What is Bleeding disorder?

A bleeding disorder is a condition that affects

the way your blood normally clots.

What is Clotting disorder?

A clotting disorders in which there is an
increased tendency for excessive
blood clotting.
BLEEDING DISORDERS
Hereditary Hemorrhagic
VESSEL WALL DISORDER
Telengiectasia

Idiopathic Thrombocytopenic
PLATELET DISORDER
Purpura

Haemophilia

Von Willebrand’s Disease

COAGULATION DISORDERS Vitamin K Deficiency

Liver Disease

Disseminated Intravascular
Coagulation
 BLOOD CLOTTING FACTORS
FACTOR NAME FACTOR NAME

I Fibrinogen VIII Antihemophilic factor

II Prothrombin IX Christmas factor / Plasma

thromboplastin component

III Tissue thromboplastin X Stuart-Prower factor

IV Calcium ions XI Plasma thromboplastin

antecedent

V Labile factor XII Hageman factor

VII Stable factor XIII Fibrin stabilizing factor

 Screening Test
•Bleeding time ( <6 minute)
Vascular integrity
Platelet number / function
•Clotting time (2-6 minute)
Coagulation defect
•Prothrombin time (11-13.5 second)
“ Extrinsic pathway ”
•Activated partial thromboplastin time (APTT) (30-45 second)
“Intrinsic Pathway”
•Thrombin time (12-14 second)
Common pathway
•Factor Assay: Factor V / Factor VIII
 Clinical Features of Bleeding Disorders
Platelet disorders Coagulation disorder
factor
Site of bleeding Skin, Mucous Deep in soft tissues
membranes (epistaxis, (joints, muscle)
gum, vaginal, GI tract)

Petechies Yes No
Ecchymosis Small, superficial Large, Deep
(“bruises”)
Hemarthrosis/muscle Extremely rare Common
bleeding
Bleeding after Yes No
cuts&scratches
Bleeding after surgery Immediate, usually mild Delayed (1-2days)
or trauma often severe
Positive Family Rare common
History
 Definition of Haemostasis
Blood must be maintained in a fluid state in order to
function as a transport system, but must be able to
solidify to form a clot following vascular injury in order
to prevent excessive bleeding.

DISORDER OF PRIMARY HAEMOSTASIS

Vessel wall abnomalities Other Important Causes
- Senile Purpura
•Congenital - Henoch Schonlein Purpura
- Hereditary Haemorrhagic - Vasculitis
Telangiectasia
•Acquired:
- Scurvy
- Ehlers-Danlos Disease
Stages of Haemostasis
Primary Haemostasis
• Response to vascular injury
• Formation of ‘platelet plug’ adhering to
the endothelial wall
• stops bleeding immediately

Secondary Haemostasis
• Formation of stable clot
• Enzymatic activation of coagulation
proteins that produce fibrin as a
reinforcement to the platelet plug
• Gradually the stable plug will be
dissolved by fibrinolysis
Hereditary haemorrhagic telangiectasia
A dominantly inherited condition caused by mutations in the genes encoding
endoglin and activin receptor-like kinase, which are endothelial cell receptors
for transforming growth factor-beta (TGF-β), a potent angiogenic cytokine.

Symptoms:
• Telangiectasia and small aneurysms are found on the fingertips, face,
tongue, nasal passages, lung and gastrointestinal tract.
• Larger pulmonary arteriovenous malformations (PAVMs) that will cause
arterial hypoxaemia due to right-to-left shunt.
• This may predispose to paradoxical embolism, stroke and cerebral abscess
• Patients present with recurrent bleeding, epistaxis, or with iron deficiency
due to occult gastrointestinal bleeding.
Management:
• Treatment can be difficult because of the multiple bleeding points but
regular iron therapy often allows the marrow to compensate for blood loss.
• Local cautery or laser therapy may prevent single lesions from bleeding.
• A variety of medical therapies have been tried but none has been found to
be universally effective.
Telengiectasia

Pulmonary
arteriovenous
malformations
(PAVMs)
 Scurvy
Cause
a) Increased requirement
• Trauma, surgery, burns,
infections
• Smoking
• Drugs (glucocorticocoids,
aspirin, indomethacin,
tetrqcycline)
b) Dietary deficiency
• Lack of dietary fruit and
vegetables for >2 months
• Infants fed exclusively on
boiled milk
Clinical features of scurvy
• Swollen gums that bleed
easily
• Perifollicular and petechial
haemorrhages
• Ecchymoses
• Haemarthrosis
• Gastrointestinal bleeding
• Poor wound healing
• Vitamin C deficiency causes
defective formation of
collagen with impaired
healing of wounds, capillary
haemorrhage and reduce
platelet adhesiveness.
Swollen gum

Ecchymosis

Haemarthrosis
 Management

A dose of 250mg vitamin C 3 times daily by

mouth should saturate tissues quickly. The
deficiencies of the patient’s diet also need to be
corrected and other vitamin supplements given
if necessary. Daily intakes of more than 1g/day
have been supported to cause of diarrhoea and
the formation of renal oxalate stress.
 Thrombocytopenia
● Decreased or abnormal production of
platelets
1. Leukemia
2. Some types of anemia
3. Viral infections, such as hepatitis C or HIV
4. Chemotherapy drugs
5. Heavy alcohol consumption
● Increased breakdown of platelets
1. Pregnancy.
2. Immune thrombocytopenia
3. Bacteria in the blood.
4. Thrombotic thrombocytopenic purpura
5. Hemolytic uremic syndrome
6. Medications
Idiopathic thrombocytopenic purpura
• Immune-mediated with involvement of autoantibodies
(IgG) directed against the platelet membrane glycoprotein
IIb/IIIa, which sensitise the platelet, resulting in premature
removal from the circulation by cells of reticulo-
endothelial system.

Clinical features:
• Spontaneous bleeding typically occurs only when the
platelet count is below 20x 109 /L.
• In children, the onset is generally sudden (acute ITP).
Purpura appears 2-3 weeks after viral infection. In most
cases the condition is self-limiting.
• The onset is insidious in adults and disease may oersist for
years (chronic ITP). It is more common in females.
• At higher counts, patients may complain of petechiae,
ecchymosis, gum bleeding, easy bruising or sometimes
epistaxis or menorrhagia.
• Symptoms or signs of connective tissue disease may be
apparent at presentation or emerge several years later.
 Investigation
• Bleeding time: Prolonged
• Platelet count: Decreased
• Prothrombin time (PT): Normal
• Activated partial thromboplastin time(aPTT):
Normal
• Bone marrow reveals an obvious increase in
megakaryocytes.
 Management
• Many patients with stable compensated ITP and a platelet count of
more than 30x 109 /L do not require treatment to raise the platelet
count, except at times of increased bleeding risk, such as surgery and
biopsy.

• First-line therapy for patients with spontaneous bleeding is with high

doses of glucocorticoids, either prednisolone (1mg/kg daily) or
dexamethasone (40mg daily for 4 days), to suppress antibody
production and inhibit phagocytosis of sensitised platelets by
reticulo-endothelial cells.

• Administration of intravenous immunoglobulin can raise the platelet

count by blocking antibody receptors on reticulo-endothelial cells,
and is combined with glucocorticoid therapy is there is severe
hemostatic failure, especially with evidence of significant mucosal
bleeding or a slow response to glucocorticoids alone.

• Persistent or potentially life-threatening bleeding should be treated

with platelet transfusion in addition to the other therapies.
 What is hemophilia ?
• An X-linked recessive disorder
• Disease manifest in males while female is
carriers

Types
Hemophilia A –Factor VIII deficiency
Hemophilia B – Factor IX deficiency
 Haemophilia A
• Factor VIII deficiency
• Most common cogenital coagulation factor deficiency.
• Factor VIII is synthesised by the liver and endothelial
cell and has half-life about 12 hours and it is protected
from peroteolysis in the circulation by binding to von
Willebrand factor(vWF)
 Haemophilia B (Christmas disease)
• aberation of the factor IX gene, which is also on the X
chromosome, result in a reduction of the plasma factor IX
level, giving rise to haemophilia B
• less common
• The frequency of bleeding episodes is related to the severity
of deficiency of the plasma factor IX level
• Although factor IX concentrates shared the problems of virus
transmission seen with factor VIII, they do not commonly
induce inhibitor antibodies (<1% patients)
• When this does occur, it may be heralded by the
development of a severe allergic-type reactions.
 Clinical Manifestation
• Hemophilia depends on the severity of deficiency of the factor
VIII or IX.
• Patients with severe haemophilia present with spontaneous
bleeding into skin, muscle and joints, retroperitoneal and
intracranial bleeding
• Baby with severe haemophilia have an increased risk of
intracranial haemorrhage should avoid head trauma
• Major morbidity of recurrent bleeding in severe haemophilia is
musculoskeletal. Bleeding is typically into large joint, especially
knee, elbow, ankles and hips
• Muscle hematoma are commonly in the calf and psoas
muscles, if early treatment is not given to arrest bleeding, a hot,
swollen and very painful joint or muscle hematoma develops
• Recurrent bleeding into joint leads to synovial hypertrophy,
destruction of the cartilage and secondary osteoarthrosis
• Hematuria (blood in urine)
• Hematochezia (bright red blood in stool)
Hemarthrosis

Hematochezia

Gingival
Bleeding
 INVESTIGATION
• Bleeding time (BT) – Normal
• Clotting time (CT) – increased
• Prothrombin time(PT) – Normal
• Partial thromboplastin time(APTT) increased
• Thrombin time(TT) – Normal
• Factor assay – VIII / IX – decreased
 Management
1. Supportive therapy
- to reduce pain and bleeding - IV administration of factor VIII -
- Ice cold packs are help to
arrest the bleeding
- Physiotherapy to prevent
joint deformity and restore
strength of muscles
- NSAID and intramuscular
injection should be avoided.
2. Specific therapy
Cryoprecipitate which is rich in
factor VIII, fibrinogen and vMF
may be used
- Vasopressin receptor agonist
DDAVP(desmopressin) which is
useful in arresting bleeding in
patients with mild or moderate
haemophilia A but not useful in
Haemophilia B
- Antifibrinolytic agent like
e-amino caproic acid(EACA) and
tranaxemic acid.
 Differential diagnosis

1. DIC (Disseminated intravascular coagulation)

2. von Willebrand disease
3. Hemophilia B or C
4. EDS (Ehlers-Danlos Syndrome)
5. Platelet function disorders(eg, Glanzmann
thrombasthenia)
 Von Willebrand disease

• common, mild bleeding disorder

• caused by impaired function of von Willebrand factor (vWF)
• Most patient with vWD have type 1 vWD,characterised by a
quantitative decrease in a normal functional protein
(quantitative defect)
• Type 2 vWD : -vWF molecules functionally
abnormal(qualitative defect)
• Depends on the site of mutation in vWD gene
 Von Willebrand Factor
• vWF is a protein synthesised by endothelial cells and
megakaryocyte, which is involved in both platelet function
and coagulation.
• acts as a carrier protein for factor VIII, to which it is non-
covalent bound
• forms bridges between platelets and subendothelial
components, allowing platelets to adhere to damaged vessel
walls, therefore deficiency of vWF leads to impaired platelet
plug formation
• Blood group antigens ( A and B) also expressed on vWF
• This reduces its susceptibility to proteolysis
• People with blood group O have lower circulating vWF levels
than individuals with non-O groups
• Rare patients carrying two defective copies of vWF gene
(‘compound heterozygosity) develop a clinically severe form
with almost undetectable level of vWF.
 Clinical features
• superficial bruising, epitaxis, menorrhagia and gastrointestinal
haemorrhage
• Bleeding episodes are usually much less common than in
severe haemophilia and excessive haemorrhage may only be
observed after trauma or surgery
• Relevance to dentistry:
- Gingival bleeding
- Hemorrhage after dental extraction
 Investigation
• Bleeding time – increased
• Clotting time – normal / increased
• PT - normal
• APTT – increased
• TT - normal
• reduced activity of vWF and factor VIII
• Can be classified using a combination of assat which include
functional and antigenic measures of vWF, multimeric analysis of the
protein and specific tests of function to determine binding to platelet
glycoprotein 1b and factor VIII

Management
• Tranexamic acid may be useful in mucosal bleeding
• Factor VIII concentrate- more serious bleeding
THROMBOTIC
DISORDER
 An acute, subacute or chronic thrombohemorrhagic
disorder occuring as a secondary complication of a
variety of disease.

It is characterized by systemic activation of the coagulation

pathways that may result in the generation of
intravascular fibrin clots throughout the body -
 Clinical Features
• thrombi found in : brain, heart, lung, kidneys,
adrenals, spleen and liver
• affected kidneys can reveal small thrombi in
glomeruli.
• in severe cases, microinfarcts or even bilateral
cortical necrosis can be seen.
• areas of hemorrhage can be seen on gross
examination
• numerous fibrin thrombi may be found in alveolar
capillaries, sometimes associated with pulmonary
edema and firbin exudation
• haemorrhage : superficial or deep
 Pathophysiological
systemic activation of coagulation

intraocular deposition of fibrin depletion of platelets and

coagulation factors

thrombosis of small and bleeding

midsize vessels with organ failure
 Investigations
peripheral smear : -
- features of microangiopathic hemolytic anaemia
- schistocyte : fragmented RBCs
bleeding time : increase
clotting time : increase
PT : increase
aPTT : increase
TT : increase
fibrinogen : decrease
factor V, VIII : decrease
fibrin degradation product : increase (activation of
fibrinolysis)
 Management
require intensive care to deal with concomitant issues, such as
acidosis, dehydration, renal failure and hypoxia
blood component therapy, such as fresh frozen plasma,
cryoprecipitate and platelets, should be given if patient is bleeding
or to cover interventions with high bleeding risk,
but should not be prescribed routinely based on coagulation tests
and platelet counts alone
prophylactic doses of heparin should be given, unless there is a
clear contraindication estbalished
thrombosis should be treated cautiously with therapeutic doses of
unfractioned heparin, unless clearly contraindicated
patients with DIC should not be treated with antifibrinolytic therapy,
eg. transexamic acid
 LIVER DISEASE
The liver plays a central role in the clotting process
The liver parenchymal cells produce most of the factors and inhibitors of the clotting and
fibrinolytic systems
Acute and chronic liver diseases are invariably associated with coagulation disorders due to
multiple causes:
1. decreased synthesis of clotting factors,
( clotting factors II, V, VII, IX, X and of antithrombin III )
2. decreases in the vitamin K-dependent factors
(prothrombin; factors VII, IX, and X; proteins C and S)
3. decreased clearance of activated factors,
4. quantitative and qualitative platelet defects,
5. hyperfibrinolysis
(mediated by an intense release of t-PA)
6. and accelerated intravascular coagulation.
 Renal Disease
The severity of the haemorrhagic state in renal failure is
proportional to the plasma urea conentration
Bleeding manifestations are those of platelet dysfunction, with
gastrointestinal haemorrhage being particularly common
The causes are multifactorial, including anaemia, mild
thrombocytopenia and the accumulation of low molecular
weight waste products, normally excreted by the kidney, which
inhibit platelet function
Treatment is by dialysis to reduce the urea concentration
Rarely, in severe or persistent bleeding, platelet concentrate
infusions and red cell transfusions are indicated
Increasing the concentration of vWF, either by cryoprecipitate
or by DDAVP, may produce haemostasis
 Vitamin K Deficiency
● -Required for the synthesis of clotting factors
II, VII, IX and X.
● Exist in 3 form:
○ Vitamin K1(phytonadione)-plant and animal
○ Vitamin K2(Menaquinone)-produced by
intestinal bacteria
○ Vitamin K3 (Menadione)- Synthetic form
● -Dietary source: Spinach, cabbage,
cauliflower and tomatoes
● Average daily intake: 70-140mcg/day
● Deficiency:
○ Due to inadequate absorption (lack of bile salts)
○ Loss of vitamin(chronic diarrhea)
○ Administration of broad-spectrum
antibiotics(suppression of bacterial intestinal
flora)

• Hence in vitamin k deficiency, there is increased

tendency to bleed:
○ Epistaxis
○ haematuria
○ gastrointestinal bleeding
○ postoperative bleeding
 Venous Thromboembolic Disease
● Also known as Venous Thromboembolism (VTE)
● Annual incidence of approx. (1:1000) in Western
population
● Most common presentations of VTE

a. Deep vein thrombosis of the leg

b. Pulmonary embolism
c. Jugular vein thrombosis
d. Upper limb DVT
e. Cerebral sinus thrombosis
Deep vein thrombosis
Pulmonary embolism
(saddle embolism)
 Predisposing Factors
1) Patient factors
• Increasing age
• Obesity
• Varicose veins
• Previous deep vein thrombosis
• Family history
• Immobility / bedridden
• Pregnancy /puerperium
• iv abuse involving femoral vein
2) Surgical conditions
• Abdominal or pelvic surgery
• Major lower limb orthopaedic
surgery
(hip fracture)
3) Medical conditions
• Myocardial infraction/ heart
failure
• Stroke
• Inflammatory bowel disease
• Nephrotic syndrome
• Maglinancy
• COPD (chronic obstructive
pulmonary disease)
4) Haematological disorders
5) Antiphospholipid
syndrome (APS)
 Prophylaxis of VTE
● All patients admitted to hospital should be assessed for
the risk of developing VTE.
● Moderate risk group
– Patients undergo major surgery with other risk factor for
VTE
– Patients with major medical illness (e.g. heart failure,
MI,stroke,inflammatory conditions, nephrotic syndrome,
sepsis )
● High risk group
– Major abdominal / pelvic or knee surgery
– Neurosurgery
 Management and prophylaxis
of VTE
● Mechanical
1. Intermittent pneumatic compression (IPC)
2. Mechanical foot pumps
3. Graduated compression stockings

• Pharmacological (anticoagulants)
1. Heparin
2. LMWH
3. Warfarin
4. Fondaparinux
 Mechanical foot pumps

Graduated
compression stockings
Intermittent pneumatic compression (IPC)
 Relevance in Dentistry
Bleeding disorders
● Nerve-block anesthetic injections are contraindicated unless there is no
better alternative and prophylaxis is provided, as the anesthetic solution
is deposited in a highly vascularized area, which carries a risk of
hematoma formation.
● In oral surgery, transfusion of appropriate factors to 50% to 100%
of normal levels is recommended when a single bolus infusion is
used in an outpatient setting. In patients with hemophilia,
additional postoperative factor maintenance may be required
after extensive surgeries. This can be done with factor infusion,
DDAVP, cryoprecipitate or fresh frozen plasma depending on the
patient’s condition.
● Care should be taken when prescribing NSAIDS, penicillins,
erythromycin and metronidazole to patients with bleeding
tendencies as they will increase the effect of warfarin which is an
anticoagulant.
 Recent updates
• People with hemophilia A produce extremely low levels of the
blood clotting protein factor VIII (FVIII). In some patients, frequent
intravenous infusions of FVIII do not work because the body
develops antibodies, or inhibitors, that bind to the standard
replacement therapy and render it ineffective. Emicizumab is
designed to fill the treatment gap for these patients. The drug
functions like FVIII by enabling blood to clot, but it has a different
structure, making it unrecognizable to FVIII antibodies.
• Patients with hemophilia A who received a single infusion of an
investigational gene therapy showed improved levels of the
essential blood clotting protein FVIII, with 11 of 13 achieving normal
or near-normal FVIII levels, according to the latest data from a trial
that followed patients for up to 19 months.
 Reference
1. Douglass A Drelich. Jan 14, 2019. Hemophilia A.
(https://emedicine.medscape.com/article/779322-overview)
2. Dharmendra J Nimavat. Dec 13, 2017. Vitamin K Deficiency Bleeding.
(https://emedicine.medscape.com/article/974489-overview)
3. Stuart Ralston Ian Penman Mark Strachan Richard Hobson.2018.
Davidson's Principles and Practice of Medicine 23rd Edition.
Elsevier. 1440pp
4. J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L.
Hauser, Dan L. Longo, Joseph Loscalzo. 2018. Harrison'sTM
Principles of Internal Medicine, 20th edition. McGraw Hill
Education. 1500pp
5. Anil K Tripathi, Kamal K Sawiani.2016. Essential Of Medicine for
Dental Students, 3rd edition. Jaypee Brothers Medical Publishers;
3rd Revised edition edition. 326 pp