Comunicación y Gerencia

Dental management
in bleeding
g disorders

Oral and maxillofacial department

O p SWU
S U

Kiti Siriwatana
 Recommended websites
http://www.labtestsonline.org/understanding/conditions/bl
eeding_disorders.html
http://www.itppeople.com/lowplate.htm
http://www.haemophilia.org.za/Vonwil2
http://www.haemophilia.org.za/Vonwil 2.htm
http://www.bloodjournal.org/cgi/content/full/90
http://www.bloodjournal.org/cgi/content/full/ 90//7/2515
2515?ck=
?ck=
nck
http://www.bmj.com/content/vol323
http://www.bmj.com/content/vol 323/issue
/issue7308
7308/images/larg
/images/larg
e/harr
e/harr6011
/h 6011.f
6011.f1
f1.jpeg
j
http://perfline.com/guidelines/aprotinin.shtml
 Do you know?
Bleeding disorders VS Blood dysclasias
Basic knowledge
g of hemostasis
Hemostasis mechanism/process
Coagulation factors
Coagulation cascade
Categorized
Is the patient bleeding?
History taking
Physical examination
Laboratory investigations
L
Local
l bl
bleeding
di VS Bl
Bleeding
di didisorders
d
a localized pathological process or a disorder of the hemostatic process
Treatment
 Hemostasis Process

•P
Primaryy hemostasis is formation of p platelet
plug at sites of injury and occurs within
seconds of injury
•Secondary hemostasis describes the
coagulation
l ti system,t which
hi h result
lt iin fib
fibrin
i
formation.
 The Hemostasis mechanism

Consists of four components:

Vascular system (endothelial cell (EC)
li i )
lining)
Platelets (number and function)
Plasma proteins (coagulation factors)
Fibrinolytic
F y mechanisms
 Vascular system (endothelial cell (EC) lining)

• Able to secrete a number of substances

• Tissue plasminogen activator Activates plasminogen
plasminogen, a plasma
protein which is converted to an enzyme, "Plasmin", which
dissolves fibrin and other plasma proteins.
• von Willebrand factor (vWF) A large polymeric protein which is a
part of factor VIII that enables platelets (through a receptor on the
surface) to adhere to collagen and the basement membrane upon
damageg to the endothelial layer.
y
• Heparin Sulphate Has a weak antithrombin (AT) action, promoting
the action of antithrombin
• Prostacyclin A product of prostaglandins which prevents platelet
aggregation and causes vasodilation (PGE2 as a dilator of arterial
vessels and NO as a dilator of smooth muscle cells)
 Platelet

The formation of the platelet plug is

referred to as primary haemostasis
The time taken for this plug to form (Bleeding
Time - BT) gives a non-specific indication of:
The state of the vascular endothelium
The number fo platelets in the circulation
Th platelets
The l t l t are functioning
f ti i correctlytl (can
(
release granules and produce pseudopodia)
Demonstrates the presence of vWF
 Platelet

• ADP from endothelium:

• Platelet adhesion
• Von Willebrand’s factor from endothelium:
• Platelet adhesion
• Thromboxane
Th b f
from platelet:
l t l t
• Platelet aggregation
• Platelet factor 3:(Thromboplastin
:(Thromboplastin))
• feeds back to accelerate the clotting cascade
 Plasma proteins (coagulation factors)

S i P
Serine Protease
t C f t
Cofactors T
Transamidase
id S b t t
Substrate
XIIa HMWK Factor VIII Fibrinogen (I)
XIa VIII

Kallikrein V

IXa Platelet Factor 3

VIIa

Xa

Thrombin ((IIa))
Plasma proteins (coagulation factors)
Factor Name

I Fibrinogen
II P th
Prothrombin
bi
III Tissue factor or thromboplastin
IV Calcium
V Proaccelerin (Labile factor)
VII Proconvertin (Stable factor)
VIII Antihemophilic factor A, Antihemophilic globulin
IX Antihemophilic factor B, Plasma thromboplastin component, Christmas
factor
X Stuart-Prower factor
XI Plasma thromboplastin antecedent, Hemophilia C, Rosenthal syndrome

XII Hageman factor

XIII Fibrin
ib i stabilizing
bili i factor,
f Laki-Lorand
ki d factor
f
Plasma proteins (coagulation factors)
• All coagulation factors are made in the liver
• Vitamin K dependent coagulation factors
• Factor II
• Factor VII
• Factor IX
• Factor X
• Protein C
• Protein S
• The oral anticoagulant,
g , warfarin
warfarin,, acts here byy blocking
g the reduction
of oxidised (inactive) vitamin K
• Other names given to these proteins include:
• Vitamin K dependent coagulation factors = prothrombin
complex.
• PIVKA - protein induced in vitamin K absence
• PPSB - prothrombin = F II, proconvertin = F VII, StuartStuart--Prower-
Prower-
Factor = F X, and antihemophilic globulin B = F IX.
 Heparin
A ti t Antithrombin
Activates A tith bi which
hi h iinhibits
hibit
IIa,XIa,IXa and Xa
 Fibrinolysis

• Fibrinolysis works in a steady state with haemostasis

• Damaged endothelium releases tissue plasminogen activator as

well as plasminogen - both of which are adsorbed to the fibrin
surface

• Plasmin degrades fibrin and dissolves: Fibrinogen, Factor V and

Factor VIII

• Excessive fibrinolysis however, will lead to bleeding

 Contact activation starts Tissue thromboplastin starts
the intrinsic pathway The extrinsic pathway
XII
VII
XI
Partial thrombo

Proth
IX
VIII
t

hrombin
X

n time
oplastin

Common pathway
n time

A ti t d X
Activated
Thrombin time

IV+V+Phospholipids (platelet)
Prothrombin--ÆThrombi
Prothrombin Thrombin by Prothrombinase
Fibrinogen (XIII)ÆFibrin monomer->Fibrin
monomer >Fibrin
Fibrin polymer

Fibrin clot
e

Coagulation Cascadecoag_cascade.pdf
 Categorized

Bleeding
eed g d disorders
so de s ca
can tthus
us be catego
categorized
ed
into four groups:
Vascular wall alteration
Disorders of platelet function or number
Disorders of clotting
g factors
A combination of the above
 Vascular wall alteration

• Scurvy
• Infections
• Chemicals
• Allergy
 Thrombocytopenic purpuras
• Primary
Primary--idiopathic
• Secondary
• Chemicals
• Physical agents (radiation)
• Systemic
y disease (leukemia)
( )
• Metastatic cancer to bone
• Splenomegaly
• Drug
• Alcohol
• Thiazide diuretics
• Estrogens
• Gold salts
• Viral or bacterial infections
 Disorders of platelet function

• Genetic defects (Bernard

(Bernard--Soulier disease)
• Drugs
• Aspirin
• NSAIDs
• Alcohol
• Penicillin,Beta
Penicillin
Penicillin,Beta-
Beta-lactam antibiotics
• Allergy
• Von Willebrand’s
Willebrand s disease
• Uremia
 Von Willebrand’s disease

the most common inherited bleeding disorder

th di
the disease is
i usually
ll less
l severe than
th haemophilia
h hili

In fact, it is often so mild, it is not diagnosed at all

Unlike haemophilia, however, which usually affects only males,

von Willebrand disease occurs in men and women equally

Von Willebrand factor causes platelet to bind to areas of a blood

vessel that are damaged

the von Willebrand protein serves as a carrier for factor VIII, factor
VIII may also be reduced
Von Willebrand’s disease
 Disorders of coagulation
Inherited
• Hemophilia
• Acquired
• Liver disease
• Vitamin deficiency
• Biliary tract obstruction
• Malabsorption
• Excessive use of broad
broad--spectrum
antibiotics
• Anticoagulation drugs
• Disseminated intravascular coagulation (DIC)
Disseminated intravascular coagulation (DIC)
• DIC is a disorder of the "clotting cascade." It
results in depletion of clotting factors in the
blood.
• Blood clotting mechanisms are activated
throughout the body instead of being localized
to an area of injury
• Eventually the blood clotting factors are used
up and not available to form clots at sites of
real tissue injury
• Result in either clotting symptoms or, more
often, bleeding. Bleeding can be severe
Disseminated intravascular coagulation (DIC)
• Stimulated by many factors
• Infection in the blood by bacteria or fungus, severe tissue
injury (as in burns and head injury),
injury) cancer
cancer, reactions to
blood transfusions, and obstetrical complications
• Risk factors
• Recent sepsis
• Recent injury or trauma
• Recent surgery or anesthesia
• Complications of labor and delivery
• Leukemia or disseminated cancer
• R
Recent bl d transfusion
blood f i reaction
i
• Severe liver disease
Comunicación y Gerencia

Detection of the Patients

Who are a Bleeder

Oral and maxillofacial department

O p SWU
S U

Kiti Siriwatana
 Who are a Bleeder?

• History taking

• Physical examination

• Laboratory investigations
 History taking
• Bleeding problems in relative
• A family history for bleeding disorders may be helpful for the
assessment of pathologic bleeding
• A medication history
• Anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs), oral
contraceptives,
t ti antibiotics,
tibi ti ethanol,
th l and
d di
dietary
t vitamin
it i K and
d
vitamin C.
• The response to past hemostatic challenge such as
trauma, tooth extraction, pregnancy, surgery, sports, and menstruation.
• Spontaneous bleeding from nose,mouth, ears,etc.
• Presence of illnesses that may have associated
bleeding problems
• liver or kidney disease,renal dialysis,leukemia,hemophilia or
malabsorption is often helpf
helpful.
l
 Five letter A

• Aspirin
• Anticoagulant
• Long--term antibiotic therapy
Long
• Alcohol
• Anticancer
 Physical examination

•If bleeding
g is suspected;
p identify
y the site and
severity, duration of bleeding and clinical setting.
•Mucocutaneous
M t bleeding
bl di suggests t a platelet
l t l t di
disorder.
d It includes
i l d
petechiae, ecchymoses, epistaxis, and genitourinary and
gastrointestinal bleeding.

•Bleeding into potential spaces (joints, fascial planes,

retroperitoneum) suggests a coagulation factor deficiency.

•Bleeding from multiple sites in hospitalized patients can be seen with

disseminated intravascular coagulation (DIC) or Thrombotic
Thrombocytopenic Purpura (TTP)
(TTP).
 Related clinical finding

•Jaundice,pallor

•Spider angiomas

•Ecchymoses

•Petechiae
P t hi

•Hyperplastic gingival tissues

•Hemarthrosis
•http://s88741803.onlinehome.us/weblog/Images/jaundice.jpg
•http://www.cs.stir.ac.uk/~pns/jaundice.jpg
•http://www.dermguy.com/dev/images/resources/spider_angioma.jpg
 Petechiae

•Petechiae are tiny little broken capillary blood

vessels
l

•~0.5
0 5 mm

•Discrete
Di t

•No
No tender

•Vascular
Vascular phase or platelet phase abnormality
•http://z.about.com/d/dermatology/1/0/Z/petechiae.jpg
•http://www.dental.mu.edu/oralpath/lesions/petechia/petechia2.jpeg
•http://www.dental.mu.edu/oralpath/lesions/petechia/petechia2.jpeg
•http://www2.musc.edu/dentistry/top40/Images/13petechiae
 Ecchymosis

•Hemorrhage under skin

•Purple-red
p in early
y time:Hematin

•Yellow-green
Yellow green in late stage:Hemosiderin
•http://www.bmj.com/content/vol323/issue7308/images/large/harr6011.f1.jpeg
• http://missinglink.ucsf.edu/lm/Dermatology
Glossary/ecchymosis.html
y y
•http://www macmed ttuhsc edu/Morgan/anemia/images/Untitled-23 jpg
•http://www.macmed.ttuhsc.edu/Morgan/anemia/images/Untitled-23.jpg
 Hematoma

•Blood clot in subcutaneous or

intramuscular layer

•Can change to ecchymosis

 Hemarthrosis

•Hemorrhage in the joint

•Most common in hemophilia

•http://www.carletonsportsmed.com/med17.jpg
•http://www.mednet.gr/pim/images-hemostasis/ht2_1.jpg
 Laboratory investigation

•Platelet count
•Bleedingg time
•aPTT
•PT
•TT
TT
•FDPs and D-dimers
•Platelet function screen
•Platelet aggregation study
•Fibrinogen
•Coagulation Factors
•Von
V Willebrand
Will b d screen
•Von Willebrand factor antigen (vWF:Ag)
•Von Willebrand factor activity (vWF:RCo)
•Factor VIII:C activity
 Screening test
• CBC

• Platelet count

• Bleeding time

• aPTT

• PT
 aPTT
•Also known as: Partial Thromboplastin Time, PTT, APTT

•Formal name: Activated Partial Thromboplastin Time (aPTT)

•As part of an investigation of a bleeding or thrombotic episode. To help

evaluate your risk of excessive bleeding prior to a surgical procedure.
procedure To
monitor heparin anticoagulant therapy.

•It represents the time for clot formation after adding calcium, phospholipids,
and kaolin to citrated blood

•It is prolonged by heparin, direct thrombin inhibitors, a deficiency or inhibitor

for factors in the intrinsic and common pathway (namely,
(namely factors IIII, V,
V VIII
VIII, IX
IX,
X, XI, XII) as well as lupus anticoagulant, vitamin K deficiency, or severe liver
disease

„Tests intrinsic and common pathways

 PT and INR

•Also known as: Prothrombin Time, Pro Time

•Formal name: Prothrombin Time, International Normalized Ratio

•To check how well blood-thinning medications (anti-coagulants) are

working
ki to prevent bl
blood
d clots;
l to help
h l detect
d and
d diagnose
di a
bleeding disorder

•It
It represents
t the
th time
ti for
f clot
l t formation
f ti after
ft the
th addition
dditi off
thromboplastin (tissue factor) and calcium to citrated blood

•It is prolonged with deficiencies of factors II

II, V
V, VII
VII, X or fibrinogen;
liver disease; vitamin K deficiency and Warfarin use

•Tests extrinsic and common pathways

 INR

•PT has imprecise and variable.

•Due to the source of thromboplastin,type of

i t
instrumentation
t ti

•International
I t ti l sensitivity
iti it iindex
d (ISI)

•INR=(PTR)
INR (PTR)

•PTR=prothrombin
PTR prothrombin time ratio
 TT

•Time to clot formation after the addition of

th
thrombinbi tto citrated
it t d bl
blood
blood:Tests
d T t ability
bilit tto fform
initial clot from fibrinogen

•prolonged by heparin, direct thrombin inhibitors,

fib i d
fibrin degradation
d ti products
d t (FDP
(FDPs),
)
paraproteins, and fibrinogen deficiency (both
q alitati e and q
qualitative quantitative).
antitati e)
 Evaluating the results of a PT (extrinsic pathway) and aPTT (intrinsic
pathway) test:
test:

•If the aPTT is abnormal and the PT is normal, you may have deficiencies
of factors VIII, IX, XI, or XII.

•If the aPTT is normal and the PT is prolonged, you may have a deficiency
of factors I, II, V, VII, or X.

•If both PT and aPTT are abnormal, you may have deficiencies in the
common pathway or to multiple factor deficiencies.
Table 1:

Evaluation of Prolonged PT or PTT

Prolonged PT and
Prolonged PT Prolonged PTT
PTT
Inherited
• Prothrombin,
• VWF, VIII, IX, XI, or fibrinogen, V, X or
• Factor VII deficiency
XII deficiency combined factor
deficiency
Acquired
• Vitamin K deficiency • Heparin • Liver disease
• Liver disease • Inhibitor of vWF, • DIC
• Warfarin use factors • Supratherapeutic
• F t VII inhibitor
Factor i hibit • VIII IX,
VIII, IX XI,
XI or XII h
heparini or WWarfarin
f i
• Antiphospholipid • Combined heparin
antibody and Warfarin use
• Direct thrombin
inhibitors
• Inhibitor of
prothrombin,
prothrombin
fibrinogen, or factor
V or X
 Dental management

•Local bleeding
•Local hemostasis
•Bleeding disorders
•Local hemostasis
•Medication
•Replacement therapy
•Local hemostasis agent Treatment
• Fibrin glue
• Surgicel,Oxicel
• Gelfoam+thrombin
•Antifibrinolytic agents
• Epsilon
Epsilon--aminocaproic acid (EACA)
• Tranexamic acid
• Factor VIII stimulant (DDAVP)
• Aprotinin (Trasylol®)
•Replacement
• Fresh frozen plasma (FFP)
• Cryoprecipitate
• Platelet concentrate
 Local therapy
• Suture/electrocautery
• Local hemostasis agent:
– Surgicel,gelfoam+thrombin
– Fibrin
Fib i glue
l
• Vacuum splint
p
• Spacial antifibrinolytic mouth wash/
antifibrinolytic agents
– Tranexamic acid,EACA
 Fibrin glue (FG)
• Two component system
• Solution 1: Thrombin/calcium
• Solution 2: Fibrinogen/tranexamic acid
• Two solutions mimic the final stages of the
clotting
c ott g cascade to form
o a fibrin
b cclot
ot
• Useful for local hemostasis,valuable tool
for adhesion,sealing,anastomosis,vascular
adhesion sealing anastomosis asc lar
and nerve grafts
 FG in oral and dental surgery
• Local hemostatic measures
– in p
pt. with bleeding
g disorders and
– In pt. on anticoagulants
• S
Sealing
li off oro-antral
t l fistula
fi t l
• Correction of p
periodontal bonyy defect
• Tissue adhesive with bone chips to
prevent bone defect
 Tranexamic acid
• A
An antifibrinolytic
tifib i l ti agentt
• Competitively
p y inhibits the activation of
plasminogen to plasmin
• Promote clot stability
• Adjunctive therapy in some bleeding
disorders.
disorders
• Superseded the use of amino caproic
acid,which has a shorter plasma half-
life,less potent and more toxic
•http://www.nature.com/bdj/journal/v198/n1/images/4811955f1.jpg
To prevent or treat serious bleeding
after dental surgery
• For oral dosage form (tablets):
• Adults and children-25 milligrams (mg) per kilogram (kg)
((11.4 mggp per ppound)) of bodyy weight
g every y six to eight
g
hours, beginning one day before surgery. After surgery,
the dose is usually 25 mg per kg (11.4 mg per pound) of
bodyy weight
g every y six to eight
g hours for two to eightg
days.
• For injection dosage form:
• Adults and children-10
children 10 mg per kg (4.5
(4 5 mg per pound) of
body weight, injected into a vein just before surgery.
After surgery, the dose is usually 10 mg per kg (4.5 mg
per pound)d) off body
b d weight,
i ht iinjected
j t d iinto
t a vein
i every sixi
to eight hours for seven to ten days.
 Tranexamic acid
• Special mouth rinse for dental surgery
– 250 mgg is disolved in 50 ml of drinking
g water
– Used by swishing and swallowing all amount
– Every 6 hours for one week
• Side effects: Nausea, vomiting,
diarrhea,vision changes, dizziness
 Tranexamic acid
• Th
The effect
ff t off ttranexamic
i acid
id (cyclokapron)
( l k ) on blood
bl d
loss after third molar extraction under a day case
general anaesthetic
g
• N. Senghore,1 and M. Harris2

1SHO Oral
O l & Maxillofacial
M ill f i l SSurgery, EEastman
t D
Dental
t l
Institute and Hospital, 256 Gray's Inn Road, London
WC1X
C 8LD;; 2Professor
8 o esso aandd Head
ead o
of Department,
epa e ,
Department of Oral and Maxillofacial Surgery, Eastman
Dental Institute and Hospital, 256 Gray's Inn Road,
London WC1X 8LD
 DDAVP
• DESMOPRESSIN (1-deamino-8-D-
g
arginine vasopressin,
p , abbreviated
DDAVP)
• A derivative of the antidiuretic hormone
(Vasopressin)
• Used for the first time to treat patients with
hemophilia A and von Willebrand disease
(vWD)
 DDAVP
• Desmopressin has also been used
prophylactically
p p y y in p
patients undergoing
g g
surgical operations characterized by large
blood loss and transfusion requirements
• The increases in the plasma levels of
factor VIII and vWF occur not only in
deficient p
patients, but also in healthy
y
individuals
Table 1. Recommended Dosages of Desmopressin and Factor VIII With
p
vWF Responses in Patients With Hemophilia
p and vWD

IIntravenous and
d subcutaneous:
b 0.3
03
Single dose µg/kg
Intranasal: 300 µg/kg
Mean factor increase over baseline 3-5 times

(range: 1.5
1.5-20
20 times)
Time to peak levels 30-60 min after intravenous injection
90-120 min after subcutaneous injection
and intranasal application
Plasma half-life 5-8 hours for factor VIII
8-10 hours for vWF
Table 2. Indication for Desmopressin in Different Types of vWD

Established Type 1, "platelet normal"

Type 2N
Type 1, "platelet low" and types 2A
Possible and 2B
Doubtful Type 3 (severe)

"Established"
Established indications are those in which desmopressin normalizes the
bleeding time and factor VIII levels, and is clinically efficacious; "Possible"
indications, those in which the effect on the bleeding time is absent or
inconsistent with little data on clinical efficacy; "Doubtful"
inconsistent, Doubtful indications,
indications those in
which desmopressin does not normalize factor VIII levels or the bleeding time,
and is not clinically efficacious.
Table 3. Indications for Desmopressin in the Treatment of Bleeding Disorders

Grading
G di off
Level of
Recommendatio
Evidence
n

Establi
shed Mild hemophilia A B III
vWD (see Table ) B III
Possib
le Congenital defects of platelet function C IV
Uremia C IV
Liver cirrhosis C IV
Drug-induced bleeding (heparin, hirudin,
antiplatelet
ti l t l t agents,
t d dextran,
t streptokinase)
t t ki ) C IV
Doubt
ful Cardiac surgery A I
General surgery A I
 All patients with VWD were diagnosed with mild type 1 VWD. Patients with VWD
were all proven responders to desmopressin (DDAVP), (desmopressin acetate), a
synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH),
that supports coagulation. The treatment protocol was:

1. Preoperatively document adequate response to DDAVP with rise in

Ristocetin Cofactor and Factor VIII at separate clinic visit
2 Preoperative
2. Preoperati e labs
3. Administer Intranasal DDAVP (Stimate®) or DDAVP IV at 0.3 mcg/kg 30
minutes prior to operating, day one, and day five after surgery.
4. Document appropriate response with rise of Ristocetin and Factor VIII to
70-90 percent normal. If inadequate response administer Humate®.
5. Restrict
5 R i flfluids
id to 1/2 maintenance
i ffor 12 hours
h post-surgery and
d after
f
each dose of DDAVP. 6. Admit for 23 hour observation.
p
7. Administer aminocaproic acid ((Amicar®)) 50mg/kg
g g four times a day
y for
five days.
 Aprotinin (Trasylol®)
• is indicated for prophylactic use to reduce
perioperative blood loss and the requirements
for blood transfusions in patients undergoing
cardiac surgery with cardiopulmonary bypass
• is a natural serine protease inhibitor with
effects on human plasmin, trypsin, plasma
and tissue kallikrein
• Aprotinin is obtained from bovine lung
The precise mechanism of action of aprotinin is still under discussion. It

has been suggested that aprotinin may act by a few avenues

• IInhibits
hibit plasmin
l i andd kallikrein,
k llik i affecting
ff ti fib
fibrinolysis;
i l i
• Inhibits contact phase activation;
• Preserve the adhesive glycoproteins in the platelet
membrane, thus increasing the resistance to damage.
Aprotinin
p p
preserves the g glycoprotein
y p receptor
p ((GIb,
GIIb/IIIa) in platelets. The GIb receptor is responsible for
platelet adhesion to endothelium ;
• Inhibits fibrinolysis and turnover of coagulation factors
and decreases bleeding;
• Prevents the expression of pro-inflammatory
pro inflammatory adhesive
glycoproteins (CD11b) in granulocytes
Replacement therapy
 Blood component preparation
Whole blood

Centrifuge 4 c

Packed Red Cells Plasma + Platelets

Centrifuge 20 c

Freeze -80 c Centrifuge 4 c Platelets Plasma

Quick Freeze -70 c
Q

Frozen Packed
red Red + Leukocytes FFP
Cells Cells Cryopre Bank
+
Slow thaw -cipitate Plasma
4 c Centrifuge
C if
 Replacement therapy
• The recommend factor level for
– Minor oral surgery
g y is 5-10%
% of normal
– Major surgery is 25-40% of normal
• Platelet
Pl t l t countt
3
– 20000 /mm:spontaneous bleeding
3
– 50000/mm:the lowest level for oral surgery
 Replacement therapy
• FFP 10-15 ml/kg increase Factor level to
20-30%/12 Hr
• PC (platelet concentrate) 1 unit/10 kg
increase
3
– 40000-60000/mm in child
3
– 5000-10000/mm in adult