C o m p l i c a t i o n s i n Or a l

and Maxillofacial
Surge ry: Manage m ent
of Hemostasis and
B l eeding Disord er s i n
S u r g i c a l P ro c e d u re s
Jay P. Malmquist, DMD, FICD

KEYWORDS
 Von Willebrand disease  Hemophilia
 Coagulation factors  Platelet disorders

Oral and maxillofacial surgeons perform a wide causing a breakdown of the clot. Clearly, the
variety of surgical procedures including the process is complex and requires a good level of
removal of teeth, various tissue biopsies, endo- understanding to allow the clinician to properly
sseous implants, and major maxillofacial surgery. manage the hemostasis.
One of the major complications of these various The causes of hemorrhage can be reduced to
surgical techniques is uncontrolled bleeding. The either local issues at the site of surgical interven-
best management of perioperative hemorrhage is tion or inherent systemic factors. The local factors
prevention. This includes proper preoperative result from tissue damage at the site of surgery.2,3
patient evaluation, knowledge of the various Poor surgical technique with injury to soft tissue,
bleeding disorders, and characterization of the hard tissue, or vessels may lead to excessive
correct methods of management. bleeding. Systemic causes include the various in-
Hemostasis in the normal patient population herited coagulation disorders, acquired coagula-
involves the interaction between four different bio- tion abnormalities, and platelet disorders. The
logic systems: (1) the blood vessel wall, (2) the following discussion evaluates various causes of
blood platelets, (3) the coagulation cascade, and bleeding and identifies both local and systemic
(4) the fibrinolytic system. Under normal conditions and pathways. Considerations of treatment for
hemostasis occurs through two independent patients with these various disorders are dis-
processes: the coagulation cascade and the cussed as to the best management options for
platelet activation pathway.1 When the integrity adequate hemostasis.
of the endothelial layer of the blood vessel is
compromised the initiation of the coagulation SYSTEMIC FACTOR PROBLEMS
process is activated. Blood vessel constriction is
the essential first stage followed by platelet adhe- Systemic factors involving inherited coagulation
sion and aggregation. At the site of injury the disorders include von Willebrand disease, hemo-
oralmaxsurgery.theclinics.com

hemostatic mechanism is initiated by local activa- philia, rare coagulation factor deficiencies, and
tion of the surfaces and the subsequent release of various platelet disorders. In addition, there are
tissue thromboplastin.2 This results in the forma- acquired coagulation abnormalities and drug-
tion of fibrin. However, in oral surgery through induced platelet defects, which interfere with
a series of triggering steps fibrinolysis may occur normal clot formation (Box 1).

Private Practice, 5415 Southwest Westgate Drive, Portland, OR 97221, USA

E-mail address: [email protected]

Oral Maxillofacial Surg Clin N Am 23 (2011) 387–394

doi:10.1016/j.coms.2011.04.006
1042-3699/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
388 Malmquist

Box 1 characterizes a group of patients with factor levels

Common medications that affect platelet between 5% and 35%. The prevalence of hemo-
function philia is about 1 in 5000 males with up to 90%
having a deficiency of factor VIII. Type B hemo-
 American Society of Anesthesiologist (ASA) philia represents only about 10% of all the diag-
 Nitroglycerin nosed hemophilia.6
 Nonsteroidal antiinflammatory drugs The classic clinical signs of a patient with a factor
deficiency are bruising, muscle and joint hemor-
 H2 antagonists
rhage, and excessive bleeding after trauma or
 Antimicrobials surgical procedures. The diagnosis must be deter-
 Penicillin mined by specific laboratory tests. The classifica-
tion often predicts the risk factors for bleeding in
 Ampicillin
the specific patient.
 Propranolol Treatment for hemophilia is through replace-
 Dipyridamole ment of factors VIII or IX. This is done through
 Sulphinpyrazone the use of purified plasma-derived concentrate or
more recently recombinant factor concentrates.
 Clofibrate Dosage depends on the severity of the bleeding
 Tricyclic antidepressants disorder.7 Surgical procedures require preopera-
tive doses of factor concentrations to allow for
adequate control of postoperative bleeding. Occa-
Von Willebrand Disease sionally, in mild cases the use of desmopressin
can raise the levels of factor VIII that allow for
Von Willebrand disease is the most common in-
adequate hemostasis after minor procedures.6
herited bleeding disorder. It affects up to 1% of
the population resulting in issues of surgical and Other Congenital Factor Deficiencies
nonsurgical bleeding. Increased easy bruising, epi-
staxis, and significant oral surgical bleeding are the It is relatively rare to encounter other factor defi-
most common manifestations of the disease. Von ciencies. These include factors V, VII, X, and XIII.
Willebrand disease results from quantitative and In addition, there can be deficiency of fibrinogen
qualitative defects in the von Willebrand factor, an and prothrombin. Each of these has an occurrence
important protein in hemostasis.4 Von Willebrand rate of less than 1 in 1 million. However, when this
disease is divided into three different categories: does occur the genetic transfer is related to
type 1 is a partial deficiency of the protein factor, autosomal-recessive traits. The replacement is
type 2 represents qualitative defects within the usually through the use of cryoprecipitate, fresh
protein, and type 3 represents a severe deficiency frozen plasma, recombinant factors, or various
of the total protein complex.5 complex concentrations of the missing specific
Treatment depends on the particular type of von agent. One of the best ways to identify these defi-
Willebrand disease. Most type I and some type II ciencies is to take a thorough complete medical
patients respond to desmopressin acetate, which history involving past surgical procedures.8,9
stimulates the release of von Willebrand factor for
endothelial cells. This raises the plasma level of the IATROGENIC COAGULATION
von Willebrand factor and factor VIII by three to five ABNORMALITIES
times. The half-life is approximately 8 to 12 hours,
Many patients are now being treated on a long-
improving the primary hemostasis, and may require
term basis with anticoagulation therapy using
additional infusions. Patients who do not respond to
warfarin or in some cases heparin. These therapies
desmopressin require pooled human plasma.4
have been researched and are now used in the
prevention and management of various thrombo-
Hemophilia
lytic events. Thrombotic and throboembolic
Hemophilia is an inherited sex-linked bleeding blockage of blood vessels are the main cause of
disorder resulting from either decreased factor ischemic events in the heart, lungs, and brain.10
VIII (hemophilia A) or factor IX (hemophilia B). The Warfarin is a vitamin K antagonist, inhibiting the
classification of hemophilia is divided into three y-carboxylation of glutamic acid on the clotting
groups: (1) severe, (2) moderate, and (3) mild. factors. Therapeutic doses of warfarin reduce the
Patients with severe hemophilia have a factor level production of functional vitamin K–dependent
of less than 1%, moderate hemophilia represents clotting factors by approximately 30% to 50%.
a level of 1% to 5%, and mild hemophilia Warfarin has two main functions: to cause
 Complications in Oral and Maxillofacial Surgery 389

anticoagulant activity and to provide an antithro- Box 2

motic effect. Warfarin’s affect is monitored by the Common drugs causing thrombocytopenia
international normalized ratio (INR; a standardiza-
tion of the prothrombin time assay). The thera-  Quinine/quinidine group
peutic INR range varies for most patients but is  Heparin
usually in the 2 to 3 range. This protects most  Gold salts
patients from various venous or arterial thrombo-
embolism events.11,12 Recently, the use of hand  Antimicrobials
laboratory devices allows the clinician to check  Antiinflammatory drugs
the therapeutic levels of warfarin at the time of  Cardiac medications and diuretics
outpatient surgery. This increases the ability of
 Benzodiazepines
the clinician to adequately evaluate the patient’s
risk factors for bleeding.  Antiepileptic drugs
Heparin is a proteoglygan that functions as  H2 antagonists
a cofactor of the naturally occurring anticoagulant  Sulfonylurea drugs
antithrombin. Because the half-life of heparin is
 Iodinated contrast agents
short (60 minutes), the therapeutic levels are main-
tained by intravenous bolus injections followed by  Retinoids
monitored infusion. The therapeutic range is moni-  Antihistamines
tored by prolongation of the activated partial  Illicit drugs
thromboplastin time. There are several different
types of heparin. Low-molecular-weight heparin  Antidepressants
has a longer half-life and can be delivered sub-  Miscellaneous drugs
cutaneously once or twice a day. Patients on  Tamoxifen
long-term therapy with heparin do not require
 Actinomycin-D
laboratory monitoring; however, when monitoring
is required a test evaluating the anit-Xa assay is  Papverine
used because the partial thromboplastin time
is not predictably prolonged.13
purpura. Often this is related to an acute infection
PLATELET DISORDERS AND ABNORMALITIES or as a portion of a greater autoimmune syndrome.15
The nonimmune causes of thrombocytopenia
Platelet disorders can routinely be divided into two are generally related to drug toxicity or some
categories: defects of function or defects related underlying disease state. Various chemothera-
to the total number of platelets. This can also peutic agents can cause thrombocytopenia result-
include a combination of defects of the total ing in increased bleeding if the overall count drops
numbers and of function. Broadly speaking, they below 50  109/L. The improvement of the platelet
can include the various thrombocytopenias, count can be accomplished by the use of platelet
defects of adhesion, aggregation defects, and transfusions before surgical procedures. It is
granular defects. In addition, there is an entire imperative that the platelets be evaluated before
category of drug-induced defects (Box 2). surgery for anyone who is being treated actively
with chemotherapeutic agents.
Throbocytopenias
In addition to the thrombocytopenias, there are
The normal range for platelet levels falls within the adhesion defects, aggregation defects, and gran-
range of 150 to 400  109/L however can vary for ular defects. Platelet adhesion defects result from
a given person into a narrower range. The platelet abnormalities of the various protein complexes.
is routinely synthesized by the bone marrow and There are four primary proteins involving the adhe-
then destroyed by the spleen. Abnormalities gener- sive receptors. Genetically there can be abnormali-
ally are placed into two broad categories: those of ties of any of these proteins resulting in poor platelet
inherited abnormalities and those of acquired adhesion and associated mucosal bleeding,
abnormalities. Acquired abnormalities are rela- surgical bleeding, or easy bruisability. When this
tively rare and usually represent a change in size diagnosis is defined, it usually requires a platelet
and are associated with a specific syndrome.14 transfusion before a surgical procedure.16,17
More common is acquired thrombocytopenia. Aggregation defects of the platelets are rare.
This condition can be related to either an immune Platelet–platelet interaction is critical to clot forma-
response or is of nonimmune origin. The most tion and depends on the integrity of the proteins in
common immune response is thrombocytopenic the integrin complex. The defect in this diagnosis
390 Malmquist

is an autosomal-recessive trait caused by qualita- contact with the platelet. Once the blood concen-
tive or quantitative problems within the protein tration is diminished there is no longer an abnormal
complex. As a result of this defect there are prob- affect on the platelet. In addition to the nonsteroidial
lems of platelet aggregation resulting in bleeding drugs several other medications that can be ob-
and in clot retraction. This not only causes acute tained over the counter can cause altered function.
bleeding issues but also impacts long-term wound Various H1 antagonists, antibiotics, antidepres-
healing. In most cases of this genetic disorder, the sants, early b-blockers, and nitroglycerine have all
signs of abnormal bleeding are diagnosed early in been implicated in causing function impairment.21
life and are related to bruising, epistaxis, and pro-
longed bleeding related to surgical procedures. SURGICAL TREATMENT CONSIDERATIONS
Granular defects can also impact the coagula- IN PATIENTS WITH VARIOUS BLEEDING
tion cascade resulting in prolonged bleeding after DISORDERS
minor surgical procedures. Essentially, platelets
contain two important storage granules: alpha Clearly, the most important aspect of bleeding
granules and dense granules. Each of these gran- complications is the ability to prevent a significant
ules is released after activation and is critical to the event from occurring. This should take into
overall hemostatic mechanism. Studies have account the proposed surgical procedure and
shown that both types of granules can be the nature of the bleeding disorder. The type of
decreased in number and lead to prolonged surgery, the location of the intervention, and the
bleeding. In rare instances there can be qualitative extent of the procedure impact how the potential
deficiencies of both granules leading to episodes problem can be avoided. Therefore, the ability to
of bleeding. Some have suggested that this is blend the issues of systemic intervention with the
caused by the absence of secreted ADP.18 local interaction of the tissues impacts the overall
Bleeding associated with milder defects of the safety and efficacy of the procedure.
granules can be treated with desmopressin; Several considerations need to be addressed
however, the outcome of this therapy is difficult with regards to the surgical event. The first is the
to predict and a trial of the desmopressin is sug- site of the surgery and ability locally to control the
gested before a major procedure. issues of bleeding. For instance, the removal of
tooth in the anterior maxilla makes local control of
that area quite easy and does not cause the clini-
Drug-Related Platelet Defects
cian to manipulate the systemic issues with regards
The most common issues with regards to platelet to bleeding abnormalities. However, dissection
function are the alteration of the platelet related deep into the neck requires adequate safe guards
to ingested drugs. There are a variety of drugs to prevent hemorrhage into the neck and subse-
both prescribed and over-the-counter medica- quent airway compromise. Therefore, the surgical
tions that alter the platelet through function or location becomes very important in the planning
through decreased numbers. stages of a procedure to prevent uncontrolled
The relationship of decreased numbers of plate- hemorrhage or hematoma formation. Such consid-
lets and medications is not uncommon. Gold erations as the type of local anesthesia block or
therapy, quinidine, and certain antibiotic combina- infiltration may be paramount to the safe manage-
tions can cause marked decreased numbers of ment of the patient and their systemic disorder. It
platelets. In addition, some patients who have may be possible to infiltrate the area with local
received heparin therapy developed thrombocyto- anesthesia, obtain good local pain control, and
penia. This can occur in 5% to 40% who receive not require the patient to undergo systemic alter-
this type of treatment.19 ation of their drug regime or various types of trans-
Platelet function can be altered by several medi- fusions. Clearly, the surgical technique for the
cations; however, the most common is aspirin removal of a single tooth may need to be altered
therapy. Aspirin attenuates platelet activity so that there is a minimum of trauma, reducing
through the blockage of the TxA2 release from need for postsurgical control of the bleeding.
the platelet. This is a permanent blockage and One of the more common questions is the influ-
renders the platelet dysfunctional for its life. This ence of oral anticoagulants on oral surgical proce-
results in aspirin therapy causing bleeding and an- dures and whether the particular anticoagulant
tithrombotic activity for the life of the platelet.20 needs to be altered. There are several studies
Several other medications can cause altered that have been completed in the last 10 years
platelet function. Unlike aspirin, the nonsteroidial stating that the discontinuance of oral anticoagula-
antiinflammatory drugs only inhibit the function of tion therapy does not lead to a higher risk of post-
the platelet during the time that the drug is in direct operative bleeding.22 It is now generally accepted
 Complications in Oral and Maxillofacial Surgery 391

Box 3 In the past, minor oral surgical procedures in

Recommended therapeutic range for warfarin patients with hemophilia or von Willebrand disease
therapy required hospitalization and associated transfu-
sions (Fig. 1). These transfusions using replace-
 Low-intensity (INR goal 2.5 with a range of ment factors carried a substantial risk of viral
2–3) infection or the formation of various factor
 Prophylaxis of venous thrombosis (high-risk inhibitors.28 Today, the use of recombinant non–
surgery) plasma-derived products reduces this risk. One of
 Treatment of venous thrombosis the key agents is desmopressin treatment, which
induces the release of factor VIII and von Willebrand
 Treatment of pulmonary embolism
factor. Often, these agents must be combined with
 Prevention of systemic embolism local hemostatic agents or antifibrinolytic agents.29
 Tissue heart valves Key preventive measures in patients with
 Acute myocardial infarction bleeding disorders include the following:
 Atrial fibrillation 1. Avoid flap procedures when possible.
 High-intensity (INR goal 3 with range of 2. Consider techniques to minimize trauma to the
2.5–3.5) area, such as limiting the number of teeth
 Most mechanical prosthetic heart valves removed or the sectioning of difficult teeth.
3. Totally eliminate the associated granulation
 Prevention of recurrent myocardial tissue in tooth sockets or the surrounding
infarction
areas.
Data from Refs.21,23–26 4. Consider primary closure where flaps have
been elevated.
5. Use nonresorbable sutures to control the
that patients with an INR of between 2 and 4 may tension on the flap and eliminate the possibility
be treated safely without discontinuation (Box 3).22 of premature breakdown of the suture
In those patients who still have some postoper- material.
ative bleeding, topical hemostatic agents are 6. Use hemostatic materials, such as the chito-
effective. More recently, dental implant therapy san dental dressing, in the surgical site topi-
has been questioned as to whether it is appro- cally to reduce bleeding.
priate to perform these procedures in the presence 7. Use lasers or electrocautery to reduce
of active anticoagulation therapy. Again, the bleeding at the time of surgical intervention.
evidence does not support stopping therapy.27 8. Use fibrin sealants, such as Tinsel, to stabilize
Larger, more invasive procedures, such as bone the fibrin clot.
grafts, may require some alteration of the INR to 9. Topical rinses, such as tranexamic acid, to
ensure that there are no postsurgical bleeding inhibit fibrinolysis.
complications. In addition to the use of warfarin 10. Use various pressure dressings to the appro-
therapy, it is also adequate to maintain low-dose priate locations of the oral cavity can be very
aspirin therapy (100 mg/day) in the face of minor beneficial to the control of bleeding even in
oral surgical procedures.23 the compromised patient.

Fig. 1. Example of a minor oral surgical procedure.

392 Malmquist

Fig. 2. (A–C) The use of the chitosan bandage for socket hemostasis.

11. Treat the patient early in the day, allowing for the wound area for 30 minutes or longer very often
observation throughout the day for any is the only procedure needed to control the
bleeding problems. bleeding. However, in more remote cases the
12. The risk of significant bleeding in patients on application of additional materials may be needed
oral anticoagulants and with a stable INR in to control the oozing or frank bleeding.
the normal therapeutic range of 2 to 4 is Various materials have been advocated for
extremely small and the risk of increased placement into the tooth socket or wound, such
thrombosis in patients who are withdrawn as gelatin materials (Gel foam); hemostatic
from anticoagulants outweighs the risk of collagen products, such as Collatape or Helistat;
bleeding from the intraoral procedure. Oral and various cellulose products or even bone
anticoagulants should not be withdrawn from wax. More recently, the use of chitosan-derived
most patients who are undergoing outpatient hemostatic bandages for intraoral use has
oral surgical procedures. changed the approach to topical hemostasis
13. Patients who are undergoing oral surgical (Fig. 2). Termed the “HemCon bandage,” this chi-
procedures and who must be covered with tosan bandage when topically applied intraorally
a single dosage of antibiotics for prophylaxis can stop the excessive bleeding through a process
against endocarditis do not need to have their independent of the intrinsic or extrinsic pathways
anticoagulant regime altered. of hemostasis. The negatively charged cells
interact with the positively charged HemCon
THE MANAGEMENT OF POSTOPERATIVE bandage forming an adhesive viscous clot, which
HEMORRHAGING seals the wound and then activates the other
various coagulation pathways. This material adds
Occasionally, and regardless of the techniques an additional pathway to stopping an acute bleed
used, there is the postsurgical episode of bleeding and allows the clinician the ability to treat those
requiring early intervention. This often occurs patients who have compromised INR readings in
within the first 24-hour period and requires addi- the face of anticoagulant therapy.30
tional treatment. The most effective way to control
the bleeding is to use an application of pressure to SUMMARY
the wound area. Very often this is not well under-
stood by the patient and even sometimes by the The possibility of postoperative bleeding exists
clinician. An adequate application of pressure to whenever a surgical procedure is undertaken.
 Complications in Oral and Maxillofacial Surgery 393

This is further complicated when the patient is 3rd edition. Concord (MA): Core Publishing; 2002.
being treated with continuous oral anticoagulant p. 349–54.
therapy to decrease the risk of thromboembolism 12. Hirsh J, Poller L. The international normalized ratio:
or has an inherited problem with a particular a guide to understanding and correcting its prob-
bleeding disorder. Particular treatment regimes lems. Arch Intern Med 1994;154:282–8.
are followed to minimize the risk of postoperative 13. Schafer AL. Low-molecular-weight heparin—an
bleeding. It is now quite clear that the alteration opportunity for home treatment of venous throm-
of anticoagulant therapy is no longer necessary bosis. N Engl J Med 1996;334(11):724–6.
to decrease the incidence of postoperative 14. Drachman JG. Inherited thrombocytopenia: when
bleeding after oral and maxillofacial surgery. The a low platelet count does not mean ITP. Blood
use of common conservative techniques in 2004;103(2):390–8.
conjunction with hemostatic materials allows for 15. Geddis AE, Kaushansky K. Inherited thrombosyto-
the continued treatment of patients who previously penias: toward a molecular understanding of disor-
were thought to be at risk for bleeding problems. It ders of platelet production. Curr Opin Pediatr
has been shown that patients who undergo oral 2004;16(1):15–22.
surgery procedures have no greater risk toward 16. Clemetson KJ. Platelet glycoproteins and their role
bleeding than patients with normal coagulation in diseases. Transfus Clin Biol 2001;8(30):155–62.
numbers. Close collaboration with the patient 17. Cattaneo M. Inherited platelet-based bleeding disor-
and their primary physician can eliminate the ders. J Thromb Haemost 2003;1(7):1628–30.
need to interfere with ongoing medications for an- 18. McNicol A, Israels SJ. Platelet dense granules:
ticoagulation therapy. Safe, effective surgery and structure, function and implications for haemostasis.
proper management of the patient can provide Thromb Res 1999;95(1):1–18.
a predictable atmosphere for healing. 19. Merritt JC, Bhatt DL. The efficacy and safety of peri-
operative antiplatelet therapy. J Thromb Thromboly-
REFERENCES sis 2002;13:97–103.
20. Antithrombotic Trialists’ Collaboration. Collaborative
1. Mann KG. Biochemistry and physiology of blood meta-analysis of randomized trials of antiplatelet
coagulation. Thromb Haemost 1999;82(2):165–74. therapy for prevention of death, myocardial infarc-
2. McNicol A, Israels SJ, Gerrard JM. Platelets. In: tion, and stroke in high risk patients. BMJ 2002;
Poller L, editor. Recent advances in blood coagula- 324:71–86.
tion. Churchill Livingston; 1993. p. 16–80. 21. Little JW, Miller CS, Henry RG, et al. Antithrombotic
3. McNicol A, Gerrard JM. Platelet morphology, aggre- agents: implications in dentistry. Oral Surg Oral
gation, and secretion. In: Lapetina EG, editor. Med Oral Pathol Oral Radiol Endod 2002;93(5):
Advances in molecular and cell biology. London: 544–51.
JAI Press; 1997. p. 2–28. 22. Berine OR. Evidence to continue oral anticoagulant
4. Hambleton J. Diagnosis and incidence of inherited therapy for ambulatory oral surgery. J Oral Maxillo-
von Willebrand disease. Curr Opin Hematol 2001; fac Surg 2005;63:540–5.
8(5):945–51. 23. Aframian DJ, Lalla RV, Peterson DE. Management of
5. Israels LG, Israels ED. Von willenbrand factor. In: dental patients taking common hemostasis altering
Israels LG, editor. Mechanisms in hematology. medications. Oral Surg Oral Med Oral Pathol Oral
3rd edition. Concord (MA): Core Publishing; Radiol Endod 2007;103(Suppl):S45.e1–11.
2002. p. 341–8. 24. Lockhart PB, Gibson J, Pond SH, et al. Dental
6. Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. management considerations for the patient with an
Lancet 2003;361(9371):1801–9. acquired coagulopathy. Part 2: coagulopathies
7. Gill JC. The role of genetic in inhibitor formation. from drugs. Br Dent J 2003;195(9):495–501.
Thromb Haemost 1999;82(2):500–4. 25. Carter G, Goss AN, Lloyd J, et al. Current concepts
8. Peyvandi F, Mannucci PM. Rare coagulation disor- of the management of dental extraction for patients
ders. Thromb Haemost 1999;82(4):1207–14. taking warfarin. Aust Dent J 2003;48(2):89–96
9. Di Paola J, Nugent D, Young G. Current therapy for [quiz: 138].
rare factor deficiencies. Haemophilia 2001;7(Suppl 1): 26. Hirsh J, Dalen JE, Deykin D, et al. Oral anticoagu-
16–22. lants, mechanism of action, clinical effectiveness,
10. Herman WW, Konzelman JL, Sutley SH. Current and optimal therapeutic range. Chest 1992;
perspectives on dental patients receiving coumarin 102(Suppl 4):312S–26S.
anticoagulant therapy. J Am Dent Assoc 1997;128: 27. Madrid C, Sanz M. What influence do anticoagu-
327–35. lants have on oral implant therapy? A systemic
11. Israels LG, Israels ED. Vitamin K. In: Israels LG, review. Clin Oral Implants Res 2009;20(Suppl 4):
Israels ED, editors. Mechanisms in hematology. 96–106.
394 Malmquist

28. Royer JE, Bates WS. Management of von Wille- and Von Willebrand’s disease. Lancet 1977;1(8017):
brands’s disease with desmopressin. J Oral Maxillo- 869–72.
fac Surg 1988;46:313–4. 30. Malmquist JP, Clemens SC, Oien HJ, et al. Hemo-
29. Mannucci PM, Ruggeri ZM, Pareti FI, et al. I-deami- stasis of oral surgery wounds with the HemCon
no-8-D-arginine vasopressin: a new pharmacolog- dental dressing. J Oral Maxillofac Surg 2008;66(6):
ical approach to the management of haemophilia 1177–83.