Presantation on bleeding disorder in pediatric patients

Seminar Presantation on;

Bleeding Disorders In Pediatrics Patient

By C- I Med. Students ; Siraj Shiferaw,

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Ambo UniversityCollage Of Medicine & Health Sceince

Department Of Medicine

Feb,25/2014

PRESANTATION OUTLINE

1. Over view of homeostasis and the blood clotting process.

2.Approach to a child with bleeding disorder.

3.Lab investigations.

4.Bleeding disorde in pediatrics patient .

-Hereditary coagulation disorders

-Acquired coagulation disorders

-Platelate disorders .

-Vascular disorders.

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1.Over view of homeostasis and the blood clotting

process.HEMOSTASIS:

The ability of the body to control the flow of blood following vascular injury is paramount to continued survival. The process of blood clotting and then the subsequent dissolution of the clot, following repair of the injured tissue.

is composed of 4 major events that occur in a set order following the loss of vascular integrity:

- Vascular constriction -limits the flow of blood to the area of injury. - Platelet aggregation –Blood platelets clump when binding to collagen that

becomes exposed following rupture of the endothelial lining of vessels. -Blood platelets become activated and aggregate at the site of injury . -Upon activation, platelets release ADP and TXA2 (which activate

additional platelets).

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• Clot formation -to insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot) forms and entraps the plug.

• Fibrinolysis -the clot must be dissolved in order for normal blood flow to resume following tissue repair. The dissolution of the clot occurs through the action of plasmin

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1.Over view of homeostasis and the blood clotting process.

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1.Over view of homeostasis and the blood clotting

process.

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2.Approach to a child with bleeding disorder HISTORY The history should determine; • The site or sites of bleeding,the severity and duration of

hemorrhage, and the age at onset.

• Was the bleeding spontaneous, or did it occur after trauma?

• Was there a previous personal or family history of similar problems?

• If a child or adolescent has had surgery that affects the mucosal surfaces, such as a tonsillectomy or major dental extractions, the absence of bleeding usually rules out a hereditary bleeding disorder

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2.Approach to a child with bleeding disorder

PHYSICAL EXAMINATION

• The P/E should focus on whether bleeding symptoms are associated primarily with the mucous membranes or skin (mucocutaneous bleeding) or with the muscles and joints(deep bleeding).

• The examination should determine the presence of petechiae, ecchymoses, hematomas, hemarthroses, or mucous membrane bleeding.

• Patients with defects in platelet-blood vessel wall interaction (VWD or platelet function defects) usually have mucocutaneous bleeding.

• Individuals with a clotting factor deficiency of factor VIII or IX (hemophilia A or B) have symptoms of deep bleeding into muscles and joints.

• Individuals with disorders of the collagen matrix and vessel wall may have loose joints and lax skin associated with easy bruising (Ehlers-Danlos syndrome).

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3.Laboratory investigations

• Blood count and film – show the number and morphology of platelets and

any blood disorder such as leukaemia or lymphoma. – The normal range for the platelet count is 150- 400 ×

109/L

• Bleeding time – measures platelet plug formation in vivo– normally between 3 and 10 minutes– Prolonged bleeding times are found in patients with

platelet function defects

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3.Laboratory investigations

• Bleeding time – Time taken for a standardized skin puncture to stop

bleeding

– Measures platelet plug formation in vivo (assessment of platelet response to limited vascular injury)

– Normally between 3 and 10 minutes

– Prolonged bleeding times are found in patients with platelet function defects

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3.Laboratory investigations

• Coagulation tests – Performed using blood collected into citrate, which

neutralizes calcium ions and prevents clotting.

– The prothrombin time (PT)

– The partial thromboplastin time (PTT)

– The thrombin time (TT)

– Correction tests

– Factor assays

– Special tests of coagulation

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3.Laboratory investigations

• Coagulation tests – The prothrombin time (PT)

• Time needed for the plasma to clot in the presence of tissue thromboplastin and calcium

• Evaluates the ability of blood to clot properly

• Normal time for clotting is 10-14s

• Prolong PT results from def of:– Factor V

– Factor VII

– Factor X

– Prothrombin

– Fibrinogen12

3.Laboratory investigations

• Coagulation tests – The partial thromboblastin time (PTT)

• Time needed for the plasma to clot in the presence of a surface activator (kaolin), cephalin and calcium.

• Normal time of clotting is 30-40s• Prolong PPT results from def of:

– Factor V– Factor VIII– Factor IX– Factor X– Factor X1– Prothrombin– Fibrinogen

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3.Laboratory investigations

• Coagulation tests – The thrombin time (TT)

• Measures clotting time of plasma after adding thrombin

• Normal clotting time is 14-16s

• Prolong TT results from: – Deficiency of fibrinogen

– Dysfibrinogenaemia

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4. BLEEDING DISORDERS IN PEDIATRICS

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4. Bleeding Disorders In Pediatrics

A. Hereditary coagulation disorders – Hemophilia A– Hemophilia B– Von Will brand's disease

B.Acquired coagulation disorders – Vitamin K deficiency – Liver disease – DIC– Coagulation disorders caused by antibodies– Massive transfusion syndrome

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4. Bleeding Disorders In PediatricsC.Platelet disorders

-Thrombocytopinic (dereased number of platelates) -Idiopathic thrombocytopenic purpura (ITP). -Thrombotic thrombocytopenic purpura (TTP). -Drug induced thrombocytopenic purpura . -Platelate function disorder - Congenital - Acquired D. Vascular disordes -Congenital -Acquired

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A. Hereditary coagulation disorders

– Uncommon

– Usually involve deficiency of one factor only

– Deficiencies of all factors have been described, but most common are:

• Hemophilia A – factor VIII deficiency

• Hemophilia B – factor XI deficiency

• Von Will brand’s syndrome

• Others are rare

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Hemophilia A (classic hemophilia)

• The most common of hereditary clotting factor deficiencies

• Due by factor VIII deficiency

• The prevalence about 1 in 5000 of the male population

• Inherited as X-linked disorder – But up to 30 % have no family history and results

from spontaneous mutationspontaneous mutation

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Hemophilia A

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Hemophilia A: X-linked

• The

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Hemophilia A

• Clinical features– Atypical profuse bleeding at circumcision

– Bruising at neonatal vaccines

– Joints and soft tissue bleeds and excessive bleeding when they start to be active

– Prolonged bleeding after teeth extraction

– Recurrent painful hemarthrosis

– Muscle haemoatomas

– Spontaneous haematouria

– GIT hemorrhage

– Spontaneous intracranial hemorrhage (rare) 23

Hemophilia A

• Clinical features– The clinical severity depend on the level of factor

VIII:C = severity of condition

– Severe = factor level < 1%

– Moderate = factor level 1 – 5%

– Mild = factor level > 5 %

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Hemophilia A

• Clinical features– Severe disease – factor level < 1%

• Frequent spontaneous bleeding from early life

• Haemarthroses are common and may lead to joint deformity

• Bleeding into muscles is also common

– Moderate disease – factor level 1 – 5 %• Post traumatic Bleeding

• Occasional apparently spontaneous episodes

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Hemophilia A

• Clinical features– Mild disease – factor level > 5 %

• Usually with bleeding only after injury or surgery

• Diagnosis in this group is often delayed until quite late in life

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Hemophilia A

• Clinical features

Massive haemorrhage in the

area of right buttock

Gross swelling from acute haemarthroses of the knee joints

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Hemophilia A

• Laboratory finding – investigations– Coagulation testing

• Prolonged activated partial thromboplastin time (APTT)

• Normal prothrombin time (PT)

• Normal bleeding time (BT)

• Factor assay (reduced level of factor VIII)

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Hemophilia A

• Treatment = factor replacement – Bleeding is treated by administration of factor VIII

concentrate by intravenous infusion.

– Minor bleedingMinor bleeding: the factor VIII:C level should be raised to 20-30%

– Severe bleedingSevere bleeding: the factor VIII:C should be raised to at least 50%

– Major surgeryMajor surgery: the factor VIII:C should be raised to 100% preoperatively and maintained above 50% until healing has occurred.

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Hemophilia A

• Treatment– Synthetic vasopressin (Desmopressin)

• An analogue of vasopressin

• Intravenous, subcutaneous or intranasal

• Produces a rise in factor VIII:C in mild hemophilia

• It avoids the complications associated with blood products

• It is ineffective in severe haemophilia

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Hemophilia A

• Supportive treatment – For treating haemarthrosis and haematomas

– Resting of affected part

– Avoid other trauma

– Social and psychological support

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Hemophilia B

• Also known as Christmas disease • Caused by a deficiency of factor IX• The inheritance and clinical features are identical

to hemophilia A• Only can be distinguished by specific

coagulation factor assays• The incidence is only about 1 in 30 000 males• Hemophilia B is treated with factor IX

concentrates

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Von Willbrand’s disease

• Hereditary coagulation abnormality caused by either:– Reduced level of vWF

– Abnormality in vWF

Due to Point mutation

or Major deletion

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Von Willbrand’s disease

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Von Willbrand’s disease

• vWF is a protein that has two roles – It promote adhesion of platelets to the endothelium

– It is a carrier molecule for factor VIII, protecting it from premature destruction

• So in vWD there is: – Defective platelet function

– Factor VIII:C deficiency

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Von Willbrand’s disease

• vWD has been classified into three types:– Type 1 vWD

• Characterized by a mild reduction in vWF and is usually inherited as an autosomal dominant

– Type 2 vWD• Loss of high-molecular-weight multimers, and it too is

usually inherited as an autosomal dominant

– Type 3 vWD• Characterized by severe reduction in vWF and usually

inhereted as autosomal recessive

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Von Willbrand’s disease

• Clinical features– Typically there is mucus membrane bleeding

(epistaxis, menorrhage...)

– The severity of symptoms are variable with types• Type 1, 2 usually mild symptoms

• Type 3 severe symptoms

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Von Willbrand’s disease

• Laboratory finding – The bleeding time is prolonged

– APTT is prolonged

– Factor VIII is low

– vWF is usually low (type 1,2)

– Platelets count is normal

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Von Willbrand’s disease

• Treatment – Depends on the severity of the condition

– May be similar to that of mild haemophilia, including the use of Desmopressin where possible

– Factor VIII or von Willebrand factor concentrates should be used to treat bleeding or to cover surgery in patients who require replacement therapy

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Haemostasis tests in hereditary coagulation disorders

Haemophilia A Haemophilia B VW disease

Bleeding time Normal Normal Prolonged

Prothrombin time

Normal Normal Normal

APTT Prolonged Prolonged Prolonged

Factor VIII Low Normal Low or normal

Factor IX Normal Low Normal

VWF Normal Normal Low

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Other coagulation factors

• Factor XI deficiency – Rare

– Seen mainly in Ashkenazi Jews

– Caused bleeding only after trauma

– Treated by factor XI

• Factor XII deficiency – Usually cause no bleeding

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B. Acquired coagulation disorders

• Acquired coagulation disorders– More common than inherited disorders

– Usually multiple clotting factors

– Includes • Vitamin K deficiency

• Liver disease

• DIC

• Coagulation disorders caused by antibodies

• Massive transfusion syndrome

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Vitamin K deficiency

-Vitamin K is a fat soluble vitamin– Obtained from green vegetables and bacterial

synthesis in the gut

– Important on coagulation factors II, VII, IX and X and on proteins C and S.

– Without it, these factors cannot bind calcium.

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Vitamin K deficiency

– haemorrhagic disease of the newborn

– Biliary obstruction

– Malabsorption of vitamin K

– Vitamin K antagonist drugs

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Liver disease

– Biliary obstruction results in malabsorption of vitamin K and therefore decresed synthesis of factors II, VII, IX and X

– Also there are decreased in factor V and fibrinogen – Dysfibrinogenemia – Thrombocytopenia.– Functional abnormalities of platelets – Hypersplenism associated with portal hypertension – DIC

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Disseminated coagulation disorders (DIC)

– There is widespread deposition of fibrin within blood vessels with consumption of coagulation factors and platelets occurs as a consequence of many disorders which release procoagulant material into the circulation or diffuse endothelial damage or generalized platelet aggregation.

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DIC: causes

• Infections– Gram neg septicaemia– Septic abortion

• malignancy – Widespread mucin

secreting adeno-carcinoma

– Acute promyelocytic leukaemia

• Hypersensitivity reactions– Anaphylaxis– Incompatible blood

transfusion

• Obstetric complications– Amniotic fluid embolism– Eclampsia, retained

placenta• Widespread tissue damage

– Following surgery/trauma– After severe burns

• Miscellaneous– Liver failure– Severe burns– Hypothermia– Snake venoms– Acute hypoxia

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DIC: pathogenesis

1. DIC may triggered by the entry of procoagulant material into circulation:– Amniotic fluid embolism– APML– Premature separation of placenta

2. Initiated by widespread endothelial damage and collagen exposure:– Septicemia– Severe burns

3. Widespread intravascular platelet aggregation– Some bacteria, viruses and immune complexes may have

direct effect on platelets.

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DIC

• F

Changes in clotting factors, platelets and fibrin degradation products (FDP) that occur in DIVC

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DIC

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DIC

• Clinical features– Bleeding, particularly from venepuncture

– Purpura

– Generalized bleeding in GIT, oropharynx, lungs, urogenital tract, vaginal bleeding

– Less frequently, microthrombi may cause skin lesions, renal failure, gangrene of fengures

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DIC

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DIC

• Laboratory finding – The platelet count is low

– Fibrinogen low

– Thrombin time is prolonged

– High level of fibrin degradation products (FDP)

– PT and APTT are prolonged in acute syndromes

• Blood film – Fragmentation of red cells

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DIC

• Treatment – Treat underlying cause

– Supportive therapy with fresh frozen plasma (FFP) and platletes concentrates

– Cryoprecipitate may also required

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C. PLATELETS DISORDERS

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C.Platelet disordersAbnormal bleeding due to; -Thrombocytopinic (dereased number of platelates) -Idiopathic thrombocytopenic purpura (ITP). -Thrombotic thrombocytopenic purpura (TTP). -Drug induced thrombocytopenic purpura .

-Platelate function disorder - Congenital eg. - Acquired eg.

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C.Platelet disorders

• Characterized by petechae, purpura and bleeding from mucous membranes

• Bleeding is uncommon with platelet counts above 50 × 109/L, and severe spontaneous bleeding is unusual with platelet counts above 20 × 109/L

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Thrombocytopenia

– Reduced platelet production in the bone marrow• The most common cause of thrombocytopenia

– Excessive peripheral destruction of platelets

– Abnormal distribution of platelets• Splenomegally

– Dilutional loss• Massive transfusion of stored blood

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Thrombocytopenia

Impaired production Increase consumption

Bone marrow failure ImmuneAutoimmune (idiopathic)

Associated with SLE, CLL

Infections

Drug-induced

Post-transfusion purpura

Feto-maternal alloimmune

Megaloblastic anaemia

Aplastic anemia

Myelofibrosis

Multiple myeloma

MDS

HIV infection DIC

Marrow infiltration TTP

Leukaemia 59

PLATELET DISORDERS

• Increased destruction of platelets

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Idiopathic thrombocytopenic purpura (ITP)

• Thrombocytopenia is due to immune destruction of platelets.

• The antibody-coated platelets are removed following binding to Fc receptors on macrophages.

• Both acute and chronic forms of ITP exists – Acute ITP more commonly seen in pediatric population

– Chronic form is more common in adults

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Idiopathic thrombocytopenic purpura

• Acute ITP– Common in children

– Usually following vaccination or infection

– Spontaneous remission is common

– 10% the disease become chronic (lasting > 6 months)

– The diagnosis is one of exclusion

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ITP

• Chronic ITP– Relatively common disorder

– Occur mainly in women between 15 – 50 years old

– This is the most common cause of thrombocytopenia without anemia and neutropenia

– Usually idiopathic but can be seen in associated with other disorders as SLE, HIV, CLL.

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ITP

• Chronic ITP: pathogenesis – The platelets are sensitized with autoantibodies

(IgG), this results in their premature removal from the circulation by the macrophages of RES, especially in the spleen.

– Normal lifespan for normal platelets is about 7 days, but in ITP this is reduced to a few hours

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ITP: pathogenesis

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Chronic ITP

• Clinical pictures – Petechial haemorrhage

– Purpura

– Easy brusing

– Menorrhagea in women

– Epistaxis

– Gum bleeding

– Major haemorrhage is rare

– Intracranial bleeding – very rare 66

Petechia

•

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Purpura

•

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Purpura

•

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Chronic ITP

• Diagnosis – CBC

• The only blood count abnormality is thrombocytopenia

• The haemoglobin concentration and WBCs count are typically normal.

– Blood film • Decreases number of platelets

• Those present are large

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Chronic ITP

• Diagnosis – Bone marrow

• The BM shows normal or increased number of megakaryocytes

– The detection of platelet autoantibodies is not essential for confirmation of the diagnosis

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Chronic ITP

• Treatment – The aim of treatment is to maintain platelets count

above the level at which spontaneous bruising or bleeding occur with minimal intervention

– In general, platelets count above 50 x 109/L dose not required treatment.

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Chronic ITP

• Treatment – Corticosteroids

• 1mg/kg/day – is the usual initial therapy

• Dose gradually reduced after 14 days

– Splenectomy • If platelets <30 x 109/L after 3 months of steroid therapy

– High dose intravenous immunoglubulin therapy• Rapid raise of platelets

• 400mg/Kg/day for 5 days or 1g/Kg/day for 2 days

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Chronic ITP

• Treatment – Immunosuppressive therapy

• Vincristin, cyclophosphamide, cyclosporine, azathioprine

– Platelets transfusion • In acute life-threatening bleeding

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D.VASCULAR BLEEDING DISORDERS

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D.Vascular bleeding disorders

• A group of disorders characterized by easy bruising and spontaneous bleeding from small blood vessels.– Bleeding mainly occur in the skin causing petechiae,

ecchymoses or both

• Caused by – Abnormality in the blood vessel themselves

– Abnormality in the perivascular connective tissues

• Can be congenital or acquired 76

D.Vascular bleeding disorders

• Congenital – Hereditary haemorrhagic telangiectasia (HHT)Hereditary haemorrhagic telangiectasia (HHT)

• Uncommon, AD disorder

• Dilated microvascular swellings

• These telangiectasia develop in the skin, mucous These telangiectasia develop in the skin, mucous membranes and internal organs (recurrent GIT membranes and internal organs (recurrent GIT haemorrhage)haemorrhage)

– Connective tissue disordersConnective tissue disorders (Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, Marfan's syndrome)

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D.Vascular bleeding disorders

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D.Vascular bleeding disorders

• Acquired– Severe infections

• Septicaemia, meningococcal infections, measles, typhoid

– Allergic• Henoch-Schönlein purpura

– Drugs• Steroids, Sulphonamides

– Others• Senile purpura, Easy bruising syndrome, Scurvy, Factitious

purpura 79

D.Vascular bleeding disorders

• Senile purpura– Atrophy of the

supporting tissues of cutaneous blood vessels

– Dorsal aspects of the forearm and hand

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REFERENCE

• Nelson textbook of pediatrix ,19th edition• Current diagnosis and treatment in pediatrics,20th edition• Pediatrics and child health lecture note for health sceince

students ,jimma university

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