Bleeding Disorders

Bleeding Disorders Dr. Ahmed Mansour , PhD Professor of Haematology Mansoura University Pediatric Hospital Mansoura Faculty of Medicine

Bleeding Disorders Haemostasis depends on 3 factors: 

Blood vessels: Through contraction of wall of vessels.



Platelets: Normal count 150.000– 400.000/mm3

Coagulation mechanism: Which depends on interaction between 13 clotting factors to form the blood clot. 

Thus, for bleeding to occur, there must be at least one of three disorders. Vascular disorder

Coagulation disorder

Platelet disorder

Number disorder

Function disorder

Platelets < 150.000/cmm

Thrombocytopenia

Thrombasthenia

Blood vessel injury

Vasoconstriction

Platelet aggregation

Platelet adhesion

Vascular phase Consolidation Platelet plug formation

Platelet phase

Prothrombin Plasma factors

Tissue thrompoplastin

Plasma phase

Thrombin

fibrinogen

Fibrin

Concept of hemostasis

Vessel injury

Vasoconstriction

Endothelial lining disruption Collagen exposure Platelet adhesion Release reaction Platelet aggregation

Von Willebrand factor ADP Thromboxane A2 Serotonin

Platelet clump Thrombin

Platelet plug

Primary hemostatic mechanism

I- Vascular Purpura Definition Bleeding disorder due to defect in blood vessels. Causes: It may be either acquired or congenital.

I- Vascular Purpura A- Acquired: Anaphylactoid purpura (Henoch Schonlein P.). Scurvy Scurvey (vit C deficiency). -Bleeding tendancy Mechanism: -

Gum Hypertrophy Platelet function -defect. Poor wound healing  Vascular defect -because Vit. (Cause????) C is essentialSub-periosteal for formation of Tender Bone cement substance that link epith cells of Bl. V. together. haemorrahge ttt → vit C 200-500mg/day oral. 

Steroid Purpura: DD

of Racjhitic rosaries

Due to prolonged use of corticosteroids either systemic - Rickets: enlarged costochondral juction or topical → thining of wall of blood vessel. - Marsmus: rounded , normal sized May be in cushing syndrome (Endogenous ↑ ). costochondral juncion, not tender Fat Embolism:-Achondroplasia: angulation , angle downword (V) tender  As in fracture-Scurvey: of long Bones. 

I- Vascular Purpura Traumatic Asphyxia: as: Severe chronic cough e.g. Whooping cough. Epileptic fits. Crushing injuries of the thorax. 

Severe infections: Subacute bacterial endocarditis, Typhoid fever, menigococcal septicemia → Due to vasculitis. 

Uremia. Diabetes Mellitus. Drugs: Penicillin, sulfa, INH, mercurials….etc. Due to hypersensitivity to drug

Purpura Facticia: “Self inflected”. Usually in the areas within reach.  More common in females. 

I- Vascular Purpura B) Congenital: Congenital Amyloidosis. Heriditary telengiactasia (Rendu-Osler-Weber disease). Autosomal dominant disease. Thin walled dilatations in the wall of blood capillaries. These dilatations lack the muscle layer so, if injured they can not contract like other normal BI.v. → severe bleeding. 

 Ehlers- Danlos Syndrome: Autosomal dominant disease characterised by:



↑ Skin Elasticity. ↑ Range of movement of joints ↑ Fragility of blood vessels.

( Hyper extensibility of joints).

Anaphylactoid Purpura Definition Allergic disorder similar to Rheumatic fever in which the allergic reaction occurs in wall of blood vessels.

Etiology May be 2ry to infection with group A B hemolytic streptococci. Or Other infections. Insect bites. Food or drug allergy.

Clinical Picture It can affect one or more of 4 systems:

Skin: 100%

Urticarial rash present Causes of Acute Abdomen:Youmaculopapular can’tMedical Diagnose anaphylactoid manily on lower limbs, Buttocks & Extensor surface of -Diabetic Ketoacidosis upperpurpura limbs. without skin Manifestations -Sickle cell crisis Ecchymosis & purpuric eruption. -Rh fever( activity) Angioneurotic edema is common. -Anaphylactoid purpura ( mesentric vasculitis) Joints: 75% -Basal pleurisy Migratory polyarthritis or arthralgia similar to that of rheumatic fever but-Uraemia the joints are not tender. -Familial Gastro-intestinal Mediterranean fever tract: 50% Severe abdominal-Porphyria pain. -Inferior wall infarction DD from Diarrhea. Mesentric Vasculitis Bloody stools. 

Renal: 25%

Appendicitis

It may be in the form of asymptomatic proteinuria and hematuria or nephrotic syndrome.

Clinical Picture

Clinical Picture

Complications Intussusception. Subarachinoid or cerebral hemorrhage.

Investigations All investigations of bleeding tendency are normal except Hiss test may be +ve. Diagnosis depends on clinical So, diagnosis depends on clinical manifestationsmanifestations with: 1- Investigations for streptococcal infection:



* ESR

* ASO Titer

2- Urine analysis:



Technique of Hiss Test? * To detect renal affection (worst prognosis) because 50% of cases → chronic renal failure.

3- Stool analysis: for occult blood. 4- Serum IgA: may be elevated. 

Treatment This disease is self limited but recurrence can occur at least within 6 months. Pencillin:



If the condition is 2ry to streptococcal infection. And if not try to detect the cause and avoid it as drugs or insect bites.

For Arthritis:



Acetyl salicylic acid as for rheumatic arthritis.

For GIT manifestations:



Corticosteroids: Prednisone 1-2mg/kg/day oral.

For renal Affection:



Immuno suppressive azothioprine.

drugs

as:

Endoxan,

and

II- Platelet Disorder Platelets are essential for Haemostasis by: Their number. Their function: Platelet aggregation .  Platelet adhesiveness. Clot retraction. Platelet factor 3 production. 

Char

acte

rs of

plate

lets

Size: 1-4 µm (younger platelets are larger) Mean platelet volume (MPV): 7.1 fl Number: 150,000-400,000/mm3 Distribution: One-third located in spleen; twothirds circulate in the blood stream

A- Platelet number defect: Thrombocytopenia:

Definition: (Normal platelet count = 150.000– Platelet count <150.000/mm3

400,000 /mm3).

Causes: Divided into 2groups according Megakaryocyte in the bone marrow: 1- Decrease Megakaryocyte in B.M:



anemia. MostAplastic Common causes of thrombocytosis in Egypt? Malignent diseases:

a- 1ry in bone marrow e.g leukemia. b- 2 ries e.g neuroblastoma. 

-Splenectomy  Metabolic disorders infilterating bone marrow: 

Gaucher’s disease.

to

A- Platelet number defect: Thrombocytopenia: Normal or ↑ Megakaryocyte in B.M: ITP “Immune Thrombocytopenic pupure” Drug induced thrombocyto penia. e.g Quinidine Hyper splenism Infection e.g. Measle & German Mensis Collagen ds: SLE Juvenile rheumatoid arthritis 

Megaloblastic Anemia DIC Repated Transfusion of stored Bl. N.B: Thus for patients with thrombocytopenia the most important investigation is bone marrow examination.

Immune Thrombocytopenic Purpura (ITP) Definition: Anti-platelet Ab is IgG Immune disorder due to destruction of the prepheral platelets by antibodies. Usually it -Specie specific -Can cross placenta causing follows viral upper respiratory tract thrombocytopenia infection by 2 -Active against homologous and weeks. autologus platelets Usually it is acute & self limiting but if it persist >6 months it chronic. Incidence: The most common cause of thrombocytopenia Female= male Common from 2 – 8 years

Char

a c te

rs of

ITP

Thrombocytopenia: (Platelet count <100,000/ml) Shortened platelet survival Presence of antiplatelet antibody in plasma Increased megakaryocytes in bone marrow

Types:((according to onset, Duration Acute: Disappear in < 6 m Chronic: Disappear in >6 m Recurrent : Disappear in < 6 m but reoccur again

Clinical Picture Petehcial & purpuric euption over any site of the body. Ecchymosis: mainly over medial aspect of tibia. Epistaxis & bleeding Gums are common manifestations. Orificial bleeding but less common. Big Haematomas. Intracranial hemorrhage: the most serious complication and occurs especially if bleeding manifestations more in upper pant of body. Spleen may be enlarged if enlarged never hugely enlarged.

Clinical Picture

Role of splenomegaly in ITP Site of formation of anti-platelet Ab. Site of distruction of Ag (platelets)-Ab complex. Splenin I & II  B.M depression decrease platelet production.

Acute - <6m - More common in children - Male= female - Seasonal variation (spring) - Platelet count < 400.00/mm3 - Very high dose of antiplatelet Ab - Good response to corticosteroids

Chronic - >6m -More common in Adult - female >Male -Any time - Platelet count> 400.00/mm3 -High Ig A -Better prognosis

Age ITP occurs in great frequency:

and ITP

between 2-8 years old age Infants less than 2 years old (infantile ITP) have the following features: --More abrupt onset. --More severe clinical course. --Platelet count < 20,000/mm3 --Poor response to treatment --Higher incidence of chronicity

Intracranial haemorrhage Usually occurs within 10 days of attack by ITP. So patient must be observed for 10 days in hospital. Occur in 10% of cases. Occur when platelet count < 10.000 / mm3

Value of Faucial examination in ITP Peticial haemorrhage in soft palate usually followed by IC hge so we can predict IC he.

Vascular

:Acquired Drug-steroids Henoch-Schollein purpura Purpura factitia Purpura fulminans (Vasculitis (e.g. SLE

Normal platelet count (Nonthrombocytopenia)

Petechiae Purpura Ecchymosis Low platelet count (Thrombocytopenia)

Congenital Hemorrhagic telangiectasia Ehler-Danlos syndrome

Platelet dysfunction

Neonates Infants Children

Congenital

Acquired

Clinical approach to Petechiae, Purpura and Ecchymosis based on platelet count

Investigation Prolonged Bleeding time (< Normal = 2 – 4 min >). Normal Coaggvlation Mostclotting important single test time. for ITP Anti-platelet Ab important single test for thrombocytopenia B.M + veMost Hess Test (fragility test). Examination Thrombocylopenia: Platelet count <150.000/mm3”. In severe cases the count is usually below 50.000/cmm. 

Detection of antiplatelet antibodies, which present up to 65% of chronic cases. So, it is good diagnostic test B.M. Examination: The most important diagnostic test. ↓ Projection or budding or surface of megakariocytes. Due to rapid release of blood platelets to peripheral circulation. 

Treatment Conservation treatment: Because the disease is self-limiting, the patient is put under observation for fear of intracranial hemorrhage. Corticosteroid: Prednisone→ 60mg/m2/day, oral, for 2-3weeks & then withdraw the drug even if there is no response. 

Indication: Orifascial bleeding: epistaxis or menorrhagia.  Extensive Purpura & Eahymosis.  Intracranial hemorrhage.  Chronic cases. 

Treatment Immuno suppressive drugs: - Azo thoprive. Vinblastine. - Cyclophosphomid .

- Vincristine.

-

 High dose of I.V Immunoglobulins: Block the receptor site of surface of Bl. platelets → competitive inhibition of antiplatelet antibodies. 

Anti-Rh D: Dose → 75µ g/kg IV infusion over 3-5 minutes period. The patient must be Rh D +ve for this mode therapy to be beneficial. 

Blood & Platelet transfusion: Blood transfusion → to compensate Bl. Loss. Platelet transfusion → in life threatening conditions e.g. I.C.Hege → to stop bleeding . 

But it has temporary effect bec. it will be destructed by antiplatelet Abs

Treatment Splenectomy: It is indicated in: Severe acute cases non-responsive to treatment.  Chronic cases with bleeding e.g menorrhagia.  Pneumococcal vaccine or longatine penicillin given to prevent septicemia.  Exclusion of collagen diseases as SLE must before splenectomy. 

medical

must be be done

Danazol: It is an androgen shown to increase platelet count. 300400mg/m2/day orally for 2-3 months. 

B- Platelet Function Defect It may be either congenital or acquired. Congenital: e.g: Glanzmann thrombasthenia Hemorrhagic thrombocythemia. Wiskott-aldrich syndrome. Von-Willebrand disease.

B- Platelet Function Defect Acquired: Drugs: Anti-inflammatory drugs: Acetyl salicylic acid i)aspirin), I buprofen. Antibiotics: Ampicillin, Gentamycin. Anaesthetics: Procaine, Xylocaine. Cardiovascular: Theophylline, papaverine. Duiretics: Furosemide, Ethacrynic acid. 

Chronic renal failure. Chronic liver disease. Scurvey (vit c deficiency). Paraprotenemia: abnormal protein coating blood platelets.

Congenital vascular disorder Hemorrhagic telangiectasia Ehler-Danlos syndrome

Congenital or Acquired Adhesion defect

Abnormal

Platelet aggregation defect

Platelet count

Normal

Defects in release reactions

Abnormal

Normal Platelet aggregation ADP Epinephrine Collagen Ristocetin

Bleeding time

Normal

Acquired vascular condition Henoch-Schollein purpura Purpura factitia

Clinical approach to nonthrombocytopenic Purpura based on bleeding time

Clot formation results from interaction between 13 coagulation factors Factor I

Fibrinogen

Factor II

Prothrombin

The Coagulation factors are Factor III Thromboplastin .

Factor IV

Calcium

Labile factor((Proaccelerin

Factor V

Activated labile factor

Factor VI

Stable factor((Procovertin

Factor VII Factor VIII

Anti hemophilic globulin

Factor IX

Christmas factor

Stuart prower factor

Factor X

Factor XI

Plasma thromboplastin antecedent factor

Factor XII Factor XIII

Hageman factor Fibrin stabilizing factor

Mechanism of blood coagulation

It occurs through 3 phases

Phase I

Concerned with formation of thromboplastin (factor III) which occurs through 2 pathways 1. Intrinsic pathway 2. Extrinsic pathway

y a w h t a p c i s n i r t n I

--Resposible for formation of plasma thromboplastin. --It depends on factors VIII, IX, XI and XII. --Its specific diagnostic test is activated partial thromboplastin time (APPT): normally 25-40 seconds.

y a w h t a p c i s n i r t x E

--Resposible for formation of tissue thromboplastin.

--Depends on factors calcium, V, VII and X

--Its specific diagnostic test is prothrombin time (PT): normally 12-20 seconds.

Extri nsic path way

VII TTP,++Ca

VIIa

Loose Platelet aggregation

Xa

X

Platelet plug

XIII

V, Va, Ca++ , PF3

Prothrombin

Fibrinogen

Thrombin Fibrin monomers

Fibrin polymers

Fibrino peptides A & B

++

Ca

XIIIa

Stable fibrin clot

Secondary haemostatic mechanism

Intrin sic path way

Prekal Kal

XIa XI IXa IX

XIIa

V, Va, Ca++ , PF3

XII

Collagen

Loose Platelet aggregation

Xa

X

HMK KAL

Platelet plug

XIII

VIII, VIIIa, Ca++ , PF3

Prothrombin

Thrombin

Fibrinogen

Fibrin monomers

Fibrin polymers

Fibrino peptides A & B

++

Ca

XIIIa

Stable fibrin clot

Secondary haemostatic mechanism

Phase II Concerned with formation of thrombin through the action of thromboplastin Prothrombin ------------ Thrombin c i f i c e p s s i It n i b m o r h t o r p test for time

Phase III -- Concerned with formation of fibrin through the action of thrombin -- Formed fibrin is stabilized by factor XIII Fibrinogen ------------ Fibrin It is specific in b m o r h t r o f t tes :(Time (TT Normally 0 2 5 1 s d n o c se

Hemophilias

There are 3 types A, B and C

Hemophilia A

Commonest hereditary coagulation disorder

Due to deficiency of factor VIII (Anti-hemophilic globulin) which is composed of 2 parts: -- Antigenic part -- Coagulation part ts n e i t a p c i l i h p ,In hemo y l n o t r a p t n a the coagul is deficient

It is inherited as X-linked recessive. So, -- it affects males only --females are carriers

Degrees: Severe -------- Factor VIII < 1% Moderate ------- Factor VIII 1-5% Mild -------- Factor VIII 5-25%

Clinical Picture 1. Bleeding from: Umbilical stump CNS hemorrhage in neonates. 2. Skin bleeding (ecchymosis): Spontaneous After minor trauma.

Clinical Picture

3. Excessive bleeding after minor

surgical procedures:

Tooth extraction. Circumcision.

4. Large intramuscular hematomas and orificial bleeding: Epistaxis Bleeding gums GIT bleeding

Clinical Picture

5. Hemoarthrosis (bleeding in joint cavity) of big joints knee, ankle and elbow

limping limitation of movement due to ankylosis

Joint will be: hot, red, tender and painful

Clinical Picture

Investigations 1. Prolonged coagulation time (CT). 2. Prolonged activated partial thromboplastin time (APTT). 3. Deficient factor VIII by specific factor assay. 4. Radiologic examination of joints with hemoarthrosis. 5. Prenatal diagnosis by amniocentesis or chorionic villus sampling

Treatment

General measures

Hemoarthrosis

Replacement therapy

Treatment

1. General measures: --- Avoid ---Trauma ---I.M injections ---Surgical procedures.

--- Local measures ---Pressure bandage ---Cold compresses ---Application of thrombin preparations on small wounds

Treatment

2. Hemoarthrosis:

--Rest of the join --Cold packs -- Physiotherapy (passive) to avoid ankylosis --Corticosteroids for recurrent cases --Aspiration of the joint can be done by a meticulous hand.

Treatment

3. Replacement therapy Increase level of factor VIII in plasma (prevent hemorrhage) 1. Fresh frozen plasma 10-15 ml/kg/12h. keeps factor VIII level between 10-20% of normal 2. Cryoprecipitate. Each unit contain 80-100 IU of factor VIII. 3. Factor VIII concentrate: Each vial (25 ml) contains 250-1500 IU of factor VIII.

Treatment

4. Fresh blood transfusion because factor VIII is unstable for correlation of blood loss: 10-20 ml/kg. 5. Desmopressin (DDAVP): Deamino-8-Darginine vasopressin

--given in mild and moderate cases -- dose: 0.3-0.4 µg/kg in 50 ml normal saline I.V over 15-20 minutes. --Concentrated form can be given intranasally. --It increases plasma level of factor VIII 4 folds

Hemophilia B

Also is X linked recessive disease. Due to deficiency of factor IX (Christmas factor) is s i s o r h t r a o m He n o m m o c s s le e Than in A typ

Hemophilia C Autosomal recessive disease. Due to deficiency of factor XI (Plasma thromboplastin antecedent factor) is s i s ro h t r a n o o m e m H m o c t pe y t no A n i Than

Sto Can b red e t r Fa bloo eate cto dt dw ran rX ith I is sfu sta sio ble n

Von Willebrand disease Pseudo-hemophilias Congenital disorder comprises both coagulation and platelet function defects X- linked recessive (inherited like hemophilia A)

Characterized by: 1. +ve family history. 2. Prolonged bleeding time with normal coagulation time. (only coagulation disorder with Prolonged bleeding time). 3. Deficiency in factor VIII activator (vW factor) So, factor VIII activity decreases to about 65%.

4. Defective platelet aggregation by restocetin. 5. Defective platelet adhesiveness. 6. The preferred treatment is factor VIII concentrate containing high levels of vW factor.

T H A N K

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