low adamts-13 activity during hemorrhagic events with disseminated intravascular coagulation.pdf

CASE REPORT

Low ADAMTS-13 activity during hemorrhagic eventswith disseminated intravascular coagulation

Yoshiaki Chinen Junya Kuroda Muneo Ohshiro Yuji Shimura Shinsuke Mizutani

Hisao Nagoshi Nana Sasaki Ryuko Nakayama Miki Kiyota Mio Yamamoto-Sugitani

Tsutomu Kobayashi Yosuke Matsumoto Shigeo Horiike Masafumi Taniwaki

Received: 3 January 2013 / Revised: 1 March 2013 / Accepted: 3 March 2013 / Published online: 14 March 2013

The Japanese Society of Hematology 2013

Abstract Disseminated intravascular coagulation (DIC)

is a life-threatening complication, and its control is

essential for therapeutic success. Recombinant human

soluble thrombomodulin alfa (rTM) is a novel therapeutic

agent for DIC. The efficacy of rTM in the treatment of DIC

is reportedly superior to that of conventional anti-DIC

treatments, such as unfractionated heparin or low molec-

ular weight heparin, but hemorrhagic events occasionally

interfere with the therapeutic benefits of rTM. We assessed

the clinical features of 20 consecutive patients who were

given rTM for DIC associated with various hematologic

disorders. Eight patients achieved remission of both pri-

mary disease and DIC, eight died due to progression of the

primary disease, and four died of various hemorrhagic

complications. Assessment of 16 biomarkers for coagula-

tion showed that the four patients who died of hemorrhagic

complications despite remission of their primary disease

showed lower ADAMTS-13 (a disintegrin and metallo-

proteinase with a thrombospondin Type 1 motif, member

13) plasma activity than other patients (P = 0.016). The

optimal cut-off level of ADAMTS-13 for predicting risk of

hemorrhagic complications was 42 % (P = 0.007). Plasma

ADAMTS-13 activity determined at diagnosis of DIC may

help predict the risk of hemorrhagic events during and/or

following DIC treatment with hematologic disorders.

Keywords ADAMTS-13 Disseminated intravascularcoagulation Hemorrhagic events Hematologic disorders

Introduction

Disseminated intravascular coagulation (DIC) is an

acquired coagulation disorder resulting from excessive

activation of the coagulation system caused by systemic

inflammation or tissue injury such as bacterial, traumatic,

obstetrical, or neoplastic diseases including leukemias or

lymphomas [15]. DIC leads to microvascular thrombi in

systemic organs and contributes to multiple organ dys-

function syndrome (MODS) [6]. Also, consumption and

subsequent exhaustion of coagulation factors and platelets

(Plts) lead to insufficient coagulation and eventually cause

severe bleeding. Although remission of the primary disease

is essential for improvement in DIC and subsequent com-

plications, supportive treatment for DIC is thus also crucial

for prevention of life-threatening bleeding and MODS

during treatment for the primary disease [6].

Unfractionated heparin and low molecular weight hep-

arin (LMWH) have been the most widely utilized for DIC

treatment [7]. Heparins have resulted in lower mortality

than other strategies for DIC [810], but their effectiveness

remains to be fully validated. Indeed, a randomized clinical

trial for examining the efficacy of unfractionated heparin

for sepsis-associated DIC was no more therapeutic than a

placebo [11]. Therefore, development of a more effective

therapeutic agent for DIC is urgently needed. Among

various new agents for DIC, such as tissue factor pathway

Y. Chinen J. Kuroda (&) M. Ohshiro Y. Shimura S. Mizutani H. Nagoshi N. Sasaki R. Nakayama M. Kiyota M. Yamamoto-Sugitani T. Kobayashi Y. Matsumoto S. Horiike M. TaniwakiDivision of Hematology and Oncology,

Department of Medicine, Kyoto Prefectural University

of Medicine, 465 Kajii-cho, Kamigyo-ku,

Kyoto 602-8566, Japan

e-mail: [email protected]

M. Ohshiro

Department of Hematology, Kyoto First Red Cross Hospital,

Kyoto, Japan

123

Int J Hematol (2013) 97:511519

DOI 10.1007/s12185-013-1308-x

inhibitor (TFPI), activated protein C, and antithrombin

(AT) [previously known as antithrombin III (AT-III)] [8, 9,

1217], recombinant human soluble thrombomodulin alfa

(rTM) is one of the most promising [18]. rTM binds to

thrombin to produce the thrombinrTM complex and

thereby convert protein C into activated protein C, which

inactivates the coagulation pathway. In addition, rTM

binds to high mobility group box-1 (HMGB1) and endo-

toxin through its lectin-like domain to suppress inflam-

mation [1921]. Results of a phase III trial showed that,

compared with heparin, rTM significantly improved DIC

associated with hematological malignancies or infections

and more effectively reduced the incidence of bleeding

complications [22]. However, it is still difficult to com-

pletely prevent bleeding complications with any type of

anti-DIC therapy including rTM, so that risk prediction for

bleeding events before DIC treatment is essential for better

therapeutic outcomes. We here report the clinical features

of four cases with hematologic diseases accompanied by

hemorrhagic complications during and/or following DIC

treatment with rTM. We also investigated which bio-

markers would help predict hemorrhagic complications

during DIC treatment by rTM with hematologic disorders.

Patients and methods

Patients and selection criteria

This study was conducted in accordance with the ethical

principles of the Declaration of Helsinki, and was approved

by the institutional review boards of our institutes. The

study design was described elsewhere [23]. Briefly, the

diagnosis of DIC was made according to the diagnostic

criteria by the Japanese Ministry of Health and Welfare

(JMHW) [23, 24]. Enrolled patients met the following

criteria: (1) hematologic disorders including DIC according

to the JMHW criteria, (2) over 15 years of age, and (3)

written informed consent obtained. Exclusion criteria were:

(1) life-threatening bleeding at the diagnosis of DIC, (2)

past history (within 1 year) of cerebrovascular disorders,

central nervous system surgery or trauma, (3) hypersensi-

tivity to protein preparations or unfractionated heparin, (4)

pregnancy, (5) undergoing dialysis therapy, (6) presence of

fulminant hepatitis, decompensated liver cirrhosis or other

serious liver disorders, (7) anticipated difficulties with

adequate drug infusion or obtaining data for assessment of

efficacy and safety, (8) enrollment in another clinical trial

within 6 months before this study, (9) treatment with

unfractionated heparin within 3 months before this study,

or (10) unsuitability determined at the discretion of the

investigators. In conjunction with treatment for primary

disease, rTM was administered for six consecutive days,

and, if needed, the treatment was extended for 7 days or

more. rTM (380 U/kg/day) was administered by intrave-

nous infusion for 30 min once daily for patients with a

serum creatinine (sCr) level of 3.9 mg/dL or less, and the

dose was reduced to 130 U/kg/day for patients with sCr of

4.0 mg/dL or more. Additional use of AT or fresh frozen

plasma (FFP) was allowed. For cases with a plasma AT

levels below 70 % or a plasma fibrinogen (Fib) levels

below 1.0 g/L, additional use of AT or fresh frozen plasma

(FFP), respectively, was allowed. The combinatory use of

other anticoagulant drugs, such as heparin or LMWH, was

prohibited.

Evaluation of patients

Patients were monitored for the effect of rTM on DIC in

terms of JMHW DIC criteria. Data for 16 markers asso-

ciated with coagulation were obtained on days 1 and 7,

and, when rTM was administered for 7 days or more, on

the last day of rTM administration as well. The markers

investigated comprised plasma levels or activities of a

disintegrin and metalloproteinase with a thrombospondin

Type 1 motif, member 13 (ADAMTS-13), activated par-

tial thromboplastin time (APTT), AT activity, Fib,

fibrinogen degradation products (FDP), HMGB1, plas-

minogen (PLG), plasminogen activator inhibitor-I (PAI-I),

plasminplasmin inhibitor complex (PIC), Plt count,

protein C activity (clot-based), protein S activity, pro-

thrombin time ratio (PT INR), soluble fibrin monomer

(SF), thrombinantithrombin complex (TAT), and von

Willebrand factor (vWF) activity.

Statistical analysis

Patients were divided into two groups according to hem-

orrhagic events. Associations between the 16 coagulation

markers before rTM treatment and hemorrhagic events

were analyzed by means of univariate analysis using the

MannWhitney U test. Categorical variables were analyzed

with Fishers exact test. The optimal cut-off level was

determined by receiver operating characteristics (ROC)

analysis. The KruskalWallis test was performed when the

patients were divided into three groups according to sur-

vival and hemorrhagic events. A P value of \0.05 wasconsidered statistically significant.

Results

Overall results

Between October 2009 and July 2011, 20 patients with

various types of hematologic disorders were enrolled in

512 Y. Chinen et al.

123

this study in our institutes: 17 had neoplastic malignant

diseases (three acute leukemias, nine malignant lympho-

mas, two myelodysplastic syndromes, one chronic myelo-

monocytic leukemia, and two multiple myelomas) and

three had benign diseases (one systemic IgG4-positive

multiorgan lymphoproliferative syndrome, one idiopathic

thrombocytopenic purpura, and one symptomatic anemia

due to anorexia nervosa). For the 17 patients with malig-

nant diseases, the causative factors for DIC were tumor

progression in six, tumor lysis syndrome by chemotherapy

in six, and severe infections in five patients. For the three

patients with benign diseases, the causative factors for DIC

were disease progression in one and infections in two.

Eight patients were alive on day 28 and 12 patients had

died by day 28. Four patients died of various types of

severe hemorrhagic events during and/or following rTM

treatment (Table 1).

Case reports

Patient no. 9 (Table 1)

An 80-year-old female was admitted to our hospital for the

treatment of advanced CD20-positive diffuse large B cell

lymphoma (DLBCL) with lymphoma-associated hemo-

phagocytic syndrome (LAHS) and DIC with JMHW DIC

score 8 (data shown in Tables 2, 3). She was treated with

concomitant systemic chemotherapy using R-CHOP, con-

sisting of rituximab, cyclophosphamide, doxorubicin, vin-

cristine and prednisolone (PSL), for DLBCL, and rTM for

DIC. On day 3, her hemoglobin level decreased from 7.0 to

6.2 g/dL and Plt count from 4.6 9 109 to 1.3 9 109/L. In

addition, her serum ferritin level increased from 5.91 to

9.488 g/L, indicating worsening of LAHS in spite of the

chemotherapy. Subsequently, methylprednisolone pulse

Table 1 Characteristics of the 20 patients enrolled in this study

No. Primary disease Clinical cause of DIC Treatment for

primary disease

Treatment for

primary disease

Outcome

on day 28

Hemorrhage

1 MDS Pneumonia and herpes encephalitis with

hemophagocytic syndrome

Antibiotic, steroid Not effective Died

2 MM Invasive pulmonary aspergillosis Antibiotic Not effective Died

3 DLBCL Disease progression Salvage therapy Not effective Died

4 DLBCL, post

allo-BMT

Disease progression Salvage therapy Not effective Died

5 MM Disease progression Induction therapy Not effective Died

6 PTCL Disease progression Induction therapy Not effective Died

7 DLBCL Disease progression Salvage therapy Not effective Died

8 AITL Mycotic meningitis Antibiotic Not effective Died

9 DLBCL Disease progression with

hemophagocytic syndrome

Induction therapy Effective Died Intestine

10 IgG4-MOLPS Disease progression Steroid Effective Died Muscle,

intestine

11 CMMoL Bacterial pneumonia Antibiotic Effective Died Brain

12 AML (M5a) Tumor lysis syndrome Induction theapy Not effective Died Urinary tract

Subcutaneous

13 DLBCL Tumor lysis syndrome Induction therapy Effective Alive

14 AITL Tumor lysis syndrome Induction therapy Effective Alive

15 AML (M3) Tumor lysis syndrome Induction therapy Effective Alive

16 ITP Bacterial pneumonia Antibiotic Effective Alive

17 Anemia due to

anorexia nervosa

Bacterial pneumonia Antibiotic Effective Alive

18 Philadelphia-

positive ALL

Tumor lysis syndrome Induction therapy Effective Alive

19 DLBCL, post

allo-BMT

Sepsis Antibiotic Effective Alive

20 MDS Tumor lysis syndrome Salvage therapy Effective Alive

AI angioimmunoblastic T cell lymphoma, AML acute myelogenous leukemia, ALL acute lymphoblastic leukemia, allo-BMT allogeneic bonemarrow transplantation, CMMoL chronic myelomonocytic leukemia, DLBCL diffuse large B cell lymphoma, IgG4-MOLPS IgG4-relatedmultiorgan lymphoproliferative syndrome, MDS myelodysplastic syndrome, MM multiple myeloma

Low ADAMTS-13 activity during hemorrhagic events 513

123

therapy and treatment with cyclosporin A were added for

the LAHS. Although her overall condition improved, she

suffered circulatory shock on day 17, when her hemoglobin

level dropped from 8.4 to 5.1 g/dL, and an enhanced CT

scan identified a huge retroperitoneal hematoma (Fig. 1a).

Despite a few therapeutic interventions with transcatheter

arterial embolization (TAE), she continued to suffer from

recurrent intraabdominal hemorrhage and died 26 days

after the initiation of R-CHOP. rTM was continued until

her death in this case.


A 79-year-old woman was admitted to our hospital for the

treatment of IgG4-related multiorgan lymphoproliferative

syndrome (MOLPS). Although treatment with PSL

resolved the symptoms associated with IgG4-MOLPS, Plt

counts continued to decrease and other laboratory tests

disclosed that she was suffering from DIC with JMHW

DIC score 8 (Tables 2, 3). rTM was started from the 15th

day of PSL treatment, but after 6 days, a complication

developed consisting of massive intramuscular hemor-

rhaging on her upper right arm which required TAE

(Fig. 1b). rTM was discontinued at this time point. Two

weeks later, the patient suffered bleeding from the duo-

denal diverticulum and eventually died of recurrent duo-

denal hemorrhage 59 days after the initiation of PSL

treatment.


A 62-year-old male with chronic myelomonocytic leuke-

mia who required periodic Plt transfusions as supportive

therapy presented with bacterial pneumonia. He had a

history of renal transplantation for chronic renal failure

24 years previously. His laboratory tests also disclosed

complication with DIC with JMHW DIC score 8 (Tables 2,

3). Treatment with antibiotics and rTM was initiated as

well as Plt transfusion on demand. rTM was discontinued

on day 6 based on the improvement of pneumonia as well

as of various coagulation markers. On day 10, he suddenly

developed dysarthria, and a brain CT scan showed multiple

hemorrhages in his right hemisphere and brain stem

(Fig. 1c). He subsequently suffered from recurrent intra-

cranial hemorrhage and died 36 days after admission.


A 73-year-old male patient visited our hospital complain-

ing of general malaise, dyspnea, fever, and gingival

bleeding for a week. Complete blood cell counts obtained

at admission showed a marked elevation of white blood

cells to 240.0 9 109/L, with 40 % consisting of myelo-

blasts and 55 % of monocytic cells, thrombocytopenia with

Plt count of 44 9 109/L, and anemia with hemoglobin

concentration 6.0 g/dL. Results of the bone marrow study

led to a diagnosis of acute myelogenous leukemia (AML),

Table 2 Coagulation biomarkers associated with patient survival and hemorrhagic events

Biomarker Normal range Pt no. 9 Pt no. 10 Pt no. 11 Pt no. 12 Patients with

hemorrhage

Patients without

hemorrhage

P

Mean SD Mean SD

ADAMTS-13 (%) 97.9 19.2(M)

113.5 27.1 (F)

19 34 37 36 31.5 8.4261 56.813 19.9273 0.016

APTT (s) 25.036.0 27 32.6 42.3 33.3 33.8 6.3293 46.323 10.4882 0.045

AT (%) 81123 106 90 91 73 90 13.4907 76.769 19.4343 0.202

FDP (mg/L) \50 42 65.3 ND 228.6 111.967 101.6771 42.746 57.0942 0.082FIG (mg/dL) 150400 185 87 362 111 186.25 124.3687 239.615 147.9288 0.624

HMGB-1 (lg/L) \1.0 1.4 12.8 12.0 53.3 19.875 22.8811 17.575 24.532 0.953PAI-1 (ng/L) \5.0 75 12 18 502 151.75 235.2196 132.375 260.9143 0.75PIC (mg/L) \0.8 2.7 8.4 2.6 8.6 5.575 3.3787 3.488 3.4875 0.211Plt (9109/L) 140340 1.3 8.3 1.4 4.4 3.85 3.297 5.708 7.067 0.785

PLG (%) 75125 71 56 90 44 65.25 19.8557 60.625 20.7264 0.75

Protein C (%) 64146 76 107 66 13 65.5 39.111 51.313 21.4902 0.335

Protein S (%) 60150 57 68 42 27 48.5 17.8606 53.938 22.8778 0.554

PT INR (ratio) 0.851.15 0.96 1.07 1.26 1.57 1.215 0.2672 1.262 0.1758 0.703

SF (mg/L) \6.1 44.3 115 10.7 [250 105 105.9905 68.256 83.531 0.385TAT (lg/L) \3.0 61.8 17.6 12.1 65.1 39.15 28.1811 76.419 157.8052 0.617vWF (%) 50155 365 69 138 318 222.5 141.5733 335.313 168.0776 0.29


123

M5a according to FAB classification [24]. Laboratory data

also showed complication with DIC with JMHW DIC score

10 (Tables 2, 3). rTM was administered during the induc-

tion chemotherapy for AML. Although leukapheresis fol-

lowed by systemic chemotherapy successfully reduced the

peripheral leukemic cells to 100.0 9 106/L within 48 h,

another complication developed in the form of tumor lysis

syndrome, in spite of sufficient hydration and the simul-

taneous administration of rasburicase. After 9 days of

chemotherapy, the patient started to suffer from intractable

urinary tract hemorrhage and massive systemic purpura. He

died of MODS after 17 days of chemotherapy and autopsy

revealed massive pleural and intraabdominal hemorrhaging.

rTM was continued throughout his treatment course.

Low ADMATS-13 activity associated

with hemorrhagic adverse events during

and/or following rTM treatment for DIC

We first conducted univariate analyses to examine the

prognostic value of pre-treatment biomarker scores for

coagulation with hemorrhagic complications during and/or

following rTM treatment for DIC in our series. As seen in

Table 2, results of the MannWhitney U test showed that

the plasma levels of ADAMTS-13 activity were signifi-

cantly lower in patients complicated by hemorrhagic events

than in others (P = 0.016).

We next subdivided the patients into three groups

according to the presence or absence of hemorrhagic events

during and/or following rTM treatment: (1) patients who

were alive on day 28 without hemorrhagic events, (2)

patients who had died by day 28 without hemorrhagic

events, and (3) patients who had died by day 28 with

hemorrhagic events. Analysis using the KruskalWallis

test showed that patients who died of hemorrhagic adverse

events had significantly lower levels of ADAMTS-13

activity than other patients (P = 0.004) (Fig. 2). It is also

noteworthy that no improvement in ADAMTS-13 activities

was seen even after rTM therapy in patients who died of

hemorrhagic complications (Table 3). To determine the

optimal cut-off point for ADAMTS-13, a ROC curve was

generated by plotting the true positive and false positive

rates for ADAMTS-13 activity. The result showed that the

best cut-off level for predicting the risk of hemorrhagic

complications was 42 %. Table 4 shows that ADAMTS-13

activity of less than 42 % was significantly associated with

a high frequency of bleeding after rTM treatment for DIC

(P = 0.007, Fishers exact test) (Table 4).

Discussion

This report deals with four cases with hematologic disor-

ders who experienced fatal hemorrhagic events during and/

Table 3 Changes in coagulation markers including ADAMTS-13 activity before and after rTM treatment

ADAMTS-13 (%) Plt (9l09/L) FIG

(mg/dL)

FDP

(case 11:

D-dimer) (mg/L)

PIC

(mg/L)

Total duration

of rTM

administration (days)

Onset of hemorrhagic

events after rTM

treatment (days)

Case 9

Day 0 19 1.3 185 42 2.7 26 17

Day 7 36 1.1 102 67.3 3

Day l7 NA 5.0 266 19.1 NA

Day l8 37 6.4 301 11.4 0.9

Case 10

Day 0 34 8.3 87 65.3 8.4 6 6

Day 6 NA 8.2 83 10 NA

Day 12 25 10.6 133 3.8 2.2

Case 11

Day 0 37 1.4 362 31.8 2.6 6 10

Day 7 33 1.6 275 6.4 1.2

Day l0 NA 1.8 240 8.1 NA

Case 12

Day 0 36 4.4 111 228.6 8.6 17 9

Day 7 38 0.8 133 71.3 3.1

Day 9 NA 0.3 262 53.8 NA

Day l4 29 0.4 236 75.5 1.9


123

or after rTM treatment for DIC. An important observation

was that, even though the disease states of the primary

disorders were under control or even improving, DIC had

continued at the onset of hemorrhagic events in all four

C

A

B

Fig. 1 Hemorrhagic complications in Cases 9, 10, and 11. CT scan identified a retroperitoneal hematoma in Case 9, b intramuscular hematomain Case 10, and c intracranial hemorrhage in Case 11

Plas

ma

ADAM

TS-1

3 ac

tivity

(%)

0

10

20

30

40

50

60

70

80

90

100

SurvivalWithout

Hemorrhage

DeathWithout

Hemorrhage

Death With

Hemorrhage

*p=0.004

Fig. 2 Association between ADAMTS-13 activity and hemorrhagicevents. KruskalWallis test demonstrated that patients who died of

hemorrhagic events showed significantly lower levels of ADAMTS-

13 activity than other patients (P = 0.004)

Table 4 Relationship between the plasma level of ADAMTS-13activity and hemorrhagic complications

ADAMTS-13 Total

[42 % \42 %

N % N % N %

With bleeding 0 0 4 20 4 20

Without bleeding 13 65 3 15 16 80

Total 13 65 7 35 20 100

Receiver operating characteristics analysis revealed that ADAMTS-

13 activity of less than 42 % was significantly associated with high

frequency of bleeding after rTM treatment for DIC (P = 0.007,Fishers exact test)

N number


123

cases. Moreover, hemorrhagic events repeated even after

the cessation of rTM treatment in two cases. Therefore, no

direct association between rTM treatment and hemorrhagic

events was evident in our series. There are similar reports

about patients who experienced hemorrhagic complications

during or after the treatment with rTM. In those reports,

however, the authors did not explicitly mention the cause-

and-effect relationship between treatment with rTM and

hemorrhagic events, but only suggested that bleeding risks

associated with rTM should be taken into account in some

situations [25, 26].

We previously identified the value of plasma ADAMTS-

13 levels for the prognosis of DIC treated by rTM [23], but

the reason for the association of low levels of ADAMTS-13

with poor prognosis was not examined. In the current study,

however, we found that low plasma levels of ADAMTS-13

were significantly associated with fatal hemorrhagic events,

which may at least partly explain the significant prognostic

value of low plasma ADAMTS-13 levels for poor outcomes

for DIC treated with rTM. It should be also noted that values

of coagulation markers including FDP, Fib, PIC, and Plt

were worse in hemorrhagic patients than in non-hemor-

rhagic patients, although the statistical significance was not

reached. These observations suggest that DIC might be

more severe in hemorrhagic patients at diagnosis. Needless

to say, there were also patients with low ADAMTS-13 level

in our study cohort who did not die of hemorrhagic events.

In most of those patients, however, the primary disorders

could not be controlled, which implies that low levels of

ADAMTS-13 may also be associated with aggressiveness

of primary diseases.

The underlying mechanism linking low ADAMTS-13

activity with hemorrhagic events remains unclear.

ADAMTS-13 protein, a member of the circulating zinc

metalloproteases, cleaves the unusually large vWF

(ULvWF) multimers in a shear-dependent manner [2729],

so that a reduction in ADAMTS-13 activity causes the

accrual of ULvWF multimers and excessive PLT clumping,

resulting in organ failure due to microvascular occlusion, as

also seen in cases with thrombotic thrombocytopenic pur-

pura or thrombotic microangiopathy (TMA) [3034]. rTM

treatment was reported to have been useful for a case with

TMA in systemic lupus erythematosus. It should be noted

that ADAMTS-13 activity was over 60 % in that case, which

is consistent with our finding [35].

Recently, several studies have reported that ADAMTS-

13 deficiency was also observed in patients with various

diseases other than TMA, such as septic shock, heparin-

induced thrombocytopenia, acute leukemia, systemic

inflammation, and DIC [3639]. In the case of DIC, dis-

seminated activation of intravascular coagulation leads to

endothelial damage and thereby causes the release of a

great deal of ULvWF from endothelium. During this

process, the systemic and persistent release of ULvWF may

deplete ADAMTS-13, thus resulting in abnormally reduced

levels of ADAMTS-13 activity [3739]. In addition, recent

studies have suggested other possible mechanisms for the

loss of ADAMTS-13 activity in DIC. For instance,

thrombin, a major player in the development of DIC,

proteolyses ADAMTS-13 [39], while several other prote-

ases also cleave ADAMTS-13 [40]. Since ADAMTS-13

deficiency results in increased leukocyte rolling in unstim-

ulated veins and increased leukocyte adhesion in inflamed

veins resulting in systemic endothelial cell damage [41],

this may promote hemorrhaging. In short, our findings

suggest that the level of ADAMTS-13 activity is associated

with endothelium damage in DIC, and that ADAMTS-13

can be used as a biomarker for vessel damage in DIC. It is

known that rTM not only acts as an anticoagulant but also

inhibits endothelial injury through binding to and inacti-

vating HMGB1 [42]. Putting this concept together with our

findings makes it conceivable that, when ADAMTS-13

activity is less than 42 %, the anticoagulant activity of rTM

may override its protective activity for endothelial cells, and

eventually lead to hemorrhagic events. If this is the case, the

administration of fresh frozen plasma may be beneficial

by controlling the anticoagulant activity of rTM so that

ADAMTS-13 can be restored to normal levels [43]. In

addition, pre-treatment APTT was also significantly lower

for patients complicated by hemorrhagic events than for

others in this study (P = 0.045), although bleeding ten-

dency is normally associated with abnormally elevated

APTT values. Because the prolonger APTT was improved

in patients those were successfully treated by rTM (data not

shown), pre-treatment APTT may not be predictive for

hemorrhagic complications or treatment outcome.

In conclusion, low plasma ADAMTS-13 activity at

diagnosis of DIC with hematologic disorders is the possible

predictor for hemorrhagic complications.

Acknowledgments This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture,

Sports, Science and Technology of Japan (M.T. and J.K.) and the

Hoansha Foundation (J.K.).

Conflict of interest The authors declare that they have no conflictof interest.

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c.12185_2013_Article_1308.pdfLow ADAMTS-13 activity during hemorrhagic events with disseminated intravascular coagulationAbstractIntroductionPatients and methodsPatients and selection criteriaEvaluation of patientsStatistical analysis

ResultsOverall resultsCase reportsPatient no. 9 (Table 1)Patient no. 10 (Table 1)Patient no. 11 (Table 1)Patient no. 12 (Table 1)

Low ADMATS-13 activity associated with hemorrhagic adverse events during and/or following rTM treatment for DIC

DiscussionAcknowledgmentsReferences

low adamts-13 activity during hemorrhagic events with disseminated intravascular coagulation.pdf

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