BLEEDING DISORDERS detailed breakdown of management

Bleeding disorders

1. BLEEDING DISORDERS LECTURER:DR.GERIGA FADHIL PRESENTER:MASIKA A.S. TEDY

2. ILO Introduction Overview of hemostasis approach to patient Coagulation tests Bleeding disorders Treatment

3. H emostasis The ability of the body to control the flow of blood following vascular injury. 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 ofvascular 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).

4. 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.

5. Approach to a child with bleeding disorder 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

6. 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)

7. 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

8. Coagulation tests – The prothrombin time (PT) • Time needed for the plasma to clot in the presence of tissue 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 – Fibrinogen

9. The partial thromboplastin 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

10. 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

11. Bleeding disorders in pediatrics

12. Classified into: 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

13. Cont : C . Platelet disorders - Thrombocytopenic ( decreased number of platelets) -Idiopathic thrombocytopenic purpura (ITP). -Thrombotic thrombocytopenic purpura (TTP). -Drug induced thrombocytopenic purpura . - Platelet function disorder - Congenital - Acquired D. Vascular disorders -Congenital -Acquired

14. 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

15. 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 mutation

16. Cont : • 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 -hallmark – Muscle haemoatomas – Spontaneous haematouria – GIT hemorrhage – Spontaneous intracranial hemorrhage (rare)

17. 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 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

18. Lab findings Coagulation testing • Prolonged activated partial thromboplastin time (APTT) • Normal prothrombin time (PT) • Normal bleeding time (BT) • Factor assay (reduced level of factor VIII )-best Treatment = factor replacement – Bleeding is treated by administration of factor VIII concentrate by intravenous infusion . DDVAP-in mild disease.

19. Tx:cont 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 Supportive treatment – For treating haemarthrosis and haematomas – Resting of affected part – Avoid other trauma – Social and psychological support

20. 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

21. Von Willbrand’s disease Hereditary coagulation abnormality caused by either: – Reduced level of vWF – Abnormality in vWF Due to Point mutation or Major deletion Autosomal dominant.

22. 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

23. Classified: 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

24. 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

25. 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 Quantitative assay of Vwf ag test. Treatment – Depends on the severity of the condition – May be similar to that of mild haemophilia , including the use of Desmopressin (DDVAP) 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

26. B. 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

27. Cont : - Biliary obstruction – Malabsorption of vitamin K – Vitamin K antagonist drugs Liver disease Biliary obstruction results in malabsorption of vitamin K and therefore decresed synthesis of factors II, VII, IX and X FFP/cryoprecipitate.

28. 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

29. DIC : causes Infections – Gram neg septicaemia – Septic abortion • malignancy – Widespread mucin secreting adenocarcinoma – 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

30. DIC : pathogenesis 1. DIC may triggered by the entry of procoagulant material into circulation: – Amniotic fluid embolism – 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.

31. Cont : 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 fingers

32. Cont : • 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 • Treatment – Treat underlying cause – Supportive therapy with fresh frozen plasma (FFP) and platletes concentrates – Cryoprecipitate may also required

33. C.Platelet disorders Abnormal bleeding due to ; - Thrombocytopinic ( dereased number of platelates ) -Idiopathic thrombocytopenic purpura (ITP). -Thrombotic thrombocytopenic purpura (TTP). -Drug induced thrombocytopenic purpura . - Platelet function disorder - Congenital eg . - Acquired eg . 5

34. 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

35. 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

36. Platelet disorders:Increased platelet destruction. 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

37. ITP 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 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.

38. 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

39. Clinical features – Petechial haemorrhage – Purpura – Easy brusing – Menorrhagea in women – Epistaxis – Gum bleeding – Major haemorrhage is rare – Intracranial bleeding – very rare

40. Petechia P urpura

41. 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 -Bone marrow • The BM shows normal or increased number of megakaryocytes – The detection of platelet autoantibodies is not essential for confirmation of the diagnosis

42. 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.

43. 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 - Immunosuppressive therapy • Vincristin , cyclophosphamide, cyclosporine, azathioprine – Platelets transfusion • In acute life-threatening bleeding

44. 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

45. Congenital – Hereditary haemorrhagic telangiectasia (HHT) • Uncommon • Dilated microvascular swellings • These telangiectasia develop in the skin, mucous membranes and internal organs (recurrent GIT haemorrhage ) – Connective tissue disorders (Ehlers- Danlos syndrome, osteogenesis imperfecta , pseudoxanthoma elasticum , Marfan's syndrome)

46. Acquired – Severe infections • Septicaemia , meningococcal infections, measles, typhoid – Allergic • Henoch-Schönlein purpura – Drugs • Steroids, Sulphonamides – Others • Senile purpura , Easy bruising syndrome, Scurvy, Factitious purpura

47. References 1. Nelson textbook of pediatrix ,19th edition 2.Current diagnosis and treatment in pediatrics,20th edition 3.Medscape MERCI!!