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HEMOPHILIA & OTHER HEREDITARY BLEEDING DISORDERS Djajadiman Gatot Novie Amelia C Hematology-Oncology Division Department of Child Health Faculty of Medicine University of Indonesia/ Dr Cipto Mangunkusumo Hospital Hereditary Bleeding Disorders Hereditary clotting factor deficiencies Single clotting factor deficiency Factor I, II, V, VII, X, XI, XIII deficiency (autosomal) Factor VIII/IX deficiency (X-linked recessive) Factor XII deficiency (non-bleeding disorder) Multiple clotting factor deficiencies F V + F VIII (autosomal recessive) Vitamin K dependent factors (F II, VII, IX, X) Von Willebrand Disease Inherited platelet disorders Wintrobe’s Clinical Hematology, 11th ed, 2004 WFH Global Survey 2012 WFH, 2013 Pathophysiology http://accessmedicine.net/ Diagnosis Beck N. Diagnostic hematology. 2009 Clinical distinctions Finding Disorders of Coagulation Disorders of Platelets or Vessel Petechiae Rare Characteristic Deep dissecting hematoma Characteristic Rare Superficial ecchymoses Common, usually large & solitary Characteristic, usually small & multiple Hemarthrosis Characteristic Rare Delayed bleeding Common Rare Bleeding from superficial cuts & scratches Minimal Persistent, often profuse Sex of patient 80-90% male Relatively more common in females Positive family history Common Rare Wintrobe’s Clinical Hematology, 11th ed, 2004 Clinical manifestation & treatment Defect Bleeding manifestation Fibrinogen variable N/ Prothrombin variable N Factor V Mild-moderate Factor VII Moderate-severe Factor VIII variable Factor IX variable Factor X variable Factor XI variable Factor XII Factor XIII PT PTT BT Treatment Cryoprecipitate PCC FFP N N rF.VIIa N N F.VIII or DDAVP(mild) N N F.IX N Plasma/PCC N N Plasma/PCC Non-bleeding N N No need severe N N cryoprecipitate N Colman RW, et al. Hemostasis & thrombosis : basic rinciples & clinical practice. 2006 Hemophilia Definition Hemophilias comprise a category of hereditary bleeding disorders resulting from congenital deficiencies of proteins involving in blood coagulation X-linked recessive disorder Hemophilia A : factor VIII (antihemophilic factor) deficiency Hemophilia B : factor IX (Christmas factor)deficiency Hemostasis & Thrombosis : Basic Principals & Clinical Practice. 4th ed, 2006 Epidemiology Hemophilia A 80-85% of hemophilia cases 1 in 5000 male births Hemophilia B 1 in 30,000 male births Am J Hematol.1998;59:288-294. Jumlah Pasien Hemofilia, 2014 1585 1270 1280 1210 1136 1084 1103 757 1706 1737 1388 850 530 180 230 Data : Himpunan Masyarakat Hemofilia Indonesia, Februari 2014 Pattern of inheritance Hemophilia in Pictures. WFH, 2005 Genetics Genes of factor VIII/IX are located on the distal part of the long arm (q) of X chromosome Female (women) are carriers F VIII & F IX gene defects : Gross gene rearrangements Insertions/deletions Single-base substitutions Approximately 30% cases have no family history (occur as a result of spontaneous novel mutations) Carrier state Normal women phenotype, usually no clinical symptoms. Obligate carriers are: daughters of a person with hemophilia mothers of one son with hemophilia and who have at least one other family member with hemophilia mothers of one son with hemophilia and who have a family member who is a known carrier of the hemophilia gene mothers of two or more sons with hemophilia Guidelines for the Management of Hemophilia, WFH 2012 Degrees of Severity Hemophilia in Pictures. WFH, 2005 Clinical Classification* Severe Coagulation factor level < 1% Moderate 1 - 5% Mild > 5% Bleeding spontaneous Episodes 1-2 x/wk 1 x/mo none Hemarthrosis common occasionally rare * Hemophilia A or B mild trauma moderate trauma Clinical manifestation Bleeding: • usually deep (hematoma, hemarthrosis) • spontaneous or following mild trauma Type: hemarthrosis hematoma intracranial hemorrhage hematuria epistaxis bleeding of the frenulum (baby) Clinical manifestation 3% 30% 2% 3% 45% 15% Hemarthrosis 2% Muscle bleed Hemophilia in Pictures. WFH, 2005 Sites of bleeding Guidelines for the Management of Hemophilia, WFH 2012 Hemarthrosis Hemophilia in Pictures. WFH, 2005 Frequency of bleeding at different sites Guidelines for the Management of Hemophilia, WFH 2012 Diagnosis Presenting history : (boy) Easy bruising in early childhood Spontaneous bleeding (particularly into the joints & soft tissue) Excessive bleeding following trauma or surgery History of abnormal bleeding in family Guidelines for the Management of Hemophilia, WFH 2012 Physical examination Hemostasis screening tests Guidelines for the Management of Hemophilia, WFH 2012 Definitive diagnosis Factor VIII and/or IX assay Genetic testing Establish diagnosis in prenatal testing of male fetuses Predict severity of disease Estimate risk of developing inhibitor To differentiate mild hemophilia A from vWD type 2N. Cost-effective carrier testing of at-risk female family members Guidelines for the Management of Hemophilia, WFH 2005 Mayo Clin Proc. 2005;80(11):1485-1499 Management of bleeding episode Stop bleeding with clotting factor within 2 hours of onset Veins should be well reserved Avoid the use of anti-aggregation drugs Home therapy Followed by comprehensive treatment First aid : RICE REST: The arm or leg should rest on pillows or be put in a sling or bandage. The person should not move the bleeding joint or walk on it. ICE: Wrap an ice pack in a damp towel and put it over the bleed. After 5 minutes, remove the ice for at least 10 minutes. Keep alternating: 5 minutes on, 10 minutes off, for as long as the joint feels hot. This may help decrease pain and limit bleeding. COMPRESSION: Joints can be wrapped in a tensor bandage or elastic stocking. This gentle pressure may help to limit bleeding and support the joint. Use compression carefully with muscle bleeds if a nerve injury is suspected. ELEVATION: Raise the area that is bleeding above the level of the heart. This may slow blood loss by lowering pressure in the area. Hemophilia in Pictures. WFH, 2005 Blood component replacement therapy factor-VIII Fresh-frozen plasma Cryoprecipitate Factor-VIII concentrate Factor-IX concentrate (unit/ml) ~ 0,5 ~ 4,0 25 - 100 - factor-IX (unit/ml) ~ 0,6 25 - 35 (ml) 200 20 10 20 Replacement therapy Dose calculation : F VIII (unit): BW (kg) x % (plasma target –patient F VIII ) x 0,5 F IX (unit): BW (kg) x % (plasma target –patient F IX ) Comprehensive care To be governed through multidiscipline approach involving experts in the field of: hematology orthopedics infectious disease nutrition dentistry occupational therapy vocational therapy psychology nursing genetics Bleeding Joint Muscle (excl.iliopsoas) Iliopsoas -initial -maintenance CNS -initial -maintenance Resp. tract -initial -maintenance Gastrointestinal -initial -maintenance Ginjal Deep laceration Operasi mayor -pre-op -post-op Tooth extraction -before procedure -after procedure Hemofilia A Plasma Target (%) Duration (day) Hemofilia B Plasma Target (%) 10-20 10-20 1-2* 2-3* 10-20 10-20 Duration (day) 1-2* 2-3* 20-40 10-20 1-2 3-5# 15-30 10-20 1-2 3-5# 50-80 30-50 20-40 1-3 4-7 8-14^ 50-80 30-50 20-40 1-3 4-7 8-14^ 30-50 10-20 1-3 4-7 30-50 10-20 1-3 4-7 30-50 10-20 20-40 20-40 1-3 4-7 3-5 5-7 30-50 10-20 15-30 15-30 1-3 4-7 3-5 5-7 60-80 30-40 20-30 10-20 1-3 4-6 7-14 50-70 30-40 20-30 10-20 1-3 4-6 7-14 50 20-40 1-3* 40 20-30 1-3* Other treatment DDAVP Genetic engineering Supportive: • antifibrinolytic agent • analgesics Physiotherapy (rehabilitation) On demand vs Prophylaxis Complications Inhibitor Development of factor-VIII inhibitor (20-30% in severe hemophilia A) Treatment of inhibitor: increase dose of F-VIII shortcut coagulation pathway : by-passing agent (F VIIa, prothrombin complex concentrate/PCC) use of F-VIII from other species ………Complications Transfusion transmitted disease In the past there were several diseases transmitted by transfusion such as: Malaria Syphilis Hepatitis HIV/AIDS With adequate screening and storage the TTD can be diminished There are still risk of transmission with: Parvovirus B 19 Creutzfeld-Jacob disease …….Complications Musculoskeletal : Synovitis Chronic hemophilic arthropathy Pseudotumors Fractures Von Willebrand Disease Introduction Estimated prevalence varied from 1% of general population to 125 cases per million population All ethnic background; severe disease have been documented in Israel, Sweden and Iran Typical symptoms : mucocutaneous bleeding Role of VWF in primary hemostasis N Engl J Med 2004;351:683-94. VWF – F VIII complex N Engl J Med 2004;351:683-94. Classification Type of VWD Definition Type 1 (≈80%) Partial quantitative deficiency of VWF Type 2 (≈20%) Qualitative defects of VWF 2A Qualitative variants with decreased platelet function (high molecular weight multimer) 2B Qualitative variants with increased binding affinity for platelet glycoprotein 1b 2M Qualitative variants with decreased platelet function (normal molecular weight multimer) 2N Qualitative variants with reduced binding of F VIII Type 3 (<1%) Complete absence of VWF Hemostasis & Thrombosis : Basic Principals & Clinical Practice. 4th ed, 2006 Pattern of inheritance Type 1 & 2 : autosomal dominant Type 3 : autosomal recessive Diagnosis Focused on 3 factors : Personal history of excessive mucocutaneous bleeding Evidence of family history of the condition Laboratory demonstration of VWF deficiency : Complete Blood Count, Bleeding Time Platelet aggregation test APTT Factor VIII:C VWF:Ag VWF:Rco VWF multimers Hemostasis & Thrombosis : Basic Principals & Clinical Practice. 4 th ed, 2006 Clinical definition of a significant bleeding trait Recurrent nosebleeds requiring medical treatment (packing, cautery, etc) or leading to anemia Oral cavity bleeding/bleeding from skin laceration lasting for at least 1 hour, restarting over the next 7 days or requiring medical treatment Prolonged bleeding associated with or following dental extraction/other oral surgery Menorrhagia requiring medical attention or leading to anemia Spontaneous GI bleeding requiring medical attention or leading to anemia, unexplained by local causes Prolonged bleeding from other skin/mucous membrane surfaces requiring medical treatment Pediatric Hematology, 3rd ed, 2006. Treatment Desmopressin (DDAVP) Blood component therapy : Cryoprecipitate Plasma derived F VIII concentrate (intermediate purity) Recombinant VWF concentrate Adjunctive therapy : Antifibrinolytic agents : tranexamic acid, aminocaproic acid Estrogen (reducing menstrual bleeding) Hemostasis & Thrombosis : Basic Principals & Clinical Practice. 4th ed, 2006 Thank you