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Dr. M. A Sofi MD; FRCP (London); FRCPEdin; FRCCSEdin.

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Presentation on theme: "Dr. M. A Sofi MD; FRCP (London); FRCPEdin; FRCCSEdin."— Presentation transcript:

1 Dr. M. A Sofi MD; FRCP (London); FRCPEdin; FRCCSEdin

2 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:

3 X-linked recessive inheritance Coagulation factor VIII, procoagulant component

4 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.

5  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%

6  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.

7  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

8  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

9  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.

10  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

11 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:

12  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).

13  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).

14  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.

15  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

16  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.

17 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.

18 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

19 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

20 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

21 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

22 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

23 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

24 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

25  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

26  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

27 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

28  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

29  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

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