Presentation on theme: "Dr. M. A Sofi MD; FRCP (London); FRCPEdin; FRCCSEdin."— Presentation transcript:
Dr. M. A Sofi MD; FRCP (London); FRCPEdin; FRCCSEdin
Hemophilia is a group of hereditary genetic disorders that impair the body's ability to control blood clotting, which is used to stop bleeding when a blood vessel is broken. Hemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, present in about 1 in 5,000– 10,000 male births. Hemophilia B (factor IX deficiency) occurs in around 1 in about 20,000–34,000 male births. Hemophilia C – Inherited deficiency of factor XI; also called Rosenthal syndrome; an autosomal recessive disorder Like most recessive sex-linked, X chromosome disorders, hemophilia is more likely to occur in males than females. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. BLEEDING DISORDERS:
Queen Victoria passed hemophilia on to some of her descendants. Ryan White an American hemophiliac who became infected with HIV/AIDS through contaminated blood products.
Disorder caused by deficiency of clotting factor VIII. Inherited but acquired forms do exist, largely in older patients, due to autoantibodies directed against factor VIII or hematological malignancy. Severity of disease depends upon levels of remaining factor activity, with normal range expressed as % HEMOPHELIA Severity of factor VIII deficiency Severity Factor VIII activity level Age of presentation Percentage of sufferers Severe disease <1%Infancy43-70% Moderate disease 1-5%Before 2 years15-26% Mild disease >5% Older than 2 years 15-31%
Inheritance is usually X- linked recessive, affecting males born to carrier mothers There is usually a clear family history but sporadic cases do occur due to novel mutations or effects of mosaicism. Females born to affected fathers can (rarely) have the disease due to homozygosity for the gene, where there is marriage to close relatives. ETIOLOGY Haemophilia A results from heterogeneous mutations in the factor VIII gene that map to Xq28. Carrier detection and prenatal diagnosis can be carried out by testing against the range of known mutations or indirectly by linkage analysis. There is marked phenotypical variability leading to a spectrum of severity.
Intramuscular hemorrhage may also occur. Gastrointestinal and mucosal hemorrhage do occur but are more often associated with haemophilia B/von Willebrand's disease. Hematuria may be a feature, which can vary from self- limiting minor episodes to gross hematuria PRESENTATION Neonatal bleeding in around a third to a half of cases. This may follow circumcision or other operative procedures. ICH occurs in approximately 5% of all untreated History of spontaneous bleeding into joints, especially the knees, ankles and elbows, without a history of significant trauma. Spontaneous haemarthroses are virtually pathognomonic
Musculoskeletal (joints): Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children) CNS: Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes Gastrointestinal: Hematemesis, melena, frank red blood per rectum, and abdominal pain Genitourinary: Hematuria, renal colic, and post circumcision bleeding PRESENTATION Signs and symptoms Depending on the level of FVIII activity, patients with hemophilia may present with easy bruising, inadequate clotting of traumatic injury or—in the case of severe hemophilia—spontaneous hemorrhage. Signs of hemorrhage include: General: Weakness, orthostasis, tachycardia, tachypnea
Hematoma formation - spontaneously or following trauma and may require fasciotomy. Moderate disease Often presents with bleeding following venepuncture. Mild disease Only bleed after major trauma or surgery, with moderate disease after minor trauma or surgery. PRESENTATION Untreated cases of severe disease Arthropathy and joint deformity - may require replacement of affected joints. Soft tissue hemorrhages - common; may cause complications, including compartment syndrome and neurological damage. Extensive retroperitoneal bleeds - with hemodynamic compromise.
Activated partial thromboplastin time (aPTT): Significantly prolonged in severe hemophilia, but may be normal in mild or even moderate hemophilia Screening tests include: PT aPTT ( Normal aPTT does not exclude the possibility of mild hemophilia ) Platelet count Laboratory findings: Laboratory studies for suspected hemophilia include: Complete blood cell count Coagulation studies FVIII assay Expected laboratory values are: Hemoglobin/hematocrit: Normal or low Platelet count: Normal Bleeding time and prothrombin time: Normal
Imaging choices are guided by clinical suspicion and the anatomic location of involvement: CT brain without contrast to assess for spontaneous or traumatic ICH MRI scans of the head and spinal column for further assessment of spontaneous or traumatic hemorrhage MRI is also useful in the evaluation of the cartilage, synovium, and joint space Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions Imaging studies:
Disorders of fibrinogen or fibrinolytic production. Platelet disorders. Blood vessel disorders. Acquired hemophilia Glanzmann Thrombasthenia Ehlers-Danlos syndrome HEMOPHELIA Differential diagnosis Haemophilia B (factor IX deficiency). Von Willebrand's disease. Vitamin K deficiency/antagonism with anticoagulants. Hemophilia C (factor XI deficiency).
Doses should be tailored to the individual - e.g., just before physical education lessons. Prophylaxis should be encouraged to continue until physical maturity is achieved. If after stopping prophylaxis further spontaneous hemorrhage occurs then prophylaxis should be reinstated. Some patients will need to have long-term prophylaxis - e.g., ICH with no other cause. MANAGEMENT Prophylaxis Children with severe hemophilia should receive prophylactic infusions (once- weekly or, ideally x 3/week of factor VIII to prevent hemarthroses and other bleeding episodes. This should begin before the occurrence of a second joint bleed or significant soft tissue bleed (associated with possible reduced risk of development of haemarthrosis in later life).
Fresh frozen plasma and cryoprecipitate should only be used in an emergency. The aim is to correct factor VIII activity to 100% for severe and to 30-50% for minor hemorrhage. Enhanced factor VIII levels are maintained for 7-10 days for severe bleeds and for 1-3 days for minor bleeds. Desmopressin and aminocaproic acid may be used to boost factor VIII activity and reduce factor VIII administration requirements. MANAGEMENT Acute bleeding episodes Patients who are able should administer their normal factor VIII, until they attend hospital. Fresh frozen plasma containing factor VIII, monoclonal-antibody purified factor VIII and recombinant factor VIII are the available sources of factor VIII used to treat acute hemorrhage, with recombinant factor VIII preferred.
Infants usually receive prophylaxis from the age of 2 years. However, if bleeding risk is high, prophylaxis at an earlier age should be considered. There is strong evidence that prophylactic treatment can preserve joint function in children with hemophilia compared to on-demand treatment. MANAGEMENT Scheduled surgical procedures Aim for % factor activity for 2-7 days after surgery. In brain or prostate surgery, nearer 100% is required. Desmopressin may help increase factor levels. Prophylaxis is usually given for those with severe disease, as intermittent recombinant factor VIII injections or continuous infusion
Mode of delivery should be informed by both obstetric and haemostatic factors. The diagnosis of hemophilia should be established using uncontaminated cord blood as soon as possible following delivery. Recombinant factor VIII should be given as soon as the diagnosis is confirmed. MANAGEMENT Pregnancy Pregnant women with hemophilia carrier should be undertaken by an experienced obstetrician in conjunction with a haemophilia expert. Fetal sexing undertaken by maternal blood sampling at around 10 week or by U/S scan between weeks. Third-trimester amniocentesis may be considered where confirmation of an affected male fetus will influence management at delivery.
Complications Degenerative joint disease due recurrent hemarthrosis. Antibody inhibitor formation affects about 25–30%. Risk of life-threatening hemorrhage. Risk plasma-derived factor VIII, infection with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). Immune toleration induction (ITI) is recommended for patients with severe hemophilia A MANAGEMENT Monitoring Prophylaxis phase clinical and laboratory markers used for monitoring. Adherence should regularly be determined and noted. Factor VIII levels routinely measured. Inhibitor levels checked at regular intervals. Radiological surveillance of joints is not needed unless there is a specific indication.
Prevention Genetic screening for carrier mothers and affected families. Patient education helps to prevent morbidity and mortality associated with acute bleeds. Medical emergency identification bracelets or similar can help to identify sufferers rapidly in case of hemorrhage/trauma, etc MANAGEMENT Prognosis Much improved with modern recombinant factor VIII and approaches near-normal life expectancy. Those infected with HIV or other blood-borne viruses carry a worse prognosis. Avoid competitive sports which will increase the risk of hemarthroses and head injuries. Encourage to take part in other sports - e.g., racquet sports, athletics or swimming
This is the most common hereditary coagulopathy in humans. It can be congenital or acquired. Pathophysiology Von Willebrand's disease (vWD) results from the deficiency or abnormal function of von Willebrand factor (vWF). vWF is a multimeric glycoprotein encoded for by gene map locus 12p13. It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions: It assists in platelet plug formation by attracting circulating platelets to the site of damage. It binds to coagulation factor VIII preventing its clearance from the plasma. Von Willebrand's Disease
Epidemiology Prevalence is as high as 1-2% in the general population on unselected screening. Worldwide incidence is around 125 per million with between 0.5 and 5 per million being severely affected. Most patients have mild disease. It is more common in females. It is more severe with blood type O. Von Willebrand's Disease
Presentation This varies according to the extent of the deficiency: Bleeding tendency from mucosa - e.g., epistaxis, menorrhagia (consider in women with no other obvious cause). Spontaneous bleeding - e.g., internal or joint bleeding (only in the most severe of cases). Delayed bleeding - May occur up to several weeks after surgery Heavy bleeding - Common after tooth extraction or other oral surgery, such as tonsillectomy and adenoidectomy Menorrhagia - Common presenting complaint in women Exacerbation of bleeding symptoms - After ingestion of aspirin Amelioration of bleeding symptoms with use of oral contraceptives Von Willebrand's Disease
Etiology I. Hereditary - three types vWD Type I, vWD Type II, and vWD Type III Within the three inherited types of vWD there are various subtypes. II. Acquired - also called pseudo-von Willebrand's disease or platelet-type; it is frequently found in: Lymphoproliferative Myeloproliferative disorders Solid tumors Immunological disorders Cardiovascular disorders e.g., aortic stenosis, Wilms'tumor, Hypothyroidism. Von Willebrand's Disease
Types of hereditary von Willebrand's disease (vWD) Type %Quantitative defect (19-45% of enzyme level present) Heterozygous for defective gene Inherited as AD Normal lifespan Occasionally easy bruising and/or menorrhagia Bleeding after dental work, major surgery Type %Qualitative defect - multimers abnormal or subgroups absent Usually AD inheritance (rarely AR) Bleeding tendency varies Four subtypes: 2A, 2B, 2M, 2N Type 3Rare - the most severe form; 1-5% of cases Quantitative - levels very low or undetectable Homozygous for defective gene AR inheritance No vWF antigen Low factor V Severe mucosal bleeding May have haemarthrosis (as in haemophilia Platelet type Rare - fewer than 70 cases described Functional mutations of vWF receptor on platelet Autosomal dominant Von Willebrand's Disease
Type 2A Abnormal synthesis or proteolysis of vWF multimers. Leads to small multimers in circulation; factor VIII still binds as normal. Type 2B Spontaneous binding of platelets with rapid clearance of platelets and large vWF multimers. Mild thrombocytopenia. Factor VIII binding normal or low normal. Desmopressin will not help, as it leads to unwanted platelet aggregation. Type 2M Low or absent binding to receptor on platelets. Factor VIII binds as normal. Type 2N Autosomal recessive rather than X-linked. Shows incomplete response to haemophilia A treatment. Factor VIII levels reduced to around 5%, as vWF has a reduced affinity for factor VIII. Von Willebrand's Disease: Subtypes of 2
The severity of vWD varies and many patients will never be diagnosed, as their disorder may never come to light Bloods including FBC, fibrinogen level, platelet count, clotting screen, factor IX levels. The platelet count and morphology are normal. Plasma levels of vWF - deficiency can be quantitative or qualitative. Quantitative deficiency - detected by vWF antigen assay. Qualitative deficiency - detected by a glycoprotein binding assay, ristocetin cofactor activity, ristocetin- induced platelet agglutination. Von Willebrand's Disease: Investigations
Factor VIII measurement: Factor VIII binds to vWF which in turn prevents the rapid breakdown of factor VIII; thus, a deficiency of vWF can also lead to deficiency of factor VIII. In type 2 vWF - factor VIII levels are normal; studies of platelet aggregation with sub-endothelium are necessary. Estrogens, vasopressin and growth hormone all elevate levels. Von Willebrand's Disease: Investigations
Conditions to consider in the differential diagnosis of von Willebrand disease include the following: Hemophilia A Hemophilia B Bernard-Soulier syndrome Platelet function defects Antiplatelet drug ingestion Fibrinolytic defects Platelet-type (or pseudo) vWD Acquired vWD Factor X Factor XI Deficiency Hemophilia A Von Willebrand's Disease: Differential diagnosis
Provide advice regarding drugs that must be avoided such as non-steroidal anti- inflammatory drugs and antiplatelet drugs. Minor bleeding problems,, may not require any treatment. The two main treatment options are: Desmopressin (DDAVP) Transfusion therapy. Platelet transfusions may be helpful with disease refractory to other therapies. DDAVP can be used to treat bleeding complications or to prepare patients for surgery. Von Willebrand's Disease: Management
Prophylaxis in major surgery or for treatment of serious bleeding episodes, vWF-containing factor VIII concentrates are the treatment of choice. DDAVP is first-line in type I vWD. In all other types, factor VIII-vWF concentrates are first line therapy In type 2B, DDAVP may cause a paradoxical drop in the platelet count and should not be used without prior testing to see how the patient responds. DDAVP is ineffective in type 3 as there are no vWF levels to boost. Patients who have alloantibodies to vWF will require recombinant factor VII. Von Willebrand's Disease: Management