Upshaw-Schulman syndrome diagnosed during pregnancy complicated by reversible cerebral vasoconstriction syndrome

Accepted Manuscript Title: Upshaw-Schulman syndrome diagnosed during pregnancy complicated by reversible cerebral vasoconstriction syndrome Authors: Mariko Tsuda, Motoaki Shiratsuchi, Yasuhiro Nakashima, Motohiko Ikeda, Hiroki Muta, Taisuke Narazaki, Toru Masuda, Daisaku Kimura, Akiko Takamatsu, Masanori Matsumoto, Yoshihiro Fujimura, Koichi Kokame, Takamitsu Matsushima, Yoshihiro Ogawa PII: DOI: Reference:

S1473-0502(18)30405-1 https://doi.org/10.1016/j.transci.2018.10.023 TRASCI 2469

To appear in: Received date: Accepted date:

18 October 2018 23 October 2018

Please cite this article as: Tsuda M, Shiratsuchi M, Nakashima Y, Ikeda M, Muta H, Narazaki T, Masuda T, Kimura D, Takamatsu A, Matsumoto M, Fujimura Y, Kokame K, Matsushima T, Ogawa Y, Upshaw-Schulman syndrome diagnosed during pregnancy complicated by reversible cerebral vasoconstriction syndrome, Transfusion and Apheresis Science (2018), https://doi.org/10.1016/j.transci.2018.10.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Upshaw-Schulman syndrome diagnosed during pregnancy complicated by

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reversible cerebral vasoconstriction syndrome

Mariko Tsuda1, Motoaki Shiratsuchi1*, Yasuhiro Nakashima1, Motohiko Ikeda2, Hiroki

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Muta1, Taisuke Narazaki1, Toru Masuda1, Daisaku Kimura1, Akiko Takamatsu1,

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Masanori Matsumoto3, Yoshihiro Fujimura4, Koichi Kokame5, Takamitsu Matsushima6,

Department of Medicine and Bioregulatory Science, Graduate School of Medical

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Yoshihiro Ogawa1,7

Sciences, Kyushu University, Fukuoka, Japan . Department of Internal Medicine, Nakatsu Municipal Hospital, Nakatsu, Japan

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. Department of Blood Transfusion Medicine, Nara Medical University, Nara, Japan

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. Japanese Red Cross Kinki Block Blood Center, Ibaraki, Japan

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. Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center,

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Suita, Japan 6

. Department of Hematology, Iizuka Hospital, Iizuka, Japan

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. Department of Molecular Endocrinology and Metabolism, Graduate School of

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Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

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Running title: USS and RCVS diagnosed during pregnancy

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Type of manuscript: Case report

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*Corresponding author

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Motoaki Shiratsuchi, MD, PhD

Department of Medicine and Bioregulatory Science, Kyushu University

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3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Tel: +81-92-642-5281

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Fax: +81-92-642-5287

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E-mail: [email protected]

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Abstract Upshaw-Schulman syndrome (USS) is an inherited type of thrombotic

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thrombocytopenic purpura (TTP) that is extremely rare, but often diagnosed during pregnancy. Reversible cerebral vasoconstriction syndrome (RCVS) is the transient

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stenosis of several cerebral arteries that is frequently diagnosed post-partum.

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We describe a 28-year-old woman with USS complicated by RCVS after delivery that

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was treated by plasma exchange with a good outcome. She was referred to our hospital

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with thunderclap headache, anemia and thrombocytopenia that occurred immediately postpartum. She was diagnosed with TTP and multiple cerebral infarctions. Plasma

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exchange promptly improved her symptoms on hospital day 3. Moreover, multiple

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stenoses of cerebral arteries indicating RCVS were resolved. Since her sister also had an

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episode of thrombocytopenia during pregnancy, inherited TTP was suspected and genetic analyses confirmed USS. Pregnancy is a risk for not only TTP, but also RCVS.

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Endothelial damage might be an underlining cause and vasospasm after delivery is a trigger of RCVS. Plasma exchange was effective against both TTP and RCVS.

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Keywords: Thrombotic thrombocytopenic purpura, Upshaw-Schulman syndrome,

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Reversible cerebral vasoconstriction syndrome, plasma exchange

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Introduction

Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia,

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mechanical hemolytic anemia and multivisceral ischemia. The cause is a functional

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deficiency of disintegrin and metalloprotease with thrombospondin type 1 repeats,

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member 13 (ADAMTS13). This is a von Willebrand factor (VWF)-cleaving

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metalloprotease that prevents the formation of unusually large VWF multimers in the circulation, which cause thrombi in the microvasculature [1]. Thrombotic

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thrombocytopenic purpura comprises inherited and acquired types. The latter is also

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known as Upshaw-Schulman syndrome (USS) accounts for < 5% of all TTP [2].

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Reversible cerebral vasoconstriction syndrome (RCVS) was first proposed by Calabrese et al. during 2007 [3]. Severe headache with or without neurological symptoms caused by multiple segmental constrictions of cerebral arteries that resolve within three months

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are features of RCVS. This condition often develops within the first week post-partum [4]. Vasoactive and immunosuppressive agents can also cause RCVS [4].

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We have experienced patients with USS that was diagnosed during pregnancy. Furthermore, brain infarctions that are complicated and resolved within weeks suggest

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RCVS.

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Case presentation

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A 28-year-old woman who had never experienced thrombotic or bleeding episodes, was

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admitted to an obstetrics clinic at 29 weeks of gestation with intrauterine fetal death. Laboratory data revealed anemia and thrombocytopenia. She developed a powerful

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headache followed by disturbed consciousness and renal insufficiency after delivery of

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the lifeless fetus. She was referred to our hospital and we found that she also had fever,

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purpura, right visual field loss, and right hemiplegia. Her blood pressure was 140/70 mmHg. Laboratory findings showed hemoglobin 5.3 g/dL, platelets 21 × 109/L, lactate dehydrogenase 1,673 U/L and haptoglobin < 10 mg/dL. The results of coagulation tests showed slightly elevated FDP and D-dimer. Autoantibodies suggesting 5

antiphospholipid antibody syndrome or vasculitis were undetectable. Magnetic resonance (MR) imaging revealed several cerebral infarctions in the left posterior to

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lateral lobes (Figure 1A, B) and MR angiography showed occlusion of the left posterior cerebral artery and stenosed bilateral internal carotid artery-middle cerebral arteries and

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the basilar artery (Figure 1D, F). Thrombotic thrombocytopenic purpura was diagnosed

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based on the findings of hemolytic anemia, thrombocytopenia, fever, renal insufficiency

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and disturbed consciousness. Three days of plasma exchange therapy obviously

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ameliorated her symptoms. She was not administered with anticoagulant therapy because of a bleeding tendency and having several infarctions throughout the brain, but

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she did receive edaravone and glycerol infusions. Stenosis of the basilar, left posterior

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cerebral and internal carotid arteries resolved after three weeks (Figure 1E,G).

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Radiological findings during the clinical course indicated that she had been complicated with RCVS.

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The placenta prematurely separated when her older sister delivered her first baby at 37 weeks of gestation. When she delivered her second baby, also at 37 weeks of gestation, her platelet count decreased to 30 × 109/L and she received a platelet transfusion.

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Thereafter, her platelet count returned to normal. Both her children had normal platelet counts.

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We suspected that the sisters had congenital TTP and therefore assessed their ADAMTS13 activity and inhibitor levels sisters and those of their parents. Table 1

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shows that ADAMTS13 activity was extremely low in the sisters and below normal in

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their parents. Their ADAMTS13 inhibitor titers were also very low. Sequencing their

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ADAMTS13 genes showed that their father and mother had c.4006C>T (p.R1336W)

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and c.1097G>A (p.C366Y) mutations, respectively. The patient and her sister had both p.C366Y and p.R1336W mutations suggesting compound heterozygotes. These results

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confirmed a diagnosis of USS.

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The TTP symptoms including hemolytic anemia and thrombocytopenia resurfaced when

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the patient developed viral enterocolitis. She recovered from TTP with only partial plasma exchange, followed by a prophylactic plasma infusion, which her sister

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declined.

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Discussion

Increased VWF secretion has been identified during the later stages of pregnancy [5]

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and a significantly higher proportion of patients have pregnancy-onset than

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non-pregnancy onset USS (23.8% vs. < 5%) [2].

Brain infarction can be followed by TTP and involve cerebral arteries of various sizes

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[6]. The etiology is thought to be small-vessel occlusion followed by edema. On the

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other hand, the etiology of large infarctions is unclear, but might be caused by

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reversible stenosis of the main cerebral arteries. This was initially reported in 2003 [6]

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and the stenosis vanished within 50 days. Therefore, it was considered to be RCVS. Although the mechanism of RCVS remains unclear, dysregulated cerebral vascular tone

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and endothelial dysfunction might play important roles [7].

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Reports indicate that 1% - 13% of RCVS occurs postpartum [4]. Water retention during

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pregnancy increases cardiac output and plasma volume by the third trimester, which results in vasodilation. These parameters rapidly normalize during the puerperal period, resulting in increased sodium concentrations and osmolality, decreased plasma volumes

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and relative vasoconstriction [8]. This dynamic change in vascular tonus might result in RCVS.

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As far as we can ascertain, only four patients with TTP who also developed RCVS have been described in the literature [5, 9]. All were female, one had systemic lupus

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erythematosus and Sjögren’s syndrome, and one each had IgA nephropathy, systemic

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sclerosis, and no identifiable underlying pathology. None were pregnant and all were

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treated by plasma exchange. Three recovered from TTP and one died of a massive

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infarction. The vascular stenosis was notably resolved in all patients. The mechanism of the association between TTP and RCVS is unclear, but both states might be caused by

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endothelial damage, which can develop later during pregnancy [10].

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Plasma exchange resolved both the TTP and RCVS in our patient. We believe that

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ADAMTS13 supplementation and repaired endothelial damage might have contributed. In conclusion, we described a patient with USS who developed postpartum RCVS.

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Pregnancy is a risk for both TTP and RCVS resulting from endothelial damage and changes in vascular tonus. Plasma exchange might be useful for treating endothelial damage and vasospasm that can result in TTP and RCVS.

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Conflict of interest

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The authors declare that they have no conflict of interest.

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References

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2017;130:1181-8. https://doi.org/10.1182/blood-2017-04-636431

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2. Moatti-Cohen M, Garrec C, Wolf M, Boisseau P, Galicier L, Azoulay E, et al.

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Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombocytopenic

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thrombotic

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https://doi.org/10.1182/blood-2012-02-408914

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3. Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: reversible

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cerebral

vasoconstriction

syndromes.

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5. Sanchez-Luceros A, Meschengieser SS, Marchese C, Votta R, Casais P, Woods AI, et al. Factor VIII and von Willebrand factor changes during normal pregnancy and Blood

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puerperium.

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6. Kondo K, Yamawaki T, Nagatsuka K, Miyashita K, Naritomi H. Reversible stenosis

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of major cerebral arteries demonstrated by MRA in thrombotic thrombocytopenic

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purpura. J Neurol. 2003;250:995-7. https://doi.org/10.1007/s00415-003-1141-x

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7. Chen SP, Fuh JL, Wang SJ. Reversible cerebral vasoconstriction syndrome: an under-recognized clinical emergency. Ther Adv Neurol Disord. 2010;3:161-71.

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https://doi.org/10.1177/1756285610361795

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8. Skidmore FM, Williams LS, Fradkin KD, Alonso RJ, Biller J. Presentation, etiology, and outcome of stroke in pregnancy and puerperium. J Stroke Cerebrovasc Dis.

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2001;10:1-10. https://doi.org/10.1053/jscd.2001.20977

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9. Paliwal PR, Teoh HL, Sharma VK. Association between reversible cerebral vasoconstriction syndrome and thrombotic thrombocytopenic purpura. J Neurol Sci. 2014;338:223-5. https://doi.org/

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10. Slavik L, Prochazkova J, Prochazka M, Simetka O, Hlusi A, Ulehlova J. The pathophysiology of endothelial function in pregnancy and the usefulness of

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endothelial markers. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub.

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2011;155:333-7. https://doi.org/10.5507/bp.2011.031

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Figure legends

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Fig. 1. Findings of brain magnetic resonance imaging and magnetic resonance

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angiography upon admission and after three weeks of plasma exchange.

admission (B).

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Diffusion-weighted MR image: apparent diffusion coefficient (A) and status upon

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Diffusion-weighted MR image (C) after three weeks of plasma exchange. Brain MRA

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upon admission (D, F) shows arterial stenosis (arrows). Brain MRA after three weeks of

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plasma exchange (E, G). MRA, magnetic resonance angiography; MRI, magnetic resonance imaging.

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Inhibitor

(%)

(Bethesda unit/mL)

< 0.5

1.1

C366Y

R1336W

Sister

2.9

0.2

C366Y

R1336W

Father

40.2

0.3

Mother

58.7

0.2

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Activity

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Patient

ADAMTS13 gene mutation

R1336W C366Y

Table 1. ADAMTS13 activity, inhibitor, and gene mutations of the patient and family

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members

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