Bleeding Disorders Hemophilia
Hemostasis * The intimal surface of blood vessels throughout the body is lined by monolayer of endothelial cells. These express anticoagulant properties that promote blood fluidity normally. At the site of vascular injury endothelial cells are activated and converted from antithrombotic to prothrombotic state or become detached exposing circulating blood to thrombogenic constituents of subendothelium.
This results in platelet adhesion that is mediated by vWF that anchors platelets to blood vessel wall by binding to platelet GPIb receptors. Then adherent platelets undergo "release" reaction discharging constituents of their storage granules such as ADP, TXA2 which causes further platelets adhesion & platelet activation. Activated platelets expose binding sites for fibrin (GP IIb-IIIa), and then fibrin is formed from plasma fibrinogen by the action of thrombin. This results from the activation of coagulation factors cascade b y either the intrinsic or extrinsic pathways.
Hemophilias Hemophilia A (HA), considered the classic form of the disease, results from a congenital deficiency of factor VIII (FVIII). Hemophilia B (HB), also called Christmas disease, is a consequence of a congenital deficiency of factor IX (FIX) Hemophilia C (deficiency of factor XI)can be distinguished from hemophilia A (deficiency of factor VIII) and hemophilia B (deficiency of factor IX) by the absence of bleeding into joints and muscles and by its occurrence in individuals of either sex. autosomal but not completely recessive because heterozygotes may have bleeding.
Epidemiology 1: 5000 male births --- All races & ethnic groups are affected --- Peak in 2nd & 3rd decades of life The annual incidence of hemophilia A in Europe and North America is approximately 1 case per 5000 male births. It is the most common X-linked genetic disease, and the second most common factor deficiency after von Willebrand disease (VWD). The incidence of hemophilia B is estimated to be approximately 1 case per 30,000 male births. In the United States, the prevalence of hemophilia A is 20.6 cases per 100,000 male individuals, with 60% of those having severe disease. The prevalence of hemophilia B is 5.3 cases per 100,000 male individuals, with 44% of those having severe disease.
Genetics X-linked recessive --- Genes located on long arm of X-chromosome --- Usually affects males --- Females are carriers transmitting disease to sons --- Female hemophiliacs may be seen in: * X-chromosome lyonization * mating between hemophiliac male & female carrier * Carrier female with Turner's syndrome * Carrier with testicular feminization
S&S --- Severity of bleeding related to level of plasma FVIII * < 1% activity --- severe disease * 1-5% activity --- moderate clinical course --- bleeding in severe cases in early infancy during circumcision or even during intrauterine life --- Spontaneous bleeding --- Acute hemarthrosescausing burning or tingling sensation followed by intense pain & swelling. The joint is swollen, hot & tender with erythema of the overlying skin. Joint stiffness & compromised mobility & maintained in a flexed position * Joint aspiration is not recommended because it may introduce infection * FVIII replacement rapidly stops bleeding, resolves hematoma & improves symptoms
* Recurrent hemarthroses result in chronic synovial hypertrophy, damage to cartilage, subchondral bone cyst formation, bony erosion & flexion contractures. Later OA changes * Dx by MRI & ultrasound since x-ray may underestimate the extent of bone & cartilage damage * Analgesics, rest, avoidance of wt bearing, avoid NSAIDs * Synovectomy surgical & non-surgical * Non-weight bearing exercises * Joint prosthesis or arthrodesis * Prevention – planned administration of FVIII 3 times per week at levels to maintain factor activity at 1-2% normal
--- Intramuscularhematomas * follow trauma or IM injection or vaccination * may compress vital structures --- Retroperitoneal hematomas * should be treated aggressively & immediately --- Mucosal hemorrhage may be seen nose, GIT, GUT --- Intracranial bleeding 2nd cause of death after AIDS
Ask about the patient's family history and bleeding symptoms. Male patients with severe hemophilia present at circumcision. Easy bruising may occur at the start of ambulation or primary dentition. The patient may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, dental extraction, and he or she may have spontaneous bleeding in soft tissues. A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (e.g. stress, exercise) may mask mild hemophilia. Physiologically low levels of all vitamin K–dependent procoagulant factors may complicate the early diagnosis of hemophilia B.
The principal sites of bleeding in patients with hemophilia are as follows: For joints, weight-bearing joints and other joints are affected. Regarding muscles, those most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve. In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia
Physical Exam Direct the examination to identify signs related to spontaneous or, with minimal challenge, bleeding in the joints, muscles, and other soft tissues. Observe the patient's stature. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice, other signs of liver failure (eg, cirrhosis from viral infection), and signs of opportunistic infections in patients who are HIV seroconverted
Differential Diagnoses Ehlers-Danlos SyndromePlatelet DisordersFactor Vvon Willebrand DiseaseFactor VIIFactor XI DeficiencyGlanzmannThrombastheniaOther Problems to Be Considered Other congenital bleeding disorders must be excluded. These may include the following: von Willebrand disease (autosomal dominant transmission) Platelet disorders (eg, Glanzmannthrombasthenia) Deficiency of other coagulation factors, ie, FV, FVII, FX, FXI, or fibrinogen Acquired hemophilia
Laboratory Studies The plasma concentration of FVIII or FIX determines the severity of hemophilia. Levels of these factors are assayed against a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII or FIX 1 U/mL. Patients' tested values ranging from 50-150% are considered in the normal range of variance. Aging, pregnancy, contraceptives, and estrogen replacement therapies are associated with increased levels. In term and healthy premature neonates, FIX values are lowered (20-50% of the normal level) and rise to normal levels after 6 months (hepatic immaturity). FVIII levels are normal during that period of life. Spontaneous bleeding complications are severe in individuals with undetectable activity (<0.01 U/mL), moderate in individuals with activity (2-5% normal), and mild in individuals with factor levels greater than 5%. ).
Hemophilia A and hemophilia B protein deficiencies of the intrinsic pathway result in abnormal whole-blood clotting times, prothrombin times (PTs), and activated partial thromboplastin times (aPTTs). FVIII and FIX activities are usually determined by using the 1-stage assay based on the aPTT.
Differentiation of hemophilia A from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand factor antigen and ristocetin cofactor activity. Bleeding time is prolonged in patients with von Willebrand disease but normal in patients with hemophilia. Laboratory confirmation of a FVIII or FIX inhibitor is clinically important when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode. For autoantibody and alloantibody inhibitors, obtain a repeat measurement of the patient's prolonged aPTT after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, use the Bethesda method to titrate the inhibitor biologic concentration. By convention, more than 0.6 BU is considered a positive result for an inhibitor, less than 5 BU is considered a low titer of inhibitor, and more than 10 BU is a high titer (neutralizing effectiveness of factor concentrate therapy to control bleeding )
℞ --- FVIII replacement * Severe cases need 50000-80000 IU per year Level 80-100% for surgery & life threatening bleeds 50% for serious bleeds 25-30% for minor bleeds (hemarthroses & hematuria) 1 IU FVIII / kg body wt = 2% activity increase 3500 IU for 70 kg adult with severe disease needs 100% level Subsequent dosing every 8-12 hours up to 10-14 days --- Cryoppt is a rich source of FVIII --- FFP --- HB vaccination at an early age --- HA vaccination --- Ancillary ttt * Anti fibrinolytic agents – EACA, tranexamic acid * DDAVP intravenously or intra nasally
FVIII inhibitors --- Allo-Abs arise spontaneously in pt with severe def --- suspected when replacement not produce the immediate relief desired in bleeding symptoms --- IgG4 type measured in Bethesda unit (BU) 1 BU = 50% activity --- ttt – porcine FVIII concentrate 50-100 U/kg -- Immune tolerance induction regimen (desensitization)
FIX deficiency: Christmas disease Same as hemophilia (hemophilia B) Less severe disease & less prevalent
Prevention Prophylactic replacement of FVIII or FIX is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and breaking the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis. This goal is achieved by administering factor 2-3 times a week. The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years. Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because a cesarean delivery may be planned or replacement therapy can be scheduled for the perinatal period.
Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases. The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization (FISH) is used. This technique circumvents pregnancy termination. In summary, data suggest that genetic correction of the hemophilias is feasible. Future prospects for RNA repair, use of gene-modified endothelial progenitors, and gene-modified stem-cell therapy are being investigated. Patients report decreasing bleeding episodes; this observation suggests that reasonable factor levels can be reached and encourage further research in this type of hemophilia treatment. Gene transfer for the treatment of hemophilia requires a combination of vector delivery systems, animal models, and clinical models and/or studies to prove its practical utility.
Complications Infection is the most important complication of hemophilia therapy. As many as 20,000 donors may contribute to a single lot of plasma-derived FVIII concentrate. The preferred source of factor are recombinant preparations, which do not show a risk of transmitting infectious disease, which is still theoretically possible with plasma-derived concentrates. Virally attenuated products have reduced the risk of hepatitis observed in most patients receiving early-developed products. Products that are not heat treated result in 90% positivity rates for hepatitis B surface antibody and hepatitis C virus. Therefore, their use is not recommended (or generally available) for routine management. More than 50% of patients with severe hemophilia who have used older products have elevations in liver enzyme levels. Outbreaks of hepatitis A infection in Europe and the United States have prompted more vigorous monitoring of product safety than before. HIV infection has been the most serious complication of hemophilia to date. In the United States, as many as 90% of adults with severe hemophilia are HIV-positive. HIV-associated immune thrombocyticpurpura is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to less than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces transient remissions. Anti-HIV medications and splenectomies may result in long-term improvement of thrombocytopenia.
Allergic reactions are occasionally reported with the use of cryoprecipitate, fresh-frozen plasma (FFP), and factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem. Thrombosis or even acute myocardial infarctions have been encountered in patients especially those with concurrent liver disease or those taking multiple doses, as during surgery. A highly purified FIX product that is preferred. The cost of treatment of an average adult patient is more than $100,000 per year. Costs are increased for the treatment of patients with inhibitors. The use of prophylactic factor has resulted in short-term increases in cost, though the long-term economic benefit of reducing the incidence of joint disease is expected to outweigh the initial expense.
Prognosis Prophylactic use of antihemophilic factors and early treatment with replacement therapy with factors that are safe from infections have dramatically improved the prognosis of patients regarding morbidity and mortality due to severe hemophilia. Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. In addition, dramatic gains in life expectancy occurred during the era of replacement therapy. The life expectancy rose from 11 years or less for patients with severe hemophilia before the 1960s to more than 50-60 years by the early 1980s. Viral complications occurred during the factor replacement era. Intracranial hemorrhages and hemorrhages of the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications. The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due to hemorrhage, even in the era of factor replacement. The life expectancy of patients having inhibitors may be slightly shorter than that of patients not having inhibitors. Approximately one quarter of children and adolescents with severe hemophilia aged 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others