medicine.Bleeding disorders.(dr.sabir) (new powerpoint)

Bleeding Disorders By Dr. Sabir M. Ameen

History 1. Site of bleeding: * Muscle & joint bleeds indicate a coagulation defect * purpura, prolonged bleeding from superficial cuts, epistaxis, GI bleeding, menorrhagia, indicate PLT disorder, thrombocytopenia or vW disease

History 2. Duration: congenital or acquired 3. Precipitating cause: if spontaneous indicate severe defect 4. surgery: dental extraction, tonsillectomy, circumcision. Bleeding immediately after surgery indicate defective PLT plug formation. Bleeding after some hours indicate failure of PLT plug stabilisation by fibrin due to coagulation defect.

History 5. Family history: * Hereditary or acquired * Negative history does not exclude a hereditary cause, as e.g: about 1/3 of cases of hemophilia have negative family history (mutations). 6. Systemic disease: Hepatic or renal failure CT disease

history 7. Drugs: almost any drug can potentially produce bleeding( cytotoxics. NSAIDs…etc)

Examination Look for: 1. anemia: BM failure, leukemia 2. purpura, bruises, bleeding in mouth 3. Telangiectasia of lips (HHT) 4. LN enlargement: leukemia, viral ( ITP) 5. Stigmata of chronic liver disease: spider nevi, clubbing, palmar erythema…etc 6. Fundal examination

Clinical Features of Bleeding Disorders Platelet Coagulation disorders fac disorders Site of bleeding Skin Deep in soft tis. Mucous membranes (joints, musc) Petechiae Yes No Ecchymoses (“bruises”) Small, superficial Large, deep Hemarthrosis / muscle bleeding Extremely rare Common Bleeding after cuts & scratches Yes No Bleeding after surgery or trauma Immediate, Delayed1-2 d usually mild often severe

Platelet Coagulation Petechiae, Purpura Hematoma, Joint bl.

Petechiae Do not blanch with pressure (cf. angiomas) Not palpable (cf. vasculitis) (typical of platelet disorders)

Screening tests for bleeding disorders Test Abnormality detected Blood count and Anaemia, leukaemia, DIC film Platelet count Thrombocytopenia aPTT Def. of all coagulation factors except VII, esp. follows VIII and IX; heparin PT Def. of F I, II, V, VII, and X; warfarin Thrombin time or Hypo-, dysfibrinogenaemia; heparin fibrinogen FDPs Bleeding time Test of platelet-vessel wall interaction

Causes of bleeding 1. Thrombocytopenia: a- viral infections b- drug-induced c- B12 or folate deficiency d- ITP, DIC, TTP/HUS ( consumption) e- BM infiltration: leukemia, MM, Ca, myelofibrosis

Causes..cont. 2. Clotting factor deficiency: a- liver disease b- drugs: warfarin, heparin c- consumption: DIC d- dilution: massive blood transfusion e- congenital: hemophilia..etc f- vit K deficiency: e.g, malabsorption

Causes…cont. 3. CT atrophy: a- old age b- steroid therapy c- wasting 4. Vessel wall disorders: A- aspirin B- Osler-Weber Rendu disease C- angiodysplasia

Thrombocytopenia The lifespan of a platelet is 7-10 days and the normal count for all ages is 150000-450000 Once released from the BM young platelets are trapped in the spleen for up to 36 hours before entering the circulation, where they have a primary haemostatic role. Congenital abnormalities of platelets can be divided into disorders of platelet production and those of platelet function. All are very rare. In general they cause moderate to severe bleeding problems.

Acquired thrombocytopenia Decreased production of platelets due to suppression or failure of the BM is the commonest cause of thrombocytopenia. In aplastic anaemia, leukaemia and marrow infiltration, and after chemotherapy, thrombocytopenia is usually associated with a failure of red and white cell production but may be an isolated finding secondary to drug toxicity (penicillamine, cotrimoxazole), alcohol, or viral infection (HIV, infectious mononucleosis). Viral infection is the most common cause of mild transient thrombocytopenia

Acquired…cont Increased platelet consumption may be due to immune or non-immune mechanisms.

Post-transfusion purpura (PTP) is a rare complication of blood transfusion. It presents with severe thrombocytopenia 7-10 days after the transfusion and usually occurs in multiparous women who are negative for the human platelet antigen 1a (HPA1a). Antibodies to HPA1a develop, and in some way this alloantibody is responsible for the immune destruction of autologous platelets.

Neonatal alloimmune thrombocytopenia (NAITP) is similar to haemolytic disease of the newborn except that the antigenic stimulus comes from platelet specific antigens rather than red cell antigens. In 80% of cases the antigen is human platelet antigen 1a, and mothers negative (about 5% of the population) for this antigen form antibodies when sensitised by a fetus positive for the antigen. Fetal platelet destruction results from transplacental passage of these antibodies and severe bleeding, including intracranial haemorrhage, can occur in utero.

Heparin-induced thrombocytopenia (HIT) occurs during unfractionated heparin therapy in up to 5% of patients, but is less frequently associated with low molecular weight heparins. It may become manifest when arterial or venous thrombosis occurs during a fall in the platelet count and is thought to be due to the formation of antibodies to heparin that are bound to platelet factor 4. The immune complexes activate platelets and endothelial cells, resulting in thrombocytopenia and thrombosis coexisting. Heparin-induced thrombocytopenia carries an appreciable mortality risk if the diagnosis is delayed.

In thrombotic thrombocytopenic purpura (TTP) the presenting features can be fever, fluctuating neurological signs, renal impairment, and intravascular haemolysis, resulting in thrombocytopenia. The condition is suspected clinically by thrombocytopenia, red cell fragmentation on the blood film, and a reticulocytosis.

Causes of acquired platelet dysfunction • Aspirin and NSAIDs • Penicillins and cephalosporins • Uraemia • Alcohol • Liver disease • Myeloproliferative disorders • Myeloma • Cardiopulmonary bypass • Fish oils

Increased consumption of platelets • Disorders with immune mechanism: Autoimmune : ITP Alloimmune : post-transfusion purpura, neonatal alloimmune thrombocytopenia Infection associated : infectious mononucleosis, HIV, malaria Drug induced : heparin, penicillin, quinine, rifampicin, sulphonamides • TTP/HUS • Hypersplenism and splenomegaly • DIC • Massive transfusion

Treatment of platelet disorders Congenital disorders: • Platelet transfusions (leucodepleted, HLA compatible and irradiated) • DDAVP • Tranexamic acid • Recombinant factor VIIa • Bone marrow transplantation

Treatment…cont Acquired disorders • Bone marrow failure Platelet transfusions if platelet count 10000 • ITP (adults) Prednisolone Intravenous immunoglobulin Splenectomy • Post-transfusion purpura Intravenous immunoglobulin Plasma exchange • Heparin-induced thrombocytopenia Anticoagulation but without heparin • Thrombotic thrombocytopenic purpura Large volume plasma exchange Aspirin when platelets 50000

Treatment…cont • DIC: Treat underlying cause Fresh frozen plasma Platelet transfusion • Hypersplenism Splenectomy if severe • Platelet function disorders Platelet transfusion DDAVP

Idiopathic thrombocytopenic purpura(ITP) It is due to auto- antibodies directed against PLT membrane glycoprotein IIb-IIIa which causes premature removal of PLTs by the monocyte-macrophage system ASSOCIATIONS—neoplasm (CLL, lymphoma), infections (HIV), autoimmune (SLE)

ITP C/F: 1. in children: sudden onset of purpura, oral or nasal bleeding, usually 2-3 wk after a viral illness 2. In adults: affects females more, with insidious onset, usually not associated with viral infection. It is characterised by remission and relapse.

ITP LAB. 1. CBC: reduced PLT count 2. BM: increased megakaryocytes

management 1. In children: usually it is self-limiting, if severe purpura or epistaxis, or PLT <10000 give steroids ( prednisolone 2mg/kg/d) If pesistent epistaxis GI bleeding, retinal hemorrhage : give PLT transfusion and IV IgG

management 2. In adults: prednisolone 1 mg/kg/d for 3-4 wk then gradually tapered over 6-8 wk, relapse may occur on tapering. Platelet recovery occurs within 3 weeks in 2/3 of pts. If platelet count did not increase after 4 weeks of treatment, consider splenectomy PLT transfusion and IVIg 1 g/kg IV daily 1–2 days, indicated in life-threatening bleeding. If the pt has two relapses , splenectomy is indicated, which is curative in 70% of patients, in the remainder the aim is to keep the patient free of symptoms rather than to raise level of PLT( e.g 5mg/d of prednisolone may be sufficient)

management In severe cases iv methylpredinsolone 1gIV dailyX3 days. with or without IVIg may be given If still not controlled give immunosuppressive drugs e.g: vincristine, cyclophosphamide

Hemophilia A Factor VIII is synthesized mainly by liver , but also by spleen, kidney, and placenta, carried by vWF, half-life in plasma is 12hr. It is X-linked recessive and affects about 1/10000, thus all daughters of hemophiliacs are carriers and 50% of sisters are carriers. If a carrier has a son, he has 50% chance of having hemophilia and a daughter has 50% chance of being a carrier

Hemophilia A C/F At around 6 mon. child develop bruises and hemarthrosis as he starts to move around. Normal level of factor VIII is 50%-150%, and severity is measured according to this level: 1. severe: <1% F VIII or IX: liable for spontaneous hemarthrosis & muscle hematoma

Hemophilia A 2. Moderate : 1-5% F VIII or IX: mild trauma or surgery causes hematoma 3. mild: 6-50% F VIII or IX: major surgery or injury results in excess bleeding. Joints commonly affected include: knees, elbows, ankles, and hips. They look hot, swollen, and very painfull and tender.

Hemophilia A With recurrent bleeding there will be synovial hypertrophy, destruction of cartilage and secondary osteoarthritis, In muscles : calf, psoas: bleeding lead to ischemia, necrosis, fibrosis which will lead to contracture & shortening of tendons e.g achilles tendon making walking difficult.

Dosing guidelines for hemophilia A Mild bleeding : Target: 30% dosing q8-12h; 1-2 days (15U/kg) Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria Major bleeding: Target: 80-100% q8-12h; 7-14 days (50U/kg) CNS trauma, hemorrhage, lumbar puncture Surgery Retroperitoneal hemorrhage GI bleeding Adjunctive therapy :  -aminocaproic acid or DDAVP (for mild disease only)

Von Willebrand’s disease Usually it is a mild bleeding disorder of many types, the commonest being type I which is autosomal dominant. vWF is synthesized by endothelial cells and megakaryocytes and has two functions: 1. carrier for F VIII 2. form bridges between PLT and subendothelial collagen

vW Dis. C/F Bruising, epistaxis, menorrhagia, GI bleeding LAB * Decreased level of vWF, increased bleeding time, increased PTT

Treatment of von Willebrand Disease Cryoprecipitate Source of fibrinogen, factor VIII and VWF DDAVP (deamino-8-arginine vasopressin)  plasma VWF levels by stimulating secretion from endothelium Not generally used in type 2 disease Dosage 0.3 µg/kg q 12 hr IV Factor VIII concentrate Virally inactivated product

Common clinical conditions associated with DIC Sepsis (Escherichia coli, N. meningitidis, malaria ) Trauma : Head injury , Fat embolism Malignancy lung,prostate,pancreatic Obstetrical complications : Amniotic fluid embolism Abruptio placentae Vascular disorders Reaction to toxin (e.g. snake venom, drugs) Immunologic disorders Severe allergic reaction Transplant rejection Activation of both coagulation and fibrinolysis Triggered by

Pathophysiology damage to endothelium -> release of tissue factor -> massive activation of coagulation cascade -> intravascular coagulation and depletion of clotting factors

Features microangiopathic hemolytic anemia, thrombocytopenia, bleeding, thrombosis, ischemia. ↑ INR, ↑ PTT, ↓ fibrinogen (although it can be normal or even elevated), ↓ factor VIII (in contrast to liver diseases, which have normal factor VIII). Schistocytes on peripheral smear

Treatment treat underlying cause and complications (hypoxia, dehydration, acidosis, acute renal failure). Replete coagulation factors if bleeding (FFP 2 U, cryoprecipitate 10 U). Anticoagulation if thrombosis (consider IV heparin)

Management of Hemostatic Defects in Liver Disease Treatment for prolonged PT/PT Vitamin K 10 mg x 3 days - usually ineffective Fresh-frozen plasma infusion (1200-1500 ml) immediate but temporary effect Treatment for low fibrinogen Cryoprecipitate (1 unit/10kg body weight) Treatment for DIC Replacement therapy

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medicine.Bleeding disorders.(dr.sabir) (new powerpoint)