Presentation on theme: "BLEEDING & CLOTTING DISORDERS"— Presentation transcript:
1BLEEDING & CLOTTING DISORDERS Dr. M. A SofiMD; FRCP (London); FRCPEdin; FRCCSEdin
2BLEEDING DISORDERS: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 disorderLike 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.
4Queen Victoria passed hemophilia on to some of her descendants. Ryan White an American hemophiliac who became infected with HIV/AIDS through contaminated blood products.
5HEMOPHELIA 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 %Severity of factor VIII deficiencySeverityFactor VIII activity levelAge of presentationPercentage of sufferersSevere disease<1%Infancy43-70%Moderate disease1-5%Before 2 years15-26%Mild disease>5%Older than 2 years15-31%
6ETIOLOGYHaemophilia 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.Inheritance is usually X- linked recessive, affecting males born to carrier mothersThere 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.
7PRESENTATIONNeonatal 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 untreatedHistory of spontaneous bleeding into joints, especially the knees, ankles and elbows, without a history of significant trauma.Spontaneous haemarthroses are virtually pathognomonicIntramuscular 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
8PRESENTATION 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, tachypneaMusculoskeletal (joints): Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)CNS: Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromesGastrointestinal: Hematemesis, melena, frank red blood per rectum, and abdominal painGenitourinary: Hematuria, renal colic, and post circumcision bleeding
9PRESENTATION 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.Hematoma formation - spontaneously or following trauma and may require fasciotomy.Moderate diseaseOften presents with bleeding following venepuncture.Mild diseaseOnly bleed after major trauma or surgery, with moderate disease after minor trauma or surgery.
10Laboratory findings:Laboratory studies for suspected hemophilia include:Complete blood cell countCoagulation studiesFVIII assayExpected laboratory values are:Hemoglobin/hematocrit: Normal or lowPlatelet count: NormalBleeding time and prothrombin time: NormalActivated partial thromboplastin time (aPTT):Significantly prolonged in severe hemophilia, but may be normal in mild or even moderate hemophiliaScreening tests include:PTaPTT (Normal aPTT does not exclude the possibility of mild hemophilia)Platelet count
11Imaging studies:Imaging choices are guided by clinical suspicion and the anatomic location of involvement:CT brain without contrast to assess for spontaneous or traumatic ICHMRI scans of the head and spinal column for further assessment of spontaneous or traumatic hemorrhageMRI is also useful in the evaluation of the cartilage, synovium, and joint spaceUltrasonography is useful in the evaluation of joints affected by acute or chronic effusions
12HEMOPHELIA Differential diagnosis Haemophilia B (factor IX deficiency).Von Willebrand's disease.Vitamin K deficiency/antagonism with anticoagulants.Hemophilia C (factor XI deficiency).Disorders of fibrinogen or fibrinolytic production.Platelet disorders.Blood vessel disorders.Acquired hemophiliaGlanzmann ThrombastheniaEhlers-Danlos syndrome
13MANAGEMENTDoses 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.ProphylaxisChildren 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).
14MANAGEMENTFresh 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.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.
15MANAGEMENTInfants 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.Scheduled surgical proceduresAim 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
16MANAGEMENTMode 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.PregnancyPregnant 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.
17MANAGEMENT Complications Monitoring 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 AMonitoringProphylaxis 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.
18MANAGEMENT Prevention Prognosis 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, etcPrognosisMuch 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
19Von Willebrand's Disease This is the most common hereditary coagulopathy in humans. It can be congenital or acquired. PathophysiologyVon 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.
20Von Willebrand's Disease EpidemiologyPrevalence 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.
21Von Willebrand's Disease PresentationThis 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 surgeryHeavy bleeding - Common after tooth extraction or other oral surgery, such as tonsillectomy and adenoidectomyMenorrhagia - Common presenting complaint in womenExacerbation of bleeding symptoms - After ingestion of aspirinAmelioration of bleeding symptoms with use of oral contraceptives
22Von Willebrand's Disease EtiologyHereditary - three typesvWD Type I, vWD Type II, and vWD Type IIIWithin the three inherited types of vWD there are various subtypes.Acquired - also called pseudo-von Willebrand's disease or platelet-type; it is frequently found in:LymphoproliferativeMyeloproliferative disordersSolid tumorsImmunological disordersCardiovascular disorders e.g., aortic stenosis, Wilms'tumor, Hypothyroidism.
23Von Willebrand's Disease Types of hereditary von Willebrand's disease (vWD)Type 160-80%Quantitative defect (19-45% of enzyme level present)Heterozygous for defective geneInherited as ADNormal lifespanOccasionally easy bruising and/or menorrhagiaBleeding after dental work, major surgeryType 220-30%Qualitative defect - multimers abnormal or subgroups absentUsually AD inheritance (rarely AR)Bleeding tendency variesFour subtypes: 2A, 2B, 2M, 2NType 3Rare - the most severe form; 1-5% of casesQuantitative - levels very low or undetectableHomozygous for defective geneAR inheritanceNo vWF antigenLow factor VSevere mucosal bleedingMay have haemarthrosis (as in haemophiliaPlatelet typeRare - fewer than 70 cases describedFunctional mutations of vWF receptor on plateletAutosomal dominant
24Von Willebrand's Disease: Subtypes of 2 Type 2AAbnormal synthesis or proteolysis of vWF multimers.Leads to small multimers in circulation; factor VIII still binds as normal.Type 2BSpontaneous 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 2MLow or absent binding to receptor on platelets.Factor VIII binds as normal.Type 2NAutosomal 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.
25Von Willebrand's Disease: Investigations The severity of vWD varies and many patients will never be diagnosed, as their disorder may never come to lightBloods 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.
26Von 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.
27Von Willebrand's Disease: Differential diagnosis Conditions to consider in the differential diagnosis of von Willebrand disease include the following:Hemophilia AHemophilia BBernard-Soulier syndromePlatelet function defectsAntiplatelet drug ingestionFibrinolytic defectsPlatelet-type (or pseudo) vWDAcquired vWDFactor XFactor XI DeficiencyHemophilia A
28Von Willebrand's Disease: Management 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.
29Von 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 therapyIn 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.