), or primary myelofibrosis (PMF).

		This case presentation documents the challenging diagnosis of PNH in the obstetric setting, in which other possible causes for a hemolytic anemia could be considered. We discuss the management of a pregnancy in the presence of PNH in a low-to-middle income setting.

		

		Keywords: Hemoglobinuria, Paroxysmal; Anemia; Obstetrics

		CMI 2019; 13(1): 1-5

		https://doi.org/10.7175/cmi.v13i1.1392

		Case Report

		Corresponding author

		Garrick Laudin

		garrick.laudin@yahoo.com 

		

		Received: 25 November 2018

		Accepted: 7 January 2019

		Published: 16 January 2019 

		
			Why Do We Describe This Case

			This case highlights a rare disease with a prevalence of 1-2 cases per million people with data on the existence of this disease in the gravid population being limited to case report data. The rarity of this condition in the general population and in maternal medicine poses a dilemma for available therapeutic options and this case demonstrates the lack of availability of drugs such as eculizumab in resource-limited countries

		

		Introduction

		Paroxysmal nocturnal hemoglobinuria is a rare disease and the estimated prevalence of this disorder is in the range of one to ten cases per million population with estimates in the pregnant population being limited to case report data [1]. The median age of onset of PNH is in the mid-thirties and can affect women of childbearing age and in some instances PNH may be diagnosed in pregnancy for the first time [1,2]. There is no demonstrable ethnic or geographic distribution of the disease [1].

		PNH represents the clonal expansion of hematopoietic stem cells that have an acquired somatic mutation in the phosphatidylinositol glycan-complementation class A (PIG-A) gene with a consequent deficiency of glycosyl phosphatidylinositol-anchored proteins including the complement-regulatory proteins CD55 and CD59. The clinical sequelae of the deficiency of these complement-regulatory proteins renders affected cells susceptible to lysis mediated via complement [3].

		Laboratory investigations corroborating the diagnosis of PNH includes the presence of hemoglobinuria, a peripheral blood smear demonstrating red blood cell fragments and an elevated lactate dehydrogenase assay [4]. Clinical diagnosis of PNH may be confirmed with peripheral blood flow cytometry demonstrating the absence or severe deficiency of GPI-anchored proteins on at least two cell lines. The detection of GPI-anchored proteins may be performed by labelling cells with monoclonal antibodies or a fluorescein-tagged proaerolysin (FLAER) reagent [4]. Bone marrow biopsy is not usually indicated in most cases.

		Pregnancy is generally discouraged in patients with PNH due to the high risk of both fetal and maternal mortality. Anemia in a pregnant patient with PNH is sometimes more severe and more frequent transfusions of packed red blood cells (PRBCs) are required [5]. Owing to the occurrence of thrombosis in up to 40% of patients with PNH, the administration of low-molecular-weight heparin (LMWH) is advised [1]. LMWH is generally administered from the time of confirmation of pregnancy to the end of the postpartum period [5].

		Eculizumab is a humanized monoclonal antibody directed against the complement C5 protein terminal, which reduces erythrocytic cellular lysis and stabilizes the plasma hemoglobin levels [6].

		Eculizumab is the only drug approved for the treatment of PNH in USA, EU, and several other countries. It is currently not available in South Africa for the treatment of PNH.

		Case Presentation

		Miss AP was a 25-year-old female who was born in Malawi and had re-located to South Africa with her husband one year prior to consultation by the internal medicine service at Kalafong Tertiary Hospital. She was a primigravida and had a normal antenatal record except for the presence of a low hemoglobin. Other than her re-location to South Africa, our patient had no recent travel history to a malaria endemic area within South Africa.

		
				
							Vital Signs

							
							Value

						
	
							Blood pressure (mmHg)

							
							104/76

						
	
							Heart rate (beats per minute)

							
							121

						
	
							Respiratory rate (breaths per minute)

							
							13

						
	
							Oral temperature (degrees Celsius)

							
							37.2

						
	
							Oxygen saturation (pulse oximetry %)

							
							95

						
	
							Finger-prick glucose (mmol/L)

							
							5.3

						


			
				Table I. Vital signs.

			

		

		At the time of consultation Miss AP had an estimated gestational age of 14 weeks with the initial consultation from the Obstetric service being for the establishment of the route cause of Miss AP’s anemia.

		Miss AP had been previously diagnosed with an anemia in Malawi for which she recalls numerous admissions for blood transfusions and specifically recalls receiving transfusions of PRBCs during bouts of malaria. Limited workup for the anemia had been performed in Malawi and a tentative diagnosis of a suspected aplastic anemia was made.

		Vital signs recorded in Table I revealed a resting tachycardia with other vitals being within normal limits. Urine dipsticks revealed trace proteinuria and 1+ blood (weak positivity for blood).

		General examination of our patient was unremarkable except for the presence of conjunctival rim pallor and non-pitting pedal edema.

		Systems examination revealed a resting tachycardia with a left parasternal border systolic murmur. Abdominal examination revealed a palpable gravid uterus with the height of the uterine fundus at 14 cm. There was no palpable lymphadenopathy and no hepatosplenomegaly. Examination of the musculoskeletal system did not demonstrate any discrepancy in the diameter of the calves.

		Blood tests revealed low levels of: white cell count, hemoglobin, and serum iron (Table II).

		
				
							Investigation

							
							Result

							
							Normal Range

						
	
							White cell count (× 109/L)

							
							2.39

							
							3.9-12.6

						
	
							Hemoglobin (g/dL)

							
							4.9

							
							11.6-16.4

						
	
							Mean cell volume (fL)

							
							105.6

							
							76-100

						
	
							Mean cell hemoglobin (pg)

							
							29.3

							
							26.1-33.5

						
	
							Red cell distribution width (%)

							
							23.1

							
							12.4-17.3

						
	
							Platelets (× 109/L)

							
							249

							
							186-454

						
	
							Smear

							
							Scanty RBC fragments

							
	
							C-Reactive Protein (mg/L)

							
							9

							
							<10

						
	
							Total bilirubin (µmol/L)

							
							30

							
							5-21

						
	
							Direct/conjugated bilirubin (µmol/L)

							
							5

							
							0-3

						
	
							Alanine transaminase (U/L)

							
							14

							
							7-35

						
	
							Aspartate transaminase (U/L)

							
							106

							
							13-35

						
	
							International normalized ratio (INR)

							
							1.01

							
							≤1.1

						
	
							Fibrinogen (g/L)

							
							4.3

							
							2-4

						
	
							D-dimers (mg/L)

							
							5.24

							
							0-0.25

						
	
							Serum iron (µmol/L)

							
							5.0

							
							8-252

						
	
							Serum ferritin (µg/L)

							
							22

							
							22-265

						


			
				Table II. Basic investigations.

				RBC = red blood cells

			

		

		Elevated levels of mean cell volume, red cell distribution width, total and direct/conjugated bilirubin, aspartate transaminase, fibrinogen, and D-dimers were also detected (Table II).

		The smear showed the presence of scanty red blood cell fragments.

		Bone marrow aspirate demonstrated features of a megaloblastosis which may be in keeping with chronic hemolysis. Overall bone marrow aspirate revealed marked hypercellularity with normal lymphocyte morphology. The bone marrow aspirate did not reveal any features of plasmacytosis with no other foreign cells noted.

		Parvovirus B19 polymerase chain reaction performed on peripheral blood was negative.

		Hemolysis specific investigations detected elevated levels of lactate dehydrogenase and low levels of haptoglobin (Table III).

		
				
							Investigation

							
							Result

							
							Normal Range

						
	
							Malaria antigen/smear

							
							Negative

							
	
							Anti-nuclear antibodies

							
							Negative

							
	
							Extractable Nuclear Antigen

							
							Negative

							
	
							Direct antibody testing (Coombs)

							
							Negative

							
	
							Lactate dehydrogenase (U/L)

							
							2673

							
							208-378

						
	
							Haptoglobin (g/L)

							
							0.07

							
							0.3-2.0

						
	
							Hemoglobin electrophoresis

							
							No abnormal hemoglobin variant

							
	
							Glucose-6-phosphate dehydrogenase levels

							
							Normal

							
	
							Vitamin B12 levels (pmol/L)

							
							484

							
							133-675

						
	
							Serum folate levels (nmol/L)

							
							55

							
							7.0-45.1

						
	
							Urine hemosiderin

							
							Positive

							
	
							FLAER test and flow cytometry

							
							PNH clone present

							


			
				Table III. Hemolysis specific investigations.

			

		

		FLAER test and flow cytometry detected the presence of a PNH clone.

		Table IV shows the PNH panel. The expression of the GPI anchored proteins, CD55 (DAF) and CD59 (MIRL) was abnormal on both neutrophils and erythrocytes. Expression of the GPI-linked proteins (CD14 on monocytes and CD16 on neutrophils) was normal. In summary, there was phenotypic evidence of PNH based on analysis of a variety of GPI-linked antibodies on red blood cells and granulocytes.

		
				
							Cell Line

							
							PNH Clone (percent %)

						
	
							CD55- erythrocytes

							
							11

						
	
							CD59- erythrocytes

							
							11

						
	
							CD14- monocytes

							
							0.0

						
	
							CD55- granulocytes

							
							71

						


			
				Table IV. PNH panel (National Health Laboratory Service—NHLS, South Africa).

			

		

		A diagnosis of classical PNH was made after systematically excluding other probable causes of a process of intravascular hemolysis. Miss AP was referred from her antenatal clinic at Kalafong Tertiary Hospital to the Obstetric service at Steve Biko Academic Hospital. She was jointly managed by Obstetric Medicine, Maternal Fetal Medicine as well as the Hematology Service. She declined termination of pregnancy after careful counselling about a guarded prognosis. Miss AP was commenced on enoxaparin (LMWH) from time of diagnosis (16 weeks) until the birth of her infant at 37 weeks. As the post-natal period in PNH is associated with a high incidence of thrombosis, she was placed on warfarin for 3 months post-delivery. Miss AP was supported during her pregnancy with folic acid and other hematinics, as well as transfusions of packed red blood cells when her hemoglobin dropped below 7g/dL. Miss AP had an uneventful pregnancy with no episodes of thrombosis and delivered a live male baby via spontaneous vaginal delivery at 37 weeks.

		Discussion

		PNH or Paroxysmal Nocturnal Hemoglobinuria is a rare disease entity which has a prevalence of 1-2 cases per million people [1]. The disease has a slight female preponderance and women of child-bearing potential are also affected [2]. The exact incidence of PNH in pregnancy is unknown and only case report data on PNH in pregnancy exists.

		PNH is a non-neoplastic human disease caused by a somatic mutation of the X-linked phosphatidylinositol glycan-complementation class A gene in hematopoietic stem cells which makes red blood cells more vulnerable to lysis mediated by complement [1,2].

		The long-term complications of PNH include a chronic intravascular hemolysis complicated by anemia, venous thromboembolism as well as bone marrow failure [1,4].

		The clinical diagnosis of PNH in the setting of an obstetric patient can be a diagnostic challenge as the range of signs and symptoms present can be confounded with various pregnancy complications like pre-eclampsia, HELLP syndrome or pregnancy-associated thrombocytopenia. It is particularly important to try and distinguish a HELLP syndrome from a PNH crisis as the two entities may show overlap in symptomatology (i.e. nausea, abdominal discomfort) and abnormal laboratory findings of intravascular hemolysis (elevated lactate dehydrogenase, elevated unconjugated bilirubin, low haptoglobin, and low platelet count) [2].

		PNH in pregnancy is associated with increased risks of complications such as thromboembolic diseases (e.g. Budd-Chiari syndrome), hypertensive disorders like preeclampsia, and cerebrovascular diseases. PNH in pregnancy can cause significant feto-maternal morbidity and mortality with the estimated maternal mortality ranging from 5.8% to 20.8%. More than 45% of pregnancies in women with PNH result in either spontaneous miscarriage or termination. Of the women who give birth, more than half deliver prematurely, an event that can have negative implications for the health of the new-born baby [3,5].

		Eculizumab is a humanized monoclonal antibody that binds to the complement protein C5 and blocks terminal complement activation. During pregnancy eculizumab has shown a low rate of maternal complications up to now. However, expertise in managing pregnant patients with PNH with eculizumab is limited. In fact, prospective trials are unlikely to be initiated, due to the rarity of the disease. The drug is still listed in pregnancy as a category C drug («animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks» [7]), but potential benefits may outweigh potential risks [5]. The cost of eculizumab, trade name Soliris®, is approximately 18,000 USD per dose, making it one of the most expensive drugs in the United States [8]. The exorbitant cost of the drug makes its use in PNH in resource-constrained countries almost unjustified.

		
			Key Points

				PNH is a rare acquired disease with an estimated incidence of 1 to 5 cases per million individuals
	The exact incidence of PNH in pregnancy is unknown as only case report data on the condition exist
	PNH results in intravascular hemolysis and other conditions in pregnancy causing hemolysis also require consideration as diagnoses
	Thrombosis is one of the most feared complications of PNH in pregnancy as it can result in fetal loss as well as significant maternal morbidity/mortality
	Standard of care for patients in resource-limited settings is mainly supportive with the use of hematinics and with the appropriate transfusion of blood products


		

		Funding

		This article has been published without the support of sponsors.

		Conflicts of Interests

		The authors declare they have no competing financial interests concerning the topics of this article.

		References

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		2.	Lauritsch-Hernandez LS, Kraehenmann F, Balabanov S, et al. Eculizumab application during pregnancy in a patient with paroxysmal nocturnal hemoglobinuria: A case report with review of the literature. Clin Case Rep 2018; 6: 1582-7; https://doi.org/10.1002/ccr3.1634

		3.	Miyasaka N, Miura O, Kawaguchi T, et al. Pregnancy outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: a Japanese experience and updated review. Int J Hematol 2016; 103: 703-12; https://doi.org/10.1007/s12185-016-1946-x

		4.	Hill A, DeZern AE, Kinoshita T, et al. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 2017; 3: 17028; https://doi.org/10.1038/nrdp.2017.28

		5.	Kelly RJ, Höchsmann B, Szer J, et al. Eculizumab in pregnant patients with Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med 2015; 373: 1032-9; https://doi.org/10.1056/NEJMoa1502950

		6.	Bastos JMC, Pinheiro PL, Rocha LC, et al. Therapeutic challenges in pregnant women with paroxysmal nocturnal hemoglobinuria: A case report. Medicine (Baltimore) 2018; 97: e12155; https://doi.org/10.1097/MD.0000000000012155

		7.	AA.VV. FDA Pregnancy Categories. Available at https://www.drugs.com/pregnancy-categories.html (last accessed January 2019)

		8.	Dinerstein C. Why Is Soliris the Most Expensive Drug In The US? American Council in Science and Health. May 27, 2017. Available at https://www.acsh.org/news/2017/05/27/why-soliris-most-expensive-drug-us-11333 (last accessed January 2019)

	