458 Case report

Postpartum thrombotic complication in a patient with paroxysmal nocturnal hemoglobinuria Gianluca Gessonia,d, Rosa Canistrob, Luca Bergaminic, Sara Valverdea, Francesca Gessonid, Giovanna Nanic, Samanta Beggiod, Pietro Spillaree and Alberto Tregnaghie Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal nonneoplastic hematopoietic stem cell disease characterized by an acquired mutation of the PIG-A gene with reduction or absence of CD55 and CD59. The absence of these proteins renders PNH erythrocytes susceptible to complement-mediated hemolysis. We report the case of a PNH patient before and during pregnancy until delivery. We observed and treated some postpartum thrombotic complications. Eculizumab should be used with caution in pregnancy. There are several reports supporting its use in these patients. This case should be considered paradigmatic of a series of clinical situations that may occur in the course of a pregnancy in patients with PNH: increased need for transfusion, need to increase the dose of Eculizumab, and insurgence of fetal sufferance. Moreover, after delivery, the patient, despite adequate prophylaxis with low-molecular-weight heparins, presented severe complications: development of pleural and peritoneal effusion, pulmonary embolism, bilateral upper limbs thrombophlebitis, and a possible abdominal angina with a

Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease that can present with bone marrow failure, hemolytic anemia, smooth muscle dystonias, and thrombosis [1–3]. The disease originates from a multipotent hematopoietic stem cell that acquires a mutation in the PIG-A gene [4,5]. The PIG-A gene product is required for the biosynthesis of the glycophosphatidylinositol anchor, a glycolipid moiety that connects several proteins to the cell membrane. Consequently, the PNH stem cell and all of its progeny have a reduction or absence of glycosyl phosphatidylinositol (GPI)-anchored proteins. Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of the disease [6,7]. CD55 inhibits C3 convertases and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting incorporation of C9 into the MAC. 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 most of the morbidity and mortality from the disease [8]. Intravascular hemolysis determines the release of free hemoglobin (Hb) into the plasma. Free plasma 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

transient paralytic ileus. All these complications were overcome and now the baby is healthy and the mother has returned to the usual therapeutic regimen. Blood Coagul Fibrinolysis 26:458–463 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

Blood Coagulation and Fibrinolysis 2015, 26:458–463 Keywords: eculizumab, pNH, pregnancy, thrombosis, transfusion a

Service of Laboratory Medicine, bOnco-Hematology Unit, cObstetrics and Gynecology Unit, dTransfusional Service and eRadiology Service, Madonna della Navicella Hospital, Chioggia, Italy Correspondence to Dott. Gianluca Gessoni, MD, Director, Clinical Pathology Department, Madonna della Navicella Hospital, Strada Madonna Marina 500, 30015 Chioggia, Venice, Italy Tel: +39 041 5534 400; fax: +39 041 5534 401; e-mail: [email protected] Received 27 May 2014 Revised 3 November 2014 Accepted 24 November 2014

Hb scavenges nitric oxide, and depletion of nitric oxide at the tissue level contributes to numerous PNH manifestations, including esophageal spasm, erectile dysfunction, renal insufficiency, and thrombosis [9–12]. The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10– 15 years. Eculizumab, a humanized mouse monoclonal antibody with anti-C5 activity, is approved for the treatment of PNH. Eculizumab protects blood cells against immune destruction by blocking terminal complement [9–12]. Thrombosis is the leading single cause of death in PNH. Pregnancy and oral contraception also increase the risk for thrombosis in PNH. Anticoagulation with low-molecularweight heparin is recommended. Pregnant women with PNH have an even greater need for folate and iron supplementation because of the intravascular hemolysis. In some cases, PNH patients may require intravenous iron during pregnancy [13–16].

Case report C.S. was born in 1978. PNH was diagnosed in August 2011 by an immunophenotypic study as reported below. Moreover, an extensive red blood cell (RBC) study, a DOI:10.1097/MBC.0000000000000250

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Postpartum thrombotic complication in a patient with PNH Gessoni et al.

459

genetic study, an evaluation of thrombophilia risk factors, and a bone marrow evaluation were performed.

was 189% (normal values within reference values.

Cytofluorimetric study

Bone marrow examination

Immunophenotypic analysis on the granulocytes CD33þ/Side scatter (SSC) high using FLAER in combination with anti-CD24 (GPI-linked molecule) showed the presence of a 75% granulocyte clone with complete deficit (type PNH3) of GPI-linked molecules (FLAER/ CD24). A type II clone with partial deficiency of GPI-linked molecules (FLAERþ/CD24) equal to 5% of granulocytes was also detected. The analysis of the granulocyte population conducted using an antibody anti-CD66b (GPI-linked molecule) has allowed to highlight only a clone type PHN3 equal to 78% of granulocytes. Immunophenotypic analysis of the monocyte population (CD33þþ/SSC intermediate) using the FLAER test in combination with the antibody to CD14 (GPI-linked molecule) showed the presence of a clone with a complete deficit (type PNH3) of GPI-linked molecules (FLAER-7-CD14) equal to 79%. A monocyte clone with partial deficiency (type PHN2) of GPI-linked molecules (FLAER/C14) corresponded to 3%. Immunophenotypic analysis of RBCs showed the presence of a clone with complete deficit (type PNH3) of GPI-linked molecule CD59 in 27% of the erythrocytes.

Granulocyte lineage was well represented and with normal maturation. Erythrocytes lineage line was markedly expanded with notes of macrocytosis and nucleus–cytoplasmic maturational asynchronism with finding suggestive for dyserythropoiesis. Inverted myelo/erythroid ratio was 1/5. Lymphocyte and plasma cells were normal. Megakaryocytes were present with normal morphology. The study has allowed a cytogenetic trisomy of chromosome 8 in 80% of metaphases examined.

Red blood cell study

Extended blood group typing: B, CcDEe, kk, MNss FyaFybþ, JkaþJkb, LeaLeb, LuaLubþ, KpaKpbþ, P1þ; direct antiglobulin test (DAT); and indirect antiglobulin test were negative at diagnosis but DAT became positive (to C3, score þþ) in June 2012, 6 months after start of Eculizumab administration. Glucose 6-phosphate dehydrogenase was 20.5 U/gHb (9.4–17.8 U/ gHb); pyruvate kinase was 62.0 U/gHb (26.5–48.7 U/gHb). Hb study: HbA0 96.2%, HbA2 2.3%, HbF 1.5%; no Hb variant was observed. Genetic study

HLA typing: A02 A66, B41 B52, Cw07 Cw12, DRB1 11 DRB1 15, DQB1 03 DQB1 06. Assays for detection of Bcr/Abl and JK2 were negative. Thrombophilia risk evaluation

Prothrombin time, activated partial prothrombin time, thrombin time, and fibrinogen and D-dimer were within normal reference values, same as physiologic coagulation inhibitors antithrombin, protein C (PC), and protein S. Assays for antiphospholipids autoantibodies (lupus anticoagulant, anticardiolipin immunoglobulin G (IgG) and immunoglobulin M (IgM) antiprothrombn IgG and IgM, anti beta 2 glycoprotein 1 IgG and IgM) were negative. Results of genetic test for FV G1691A, FII G20210A, MTHFR C677T, and A1298C were consistent with a normal genotype; moreover, homocysteine and resistance to activated PC were normal. FVIII activity

80–120%); FIX activity was

Relevant laboratory tests

Erithropoietin 318 mU/ml (5 – 15 mU/ml), serum iron 31 ng/dl (50 – 170 ng/ml), transferrin 287 mg/dl (200 – 400 mg/dl), ferritin 19 ng/ml (10 – 160 ng/ml), aptoglobin 90 ml/min per 1.73 mg). The study of LDH isoenzymes showed a marked increase in LAD-1 probably originated from erythrocytes. Time course of the main laboratory parameters is reported in Fig. 1. Moreover, during the course of the disease, we observed a steady increase in ferritin that, in February 2014, had increased to 1500 ng/ml, whereas aptoglobin was always below the threshold of sensitivity of the method used (5 mg/dl). Following the first major hemolytic crisis in November 2011, in December 2011 treatment with Eculizumab was started together with transfusion support with washed packed red cells concentrates (mean Hb contents 45 g of Hb per unit), as reported in Fig. 2. As reported in Fig. 3, the mean Hb concentration before transfusion was 70 g/l (from 61 to 82 g/l); the mean Hb concentration after transfusion of two units of washed packed red cells concentrates was 89 g/l (from 91 to 110 g/l) with a median raise in Hb concentration of 18 g/l (from 14 to 28 g/l). C.S. considered motherhood of great importance for her life and, warned and made aware of the risks of pregnancy, she decided, along with her partner, to stop the anticonception therapy. She became pregnant in November 2012. During pregnancy the patient showed an increase in disease activity as demonstrated by the increased demand for Eculizumab to control the hemolytic crisis and the increased need for transfusion support, as shown in Figs 2 and 3. Prophylaxis of thromboembolic events was performed with Enoxaparin 3000 U/day. The pregnancy continued without major complications until the 38th week when an election surgical delivery was performed on 18 July 2013 for fetal sufferance. On the

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460 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 4

Fig. 1

(a)

(b) 450 400 350 300 250 200 150 100 50 0

1200 1000 800 600 400 200

O ct D -11 ec Fe 11 bA 12 pr Ju 12 nA 12 ug -1 O 2 ct D -12 ec Fe 12 bA 12 pr Ju 13 nA 13 ug -1 O 3 ct -1 3

O ct D -11 ec Fe -11 b A -12 pr Ju -12 n A -12 ug O -12 ct D -12 ec Fe -12 b A -12 pr Ju -13 n A -13 ug O -13 ct D -13 ec Fe -13 b14

0

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(d) 200 180 160 140 120 100 80 60 40 20 0

6000 5000 4000 3000 2000 1000

O ct D -11 ec Fe 11 bA 12 pr Ju 12 nA 12 ug O 12 ct D 12 ec Fe 12 bA 12 pr Ju 13 nA 13 ug O 13 ct D 13 ec -1 3

O ct D -11 ec Fe -11 b A -12 pr Ju -12 n A -12 ug O 12 ct D 12 ec Fe -12 b A -12 pr Ju -13 n A -13 ug O 13 ct D -13 ec Fe -13 b14

0

Time course of main laboratory parameters: ferritin (a), reticulocytes (b), total bilirubin (c), and lactate dehydrogenase (d).

second day, the patient complained of sudden dyspnea. The suspected diagnosis was pulmonary embolism: a transthoracic ultrasound scan showed signs of a modest

pulmonary hypertension, an ultrasound scan of the abdomen showed a small perihepatic fluid collection, and a standard thoracic computed tomography (CT) scan

Fig. 2

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3

2 Eculizumab 900 mg doses PRC units

1

Jan-14

Feb-14

Nov-13

Dec-13

Sep-13 Oct-13

Aug-13

May-13 Jun-13 Jul-13

Feb-13 Mar-13 Apr-13

Dec-12 Jan-13

May-12 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12

Oct-11 Nov-11 Dec-11 Jan-12 Feb-12 Mar-12 Apr-12

0

Treatment with Eculizumab and transfusion. This figure reports the monthly need of Eculizumab (reported as number of 900 mg doses) and blood transfusion (reported as number of washed packed red cell units). As reported during pregnancy, the patient received 24 doses of Eculizumab (900 mg) with an average requirement of 2.6 doses/month and was transfused with 26 units of washed red cell concentrate packet, with an average requirement of 2.8 U/month. In the year prior to pregnancy, the patient received 21 doses of Eculizumab (900 mg) with an average requirement of 1.7 doses/month and was transfused with 18 units of washed red cell concentrate packet, with an average requirement of 1.5 U/month.

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Postpartum thrombotic complication in a patient with PNH Gessoni et al.

Fig. 3

461

Fig. 4

120 100 80 60 40 20

22 -0 012 4 05 -20 -0 12 6 05 -20 -0 12 8 05 -20 -1 12 0 05 -20 -1 12 2 05 -20 -0 12 2 05 -20 -0 13 405 20 -0 13 6 05 -20 -0 13 8 05 -20 -1 13 0 05 -20 -1 13 205 20 -0 13 220 14 05

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20

-0 05

2-1

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05

-1

0-

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0

Hb pre

Hb post

Hemoglobin level before and after blood transfusion. This figure reports hemoglobin level before (Hb pre) and after (Hb post) transfusion. In each episode the patients have been transfused with two units of washed packed red cell concentrates. The rise in mean hemoglobin after blood transfusion was 18.6 g/l (from 14 to 28 g/l).

showed a bilateral pleural effusion with signs of pulmonary embolism. The patient was treated for pulmonary embolism and discharged on 24 July with the prescription of Enoxaparin 3000 U/day. On 29 July, the patient presented to our hospital again with abdominal pain. The bowel was closed to feces and gas. An abdominal ultrasound scan showed the presence of ascites, with numerous air–fluid levels, without signs of kidney stones or gallstones. An ultrasound study of the veins of the upper and lower limbs showed bilateral thrombophlebitis of the upper limbs. A thoracic angio CT scan confirmed the presence of a new pulmonary embolism (Fig. 4). C.S. was clinically in a very critical situation and transferred to a referral hematology center from where she was sent back to our hospital after 5 days. C.S. overcame thromboembolic complications that she suffered. Currently, hemolytic disease is in fairly good compensation and the requirements of Eculizumab and the need for transfusion support are similar to those prior to pregnancy. The child is alive and in good health.

Discussion Before introduction of Eculizumab too many young women with PNH were told that pregnancy was a nogo area, partly because it could make anemia worse, but even more because of the threat of thrombosis [13–16]. Pregnant women with PNH have a great need for folate and iron supplementation and an important precaution was low-molecular-weight heparin throughout pregnancy

Thoracic angio computed tomography scan with intravenous contrast media: the axial view at the pulmonary artery bifurcation shows large thrombotic material all along the right pulmonary artery and the distal tract of the left one (arrows). It appears as low-density defects that lie on the pulmonary vessel’s walls reducing the diameter of the true vascular lumen.

and puerperium; red cell transfusions were provided as necessary. Of course great attention was given to possible signs and symptoms of venous thrombosis, including postpartum [13–16]. Despite these precautions pregnancy in PNH patients, in the pre-Eculizumab period, was burdened by increased maternal mortality rates (from 8% [17] to 20% [13]). The Eculizumab label includes the phrase that it should be used in pregnancy ‘only if potential benefit outweighs risk’. This is of course a standard precaution of the manufacturer for medicolegal cover [13–19]. But in our opinion and supported by data from literature, in a highly motivated couple it would seem absurd to withdraw Eculizumab at a time when the patient most needs protection from intravascular hemolysis and thrombosis [13–19]. Moreover, Eculizumab with a hybrid Fc portion with IgG2 and IgG4 components is designed to abolish any effectors mechanisms of the antibody. Because IgG2 isotypes do not cross the placenta, there should be little impact on the fetus [13–19]. In support of this position, in recent years several reports of pregnancies carried to a successful conclusion in patients with PNH have been published [13–19]. The clinical case that has been reported in this article, in our opinion, should be considered paradigmatic of a series of clinical situations that may occur in the course of a pregnancy in patients with PNH. First is the observation that during pregnancy the disease activity apparently is increased as shown by the increased need for transfusion

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462 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 4

(26 units during pregnancy against the 18 of the previous 12 months) resulting from more frequent hemolytic crisis but also by the increased use of Eculizumab (24 doses of 900 mg during pregnancy to 21 in the previous 12 months). In the 37th week of pregnancy, for the onset of fetal distress, we proceeded to a surgical birth without encountering any major problems in obstetric surgery or anesthesia [20–22]. Despite adequate prophylaxis with low-molecular-weight heparins (3000 U/day) the patient developed, over a period of 2 weeks after giving birth, some severe complications: development of pleural and peritoneal effusion, pulmonary embolism, bilateral upper limbs thrombophlebitis, and a possible abdominal angina with a transient paralytic ileum. All these complications were overcome. Currently hemolytic crisis is under control using Eculizumab 900 mg every 10–12 days; C.S. after delivery received 10 packed red cell concentrates (2 each episode on day 16/09/13, 24/ 09/13, 18/12/13 and 27/01/14, 17/02/14). Furthermore, because of the substantial increase in the values of ferritin (1500 mg/l) the patient was placed on iron chelation therapy with Desferrioxamine 30 mg/kg 25 as subcutaneous injection over a period of 8–12 h each day. Women with PNH can have serious morbidity and increased mortality during pregnancy. In a series of 24 patients a mortality rate of 20% (5 deaths in 24 women) was reported; three deaths were attributed to venous thromboembolism and two to infections. The incidence of clinically apparent venous thromboembolism during pregnancy in women with PNH is about 10%, and these events are associated with a high risk of mortality [23,24]. Moreover, in women with PNH, anemia from hemolysis, underlying bone marrow failure, or both frequently worsen during pregnancy. Usually the majority of delivery can be accomplished vaginally, although premature delivery may be necessary. Ray et al. [23] identified three infant deaths among 34 births for a perinatal mortality rate of 9%. All surviving infants had normal growth and development after delivery [23,24].

thromboembolic complications were observed: two episodes of pulmonary embolism with development of pleural effusion, bilateral upper limbs thrombophlebitis, an episode of abdominal angina with development of ascites, and a transient paralytic ileum. These complications were treated and resolved without sequels.

Acknowledgements All authors are employees of the Italian Heath Service and do not have affiliate relationships, sharing, consulting with companies mentioned in this article. Consent: Written consent for preparation and presentation of this case report was obtained from C.S. Authorship: R.C. was the hematologist who has followed the patient. L.B. and N.G. were gynecologists who have followed the pregnancy of C.S. P.S. and A.T. were radiologists who performed the study imaging of thromboembolic complications. S.V., F.G., S.B., and G.G. followed laboratory diagnosis and transfusional support. The manuscript was prepared by R.C. and S.V. and revised by A.T. and G.G. The whole group of authors has been coordinated by G.G. Conflicts of interest

There are no conflicts of interest.

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Conclusion

This case report, in our opinion, has many points of interest. In the first place, as already reported in the literature, it militates for the possibility of use of Eculizumab in patients with PNH even during pregnancy. Secondly, it confirms the observation that pregnancy appears to increase the activity of the disease. In fact, C.S., during pregnancy, had a need for increasing doses of Eculizumab to control the hemolytic crisis, and despite the use of greater doses of the drug, the need for transfusions was significantly higher compared with prepregnancy and postpartum periods. Moreover, around 38th week of pregnancy, a mild fetal sufferance was observed and a cesarean section was performed. Postpartum, despite thrombosis prophylaxis with low-molecularweight heparins at full dosage, a number of serious

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Postpartum thrombotic complication in a patient with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal nonneoplastic hematopoietic stem cell disease characterized by an acquired mutation of the PIG-A...
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