Perioperative management of MYH9 hereditary macrothrombocytopenia (Fechtner syndrome)

Perioperative management of MYH9 hereditarymacrothrombocytopenia (Fechtner syndrome)Kathleen Selleng1, Lena E. Lubenow1, Andreas Greinacher1, Theodore E. Warkentin2,3

1Department of Transfusion Medicine and Immunology, Ernst-Moritz-Arndt University, Greifswald, Germany; 2Department of Pathology and

Molecular Medicine; 3Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada

Mutations of MYH9 – the gene for non-muscle myo-

sin heavy chain IIA (NMMHC-IIA) – are associated

with a heterogeneous group of hereditary macro-

thrombocytopenias (May–Hegglin anomaly, Sebastian

platelet syndrome, Fechtner syndrome, Epstein syn-

drome) characterized by thrombocytopenia with giant

platelets (‘macrothrombocytopenia’) and leukocyte

inclusions, often accompanied by abnormalities in renal

tubules (proteinuric glomerulonephritis), lenses (cata-

racts), or cochlea (sensorineural deafness) (1–3).

Despite thrombocytopenia, most patients either do not

bleed or have minor hemorrhagic tendencies. Indeed,

the major risk to the patient can be inappropriate

treatment with long-term corticosteroids or splenectomy

for misdiagnosed chronic autoimmune thrombocyto-

penia (4).

MYH9-related diseases exhibit autosomal dominant

inheritance, typically with a heterozygous MYH9 gene

mutation. Approximately 20% of cases are sporadic (2,

5, 6), and somatic mosaicism has been reported (7).

Abstract

Objective: Hereditary thrombocytopenias characterized by mutations in the gene for non-muscle myosin

heavy chain IIA (NMMHC-IIA) are known as MYH9-related hereditary macrothrombocytopenia, and include

the May–Hegglin anomaly, Sebastian platelet syndrome, Fechtner syndrome, and Epstein syndrome.

Despite the presence of thrombocytopenia, these patients often have only mild or non-bleeding pheno-

types. A major risk for these patients can be inappropriate treatment with long-term corticosteroids or

splenectomy for misdiagnosed chronic autoimmune thrombocytopenia, as well as inadequate peri- and

postoperative management. Methods: Using the case of a 44-yr-old male with Fechtner syndrome (macro-

thrombocytopenia, leukocyte inclusions, sensorineural deafness, glomerulonephritis) who underwent

neurosurgery for an intracerebral arteriovenous malformation, we describe current methods to diagnose

hereditary MYH9-related macrothombocytopenia by analysis of the blood smear, immunofluorescence

staining of the NMMHC-IIA in leucocytes, and by MYH9-gene sequencing. Results: Clusters of NMMHC-

IIA in granulocytes and a R1165C mutation in the MYH9-gene in two macrothrombocytopenic family mem-

bers confirmed the diagnosis of a MYH9-related disease. The patient had no bleeding diathesis by history

or physical examination. Thus no perioperative prohemostatic pharmacologic therapies or transfusions

were given, with only minimal bleeding observed. Postoperative antithrombotic thromboprophylaxis was

not given because of anticipated enhanced risk for bleeding. However, the patient developed symptomatic

pulmonary embolism on postoperative day 6, which was successfully managed with 8 months of

anticoagulation. Conclusion: MYH9-related hereditary macrothrombocytopenia does not necessarily protect

against postoperative venous thromboembolism, and affected patients who do not evince bleeding diathe-

sis should be considered for routine postoperative pharmacologic thromboprophylaxis.

Key words hereditary macrothrombocytopenia; MYH9-related disorder; Fechtner syndrome; pulmonary embolism; thromboprophylaxis

Correspondence Dr Theodore E. Warkentin, Hamilton Regional Laboratory Medicine Program, Room 1-180A, Hamilton Health

Sciences (General Site), 237 Barton St. E., Hamilton, ON, Canada L8L2X2. Tel: 905 527 0271 (ext. 46139); Fax: 905 577 1421; e-mail:

[email protected]

Accepted for publication 1 June 2007 doi:10.1111/j.1600-0609.2007.00913.x

CASE REPORT

European Journal of Haematology ISSN 0902-4441

ª 2007 The Authors

Journal compilation 79 (263–268) ª 2007 Blackwell Munksgaard 263

Genotype–phenotype correlation studies (8) suggest that

mutations in the C-terminal coiled coil region or trunca-

tion of the tailpiece is preferentially associated with

hematologic-only phenotypes (May–Hegglin anomaly,

Sebastian platelet syndrome), while mutations of the

head ATPase domain frequently are associated addition-

ally with nephropathy and ⁄or hearing loss (Fechtner syn-

drome, Epstein syndrome). However, this genotype–

phenotype pattern is not strictly applicable; a family car-

rying the same mutation in the MYH9 gene can show a

broad variety in the manifestations of non-hematologic

features. Furthermore, renal impairment, hearing loss

and cataracts rarely manifest during childhood, and at

widely differing ages during adulthood. There is evidence

that other protein abnormalities could explain some of

these phenotypic variations (9).

For patients with hereditary macrothrombocytopenia

requiring major surgery, there is uncertainty regarding

appropriate perioperative strategies to optimize hemosta-

sis (10) but also to prevent venous thrombosis. We

encountered a patient with MYH9-related macrothromb-

ocytopenia, leukocyte inclusions, sensorineural hearing

loss, and glomerulonephritis (Fechtner syndrome) requi-

ring neurosurgical resection of an arteriovenous malfor-

mation (AVM), whose postoperative course was

complicated not by bleeding but by pulmonary embol-

ism. This illustrates the potential for serious venous

thromboembolism in these patients despite their thromb-

ocytopenia.

Case report

Patient hemostatic history and laboratory investiga-tions

A 44-yr-old male of middle eastern descent, scheduled to

undergo neurosurgery for a posterior parietal AVM, was

referred for perioperative management of presumed chro-

nic autoimmune thrombocytopenia of at least 15 yr dur-

ation. He had previously undergone appendectomy and

tonsillectomy, and had sustained rib fractures, without

any significant bleeding or need for blood transfusions.

He also had progressive sensorineural hearing impair-

ment (confirmed by audiometry) and renal biopsy (with-

out bleeding) performed 2 yr earlier for proteinuria,

which was reported as showing ‘focal segmental

sclerosing glomerulonephritis’ without inflammation,

vasculitis, thrombosis, or deposition of immunoglobulin

or complement.

Hemoglobin was 124 g ⁄L, white blood cell count

8.4 · 109 ⁄L with normal leukocyte differential, and

platelet counts ranged from 40 to 90 · 109 ⁄L by the

electronic particle counter, with a mean platelet volume

(MPV) of 12.1 fL (normal, 7.4–10.4 fL). The patient’s

peripheral blood film revealed a platelet count estimated

to be about 100–120 · 109 ⁄L, giant platelets with

normal granulation, and faint blue-staining small

inclusion bodies within the granulocytes; the bleeding

time was 9 min (Ivy method, normal, 3–8 min). Inter-

national normalized ratio (1.0) and aPTT (25 s) were

normal. The serum creatinine was normal (73 lmol ⁄L).The patient exhibited proteinuria (1.28 g ⁄L; normal

<0.15 g ⁄L). Bone marrow aspiration and biopsy

revealed normal cellularity and normal trilineage

hematopoiesis; megakaryocytes were adequate, marrow

cytogenetics revealed no clonal chromosomal

abnormalities.

The patient’s 8-yr-old son also had macrothrombo-

cytopenia (124 · 109 ⁄L; MPV > 15 fL). However, the

other two children, and the patient’s wife, had normal

platelet counts (336, 260, and 275 · 109 ⁄L) and normal

MPVs (6.8, 7.9, and 7.7 fL) (Fig. 1).

Neurosurgery for AVM and postoperative pulmonaryembolism

The patient underwent image-guided left and right pari-

etal craniotomies to remove a parietal dural AVM

located near the superior sagittal sinus, with duraplasty.

No prophylactic or therapeutic administration of phar-

macologic prohemostatic therapy, such as tranexamic

acid or desmopressin, or blood products was given. The

estimated intraoperative blood loss was only 140 mL.

Also, no postoperative pharmacologic thromboprophy-

laxis was given, because of expected high risk for bleed-

ing and the patient was discharged on postoperative day

5. The next day the patient returned to hospital because

of abrupt-onset of dyspnea and left-sided pleuritic chest

pain. Spiral computed tomography (CT) confirmed pul-

monary embolism. The patient received therapeutic-dose

parenteral anticoagulation in-hospital, followed by

8 months of outpatient warfarin anticoagulation. No

bleeding complications were observed during anticoagu-

lant treatment.

Materials and methods

Informed written consent was obtained from the patient

and family members for performing the studies des-

cribed, and for preparing the case for publication.

Screening for MHY9 granulocyte inclusions

Immunofluorescence labeling was performed as described

(11), with minor modifications. In short, air-dried periph-

eral blood smears were fixed in ice-cold acetone (unfixed

blood smears can be sent within 1 wk by mail to the

laboratory in Greifswald, Germany), blocked with 10%

Hereditary macrothrombocytopenia Selleng et al.

264ª 2007 The Authors

Journal compilation 79 (263–268) ª 2007 Blackwell Munksgaard

goat serum, incubated with a rabbit anti-NMMHC-IIA

antibody (BT561; Biomedical Technologies, Stoughton,

MA, USA) for 45 min. at room temperature, washed,

incubated with a fluorescence-labeled goat antirabbit

antibody (Alexa Fluor-568; Molecular Probes, Eugene,

OR, USA) for 45 min. in the dark. The slides were

enclosed in mounting medium (Dako Cytomation fluor-

escence mounting medium; DAKO corporation, Carpin-

teria, CA, USA), overlaid with a cover slip, and assessed

by a fluorescence microscope at 1000· with immersion

oil.

Genetic studies

DNA was prepared and screened for published MYH9

mutations using RFLP- and SSP-PCR methods. RFLP-

PCR was performed as described (6), whereas the

SSP-PCR methods were developed in-house (detailed

protocols can be obtained on request from the laborat-

ory in Greifswald); the mutation was further confirmed

by direct DNA sequencing.

Results

The MPVs of both the patient and the affected child

were >12 fL with a broad-based platelet distribution

curve (Fig. 1). The peak at the beginning of the leuko-

cyte distribution curve observed in both the patient and

his son (see Fig. 1, arrows) is typical for macrothrombo-

cytopenia, as the particle counters classify the largest-

sized platelets as white blood cells. Granulocyte

inclusions seen by light microscopy were confirmed by

immunofluorescence using anti-NMMHC-IIA antibodies

as being clusters of myosin (Fig. 2).

Genetic analysis using RFLP-PCR in both macro-

thrombocytopenic family members revealed a mutation

at nucleotide position 3493, which corresponds to amino

acid position 1165. Subsequent nucleotide sequence ana-

lysis confirmed the mutation as C3493 fi T resulting in

an R1165C amino acid change. The other two children

as well as their mother showed normal blood smears, no

inclusion bodies in the granulocytes, and the MYH9-

gene wild type at position 1165.

PLT 40–90 x 109/LMPV 12.1 f1

01x421TLP 9 L/Lf51>VPM

01x633TLP 9 L/Lf8.6VPM



Platelet histogram White blood cell histogram

Platelets could not bedetected by the electronic particle counter.

Figure 1 Family tree of the patient with MYH9-related macrothrombocytpenia; the filled symbols indicate the patient and his son with the MYH9

gene mutation R1165C. Platelet counts, mean platelet volume, and cell counter histograms for platelets and white blood cells of all family mem-

bers are shown. The broad platelet distribution curve and the peak at the beginning of the white blood cell histogram curve (indicated by arrows)

are typical features of giant platelet disorders.

Selleng et al. Hereditary macrothrombocytopenia

ª 2007 The Authors


Discussion

Mutations in the MYH9 gene can result in autosomal

dominant giant platelet syndromes. Diagnostic and

therapeutic uncertainties often pose greater risk to the

patient than the disease itself. The present case illustrates

that avoidance of heparin for thrombosis prophylaxis

after major surgery can result in pulmonary embolism in

patients with MYH9-related thrombocytopenia despite

the reduced platelet count. Diagnosis of MYH9-related

macrothrombocytopenia should be suspected in patients

with large platelets, a high MPV, a broad platelet histo-

gram, and a peak preceding the leukocyte histogram

(Fig. 1). Often the easiest diagnostic approach is to per-

form routine complete blood counts in first-degree rela-

tives, with diagnostic confirmation using

immunofluorescence studies of leukocytes using anti-

NMMHC-IIA antibodies.

Patients with MYH9-related disorders show a continu-

ous spectrum of clinical manifestations without clear

boundaries among the various reported syndromes and

without a clear genotype–phenotype correlation

(Table 1). The only two consistent findings in all patients

are macrothrombocytopenia and abnormal distribution

of NMMHC-IIA within leukocytes, whereas the expres-

sion of nephritis, deafness, and cataracts is variable.

Among the five previously described families with the

R1165C mutation (the mutation found in our patients),

two phenotypes – Sebastian platelet syndrome and

Fechtner syndrome – have been reported. Macrothromb-

ocytopenia was found in all, whereas in two of the five

families renal dysfunction, impaired hearing and cata-

racts were observed (6, 8, 12); in another family, hearing

loss and cataracts were observed (2), whereas the two

remaining families presented with macrothrombocytope-

nia and leukocyte inclusion bodies only (6, 8, 13). An

enhanced bleeding tendency (easy bruising, mucous

membrane bleeding) was reported only for one family

(12).

In two large reviews of 77 families (2) and 85 families

(8) with MYH9-related macrothrombocytopenia (with

overlapping cases in the two reviews), bleeding complica-

tions were of minor importance. Also, Balduini et al.

(14) noted that bleeding in patients with hereditary

macrothrombocytopenia tended to be mild. When pre-

sent, the most common symptoms of impaired hemosta-

sis are easy bruising, prolonged menstrual periods, and

epistaxis (4). Seri et al. (2) described microhematuria in

43.5% of the affected patients. However, this more likely

represents manifestation of nephritis rather than a bleed-

ing diathesis (2). Patients with higher bleeding risk usu-

ally evince the first hemorrhagic symptoms during

infancy, with bleeding severity remaining stable thereaf-

ter. These features suggest that an estimate of surgical

bleeding risk secondary to MYH9-related disease is lar-

gely suggested by the bleeding history.

There is very limited experience with neurosurgical

interventions in patients with MYH9-related macro-

thrombocytopenia. Sehbai et al. (15) reported a patient

with May–Hegglin anomaly, platelet counts between 40

and 60 · 109 ⁄L, and lack of bleeding history who under-

went craniotomy after administration of desmopressin,

without bleeding complications. Based on the uneventful

history vis-a-vis bleeding diathesis, we considered the

bleeding risk during neurosurgery in our patient to be

low and thus surgery was performed without prohemo-

static agents such as desmopressin or antifibrinolytic

therapy, or transfusional support.

Further, heparin thromboprophylaxis was not given

postsurgery, as thrombocytopenic patients (including those

with macrothrombocytopenia) are generally assumed to be

more likely to have a bleeding tendency than a risk for

thrombosis. However, the risk for platelet-dependent bleed-

ing and venous thrombosis are only very weakly (if at all)

correlated with each other, and clearly based on our

patient’s clinical course, venous thrombosis can occur

despite MYH9-related macrothrombocytopenia. At least

A B C

Figure 2 Immunofluorescence staining of granulocytes for myosin clusters using anti- non-muscle myosin heavy chain IIA (NMMHC-IIA) antibody:

(A) patient with R1165C mutation, (B) affected son of the patient with R1165C mutation, (C) non-affected son of the patient.




for one patient with MYH9-related disease recurrent

thrombosis has been described (16). Despite a history of

epistaxis and bleeding gums since childhood (platelet counts

between 18 and 56 · 109 ⁄L), this patient with Fechtner syn-

drome (MYH9-R702H) developed at least four episodes of

venous thrombosis, beginning at 23 yr of age (spontaneous

proximal deep-vein thrombosis and pulmonary embolism),

with recurrences of deep-vein thrombosis (4 months later),

caval vein thrombosis (12 yr later), and thrombotic occlu-

sions of the arteriovenous fistulae (because of hemodialysis

for Fechtner syndrome-related renal failure). No cause for

thrombophilia was identified in this patient (except hype-

rhomocysteinemia) despite an extensive investigation.

Neurosurgical procedures are a major risk factor for

thrombosis (17–21). It is a Grade 1A recommendation

of the American College of Chest Physicians (ACCP)

that thromboprophylaxis should be routinely used in

patients undergoing major neurosurgery (21). In our

patient, thrombocytopenia was judged as a risk factor

for bleeding complications and was the reason against

the use of pharmacologic thromboprophylaxis. How-

ever, when postoperative pulmonary embolism was

diagnosed, the patient required therapeutic-dose antico-

agulant therapy for an extended period. This arguably

was associated with a much higher bleeding risk than

short-term perioperative thromboprophylaxis with hep-

arin. The occurrence of pulmonary embolism in this

patient with MYH9-related macrothrombocytopenia

illustrates that protection against venous thromboembo-

lism is not necessarily afforded by this platelet

disorder. When a careful preoperative history and

physical examination suggest that there is no (or

minimal) bleeding diathesis despite MYH9-related

macrothrombocytopenia postoperative pharmacologic

thromboprophylaxis may well be appropriate.

Acknowledgements

We thank the patient and his family for permission to

publish this history.

Table 1 MYH9-related disease

Families with macrothrombocytopeniaand inclusion bodies only Exon Mutation

Families with additional symptoms;e.g. deafness and ⁄ or nephritis and ⁄ or cataract

Exons encoding the globular head

del N76-S81 1 (7)

2 1 N93K

1 A95T

1 S96L 3

1 10 K371N

16 R702C 7

R702H 4

R705H 11

1 (22) Q706E

Exons encoding the coiled-coil domain of NMMHC-IIA

24 del E1066-A1072 1 (2)

1 25 S1114P

1 T1155I

2 R1165C 42

26 R1165L 2

1 delL1205-Q1207

1 D1424H 2

5 30 D1424N 8

1 D1424Y 1

31 V1516L 1 (23)

37 I1816V 1

15 38 E1841K 5

1 5774delA preterm

1 5779delC preterm

13 40 R1933X

1 5828delG preterm

E1945X 1 (2)

To date, 26 MYH9 mutations have been identified in 91 unrelated families. Data are taken from Dong et al. 2005 (8) unless otherwise indicated.

Values in parenthesis indicate references.1Non-syndromic deafness without hematological symptoms.2Including the family of the present report.

Selleng et al. Hereditary macrothrombocytopenia

ª 2007 The Authors


Financial support

This study was funded by the Heart & Stroke Founda-

tion of Ontario (#T-5207 and #T-6157); Deutsche For-

schungsgemeinschaft (Gr 1096 ⁄2-4); German Federal

Ministry for Education and Research (NBL3 program,

reference 01-ZZ0403), Deutsche Forschungsgesellschaft

(Graduiertenkolleg GRK-840), Landesforderungs-

programm EFRE.

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Perioperative management of MYH9 hereditary macrothrombocytopenia (Fechtner syndrome)