Bleeding and Clotting Disorders of Oral Cavity

Platelets or thrombocytes are the formed elements of blood. Platelets are small colorless, non-nucleated and moderately refractive bodies.

Platelet is constituted by:

  1. Cell membrane or surface membrane
  2. Microtubules
  3. Cytoplasm.

Cell membrane of platelet contains lipids in the form of phospholipids, cholesterol and glycolipids, carbohydrates as glycocalyx and glycoproteins and proteins.

Microtubules form a ring around cytoplasm below the cell membrane. Microtubules are made up of polymerized proteins called tubulin.

Cytoplasm of platelets contains the cellular organelles, Golgi apparatus, endoplasmic reticulum, mitochondria, microtubule, microvessels, filaments and granules.

Granules present in cytoplasm of platelets are of two types:

  • Alpha granules
  • Dense granules.

Alpha granules contain:

  • Clotting factors – fibrinogen, V and XIII
  • Platelet-derived growth factor
  • Vascular endothelial growth factor (VEGF)
  • Basic fibroblast growth factor (FGF)
  • Endostatin
  • Thrombospondin

Dense granules contain:

  • Nucleotides
  • Serotonin
  • Phospholipid
  • Calcium
  • Lysosomes.

Normal platelet count is 2,50,000/cu mm of blood. It ranges between 2,00,000 and 4,00,000/cu mm of blood.

Platelets have three important properties (three ‘A’s):

  • Adhesiveness
  • Aggregation
  • Agglutination.

It is the property of sticking to a rough surface. During injury of blood vessel, endothelium is damaged and the sub-endothelial collagen is exposed. While coming in contact with collagen, platelets are activated and adhere to collagen.

  • Collagen.
  • Thrombin.
  • ADP.
  • Thromboxane A2.
  • Calcium ions.
  • P-selectin.
  • Vitronection.

Aggregation is the grouping of platelets. Filopodia help the platelets aggregate together.

During activation, the platelets change their shape with elongation of long filamentous pseudopodia which are called processes or filopodia.

  • Adenosine Diphosphate (ADP).
  • Thromboxane A2.
  • Platelet-activating factor (PTA).

Agglutination is the clumping together of platelets. Aggregated platelets are agglutinated by the actions of some platelet agglutinins and platelet-activating factor.

  • Platelets secrete 5-HT (5-hydroxytryptamine), which causes the constriction of blood vessels.
  • Due to the adhesive property, the platelets seal damage in blood vessels like capillaries.
  • By formation of temporary plug, the platelets seal the damage in blood vessels.
  • Collagen, which is exposed during damage of blood vessels.
  • Von Willebrand factor.
  • Thromboxane A2.
  • Platelet-activating factor.
  • Thrombin.
  • ADP.
  • Calcium ions.
  • P-selectin: Cell adhesion molecule secreted from endothelial cells.
  • Convulxin: Purified protein from snake venom.
  • Nitric oxide.
  • Clotting factors: II, IX, X, XI and XII.
  • Prostacyclin.
  • Nucleotidases which breakdown the ADP.

Average lifespan of platelets is 10 days. It varies between 8 and 11 days. Platelets are destroyed by tissue macrophage system in spleen. So, splenomegaly (enlargement of spleen) decreases platelet count and splenectomy (removal of spleen) increases platelet count.

Hemostasis is defined as arrest or stoppage of bleeding.

  • Vasoconstriction.
  • Platelet plug formation.
  • Coagulation of blood.
  • Immediately after injury, the blood vessel constricts and decreases the loss of blood from damaged portion.
  • Cut in blood vessels leads to damage of endothelium and exposure of collagen.
  • Platelets adhere to this collagen and get activated that secrete serotonin and other vasoconstrictor substances.
  • Adherence of platelets to the collagen is accelerated by von Willebrand factor.
  • This factor acts as a bridge between a specific Glycoprotein of platelet and collagen fibrils.
  • Platelets get adhered to the collagen of ruptured blood vessel and secrete adenosine diphosphate (ADP) and thromboxane A2.
  • These two substances attract and activate more platelets.
  • Platelets aggregation forms a loose temporary platelet plug or temporary hemostatic plug.
  • This temporary plug closes the ruptured vessel and prevents further blood loss.
  • Platelet aggregation is accelerated by platelet activating factor (PAF).

During this process, the fibrinogen is converted into fibrin. Fibrin threads get attached to the loose platelet plug, which blocks the ruptured part of blood vessels and prevents further blood loss.

Coagulation or clotting is defined as the process in which blood loses its fluidity and becomes a jelly-like mass few minutes after it is shed out or collected in a container.

  • Coagulation of blood occurs through a series of reactions due to the activation of a group of substances.
  • Substances necessary for clotting are called clotting factors.
  • Thirteen clotting factors are identified:
  1. Factor I Fibrinogen.
  2. Factor II Prothrombin.
  3. Factor III Thromboplastin (Tissue factor).
  4. Factor IV Calcium.
  5. Factor V Labile factor (Proaccelerin or accelerator globulin).
  6. Factor VI Presence has not been proved.
  7. Factor VII Stable factor.
  8. Factor VIII Antihemophilic factor (Antihemophilic globulin).
  9. Factor IX Christmas factor.
  10. Factor X Stuart-Prower factor.
  11. Factor XI Plasma thromboplastin antecedent.
  12. Factor XII Hageman factor (Contact factor)
  13. Factor XIII Fibrin-stabilizing factor (Fibrinase).

In general, blood clotting occurs in three stages:

  • Formation of prothrombin activator
  • Conversion of prothrombin into thrombin
  • Conversion of fibrinogen into fibrin.

Formation of prothrombin activator occurs through two pathways:

  • Intrinsic pathway
  • Extrinsic pathway.

In this pathway, the formation of prothrombin activatoris initiated by platelets, which are within the blood itself.

  • During injury, the blood vessel is ruptured. Endothelium is damaged and collagen beneath the endothelium is exposed.
  • When factor XII (Hageman factor) comes in contact with collagen, it is converted into activated factor XII in the presence of kallikrein and high molecular weight (HMW)
  • The activated factor XII converts factor XI into activated factor XI in the presence of HMW kinogen.
  • The activated factor XI activates factor IX in the presence of factor IV (calcium).
  • Activated factor IX activates factor X in the presence of factor VIII and calcium.
  • When platelet comes in contact with collagen of damaged blood vessel, it gets activated and releases phospholipids.
  • Now the activated factor X reacts with platelet phospholipid and factor V to form prothrombin activator. This needs the presence of calcium ions.
  • Factor V is also activated by positive feedback effect of thrombin.

In this pathway, the formation of prothrombin activator is initiated by the tissue thromboplastin, which is formed from the injured tissues.

  • Damaged tissues release tissue thromboplastin (factor III) that contains proteins, phospholipid and glycoprotein, which act as proteolytic enzymes.
  • Glycoprotein and phospholipid components of thromboplastin convert factor X into activated factor X, in the presence of factor VII.
  • Activated factor X reacts with factor V and phospholipid component of tissue thromboplastin to form prothrombin activator. This reaction requires the presence of calcium ions.

Blood clotting is all about thrombin formation. Once thrombin is formed, it definitely leads to clot formation.

  • Prothrombin activator that is formed in intrinsic and extrinsic pathways converts prothrombin into thrombin in the presence of calcium (factor IV).
  • Once formed thrombin initiates the formation of more thrombin molecules. The initially formed thrombin activates Factor V. Factor V in turn accelerates formation of both extrinsic and intrinsic prothrombin activator, which converts prothrombin into thrombin. This effect of thrombin is called positive feedback

The final stage of blood clotting involves the conversion of fibrinogen into fibrin by thrombin.

  • Thrombin converts inactive fibrinogen into activated fibrinogen due to loss of 2 pairs of polypeptides from each fibrinogen molecule. The activated fibrinogen is called fibrin monomer.
  • Fibrin monomer polymerizes with other monomer molecules and form loosely arranged strands of fibrin.
  • Later these loose strands are modified into dense and tight fibrin threads by fibrin-stabilizing factor (factor XIII) in the presence of calcium ions. All tight fibrin threads are aggregated to form a meshwork of stable clot.

Blood clot is defined as the mass of coagulated blood which contains RBCs, WBCs and platelets entrapped in fibrin meshwork.

After the formation, the blood clot starts contracting. After about 30 to 45 minutes, the straw-colored serum oozes out of the clot. The process involving the contraction of blood clot and oozing of serum is called clot retraction.

Lysis of blood clot inside the blood vessel is called fibrinolysis. It helps to remove the clot from lumen of the blood vessel. This process requires a substance called plasmin or fibrinolysin.

Substances which prevent or postpone coagulation of blood are called anticoagulants.

Three types:

  • Anticoagulants used to prevent blood clotting inside the body, i.e. in vivo.
  • Anticoagulants used to prevent clotting of blood that is collected from the body, i.e. in vitro.
  • Anticoagulants used to prevent blood clotting both in vivo and in vitro.

Heparin is used as an anticoagulant both in vivo and invitro.

Mode of action

  • Prevents blood clotting by its antithrombin activity. It directly suppresses the activity of thrombin
  • Combines with antithrombin III (a protease inhibitor present in circulation) and removes thrombin from circulation.
  • Activates antithrombin III.
  • Inactivates the active form of other clotting factors like IX, X, XI and XII.
  • Prevent blood clotting by inhibiting the action of vitamin K.
  • Vitamin K is essential for formation of various clotting factors, namely II, VII, IX and X.
  1. EDTA

Ethylenediaminetetraacetic acid (EDTA) is a strong anticoagulant. It is available in two forms:

  • Disodium salt (Na2 EDTA).
  • Tripotassium salt (K3 EDTA).

Mechanism of Action

These substances prevent blood clotting by removing calcium from blood.

  • Sodium, ammonium and potassium citrates are used as Anticoagulants
  • Citrate combines with calcium in blood to form insoluble calcium citrate.
  • Like oxalate, citrate also removes calcium from blood and lack of calcium prevents coagulation.
  • Bleeding time.
  • Clotting time.
  • Prothrombin time.
  • Partial prothrombin time.
  • International normalized ratio.
  • Thrombin time.
  • Bleeding time (BT) is the time interval from oozing of blood after a cut or injury till arrest of bleeding.
  • Determined by Duke method using blotting paper or filter paper method.
  • Normal duration is 3 to 6 minutes.
  • Time interval from oozing of blood after a cut or injury till the formation of clot.
  • Determined by capillary tube method.
  • Normal duration is 3 to 8 minutes.
  • Time taken by blood to clot after adding tissue thromboplastin to it.
  • It indicates the total quantity of prothrombin present in the blood.
  • Normal duration of prothrombin time is 10 to 12 seconds.
  • Prolonged in deficiency of prothrombin and other factors like factors I, V, VII and X.
  • Partial prothrombin time (PPT) is the time taken for the blood to clot after adding an activator such as phospholipid, along with calcium to it.
  • It is also called activated partial prothrombin time (APTT).
  • Useful in monitoring the patients taking anticoagulant drugs.
  • Normal duration of partial prothrombin time is 30 to 45 seconds.
  • Prolonged in heparin or warfarin therapy and deficiency or inhibition of factors II, V, VIII, IX, X, XI and XII.
  • It is rating of a patient’s prothrombin time when compared to an average.
  • Blood takes longer time to clot if INR is higher.
  • Normal INR is about 1.
  • Patients on anticoagulant therapy for atrial fibrillation, INR should be between 2 and 3.
  • For patients with heart valve disorders, INR should be between 3 and 4.
  • But, INR greater than 4 indicates that blood is clotting too slowly and there is a risk of uncontrolled blood clotting.
  • Thrombin time (TT) is the time taken for the blood to clot after adding thrombin to it.
  • It investigates the presence of heparin in plasma or to detect fibrinogen abnormalities.
  • Normal duration of thrombin time is 12 to 20 seconds.
  1. Vessel Wall Disorders
  • Scurv.y
  • Cushing’s syndrome.
  • Ehlers-Danlos syndrome.
  • Rendu-Osler-Weber syndrome.
  1. Platelet Disorders
    I. Thrombocytopenic—quantitative platelet deficiency
  • May-Hegglin anomaly.
  • Wiskott-Aldrich syndrome.
  • Neonatal alloimmune thrombocytopenia.

II. Nonthrombocytopenic—qualitative or functional platelet defect

  • Glanzmann’s thrombasthenia.
  • Platelet-type von Willebrand’s disease.
  • Bernard-Soulier syndrome.

B. Acquired

I. Thrombocytopenic—quantitative platelet deficiency

  • Autoimmune or idiopathic thrombocytopenia purpura.
  • Thrombotic thrombocytopenia purpura.
  • Cytotoxic chemotherapy.
  • Drug-induced (eg, quinine, quinidine, gold salts, trimethoprim etc.
  • Leukemia.
  • Aplastic anemia.
  • Myelodysplasia
  • Systemic lupus erythematosus.
  • Associated with infection: HIV, mononucleosis, malaria.
  • Disseminated intravascular coagulation.

II. Nonthrombocytopenic—qualitative or functional platelet defect

  • Drug-induced (eg, by aspirin, NSAIDs, penicillin, cephalosporins).
  • Uremia.
  • Alcohol dependency.
  • Liver disease.
  • Myeloma, myeloproliferative disorders, macroglobulinemia.
  • Acquired platelet-type von Willebrand’s disease.
  1. Coagulation Disorders

I. Congenital

  • Hemophilia A.
  • Hemophilia B.
  • Von Willebrand’s Disease


  • Anticoagulant-Related coagulopathies.
  • Disease-related coagulopathies
  1. Fibrinolytic Disorders
  • Also known as vascular purpura. There is mild bleeding that is confined to the skin, mucosa. Occur due to:
  1. Damage to capillary
  2. Abnormalities in the vascular sub endothelial matrix or extravascular connective tissue bed.
  3. Abnormal vessel formation.

Vitamin C deficiency causes Scurvy.

Seen commonly in:

  • Infants on non-supplemented processed milk.
  • Elderly people.
  • Alcoholics.
  • Smokers.
  • Drug addicts

Vitamin C is the co-factor in:

  • Collagen synthesis.
  • Neuromodulation.
  • Immune responses-chemotaxis.
  • Oxidative metabolism.
  • Scavenging of damaged free radicals.
  • It affects hydroxylation of proline leading to lack of collagen formation.
  • Lack of connective tissue support to the capillary walls leads to vascular fragility resulting in bleeding tendency which produces petechiae and ecchymoses.

Bleeding abnormalities:

  • Petechiae
  • Perifollicular and subperiosteal hemorrhage.
  • Ecchymoses
  • Purpura
  • Bleeding gums.
  • Hemarthrosis

Other manifestations:

  • Bone pain.
  • Osteoporosis.
  • Athralgias.
  • Myalgias.
  • Edema.
  • Ascites.
  • Cardiomegaly
  • Electrocardiographic abnormalities suggestive of cardiac disease.

Fatigue, lassitude, and emotional changes (depression and hypochondriasis).

Oral scurvy is characterized by:

  • Intense red, painful swollen gingiva that bleeds spontaneously on slightest provocation, resulting in hemorrhages/purpuras/bruising.
  • The general discoloration that results from bleeding and blood breakdown is called scurvy siderosis.

Severe periodontal syndrome characterized by ulcerative gingivitis and rapid periodontal pocket development with tooth exfoliation. It is often associated with fetid odor and poor oral hygiene.

Hematological abnormalities, medication side effects, infections, ulcerative gingivitis, collagen vascular disorder, deep venous thrombosis, vitamin deficiencies, trauma to legs and joints.

  • Dietary history.
  • Measurement of vitamin C levels in serum, leukocytes, and urine.
  • Plasma vitamin C concentration < 11 mmol/L (0.2 mg/dL.) is indicative of scurvy.
  • Vitamin C rich diet.
  • Administration of 1 g/d of vitamin C supplements

The EDS comprise a heterogeneous group of connective tissue diseases sharing clinical manifestations in skin, ligaments and joints, blood vessels and internal organs.

The disease is caused by an inherited defect.2 loci have been identified:

  • One on chromosome arm 9q33–q34.
  • Second on chromosome arm 12q.



      I: Severe or classic

  • Skin hyperelasticity and fragility
  • Dystrophic scars
  • Joint hypermobility
  • Abnormal bleeding tendency

          II: Moderate

  • Symptoms less pronounced than in type

     III: Familial hypermobility

  • Joint hypermobility
  • Multiple dislocations
  • Skin hyperelasticity
  • Absence of dystrophic scars
  • Normal coagulation

        IV:Vascular (Sack-Barabas) A, B, C, D

  • Vascular fragility (arterial rupture)
  • Moderate hypermobility of finger joints
  • Perforation of certain hollow organs (uterus, intestine)

       V: Chromosome X-linked

  • Similar to types II and III

             VI: Ocular A, B

  • Hyperelasticity of the skin
  • Joint hypermobility
  • Detached retina
  • Severe scoliosis

VII: Arthrochalasis multiplex congenita A,B,C

  • Congenital luxation of the hips
  • Multiple joint dislocations
  • Moderate hyperelasticity of the skin
  • Small stature

             VIII: Periodontal

  • Generalized early-onset periodontitis
  • Moderate joint hypermobility
  • Variable skin hyperelasticity
  • Shin ecchymoses

In instances in which the skin extensibility is pronounced, the patient has become known as the circus rubber man.

It is the ability of patients of EDS to touch the tip of the nose with the tip of their tongue.

In patients with hyper-extensible joints in Ehler Danlos syndrome, they are able to fold their forearms at the back and oppose their palms to say “Namaskar,” demonstrating the hyper extensible joints.

Easy eversion of upper eyelid.

  • Oral mucosa becomes excessively fragile and bruised easily with normal colour.
  • The gingival tissues appeared fragile and bled after tooth brushing.
  • Gingival hyperplasia and fibrous nodules.
  • Failure in eruption of the permanent teeth.
  • Dentinal aberrations like pulp stones, short and deformed roots.
  • A high incidence of caries in the deciduous teeth.
  • Spontaneous fractures of teeth have been reported.
    Early onset of generalized periodontitis.
  • A supple tongue.
  • Hypoplastic changes in the enamel.
  • Physical therapy (used to rehabilitate those with joint and muscle instability)
  • Surgery to repair damaged joints.
  • Drugs to minimize pain(acetaminophen, ibuprofen).

Prevent injuries and protect joints by:

  • Avoid contact sports.
  • Avoid lifting weights.
  • Use sunscreen to protect the skin.
  • Avoid harsh soaps that may over dry the skin or cause allergic reactions.
  • Use assistive devices to minimize pressure on your joints.

Oslerñ-Weberñ-Rendu syndrome, or hereditary hemorrhagic telangiectasia (HHT), is a rare genetically determined autosomal dominant disorder identified by the triad of telangiectasia, recurrent epistaxis, and a positive family history for the disorder.

  • HHT type-1 and type-2 (due to defective Endoglin).
  • HHT type-3 involves mutations of the long arm of chromosome 5 (5q31.1-32)
  • Type-4 maps to the short arm of chromosome 7 (7p14).
  • A HHT juvenile polyposis overlap syndrome due to mutations of SMAD4.
  • Variable and age-dependent.
  • Epistaxis
  • Appears as punctuate or splinter-like telangiectasias located on the lips, oral mucosa, upper extremities, nail beds, and trunk.
  • Vascular involvement of internal organs like GIT, lungs, and central nervous system.
  • Pulmonary AVMs, such as right-to-left shunts cause hypoxemia.
  • Cerebral AVMs can lead to headaches, migraines, brain abscesses, seizures, paraparesis, ischemia, strokes.
  • Absence of a filtering capillary bed allows emboli to reach the systemic circulation and cause cerebral abscesses and stroke.
  • Gastrointestinal bleeding leads to in iron deficiency anemia or acute gastrointestinal hemorrhage.
  • Vascular lesions may be present as telangiectasias, arteriovenous malformations (AVM), or aneurysms.
  • Mucocutaneous lesions bleed profusely with minor trauma or even spontenously.
  1. Perioral & intraoral angiomatous nodule and telangiectases involving:
  • Lip.
  • Tongue.
  • Palate.
  1. They may bleed during dental manipulation.

Based on Curaçao criteria, established by the Scientific Advisory Board of the HHT Foundation International, Inc., viz.

  1. Epistaxis: spontaneous and recurrent;
  2. Telangiectasias: multiple, at characteristic sites,including lips, oral cavity, fingers, and nose.
  1. Presence of internal lesions: GI telangiectasia, pulmonary, hepatic, cerebral, and spinal AVMs; and (4) family history: first-degree relative with HHT according to these criteria.

The diagnosis is considered definite if any three of the above mentioned criteria are present and possible if any two of the criteria are present.

CREST syndrome, hereditary benign telangiectases, and ataxia-telangiectasia.

  • Depending upon its severity.
  • Cryotherapy.
  • Laser ablation.
  • Electrocoagulation.
  • Blood replacement.
  • Iron supplements.

The disease is seldom so severe that life is endangered.

  • Occur due to excessive exogenous or endogenous corticosteroid intake or production.
  • Leads to general protein wasting and atrophy of supporting connective tissue around blood vessels.
  • Skin bleeding or easy bruising occur.

Irregularly shaped purpuric areas on armsand hands, due to tears in small bloodvessels in aged persons known as purpura senilis.

Thrombocytopenias occur when platelet quantity is reduced due to:

  • Decreased production in the bone marrow.
  • Increased sequestration in the spleen.
  • Accelerated destruction.

Thrombocytopathies or qualitative platelet disorders occur due to defects in any of platelet reactions:

  • Adhesion.
  • Aggregation.
  • Granule release.

Eduard Glanzmann was a Swiss pediatrician who first discovered the condition of thrombasthenia in 1918. Formerly known as “hereditary hemorrhagic thrombasthenia”.

Deficiency or dysfunction of glycoprotein (GP) IIb and IIIa, which are the receptors of fibrinogen. Hence, no fibrinogen bridging can occur and bleeding time is significantly prolonged, clot retraction is diminished and platelets do not aggregate during blood coagulation or after addition of ADP (adenosine diphosphate).

Classified by Caen in 1972, depending on the level of GPIIb-IIIa present:

  • Type 1 (severe): < 5% of normal GPIIb-IIIa levels.
  • Type 2 (less severe): 10 to 20% of normal GPIIb-IIIa levels.

Type 3 (variant): Normal levels of GPIIb-IIIa, but functionally inactive.

  • Nose bleeds.
  • Purpura.
  • Gastrointestinal bleeding.
  • CNS hemorrhage.
  • Hematuria.
  • Muscle hematoma.
  • Hemarthrosis.
  • Menorrhagia.
  • Unexplained spontaneous bleeding from mucous membranes.
  • Gingival bleeding during teething or shedding of deciduous teeth.
  • Petechiae, ecchymoses or purpura on mucous membranes.
  • Prolonged bleeding times.
  • Decreased or absent clot retraction.
  • Abnormal platelet aggregation responses to physiologic stimuli.
  • Normal levels of plasma von Willebrand factor and the normal platelet GPIb/IX content.
  • Reduced second wave of aggregation at low doses of ristocetin reflects the impaired GPIIb-IIIa function.
  • Antifibrinolytic agents – tranexamic acid or topical thrombin and YAG laser to control minor bleeding.
  • Immunoabsorption is the removal of antibodies to platelets by plasma exchange with the use of protein-A sepharose columns which may transiently restore platelet efficacy.
  • Allogenic marrow transplant.

Von Willebrand’s disease, Bernard-Soulier syndrome and platelet secretory defects.

  • First recognized by two French hematologists, Jean Bernard and Jean Pierre Soulier in the year 1948
  • Also known as Hemorrhagiparous thrombocytic dystrophy, Congenital hemorrhagiparous thrombocytic dystrophy
  • It is a hereditary bleeding disorder affecting the megakaryocyte/platelet lineage and characterized by bleeding tendency, giant blood platelets and low platelet counts.

The disorder is caused by a deficiency in glycoprotein (GP) Ib/IX/V, which is a protein found on the surface of platelets.

Symptoms manifest rapidly after birth or during early childhood.

  • Purpura.
  • Epistaxis.
  • Menorrhagia.
  • Gastrointestinal bleeding and hematuria (rarely).
  • Severe bleeding episodes are associated with trauma and surgical procedures.
  • However, the severity and frequency of bleeding vary between individuals.
  • Bleeding mainly affects mucocutaneous tissues.
  • Four different features of BSS may contribute to the hemorrhagic diathesis:

          a) Thrombocytopenia.

          b) Abnormal platelet interaction with vWF.

          c) Abnormal platelet interaction with thrombin.

         d) Abnormal platelet coagulant activity.

  • Gingival bleeding.
  • Severe bleeding episodes are associated during dental extractions.
  • Bleeding times are moderately (5–10 min) to severely (>20 min) prolonged.
  • Presence of a small number of very large platelets with a rounded shape (main volume 11–16 μm3; diameter 4–10 μm).
  • Blood cell counts.
  • Examination of blood smears.

Platelet counts typically range from 20,000 to 100,000/μl.

WiscottAldrich syndrome, X-linked thrombocytopenia, May-Hegglin syndromes.

  • Avoid traumas, antiplatelet medication such as aspirin, to maintain adequate dental hygiene and to use contraceptive in female at puberty.
  • Treatment of bleeding or prophylaxis during surgical procedures requires blood or platelet transfusion.
  • Desmopressin and rFVIIa administration shorten the bleeding time.
  • Also known as Hypogammaglobulinemia M.
  • X-linked immunodeficiency disease with a characteristic clinical phenotype that includes thrombocytopenia with small platelets, eczema, recurrent infections caused by immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies.
  • Results from an X-linked genetic defect in a protein; Wiskott-Aldrich syndrome protein (WASp).
  • The gene resides on Xp11. 22–23, and its expression is limited to cells of hematopoietic lineage.
  • Petechiae and a purpuric rash or ecchymoses of skin.
  • Eczema(allergic in nature).
  • Boils, otitis media, bloody diarrhea, and respiratory infection.
  • Increased susceptibility to infection
  • Low Serum IgM levels.
  • Normal IgG levels.
  • IgA and IgE levels may be normal or elevated.
  • Patients have T- and B-cell abnormalities.
  • Occurrence of a lymphoreticular malignant neoplasm
  • Spontaneous bleeding of the gingival, GIT and nose.
  • Palatal petechiae.
  • Platelet count 18,000 and 80,000 per cubic millimeter.
  • Prolonged bleeding time.
  • Size of platelets smaller than normal.
  • Alterations in the cell membrane.
  • Deficiency of the adenosine diphosphate nucleotide storage pool.
  • No specific treatment.
  • Death usually occurs within the first five years(due to infection & hemorrhage).
  • Antibiotics and platelet transfusions.
  • Bone marrow transplantation.
  • May Hegglin anomaly was first described by May in 1909 and in 1945 by Hegglin.
  • May Hegglin anomaly (MHA) is a rare autosomal dominant disorder characterized by variable thrombocytopenia and well defined basophilic cytoplasmic inclusion bodies (resembling Dohle bodies) in the granulocytes
  • Mutation of MYH9 gene present in chromosome 22q12–13.
  • The mutation results in disordered production of non-muscle myosin heavy chain type IIA.
  • This leads to macrothrombocytopenia secondary to defective megakaryocytic maturation and fragmentation.
  • Leukocyte inclusions are precipitates of myosin heavy chains.
  • Neutrophil and platelet function is considered to be normal.
  • Abnormal bleeding in the form of epistaxis.
  • Gingival bleeding,
  • Easy bruising.
  • Menorrhagia.
  • Excessive bleeding associated with surgical procedures.
  • Complete blood count.
  • Decrease platelet count but degree of thrombocytopenia varies (40–80 × 109/l).
  • Platelets are enlarged but morphology is normal.
  • Increased amount of disorganized microtubule.
  • PBS shows cytoplasmic inclusion bodies (resembling Dohle bodies) in neutrophils, monocytes, eosinophils and basophils.
  • The inclusions are large, spindle shaped, pale blue staining bodies.
  • Prolong bleeding time.
  • Platelets aggregate normally in response to various agonists.
  • No clinically significant bleeding problems so no treatment is required.
  • Platelet transfusions (in severe bleeding)
  • Idiopathic or immune thrombocytopenia purpura (ITP)
  • Thrombotic thrombocytopenia purpura (TTP),
  • Also known as idiopathic thrombocytopenic purpura.
  • It is a hematologic disorder characterized by isolated thrombocytopenia without a clinically apparent cause. 
  • Caused by platelet destruction via immune-mediated mechanisms and inadequate platelet production
  • Based on duration (acute or chronic) and age (childhood or adult).
  • According to International working group of experts(2009) defined the phases of ITP as:

A. Newly diagnosed ITP (lasting within 3 months from diagnosis),

B. Persistent ITP (lasting between 3 and 12 months from diagnosis),

C. Chronic ITP (lasting for more than 12 months), excluding the term “acute”

  • Easy bruising of the skin.
  • Petechiae.
  • Ecchymosis.
  • Epistaxis.
  • Petechiae, ecchymoses or haematomas in easily traumatized areas like:

A. Buccal mucosa.

B. Lateral borders of the tongue.

C. Limit between the soft and hard palate.

  • Spontaneous gingival and mucocutaneous hemorrhage
  • Based principally on history, physical examination, complete blood count, and peripheral smear examination.
  • Low platelet count without identification of alternative causes of thrombocytopenia
  • Sometimes severe ITP (platelets less than 10,000/μL) do not bleed, while excessive bleeding occurs with higher counts.
  • Antibody mediated platelets destruction causes a rise in the generation of young platelets that are more efficient in managing hemostasis
  • Patients with platelet counts under 30.000/μL required consultation with a hematologist
  • Use of corticosteroids (dexamethasone, methylprednisolone, prednisone) or intravenous infusion of immunoglobulin or intravenous infusion of anti-D when the platelet count is under 30,000/μL
  • Dental treatments should perform with a platelet count over 50.000/mm3and in consultation with the patient’s hematologist.
  • Drugs with anti-platelet aggregation effect like acetylsalicylic acid and nonsteroidal anti-inflammatory drugs must be avoided.
  • Antibiotics to minimize the risk of postoperative infections.
  • First described in 1925 by Moschcowitz. 
  • Thrombotic thrombocytopenic purpura (TTP) is an aggressive form of thrombotic microangiopathy which results in multi-organ dysfunction as a consequence of widespread microvascular ischemia

Severely decreased activity of the metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13)

Predisposing factors:

  • Metastatic malignancy.
  • Pregnancy.
  • Mitomycin C.
  • High-dose chemotherapy

Classic “pentad” of fever, thrombocytopenia, microangiopathic hemolytic anemia, renal dysfunction, and neurological symptoms.

Central nervous system:

  • Confusion.
  • Visual disturbance.
  • Seizure.
  • Focal neurological signs (eg, aphasia, hemiparesis).
  • Coma.


  • Acute kidney injury

Heart dysfunction:

  • Conduction defects,
  • Congestive cardiac failure,
  • Raised serum troponin.
  • Thrombocytopenia lead to “external” bleeding.

Symptoms and signs:

  • Bruising.
  • Petechiae.
  • Menorrhagia.
  • Epistaxis.
  • Hematuria.
  • Gastrointestinal hemorrhage.
  • Nonspecific abdominal pain.
  • Nausea.
  • Nonspecific constitutional symptoms.
  • Fever and jaundice. 
  • Microvascular infarcts in gingival and other mucosal tissue.
  • Infarcts are rich in platelets.
  • Demonstration of a profound decrease in ADAMTS13 enzyme activity (usually <10%) in the plasma 
  • Detection of autoantibodies directed against ADAMTS13
  • Blood group and antibody screen, direct antiglobulin test, cytomegalovirus serology.
  • Autoantibody screen (eg, antinuclear antibodies, rheumatoid factor, lupus anticoagulant testing)
  • CT/MRI brain, echocardiogram, electrocardiogram.
  • Other imaging and investigations to exclude malignancy as directed by clinical history and examination.
  1. Acquired TTP
  • Plasma exchange (PEX).
  • PEX is initiated at 1.5× plasma volume (PV) (60 mL/kg). In the case of confirmed TTP, PEX at 1.5× PV is continued for at least the first 3 days.
  • Daily PEX should be continued until 2 days after platelet count normalizes (>150 × 109/L), and can be safely stopped outright without any weaning schedule.


  • Rituximab (RTX) is a monoclonal antibody that targets the CD20 antigen present on B lymphatic cells. RTX is used in refractory and/or relapsed TTP with a high response. However, there have been few studies on RTX in the treatment of acute aTTP. Because of the high mortality and recurrence rate in patients with aTTP, RTX rapidly depletes circulating B lymphocytes, resulting in a reduction in the antibody of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13).
  • Reduced-dose rituximab (200 mg) is associated with higher rates of re-treatment than the standard dose (375 mg/m2).


  • Used to achieve relatively rapid immu­nosuppression.
  • Higher doses of methylprednisolone (10 mg/kg/day) are more effective.
  • Methylprednisolone 1g intravenously daily for 3 days, with the first dose typically administered immediately after the first PEX.

Supportive care

  • Antiplatelet agents: Low-dose aspirin
  • Antithrombotic therapy.
  • Hepatitis B prophylaxis.
  • Folic acid.
  1. Congenital TTP
  • Plasma infusions every 3–4 weeks in order to replace functional ADAMTS13 and prevent symptomatic TTP episodes.
  • Therapeutic dose 10–15 mL/kg of FFP/SDP.

It is group of hereditary disorders caused due to the deficiency of one or more clotting factors leading to prolonged clotting time and excessive bleeding tendencies that may be fatal.

It is broadly divided into:

  • Hemophilia A (deficiency of factor VIII).
  • Hemophilia B or Christmas disease (deficiency of factor IX).
  • Hemophilia C or Rosenthal syndrome (deficiency of factor XI).

Other variants include:

  • Parahemophilia (Owren’s disease)-factor V deficiency.
  • Acquired hemophilia.
  • Caused due to factor VIII deficiency, the gene for which is located on the long arm of the X chromosome at Xq28 and consists of 26 exons.
  • X-linked recessive trait that affects males (hemizygous).
  • The trait is carried in the female (heterozygous) without clinical evidence of the disease.
  • It occurred in Great Britain’s Queen Victoria’s family and became to be known as the “Royal disease”.
  • Easy bruising.
  • Massive hemorrhage after trauma or minor surgical procedures.
  • Spontaneous hemorrhage from the middle ear.
  • Epistaxis.
  • Bleeding into the joints causing hemarthrosis.
  • Bleeding into soft tissues.
  • Weight-bearing joints become hot, tender, and painful, leading to synovial hypertrophy.
  • Destruction of cartilage and secondary osteoarthritis.
  • Tissue hemorrhage forms tumor-like masses termed as “pseudotumors of hemophilia.”


  • Chronic hemophilic arthropathy.
  • Synovitis.
  • Contractures.
  • Pseudotumor formation.
  • Development of inhibitors against factor VIII.
  • Gingival bleeding.
  • Post-extraction hemorrhages.
  • History of multiple oral bleeding events.
  • Poor oral hygiene and iatrogenic factors also induce oral bleeding.
  • Oral ulcerations and ecchymosis involving lips and tongue.

Laboratory diagnosis demonstrates:

  • Normal platelet count.
  • Normal bleeding time (BT).
  • Normal prothrombin time (PT).
  • Prolonged activated partial thromboplastin time (APTT),
  • It is also known as factor IX deficiency, or Christmas disease.
  • It was originally named “Christmas disease” after the first person diagnosed with the disorder back in 1952.
  • Hereditary blood coagulation disorder.
  • Females with one defective factor IX gene are carriers (they don’t have symptoms).
  • Bleeding is the main symptom 
  • Bleeding into joints and associated pain and swelling.
  • Blood in the urine and stool.
  • Bruising excessive bleeding following circumcision.
  • Gastrointestinal tract and urinary tract hemorrhage.
  • Nosebleeds.
  • Prolonged bleeding from cuts, and surgical procedure.
  • Gingival bleeding.
  • Post-extraction hemorrhages.
  • Physiologic processes of tooth eruption and exfoliation produce prolonged hemorrhage.

Laboratory diagnosis demonstrates:

  • Normal platelet count.
  • Normal bleeding time (BT).
  • Normal prothrombin time (PT).
  • Prolonged activated partial thromboplastin time (APTT).
  • Infusion of factor IX concentrates.
  • Amount infused depends upon the severity of bleeding.
  • Hepatitis B vaccine because of increased risk of developing hepatitis due to exposure to blood products. Depending on the severity of the disease,
  • Factor IX concentrate may be given prior to dental extractions.
  • FXI deficiency was first described in 1953 by Rosenthal.
  • Hemophilia C, caused by deficiency of Factor XI, is a rare coagulation disorder.
  • FXI (PTA)is a plasma glycoprotein that is activated in the intrinsic coagulation pathway.
  • The normal blood range of FXI is 70-150 U/dL.
  • In Heterozygous cases blood level is 30-60 U/dL.
  • In Homozygous or compound heterozygous blood levels are below 20 U/dL.
  • Rare and mild disorder.
  • Bleeding symptoms are mild.
  • Hemorrhages due to major surgery or trauma can be controlled with infusions of fresh frozen plasma.
  • Normal bleeding time (BT),
  • Normal prothrombin time (PT).
  • Slightly prolonged partial thromboplastin time (PTT).
  • Fresh frozen plasma.
  • Factor XI concentrate.
  • Hormone therapy( in form of birth control pills, injections ).
  • DDAVP or synthetic hormone desmopressin.
  • Rare disorder.
  • Activated factor XII is important in the conversion of plasminogen to plasmin and prekallikrein to kallikrein, both of which aid in fibrinolysis.
  • The impaired fibrinolytic system puts the deficient patient at risk of thrombosis.
  • Avoid the use of any antifibrinolytic agents intraoperatively and to closely monitor the patient postoperatively for any embolic events.
  • Prolonged Prothrombin time(PT) and partial thromboplastin time (PTT)
  • Clinical symptoms are nonexistent.
  • Treatment is therefore contraindicated.
  • Stuart factor deficiency.
  • Rare disorder.
  • Transmitted as an autosomal recessive trait.
  • Sign and symptoms same as hemophilias A and B when levels of factor X are < 1% of normal.
  • Prolong PT
  • Prolong PTT
  • Normal bleeding time.
  • Also known as parahemophilia.
  • Proaccelerin deficiency, responsible for the conversion of prothrombin to thrombin.
  • Rare disorder
  • Transmitted as autosomal recessive trait.
  • Both genders are affected.
  • Exhibit a severe bleeding tendency.
  • Spontaneous epistaxis.
  • Bleeding into the gastrointestinal tract.
  • Menorrhagia.
  • Cutaneous ecchymoses
  • Hematomas
  • Intraocular hemorrhage and hemorrhage into CNS.
  • Spontaneous gingival bleeding
  • Prolonged bleeding following dental extractions.
  • Blood platelet level is normal.
  • Prolong clotting time and prothrombin time.
  • Normal bleeding time.
  • Reduction of plasma proaccelerin.
  • No effective treatment for parahemophilia.
  • Transfusions of freshly frozen plasma.
  • Prognosis is good.
  • It is a severe bleeding diathesis caused by autoantibodies which impair the function of the coagulation factor VIII.
  • These antibodies are defined as the circulating anticoagulant, or factor VIII inhibitor.
  • Etiology is unknown.
  • Idiopathic origin.
  • Conditions like:

a. Autoimmune disorders.

b. Cancer

c. Puerperium.

  • Common in both males and females.
  • Massive subcutaneous blood extravasations
  • Mucosal hemorrhages.
  • Normal prothrombin time.
  • Normal thrombin time.
  • Normal bleeding time.
  • Normal platelet count and fibrinogen concentration
  • 2- or 3-fold prolongation of the activated partial thromboplastin time (APTT).

In prophylaxis and treatment of bleedings: Transfusions of fresh frozen plasma and cryoprecipitate.

In the immunosuppressive treatment, prednisone and cyclophosphamide (CTX) are first-line therapy.

  • Factor XIII deficiency is inherited as an autosomal recessive disorder.
  • Only homozygous-recessive patients with severe deficiencies have clinical symptomatology.


  • Manifest at any age,
  • Diagnosis is often made during infancy.
  • Haemorrhages are delayed (12–36 h) after trauma or surgery.

Acquired: Associated with

  • Hepatic failure.
  • Inflammatory bowel disease.
  • Myeloid leukaemia.
  • Subcutaneous bleeding.
  • Delayed umbilical cord bleeding.
  • Muscle haematoma.
  • Haemorrhage after surgery.
  • Intracerebral bleeding.
  • Normal bleeding time (BT).
  • Normal prothrombin time (PT).
  • Normal activated partial thromboplastin time (APTT).

Other tests:

  • Clot Solubility Test.
  • Factor XIII Activity Assay.
  • Molecular Diagnosis of Factor XIII Deficiency.
  • An algorithm for diagnosis of FXIII deficiency.
  • Fresh frozen plasma (FFP) or cryoprecipitate.
  • New recombinant factor XIII (rFXIII) as a monthly replacement therapy (35 IU/kg intravenous).
  • There is generally not a complete absence of fibrinogen in acquired form of the disease as there is in the congenitaltype, and this accounts for the difference in use of the terms ‘afibrinogenemia’ and ‘hypofibrinogenemia’.
  • Clinical features in both forms are almost identical.
  • The commonest manifestations of afibrinogenemia are:

A. Umbilical stump bleeding (which can be life threatening).

B. Bleeding from mucosal surfaces.

C. Menorrhagia

D. Epistaxis.

E. Bleeding in the oral cavity (Gingival).

F. Musculoskeletal bleeding (including hemarthroses).

G. Recurrent episodes of intracranial hemorrhage.

H. Bleeding tendency is highly variable (ranging between very few up to several episodes/year).

I. Bleeding after minor trauma and excessive bleeding during interventional procedures.

  • Normal red blood cell.
  • White blood cell.
  • Platelet counts (occasionally thrombocytopenia).
  • PT prolonged or incoagulable.
  • PTT prolonged or incoagulable
  • Occasionally prolong bleeding time.
  • Peripheral blood fails to clot even after the addition of thrombin.
  • Tourniquet test is normal.
  • ESR is zero, the cells remain suspended even after 24 hours.
  • It is named after the Finnish doctor, Erik von Willebrand (1870-1949)
  • It is a large multimeric glycoprotein present in plasma.
  • It is synthesized in Weibel-Palade bodies in endothelium, α-granules of platelets (megakaryocytes) and sub-endothelial connective tissue.
  • Plasma protein which allows or helps the platelets to stick with each other and form a clump is the von Willebrand factor (VWF).
  • It also carries factor VIII.
  • Decrease or defect in plasma levels of von Willebrand factor, the ability of the blood to clot decreases leading to a heavy and continuous bleeding after an injury which is termed as von Willebrand disorder or disease (VWD).

Inherited forms:

Major form-

  • Type 1.
  • Type 2.
  • Type 3.
  • Platelet type.

The international society of thrombosis and homeostasis classified VWD based on the definition of qualitative and quantitative defects. According to this classification, type 2 VWD is again classified into:

  • Type 2A.
  • Type 2B.
  • Type 2M.
  • Type 2N.
  • Type 1 and type 2 are inherited if the gene is passed on to the offspring from either of the parent.
  • Type 3 is inherited only if the gene is passed from both the parents.
  • Acquired VWD is seen in patients with auto antibodies.
  1. Typically type 1 VWD manifests mild mucocutaneous bleeding. Symptoms include:
  • Bruising.
  • Epistaxis.
  • Heavy menstrual bleeding in reproductive age.
  • Heavy blood loss during delivery.
  1. If the VWF levels are lower than 15 IU/dl, symptoms can be more severe.
  2. Type 2A VWD manifest mild to moderate mucocutaneous bleeding.
  3. Type 2B VWD have mild to moderate mucocutaneous bleeding, thrombocytopenia which worsened during stress.
  4. Type 2M VWD also typically has mild to moderate mucocutaneous bleeding.
  5. Type 2N VWD symptoms similar to mild hemophilia A, includes excessive bleeding during surgery.
  6. Acquired VWD individuals also present with mild to moderate bleeding.

APTT, activated partial thromboplastin time; FVIII:C, factor VIII coagulant; VWF:AG, VWF antigen; VWF:RCO, VWF ristocetin cofactor; VWF:CB, VWF collagen binding; RIPA, ristocetin-induced platelet agglutination; CT, closure time; VWD, von Willebrand Disease.

Laboratory Assay

Pathophysiological Significance

Type 1 VWD

Type 2A VWD

Type 2BVWD

Type 2M VWD

Type 2N VWD

Type 3 VWD


Reflects the degree of reduction of FVIII

Prolonged or normal

Prolonged or normal

Prolonged or normal

Prolonged or normal



Platelet count

Increased affinity for GpIb in type 2B



Low or normal




PFA-100 (CT)

Simulates primary hemostasis after injury to a small vessel

Prolonged, no closure

Prolonged, no closure

Prolonged, no closure

Prolonged, no closure


Prolonged, no closure


FVIII-VWF interaction

Low or normal

Low or normal

Low or normal

Low or normal

Proportionally low

Low (<10 IU/dL)


Antigen concentration


Low or normal

Low or normal

Normal or low

Normal or low

Very low (<5 IU/dL)


VWF–GPIb interaction as mediated by ristocetin in vitro


Very low

Variably low


Normal or low

Very low (<5 IU/dL)


VWF–collagen interaction

Low, rarely normal

Very low


Low or normal

Normal or low

Very low (<5 IU/dL)

VWF:RCo/VWF:Ag ratio


Normal (>0.6)

Low (<0.6)

Low (<0.6)

Low or normal

Normal (>0.6)


RIPA using patient’platelets

Threshold ristocetin concentration inducing patient’s platelet-rich plasma aggregation

Reduced or normal

Reduced or normal

Occurs at lower concentrations than in normal subjects

Reduced or normal



VWF multimer pattern

Multimeric composition of VWF

Normal pattern, VWF reduced

Large to intermediate multimers missing

Large multimers missing

Normal VWF multimer distribution (but with possible abnormal bands)


Multimers absent

  • Elevation of the plasma concentrations through the release of endogenous VWF from endothelial cells with desmopressin (DDAVP) or replacement therapy of VWF with human plasma-derived (pd) low-purity FVIII-VWF concentrates or a high-purity VWF product.
  • DDAVP (1-deamino-8-d-arginin-vasopressin), a synthetic analog of the antidiuretic hormone vasopressin, V2 agonist, increases VWF and FVIII in plasma without significant side effects.
  • DDAVP can be administered intravenously (0.3 mcg/kg diluted in 50–100 ml saline and infused over 30 min), subcutaneously (0.3 mcg/kg), or intranasally (fixed doses of 300 mcg in adults and 150 mcg in children).
  • In whom DDAVP is either ineffective or contraindicated, replacement therapy with pd-VWF/FVIII concentrates is the treatment of choice.

Due to:

  1. Drugs (anticoagulant):
  • Heparin.
  • Coumarin: Warfarin and Dicumarol.
  1. Diseases: liver diseases and deficiency of vitamin K.
  • Used for acutely intentional anticoagulation because of its short duration of action (3 to 4 hours).
  • For chronic therapy it used with coumarin drugs.
  • It binds with antithrombin III and inhibit activation of Fs IX, X, and XI, thereby reducing thrombin generation and fibrin formation.
  • For acute anticoagulation, iv infusion of 1,000 units of unfractionated heparin per hour, sometimes a bolus dose of  5,000-unit are given to raise the aPTT to 1.5 to 2 times the pre-heparin aPTT or5,000 to 10,000 units given sub-cutaneously every 12 hours.
  • Prophylaxis or treatment for venous thromboembolism,
  • Prophylaxis in medical and surgical patients.
  • Bleeding at surgical sites
  • Bleeding into the retroperitoneum.

Newer biologically active low-molecular-weight heparins when administered subcutaneously once or twice daily are less likely to result in thrombocytopenia and bleeding complications.

  • Protamine sulfate.

The criteria for diagnosis of HIT include:

  • Normal platelet count before the commencement of heparin
  • Thrombocytopenia defined as a drop in platelet count by 30% to <100×109/l or a drop of >50% from the patient’s baseline platelet count
  • Onset of thrombocytopenia typically 5–10 days after initiation of heparin treatment, which can occur earlier with previous heparin exposure (within 100 days).
  • Acute thrombotic event.
  • The exclusion of other causes of thrombocytopenia.
  • The resolution of thrombocytopenia after cessation of heparin.
  • HIT antibody seroconversion.
  • Include warfarin and dicumarol.
  • Used as chronic anticoagulant therapy.
  • It has a longer duration of action,
  • Decrease coagulant activity by 50% in 12 hours and 20% in next 12 hours.
  • Coagulation returns to normal in 2 to 4 days following discontinuation of therapy
  • They slow thrombin production and clot formationby blocking the action of vitamin K.
  • So levels of vitamin K–dependent Fs II, VI, IX, and X (prothrombin complexproteins) are reduced.
  • PT/INR is used to monitor anticoagulation levels.
  • Depends on the indication for anticoagulation, vary from a PT of 18 to 30 seconds (INR of 1.5 to 4.0).
  • To maintain adequate anticoagulation doses of 2.5 to 7.5 mg required daily.
  • Paroxysmal atrial fibrillation and porcine heart valves-Minimal anticoagulation required (INR target 1.5–2.0).
  • Venous thrombosis- intermediate-range of coagulation required (INR 2.0–3.0).
  • Mechanical prosthetic heart valves and hypercoagulable states –Intense anticoagulation required (INR target 3.0–4.0).
  1. Recurrent thrombotic phenomena:
  • Pulmonary embolism.
  • Venous thrombosis.
  • Stroke.
  • Myocardial infarction.
  1. Atrial fibrillation
  2. With prosthetic heart valves.
  • Risk of intramuscular bleeding and hematoma formation after IM injections.
  • Avoid Intramuscular injections in anticoagulated patients.
  1. Drugs that increase coumarin potency i.e., elevateINR:
  • Metronidazole.
  • Penicillin.
  • Erythromycin.
  • Cephalosporins.
  • Tetracycline.
  • Fluconazole/ ketoconazole.
  • Chloral hydrate.
  • Propoxyphene

Drugs that reduce its potency i.e., decrease INR:

  • Barbiturates.
  • Ascorbic acid.
  • Dicloxacillin.
  • Nafcillin.
  • Fresh frozen plasma.
  • Vitamin K over the course of 12 to 24 hours.
  • Wide range of hemostatic defects depending upon the extent of liver damage.
  • Impaired protein synthesis, that leads to reduction in:
  1. Important clotting factors
  2. Clotting inhibitors
  • Abnormal vitamin K–dependent factor and fibrinogen molecules have been encountered.
  • Thrombocytopenia and thrombocytopathies present.
  • Acute or chronic hepatocellular diseases leads to decreased vitamin K–dependent factor levels, especially Fs II, VII, IX, and X and protein C, other factors still being normal.
  • Fat-soluble vitamin
  • Absorbed from small intestines
  • Stored in the liver.
  • Deals with hemostasis.
  • Associated with the production of poorly functioning vitamin K–dependent Fs II, VII, IX, and X.

Deficiency is rare but may occur due to:

  • Inadequate dietary intake.
  • Intestinal malabsorption.
  • Loss of storage sites due to hepatocellular disease.
  • Biliary tract obstruction.
  • Long-term use of broad-spectrum antibiotics like cephalosporins.
  • Liver can store vitamin K for 30-days.
  • Coagulopathy due to deficiency of vitamin K can be restored by supplementing Vitamin K injection.
  • DIC is a hypercoagulable state.
  • DIC accompanied by secondary fibrinolysis.
  • Some potent stimuli activate both F XII and tissue factor which forms micro thrombi and emboli throughout the microvasculature. These stimuli include:
  • Obstetric complications.
  • Metastatic cancer.
  • Massive trauma.
  • Infection with sepsis.

Thromboembolic events lead to rapid consumption of both coagulation factors and platelets while creating Fibrinogen degradation products (FDP’s) that have anti-hemostatic effect.

  • Bleeding at skin and mucosal sites.
  • DIC is generally chronic and mild but acute DIC can produce massive life threatening hemorrhage.

Fibrinolytic system disorders lead to:

  • When clot breakdown is enhanced – hemorrhage.
  • When clot breakdown mechanisms are retarded – excessive clotting and thrombosis.
  • Leads to bleedings.
  • Caused due to deficiency of α2-plasmin inhibitor or plasminogen activator inhibitor.
  • Laboratory tests are normal except decreased level of fibrinogen and increased FDP levels.
  • Deficiency of F XIII also leads to hemorrhage.
  • Primary fibrinolysis treated with fresh frozen plasma and anti fibrinolytics.

Accompanies DIC, which predisposes the patient to thromboembolism due to reduced fibrinolysis for which activators of the fibrinolytic system (TPA, streptokinase, and urokinase) are frequently used to accelerate lysis of clot in cases of myocardial infarction or thrombotic stroke.

Steps of identification of patient with bleeding disorder:

  • Family history of bleeding disorders – Identifies the inherited disorders.
  • Past bleeding history following surgical procedures- Identify the risk.
  • Use of any medications with hemostatic effect eg:
  1. Coumarin anticoagulants.
  2. Heparin.
  3. Aspirin.
  4. NSAIDs.
  5. Cytotoxic chemotherapy,
  • Active medical conditions like:
  1. Hepatitis.
  2. Cirrhosis.
  3. Renal disease (fibrininolytic defect at level of plasminogen activator – hypercoagulable state).
  4. Hematologic malignancy.
  5. Thrombocytopenia.
  • History of heavy alcohol ingestion.
  • Review of system approach:


Vascular or Platelet Disorders

Coagulation Disorders

Bleeding from superficial cuts and scratches

Persistent, often perfuse


Delayed bleeding



Spontaneous gingival bleeding







Characteristic,usually small and multiple

Characteristic, usually large and solitary




Deep dissecting hematomas






Platelet Disorders

A. Thrombocytopenias (ITP)

  1. Platelet transfusions to maintain the minimum level of 10,000 to 20,000/mm3 to prevent spontaneous bleeding.
  2. Corticosteroids for ITP.
  3. Splenectomy:
  • Prevent production of antiplatelet antibody.
  • Prevent sequestration
  • Removal of antibody-labeled platelets.

B. For Thrombotic Thrombocytopenias (TTP)

  • Plasma exchange therapy.
  • Aspirin/dipyridamole.
  • Corticosteroids has lowered the mortality.
  • Previously fresh frozen plasma (FFP) infusions were used.

C. For thrombocytopenia of Wiskott-Aldrich syndrome:

  • Platelet transfusions.
  • Splenectomy.
  • Bone marrow transplantation.

D. For Glanzmann’s thrombasthenia: (Congenital thrombocytopathic disorder)

  • Periodic random platelet transfusions (risk of antiplatelet isoantibodies formation), so afterwards (HLA)–matched platelets used.
  • In severe cases of thrombasthenia and life threatening bleedings plasmapheresis done  to remove circulating isoantibodies
  1. Hemophilias A and B

B. Factor VIII concentrate (purified antihemophilic factor):

  • Dosed by units.
  • I unit = amount present in 1 ml of pooled fresh normal plasma.
  • I unit raised FVIII levels by 2%.
  • For patient of 70 kg approx, about 3500 units are required to raise his factor level from <1% to 100%.
  • A dose of 40U/kg FVIII concentrate is used to raise FVIII level to 80-100% in severe hemophilics.

C. Highly purified FIX concentrate(PCC)ie prothrombin complex concentrate:

  • Used for treatment of hemophilia B.
  • Contain Fs II, VII, IX, and X.
  • I unit raises F IX level by 1 to 1.5%.

D. Cryoprecipitate

  • It is the cold insoluble precipitate remaining after FFP is thawed for 1 hour at 4°C.
  • I unit =10-15ml.
  • 1 unit of Cryoprecipitate contains:
  1. 80 units of F VIII and vWF.
  2. 150 – 250 mg fibrinogen.
  3. FXIII
  • Used to treat hemophilia A and vWD (Rarely)


  • Chances of viral infections.
  • Large volumes required to raise factors levels adequately for hemostasis.

E. FFP(fresh frozen plasma):

  • I unit = 150-250ml.
  • 1 unit raises F IX levels by 3%.
  • FFP contains nearly all coagulation factors in normal
  • Concentrations to control bleeding in patients with mild hemophilia B.
  • Contains Fs II, VII, IX, X, XI, XII, XIII and heat labile V and VII.

F. Desmopressin acetate (DDAVP)

  • It is 1-deamino-8-D-arginine vasopressin.
  • Synthetic analogue of ADH(antidiuretic hormone).
  • Used to treat mild to moderate hemophilia A and type I vWD.
  • Dose: 0.3 μg/kg body weight by intravenous or subcutaneous route.
  • Also used as intranasal spray (contains 1.5 mL of desmopressin per milliliter).
  • Each pump spray of 0.1 ml delivers 150 μg. of drug.
  • Children require 1 nostril spray while adults 2 nostril spray.

Peak plasma levels:

  • 30 to 60 minutes after intravenous injection
  • 90 to 120 minutes after subcutaneous or intranasaly.


  • Cost effective.
  • Absence of risk of viral transmission.


  • Ineffective in severe hemophilia A.
  • Prolonged use of DDAVP results in exhaustion of F VIII storage sites and decrease hemostatic effect, hence  antifibrinolytic agents are useful adjuncts to DDAVP therapy.
  1. Viral transmission:
  • Hepatitis B and C.
  • Cytomegalovirus.
  • Human immunodeficiency virus (HIV).
  1. Thromboembolic disorder:

By use of factor IX complex concentrate leads to:

  • Deep venous thromboses.
  • Myocardial infarctions.
  • Pulmonary emboli.
  1. DIC – Due to high levels of activated clotting factors, such as Fs VIIa, IXa, and Xa, that cannot adequately be cleared by the liver.
  2. Development of a F VIII or F IX inhibitor:
  • Serious complication.
  • Inhibitors include circulating antibodies of the IgG class which neutralizes the coagulant activity of F VIII or F IX.
  • Inhibitors develop in 10 to 15% of patients with severe hemophilia A and less Commonly with hemophilia B.
  • Genetic predisposition is seen.
  • Inhibitor levels are measured by Bethesda inhibitor assay and is designated as Bethesda units (BU).
  • On the basis of inhibitor titers, patients are classified as:
  1. Low level: < 10 BU/ml
  2. High level: > 10 BU/ml

On the basis of response, patients are classified as:

  1. Low responders: Maintains low titers with repeated exposures to factor concentrates.
  2. High responders: Shows brisk elevation in titer due to the amnestic response, difficult to manage.
  • Patients with low titers are low responders and vice versa.
  • 75% of hemophilia A patients are high responders, while only 25% are low responders.
  • Low-responder patients are treated conventionally with FVIII concentrates.
  • High responder patients are treated with higher doses of porcine F VIII.
  • Patient with low-level (< 10 BU) F IX inhibitors requires higher doses of F IX complex concentrates to achieve hemostasis.
  • Recombinant F VIIa is an alternative treatment option for patients with hemophilia A or B with inhibitors by enhancing the extrinsic pathway.
  1. Depends on the type and the severity of bleeding.
  • Type I – DDAVAP.
  • Type II & Type III – Intermediate-purity F VIII concentrates or cryoprecipitate or FFP (Rarely).
  • Type IV – Platelet concentrate infusions.
  1. Additional therapy for site-specific bleeding:
  • Estrogens or oral contraceptive agents for menorrhagia.
  • Local hemostatic agents and antifibrinolytics for dental procedures.
  • Rarely, circulating plasma inhibitors of vWF are seen in multiple transfused patients for which cryoprecipitate infusion can be used which cause transient neutralization of these inhibitors
  1. Liver Disease
  • Bleeding due to deficiency of vitamin K–dependent clotting factors (Fs II, VII, IX, and X)can be treated with vitamin K injections for 3 days IV or s/c
  • FFP used for immediate hemorrhage control.
  • DDAVP therapy for cirrhotic patients.
  • Anti-fibrinolytic drugs, if used cautiously, reduces need for blood and blood product substitution.
  1. Renal Disease
  • In uremic patients, hemodialysis and peritoneal dialysis improve platelet function abnormalities and clinical bleedings.
  • Acute preparation for urgent surgery: cryoprecipitate and DDAVP decrease bleeding time.
  • Conjugated estrogen preparations and recombinant erythropoietin beneficial for uremic patients with chronic abnormal bleeding.
  1. Disseminated Intravascular Coagulation (DIC)
  • Treated with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin, to prevent thrombin from acting on fibrinogen thereby preventing further clot formation.
  • Replacement of deficient coagulation factors with FFP and correction of the platelet deficiency with platelet transfusions may be necessary for improvement or prophylaxis of the hemorrhagic tendency of DIC prior to emergency surgical procedures.

Dental management depends upon:

  1. Type and severity of the bleeding disorder.
  2. Type and invasiveness of the dental procedure.
  • Less modification is needed with mild coagulopathies.
  • When significant bleeding is expected, two things to be considered:
  1. Restoration of hemostatic system preoperatively to an acceptable range.
  2. To support coagulation with adjunctive and/or local measures.

For reversible coagulopathies (anticoagulant therapy)

  • Remove the causative agent.
  • Treat the primary illness or defect.
  • For irreversible coagulopathies(hemophilia A or B).
  • Replace missing or defective element from an exogenous.
  • Before starting any dental procedure, assessment of coagulopathy and delivery of appropriate therapy should always be accomplished in consultation with a hematologist.                                                                                                                                                                                               
  • If platelet counts ≤ 50,000/mm3platelet transfusions required prior to dental extractions or other oral surgical procedures.
  • 1unit raises platelet count by 10,000 to 12,000/mm3.
  • 6 units of platelets are commonly infused at a time.
  • Thrombasthenic patient needing dental extractions are best treated with microfibrillar collagen and antifibrinolytic drugs.

For extensive surgeries:

  • Aspirin to be stopped for 1 to 2 weeks prior to extensive oral surgical procedures because antiplatelet activity of aspirin remains for the 8- to 10-days.
  • Local hemostatic measures.

For minor surgeries: Local hemostatic agents to prevent postoperative oozing.

For urgent major surgeries:


  • Decrease aspirin-induced prolongation of the BT.
  • Prevent aspirin-related postoperative oozing.
  • Eliminates need for platelet infusion.

Chemotherapy-associated oral hemorrhages: Are related to thrombocytopenia, managed by:

  • Transfusions of HLA-matched platelets.
  • FFP.
  • Topical antifibrinolytics.
  1. Hemophilias A and B
  2. Von Willebrand’s Disease

For oral surgical procedures


  • Preoperatively, factor levels of 40 to 50% of normal activity to be obtained.
  • Post operatively, factor maintenance for extensive surgeries achieved by:

A. Infusion of factor concentrates.


C. Cryoprecipitate.


  • Postoperative bleeding due to fibrinolysis usually starts 3 to 5 days after surgery and can be controlled by local measures and antifibrinolytics.
  • Continuous oozing from unstable fibrinous clots requires their removal and the repacking of extraction socket with hemostatic agents.
  • Recommended doses to get factor levels of 40 to 50% for F VIII is 20–25 U/kg and for F IX is  dose 40–50 U/kg.
  • Higher hemostatic factor levels are required for larger wound like:

A. Extraction of multiple or multirooted teeth.

B. Gingival bleeding.

C. Tooth mobility.

D. Periapical lesions.

  • Deficient factor activity levels required for postextraction hemostasis varies:

A. From 3.5 to 25% for deciduous teeth

B. From 5.5 to 20% for permanent teeth.

  • Intermittent replacement therapy.
  • Continuous intravenous factor infusion therapy.
  • Single preoperative factor concentrate infusion combined with an antifibrinolytic mouthwash.
  • DDAVP is used with mild to moderate hemophilia A and vWD to raise FVIII for dental extractions without transfusion
  1. Topical pressure.
  2. Surgical/ pressure packs.
  3. Vasoconstrictors.
  4. Sutures.
  5. Surgical stents.
  6. Topical thrombin.
  7. Absorbable hemostatic materials.
  8. Microfibrillar collagen.
  • Aids patient comfort.
  • Decreases blood clot size.
  • Protects clots from masticatory trauma and subsequent bleeding.
  • Stabilizes and protect packing.
  • Resorbable and non-resorbable equally effective.
  • Placed against the bleeding bony surface of extraction socket.
  • Attract platelets, starts release phenomenon and triggers the aggregation of platelets to form thrombi in the interstices of fibrous clot.

It directly converts fibrinogen in to fibrin.

  • Gelatin sponge with intrinsic hemostatic properties.
  • Collagen sponge(3”x4” sponge).
  • Causes vasoconstriction of microvasculatures and further prevent oozing.
  • Fabricated carefully.
  • Avoid traumatic irritation to surgical site.
  • Full liquid diet for first 24 to 48 hours.
  • Soft diet for 1 to 2 weeks.
  1. E-aminocaproic acid(EACA).
  2. Tranexamic acid (AMCA).
  • Inhibits fibrinolysis by blocking the conversion of plasminogen to plasmin, thereby stabilizes the clot.
  • Postsurgical use of EACA significantly reduces the quantity of factor required to control bleeding.



  • Topically – 50mg/kg
  • Oral rinses – 25% (250 mg/ml), 6 hourly for 7 to 10 days.
  • Systemically – Orally or intravenously, 75 mg/kg (up to 4 g) every 6 hourly till bleeding stops.


  • Oral rinses – 4.8% oral rinse, 10 times more potent than was EACA
  • Systemically – Orally or intravenously, 25 mg/kg every 8 hourly till bleeding stops.
  • Used locally.
  • When used in combination with antifibrinolytics, has allowed reduction in factor concentrate replacement levels in hemophilics undergoing dental surgeries.


  • Cryoprecipitate
  • 10,000 units topical thrombin powder diluted in 10 mL saline and 10 mL calcium chloride.

Mode of action:

When dispensed over the wound simultaneously, the cryoprecipitate and calcium chloride precipitate almost instantaneously to form a clear gelatinous adhesive gel.

Patients who opt for treatment without anesthesia:

  • Hypnosis.
  • Intravenous sedation with diazepam, or nitrous oxide/oxygen analgesia.

Above measures used as adjuncts to control anxiety, drastically reduce or totally eliminate the need for LA.

  • Intrapulpal anesthesia is safe and effective following access for pulp extirpation.
  • Pdl and gingival papillary injections used with little risk when given slowly with minimal volume.
  • Anesthetics with vasoconstrictors to be used when possible.
  • Buccal, labial, and hard palatal infiltration attempted for maxillary teeth when given slowly and applying local pressure to the injection site for 3 to 4 minutes in patients with mild disease.
  • If hematoma develops, ice packs should be applied to the area for vasoconstriction, and emergency factor replacement to be carried out.
  • For block injections minimal coagulation factor levels should be 20 to 30%.
  • Since, solutions are deposited in highly vascularized loose connective tissue with no distinct boundaries, a dissecting hematoma is possible.
  • Extravasation of blood into the soft tissues of the oropharyngeal area in hemophiliacs can produce gross swelling, pain, dysphagia, respiratory obstruction, and death due to asphyxia.
  • Dental treatment under general anesthesia is indicated when patient is quite anxious and non cooperative and multiple treatment needs.
  • Oral endotracheal intubation is preferred over nasal endotracheal intubation (risk of nasal bleeding).
  • IM injections better to be avoided because of risk of hematoma formation.
  • Aspirin and other NSAIDs for pain control are contraindicated as they have antiplatelet activity.

Periodontal health for the hemophiliac is important because:

  • Hyperemic gingiva leads to spontaneous bleeding
  • Periodontitis leads to tooth morbidity, necessitating extraction.
  • Patient with bleeding diathesis neglect their oral hygiene due to fear of tooth brush induced bleeding.
  • Periodontal probing, supragingival scaling and polishing can be done routinely.
  • Careful subgingival scaling with fine scalers rarely warrants replacement therapy.
  1. Severely inflamed and swollen tissues:
  • Chlorhexidine oral rinses.
  • Gross débridement with a U/S or hand scalers to allow gingival shrinkage before deep scaling.
  1. Deep subgingival scaling and root planning:
  • Done quadrant wise.
  • Locally applied pressure along with antifibrinolytic oral rinses postoperatively.
  1. Local block anesthesia for deep scaling:

Factor levels to be raised to minimum of 30%.

  1. Periodontal surgical procedures:
  • Factor levels to be raised to minimum of 50%.
  • Periodontal packs aids hemostasis and protects the surgical site
  • These procedures do not result in significant hemorrhage.
  • Rubber dam isolation because:
  1. Minimize the risk of lacerating soft tissue.
  2. Avoid creating ecchymoses and hematomas with high speed evacuators or saliva ejectors.
  3. Select a tooth clamp carefully (traumatize the gingival).
  • Matrices, wedges, and a hemostatic gingival retraction cord may be used with caution.
  • Removable prosthetic appliances can be fabricated without complications.
  • Careful post-insertion adjustment to be done to avoid trauma.
  1. No contraindications to root canal therapy except:
  • Instrumentations beyond the apex.
  • Over filling the root.
  • Intra pulpal epinephrine sufficient to achieve hemostasis.

2. Endodontic surgical procedures require the same factor replacement therapy as do oral surgical procedures.

  • Occasional prolonged oozing after exfoliating primary teeth.
  • Administration of factor concentrates (stored in blood bank between 20C & 80C) and extraction of the deciduous tooth with curettage is required for patient comfort and hemorrhage control.
  • Gauze pressure sufficient to obtain hemorrhage control and seepage usually stops in 12 hours.
  • Pulpotomies can be performed without excessive pulpal bleeding.
  • Stainless steel crowns should be prepared to allow minimal removal of enamel at gingival areas.
  • Topical fluoridation and pit-and-fissure sealants are important (decrease need for extensive restorative procedures).
  • Avoid mucosal laceration by orthodontic bands, brackets, and wires.
  • Bleeding from minor cuts responds to local pressure.
  • Fixed orthodontic appliances are preferred over removable functional appliances.
  1. Management of such patients depends upon:
  • Degree of anticoagulation achieved.
  • Dental procedure planned.
  • Level of thromboembolic risk.
  1. Higher INRs result in higher bleeding risk from surgical procedures.
  2. Preparation of the anti-coagulated patient for surgical procedures depends on extent of bleeding expected.
  3. INR values > 3.5 to 4.0- No surgical treatment recommended.
  4. INR values< 3.5 to 4.0 – Minor surgical procedures done with local measures but no coumarin modifications if minimal bleeding expected.
  5. INR of < 3.5 to 4.0- When moderate bleeding is expected local measures and INR reduction to be considered.
  1. When significant bleeding is expected, local measures with reduction of anticoagulation to an INR of < 2.0 to 3.0.
  2. For periodontal flap surgery or multiple bony extractions INR should be < 1.5.
  3. For patient with moderate thromboembolic and hemorrhagic risks, coumarin therapy is maintained at therapeutic doses with the use of local measures.
  4. When thrombotic and embolic complications is small and hemorrhagic risk is high, coumarin therapy can be withdrawn 2 days prior to surgery, with prompt re-institution postoperatively.

For high-risk cardiac patients 

  • For High-bleeding-risk in surgical procedures, patients  managed  safely with a combination
  • Heparin-coumarin combination that allows maximal hemostasis with minimal non anticoagulated time (14–18 hours for 2-hour surgery, as opposed to 3–4 days with the coumarin discontinuation method)
  • Coumarin is withheld 24 hours prior to admission.
  • Heparin therapy, instituted on admission but stopped 6 to 8 hours prior to surgery to allow adequate surgical hemostasis.
  • Surgery accomplished with normal PT/INR and aPTT.
  • Heparin is reinstituted 6 to 8 hours after surgery when an adequate clot has formed.
  • Bolus dose of heparin (typically a 5,000 U bolus) carries a greater risk of postoperative bleeding than does gradual reinfusion (typically 1,000 U/h).

Use of local hemostatic agents:

  • Microfibrillar collagen, oxidized cellulose, or topical thrombin is recommended for anticoagulated patients.
  • Fibrin sealant: Control bleeding from oral surgical procedures in therapeutically anticoagulated patients with INRs from 1.0 to 5.0, with minimal bleeding complications.
  • Antifibrinolytic mouthwash (Pause mouth wash) is also effective.

Senile purpura (SP) is the term used to describe ecchymosis/purpuric lesions that occur in the elderly individuals who are otherwise healthy.

  • Consequence of physiologic aging due to laxity of the connective tissue.
  • Any minor trauma to the blood vessels results in ecchymosis or purpura.
  • With aging, there is reduction in elastic and collagen fibers with increased susceptibility to external trauma.
  • Chronic usage of certain drugs like the nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or anticoagulants.
  • Deficiency of zinc.
  • Underlying liver disorders.
  • Non-palpable purpuric or ecchymotic spots on the extensor surfaces of the arms and feet and are non-tender.
  • Intraorally, presents as ecchymosis commonly occurring on the palate, tongue, and on the lips.
  • Minor trauma from the ill-fitting dentures resulted in palatal ecchymosis.
  • Histopathologically, SP shows vascular ectasia with extravasated erythrocytes, with degenerated collagen fibers and no vasculitis.

Ecchymosis and purpura due to other causes such as myleodysplastic syndrome, leukemia, qualitative and quantitative platelet disorders, and coagulative disorders.

SP, a common dermatologic condition with no clinical outcome, requires no special management protocol. The patient needs to be reassured about the benign nature of the disease and cautioned about minor trauma as an etiologic factor. Furthermore, careful handling of oral mucosal tissues is of greatest importance in avoiding oral ecchymosis.

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