This would give an idea of the various bleeding disorders, associated clotting factors and more specifically management in the dental office of the patients with bleeding disorders
2. CONTENT
S
Introduction
History
Identifying clotting factors
Physiology of Blood Clotting
◦ Hemostasis
◦ Bleeding disorders
-Vascular disorders
-Coagulation disorders
-Platelet disorders
Dental Evaluation
Dental considerations
Recent Advancements
Public Health Aspect of Bleeding Disorders
Summary
Conclusion
References
2
3. A group of disorders characterized by defective haemostasis
with abnormal bleeding.
The cause may or may not be related to platelet abnormalities.
These causes are broadly divided into 4 groups :
1) Due to vascular abnormality.
2) Due to platelet abnormality.
3) Disorder of coagulation factor.
4) Combination of all these as in disseminated intravascular
coagulation.
3
4. 12th century Arab physician named Albucasis
1800 - U.S., the transmission of hemophilia from
mothers to sons.
1803, a Philadelphia physician named Dr. John
Conrad Otto wrote an account of "a hemorrhagic
disposition existing in certain families."
The word "Hemophilia" first appeared - University of
Zurich in 1828.
4
HISTORY
6. 1960s - clotting factors were identified and named.
1950s , early 1960s - hemophilia and other bleeding
problems were treated with whole blood or fresh
plasma.
There wasn't enough of the factor VIII or IX proteins in
these blood products to stop serious internal bleeding.
1960 - cryoprecipitate by Dr. Judith Pool
1960s , early 1970s - concentrates containing factor
VIII and IX (freeze-dried powdered concentrates)
1990s - modern treatment-safer factor concentrates
6
15. PROVIDES ASSESSMENT OF PLATELET
COUNT AND FUNCTION
NORMAL VALUE
2-8 MINUTES
15Robbins Basic Pathology , 10th Edition, Elsevier
16. PROTHROMBIN TIME
Measures Effectiveness of the Extrinsic PathwayMeasures Effectiveness of the Extrinsic Pathway
Mnemonic - PETMnemonic - PET
NORMAL VALUENORMAL VALUE
10-15 SECS10-15 SECS
16Robbins Basic Pathology - 10th Edition - Elsevier
17. Measures Effectiveness of the Intrinsic
Pathway
Mnemonic - PITT
NORMAL VALUENORMAL VALUE
25-40 SECS25-40 SECS
17Robbins Basic Pathology - 10th Edition - Elsevier
18. THROMBIN TIME
Time for Thrombin To Convert
Fibrinogen Fibrin
A Measure of Fibrinolytic Pathway
NORMAL VALUENORMAL VALUE
9-13 SECS9-13 SECS
18
Robbins Basic Pathology - 10th Edition - Elsevier
30. Bruising
Spontaneous bleeding
Bleeding into joints and associated
pain and swelling
Gastrointestinal tract and urinary
tract hemorrhage
Blood in the urine or stool
Prolonged bleeding from cuts,
tooth extraction, and surgery
People whose clotting activity is 5
percent of normal may have only
mild hemophilia.
30
31. INFUSION OF CRYOPRECIPITATE OR DESMOPRESSIN
ACETATE (DDAVP)
DESMOPRESSIN INJECTION OR STIMATE NASAL
SPRAY.
CRYOPRECIPITATE
31
NOTE:
Avoid certain drugs that can aggravate bleeding problems:
Aspirin
Heparin
Warfarin
Certain analgesics such as nonsteroidal anti-inflammatory
drugs
32. MASAC made recommendations for treatment of hemophilia in
November of 1999.
1. Factor VIII products for patients who are HIV seronegative,
including Recombinant factor VIII,
2. Immunoaffinity purified factor VIII concentrates
3. Cryoprecipitate is not recommended because of the risk of HIV
and hepatitis infection.
4. Mild hemophilia A should be treated with desmopressin, in a
DDAVP injection or Stimate nasal spray.
32
Chronic joint deformities
Intracerebral hemorrhage
COMPLICATIONS
34. Christmas disease- deficiency in clotting factor IX.
More common than Hemophilia B, Incidence - one in 34,500 men.
34
Symptoms include:
Nose bleeds , Bruising
Spontaneous bleeding
Bleeding into joints and associated pain and swelling
Gastrointestinal tract and Urinary tract hemorrhage
Blood in the urine or stool
Prolonged bleeding from cuts, tooth extraction, surgery,
following circumcision
People whose clotting activity is 5% of normal may have only
mild hemophilia.
36. DIAGNOSIS:
A doctor may suspect hemophilia in a child whose bleeding is unusual.
A laboratory analysis of blood samples
Determine the severity by testing the activity of factor IX.
36
Treatments:
• Infusing the missing clotting factor.
•To prevent a bleeding crisis- taught to administer factor IX concentrates at home
at the first signs of bleeding.
•Factor IX concentrate may be given prior to dental extractions and surgery to
prevent bleeding.
•Milder forms of hemophilia need to have dental or other surgery, the drug
desmopressin acetate (DDAVP) may be given to improve clotting temporarily so
that transfusions can be avoided.
37. MASAC made recommendations for treatment of
hemophilia B in November of 1999
• Recombinant factor IX products for patients who are HIV
seronegative,
• Patients who are HIV-seropositive should also be treated with
high purity products such as immunoaffinity purified and
recombinant factor VIII products.
• For patients with inhibitors to factors VIII and IX, there is
Recombinant Factor VIIa (NovoSeven). Produced by baby
hamster kidney cells, no human albumin or other proteins are
used in its production, reducing virus risk.
There is also Porcine factor VIII (Hyate C) and activated
prothrombin complex concentrates
37
38. • Chronic joint deformities,
• Intracerebral hemorrhage
may also occur.
• Thrombosis may occur
following use of factor IX
concentrate.
38
40. Classifications:
• Type I:
1. Most common and mildest form of von Willebrand
disease.
2. Levels of von Willebrand factor are lower than
normal, reduced levels of factor VIII.
• Type II:
Von Willebrand factor itself has an abnormality.
Depending on the abnormality, they may be classified as:
Type Iia - the level of von Willebrand factor is reduced, as is the ability of
platelets to clump together.
Type Iib -although the factor itself is defective, the ability of platelets to
clump together is actually increased.
40
41. Type III:
Severe von Willebrand disease. Total absence of von
Willebrand factor, and factor VIII levels are often less
than 10%.
Pseudo (or platelet-type) von Willebrand
disease:
Resembles Type IIb von Willebrand disease, but the
defects appears to be in the platelets, rather than the
von Willebrand factor.
41
42. Inheritance Pattern
occurs in men and
women equally.
Types I and II are
usually inherited in what
is known as a "dominant"
pattern.
Type III von Willebrand
disease, however, is
usually inherited in a
"recessive" pattern.
42
43. History of bleeding problems.
A child bruises easily or has bleeds excessively after a skin cut,
tooth extraction, tonsillectomy or other surgery.
Hormonal changes, stress, pregnancy, inflammation and
infections may stimulate the body to increase production of the
von Willebrand factor and temporarily improve clot formation.
43
SymptomS and diagnoSiS
1. Normal platelet count.
2. Prolonged bleeding time.
3. Reduced von willebrand factor level.
4. Reduced platelet adhesion may occur.
5. Reduced or increased platelet aggregation (platelet aggregation test).
6. Ristocetin cofactor is reduced.
diagnoStic SignS can include:
44. MASAC made recommendations for treatment of von
Willebrand disease in November of 1999.
They include:
• Stimate, desmopressin acetate. (DDAVP),nasal spray or injection
• Viral-inactivated factor VIII preparations rich in von Willebrand factor, such
as Alphanate, Humate-P and Koate DVI, are recommended.
• Cryoprecipitate is not recommended except in life-threatening emergencies
because of the risk of HIV and hepatitis infection.
44
After surgery, hemorrhaging may occur. The condition is worsened by
the use of aspirin and other nonsteroidal anti-inflammatory drugs.
Women may have risks during pregnancy and childbirth.
complicationS:
45. Fibrinogen, also known as factor I, is needed for
most types of platelet aggregation.
It's the last step in the clotting process—the
"glue" that holds the clot together.
Congenital Fibrinogen defects:
They include:
• Afibrinogenemia
• Hypofibrinogenemia
• Dysfibrinogenemia
45
Factor I Deficiency (Afibrinogenemia)
46. inHeRitance patteRn
The disorder is not sex-linked
Affects both males and females with equal frequency.
Autosomal recessive.
DIAGNOSIS
predisposed to form blood clots
(thrombosis)
46
47. Treatments
-Hypofibrinogenemia or dysfibrinogenemia need
no treatment.
-Those who require treatment may be given
cryoprecipitate or fresh frozen plasma.
The goal of treatment is to raise the patient's
fibrinogen level to 100 mg/dL for minor bleeding
and up to 200 mg/dL for surgery or severe bleeding.
(One unit of fresh frozen plasma has about 450 mg
of fibrinogen).
47
48. Complications
-Risk of thrombosis.
-In women, menstrual bleeding can be a severe
problem and must be controlled
48
49. Factor II Deficiency (Prothrombin)
Prothrombin is a vitamin K-dependent proenzyme that
functions in coagulation.
1)a congenital version called hypoprothrombinemia,
2)acquired version called dysprothrombinemia.
congenital, factor II deficiency is extremely rare.
Acquired factor II deficiency is more common. It results from
vitamin K deficiency, severe liver disease and therapeutic use
of anticoagulant drugs.
49
50. Inheritance Pattern
Rare inherited disorder that results in
deficient blood clotting.
The disorder is not sex-linked as is
hemophilia.
It affects both males and females with equal
frequency.
It is autosomal recessive.
50
51. Symptoms include:
• umbilical cord bleeding at birth
• nose bleeds
• abnormal menstrual bleeding
• abnormal bleeding after delivery
• bleeding after trauma
• bleeding after surgery
• easy bruising
Signs and Tests:
• prolonged prothrombin time
• prolonged partial thromboplastin time
• factor II assay showing decreased activity
• levels of prothrombin ranging from 2% to 50% of normal
51
52. MASAC made recommendations for
treatment of factor II deficiency in
November of 1999.
• Prothrombin complex concentrates (PCCs)
can be used, but these products vary
considerably in the amount of factors they
contain.
• Fresh frozen plasma can be used as along as
it is processed to reduce the risk of viral
infection.
52
53. Complications :
Bleeding has to be
controlled in instances of
trauma or surgery, or else
bleeding into the brain or
skull can occur.
53
54. Owren's disease or parahemophilia.
This deficit was identified in Norway in 1943.
150 cases have been reported, occurring in both men and
women.
The exact frequency of this rare disorder is unknown, but is
estimated to be one per 1 million
54
Factor V Deficiency (Para hemophilia)
The disorder is not sex-linked.
It affects both males and females with equal frequency.
It is autosomal recessive
Several families with combined deficiencies of factors V and VIII
have been reported.
Inheritance Pattern
55. SymptomS and diagnoSiS :
Symptoms include:
bleeding into the skin
excessive bruising with minor injuries
nose bleeds
bleeding of the gums
excessive menstrual bleeding
prolonged or excessive loss of blood with surgery or trauma
diagnoSing tHe deficiency involveS teStS
and SignS SucH aS:
factor V assay showing decreased activity
slightly prolonged bleeding time (in some people)
prolonged partial thromboplastin time
prolonged prothrombin time
55
56. Treatments:
-There are no commercially available concentrates of factor V, so
fresh plasma or fresh frozen plasma infusions are used.
-The half-life of factor V is 24 hours.
-This is an inherited disorder; there is no known prevention.
56
Complications:
-Dangerous hemorrhaging can occur if bleeding isn't controlled
quickly.
- If platelets are used as a source of factor V, antiplatelet
antibodies can be induced.
57. Extremely rare disorder
Can be inherited or acquired by people who do not have
hemophilia who take Coumadin, a drug used to inhibit
blood clotting.
1in 500,000 males and females.
Congenital factor VII deficiency
Not sex-linked
It affects both males and females with equal frequency.
autosomal recessive
57
Factor VII Deficiency (Proconvertin or Stable Factor)
59. Symptoms:
bleeding of mucous membranes
spontaneous nosebleeds
excessive bruising
prolonged menstrual bleeding
bleeding into muscles
bleeding into joints
59
Diagnosis : testing for factor VII in the blood.
60. Signs and tests:
Prolonged prothrombin time
Normal partial thromboplastin time
Decreased factor VII assay
60
MASAC made recommendations for treatment of Factor VII
deficiency in November of 1999. They include:
• Recombinant factor VIIa (NovoSeven).
• Prothrombin complex concentrates (PCCs) can be
used, but these products vary considerably in the amount of
factors they contain.
• Fresh frozen plasma can be used as along as it is
processed to reduce the risk of viral infection.
TREATMENTS
61. Complications :
These can include hemorrhages, strokes or other neurological problems
related to central nervous system bleeding.
• Fatal intracranial bleeding caused by birth trauma has occurred.
• Menstrual bleeding may also be severe.
61
62. Source of vitamin K Green vegetables
Synthesized by intestinal flora
Required for synthesis Factors II, VII, IX ,X
Protein C and S
Causes of deficiency Malnutrition
Biliary obstruction
Malabsorption
Antibiotic therapy
Treatment Vitamin K
Fresh frozen plasma
62
68. Definition:
Thrombocytopenia is any disorder in which the
platelet count is below 1,50,000/CC OF BLOOD.
68
THROMBOCYTOPENIA
Immune-mediated
Idioapthic
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic
anemia
69. CAUSES, INCIDENCE, AND RISK
FACTORS
Thrombocytopenia is often divided into three major causes of low platelets:
1) Low production of platelets in the bone marrow
2) Increased breakdown of platelets in the bloodstream (called
intravascular)
3) Increased breakdown of platelets in the spleen or liver (called
extravascular
69
1)Disorders that involve low production in the bone marrow include:
-Aplastic anemia
-Cancer in the bone marrow
-Infections in the bone marrow (rare)
-Drugs (very rare)
71. -Bruising
-Nose bleeds or bleeding in the mouth
` -Rash (pinpoint red spots)
-Other symptoms may be present as well, depending on the
cause of the condition.
Mild thrombocytopenia can occur without symptoms.
71
-CBC shows low platelets
-Bone marrow aspiration or Biopsy may be normal or may show
low megakaryocytes (platelet precursors) or an infiltrating disease.
-PTT clotting study is normal
-PT clotting study is normal
-Platelet associated antibodies may be present
Symptoms:
SignS and teStS:
80. Clinical situation Guidelines
INR therapeutic-5 Lower or omit next dose;
Resume therapy when INR is therapeutic
INR 5-9; no bleeding Lower or omit next dose;
Resume therapy when INR is therapeutic
Omit dose and give vitamin K (1-2.5 mg po)
Rapid reversal: vitamin K 2-4 mg po (repeat)
INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessary
Resume therapy at lower dose when INR therapeutic
Chest 2001:119;22-38s (supplement)
80
81. Clinical situation Guidelines
INR > 20; serious bleeding Omit warfarin
Vitamin K 10 mg slow IV infusion
FFP or PCC (depending on urgency)
Repeat vitamin K injections every 12 hrs as
needed
Any life-threatening bleeding Omit warfarin
Vitamin K 10 mg slow IV infusion
PCC ( or recombinant human factor VIIa)
Repeat vitamin K injections every 12 hrs as
needed
Chest 2001:119;22-38s (supplement)
81
82. 1. Is the bleeding local or due to a hemostatic failure?
1. Local: Single site of bleeding usually rapid with minimal
coagulation test abnormalities
2. Hemostatic failure: Multiple site or unusual pattern with
abnormal coagulation tests
1. Evaluate for causes of peri-operative hemostatic failure
1. Pre-existing abnormality
2. Special cases (e.g. Cardiopulmonmary bypass)
1. Diagnosis of hemostatic failure
1. Review pre-operative testing
2. Obtain updated testing
82
Queiroz, S.I.M.L., Silvestre, V.D., Soares, R.M. et al. Clin Oral Invest (2018).
https://doi.org/10.1007/s00784-017-2327-4
83. CBC and smear Platelet count Thrombocytopenia
RBC and platelet morphology TTP, DIC, etc.
Coagulation Prothrombin time Extrinsic/common pathways
Partial thromboplastin time Intrinsic/common pathways
Coagulation factor assays Specific factor deficiencies
50:50 mix Inhibitors (e.g., antibodies)
Fibrinogen assay Decreased fibrinogen
Thrombin time Qualitative/quantitative
fibrinogen defects
FDPs or D-dimer Fibrinolysis (DIC)
Platelet function von Willebrand factor vWD
Bleeding time In vivo test (non-specific)
Platelet function analyzer (PFA) Qualitative platelet disorders
and vWD
Platelet function tests Qualitative platelet disorders
83
85. Sex-linked recessive
Factors VIII and IX deficiencies cause bleeding
Prolonged PTT; PT normal
Autosomal recessive (rare)
Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding
Prolonged PT and/or PTT
Factor XIII deficiency is associated with bleeding and
impaired wound healing
PT/ PTT normal; clot solubility abnormal
Factor XII, prekallikrein, HMWK deficiencies
do not cause bleeding
85
86. 5-10% of patients - prolonged bleeding time
Most of the prolonged bleeding times are due to
aspirin or drug ingestion
Prolonged bleeding time does not predict excess
surgical blood loss
Not recommended for routine testing in
preoperative patients
86
93. Transfusion reactions
◦ Higher incidence than in RBC transfusions
◦ Related to length of storage/leukocytes/RBC mismatch
◦ Bacterial contamination
Platelet transfusion refractoriness
◦ Alloimmune destruction of platelets (HLA antigens)
◦ Non-immune refractoriness
Microangiopathic hemolytic anemia
Coagulopathy
Splenic sequestration
Fever and infection
Medications (Amphotericin, vancomycin, ATG, Interferons)
93
94. Mechanism
◦ Prevent activation plaminogen -> plasmin
Dose
◦ 50mg/kg po or IV q 4 hr
Uses
◦ Primary menorrhagia
◦ Oral bleeding
◦ Bleeding in patients with thrombocytopenia
◦ Blood loss during cardiac surgery
Side effects
◦ GI toxicity
◦ Thrombi formation
94
95. Mechanism
◦ Increased release of VWF from endothelium
Dose
◦ 0.3µg/kg IV q12 hrs
◦ 150mg intranasal q12hrs
Uses
◦ Most patients with von Willebrand disease
◦ Mild hemophilia A
Side effects
◦ Facial flushing and headache
◦ Water retention and hyponatremia
95
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KUMAR S MP
96. Mechanism
◦ Direct activation of common pathway
Use
◦ Factor VIII inhibitors
◦ Bleeding with other clotting disorders
◦ Warfarin overdose with bleeding
◦ CNS bleeding with or without warfarin
◦ Dose
◦ 90 µg/kg IV q 2 hr
◦ “Adjust as clinically indicated”
Cost (70 kg person) - $1 per µg
◦ ~$5,000/dose or $60,000/day
96
Vol 9, Issue 3, 2016, LOCAL HEMOSTATIC AGENTS IN THE MANAGEMENT OF BLEEDING IN ORAL
SURGERY, KUMAR S MP
97. Identify and correct any specific defect of
hemostasis
◦ Laboratory testing is almost always needed to establish the cause of
bleeding
◦ Screening tests (PT,PTT, platelet count) will often allow placement
into one of the broad categories
◦ Specialized testing is usually necessary to establish a specific
diagnosis
Use non-transfusional drugs whenever possible
RBC transfusions for surgical procedures or large
blood loss
97
98. Good thorough medical historyGood thorough medical history
a physical examination
screening clinical lab tests
excessive bleeding following surgical procedure
Family HX
Personal HX
Medications
Past & Present Illness
Spontaneous Bleeding
98
99. FIVE DRUGS THAT INTERFERE WITH
HEMOSTASIS
ASPIRIN
ANTICOAGULANTS
ANTIBIOTICS
ALCOHOL
ANTICANCER
99
101. LOW RISK
Patients with No History of Bleeding Disorders
Normal Laboratory Results
MODERATE RISK
Patients on Chronic Oral Anticoagulant
Therapy. PT is 1.5 - 2 Times Control Range
Patients on Chronic Aspirin Therapy
HIGH RISK
Patients with Known Bleeding Disorders
Patients without Known Bleeding Disorders Who Have
Abnormal Laboratory Results
101
102. PASSIVE AGENTS ACTIVE AGENTS
COLLAGEN-BASED PRODUCTS
•Microfibillar collagen (Avitene)
•Absorbable collagen hemostat sponge
(Helistat)
•Others : Colla-Cote, Colla-Tape,
Colla-Plug, Helistat
CELLULOSE-BASED PRODUCTS
•Oxidized regenerated cellulose (Surgicel)
•ActCel
•Gelitacel
POLYSACCHARIDE HEMOSPHERES
THROMBIN
FLOSEAL (FLOWABLE HEMOSTATIC
AGENT)
SEALANTS
•Fibrin sealant (tisseel)
•Albumin-derived hemostats (bioglue)
Vol 9, Issue 3, 2016, LOCAL HEMOSTATIC AGENTS IN THE MANAGEMENT OF BLEEDING IN ORAL SURGERY, KUMAR S MP 102
103. 103
NEWER HEMOSTATIC AGENTS
•CHITOSAN-BASED PRODUCTS
•POLYSACCHARIDE-BASED HEMOSTATS
Poly-N-acetyl glucosamine-based materials
QuikClot (inorganic hemostat)
•HEMOSTATIC SOLUTIONS
Styptics
Tannic acid
Lysine analogs
Tranexamic acid
Epsilon aminocaproic acid
Hemocoagulase (botroclot)
•BONE HEMOSTATS
Bone wax
Ostene
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SURGERY, KUMAR S MP
104. LOW RISK PATIENTS
Normal Protocol
Pressure Pack theory
Ice Pack
MODERATE RISK PATIENTS
Anticoagulants - Consult Physician
Aspirin Therapy - BT, Consult Physician
HIGH RISK PATIENTS
Close Coordination with Physician
Hospitalization (Platelet Transfusion)
(Factor Replacement)(Vit K Therapy) (Dialysis)
104
107. 107
1. Pressure Pack using local anesthetic agent.
2. Placement of suture
3. Use of topical hemostatic agents
4. If topical hemostatic agents are not present:
Use, Boiled tea leaves – Tannic acid.
Vol 9, Issue 3, 2016, LOCAL HEMOSTATIC AGENTS IN THE MANAGEMENT OF BLEEDING IN ORAL SURGERY, KUMAR S MP
Hemostatic, antibacterial biopolymers from Acacia arabica (Lam.) Willd and Moringa oleifera (Lam.) as potential wound
dressing materials.Monica B Parwani L, Sharma V, Ganguli J, Bhatnagar,A, Oct 2013, NISCAIR-CSIR, 804-810
108. Hemophilia A - 1 in 5,000 live male births. - INDIA
The number of people with hemophilia in the United States is estimated to be
about 20,000 individuals.
The worldwide incidence of hemophilia is estimated at more than 400,000
people.
108
Kar, A., Phadnis, S., Dharmarajan, S., & Nakade, J. (2014). Epidemiology & social costs
of haemophilia in India. The Indian Journal of Medical Research, 140(1), 19–31.
110. New clotting products and drugs - desmopressin acetate
also known as DDAVP.
Synthetic (not derived from plasma) clotting products that
take advantage of recombinant technologies.
Better screening methods to detect and remove viruses and
other agents from factor concentrates and blood products:
Improved surgical options
Advanced genetic testing methods
Medically supervised home-infusion therapy
Prophylactic treatment
110
RECENT ADVANCEMENTS
112. CONCLUSIONS:
The history (medical /family history) is extremely
important in evaluating patients with disorders of
hemostasis.
Dental extractions are a very common major stresses
of the haemostatic mechanism, and a prior history of
excessive bleeding following an extraction is
important.
So, thorough understanding and knowledge about
bleeding disorders is very much needed for dental
professionals to minimize the complications of many
treatment procedures.
112
113. Davidson’s “principles and practice of medicine-19th edition;-
Hanslet, Chilvers, Boon, Colledge, Hunters.
Medical emergencies in the dental practice –malammed; 5th
edition
Bailey and Love’s Short practice of surgery-23rd edition;
Russel, Williams, Bulstrode;
Complications in Oral and Maxillofacial surgery-1st edition;
Kaban, Pogrel, Perrot.
Concise Medical Physiology;-5th edition; Chaudhari
Systemic disease in dental treatment-1st edition;-
Michael.J.Tullman, Spencer.W.Redding.
Clinical hematology-7th edition;-Maxwell.M.Wintrobe.
www.hemophilia.org
www.google.com
113
REFERENCES: