Pathogenesis and Clinical Manifestations
Hemophilia is an X-linked recessive hemorrhagic disease due to mutations in the F8 gene (hemophilia A or classic hemophilia) or F9 gene (hemophilia B). The disease affects 1 in 10,000 males worldwide, in all ethnic groups; hemophilia A represents 80% of all cases. Male subjects are clinically affected; women, who carry a single mutated gene, are generally asymptomatic. Family history of the disease is absent in ∼30% of cases and in these cases, 80% of the mothers are carriers of the de novo mutated allele. More than 500 different mutations have been identified in the F8 or F9 genes of patients with hemophilia A or B, respectively. One of the most common hemophilia A mutations results from an inversion of the intron 22 sequence, and it is present in 40% of cases of severe hemophilia A. Advances in molecular diagnosis now permit precise identification of mutations, allowing accurate diagnosis of women carriers of the hemophilia gene in affected families.
Clinically, hemophilia A and hemophilia B are indistinguishable. The disease phenotype correlates with the residual activity of FVIII or FIX and can be classified as severe (<1%), moderate (1–5%), or mild (6–30%). In the severe and moderate forms, the disease is characterized by bleeding into the joints (hemarthrosis), soft tissues, and muscles after minor trauma or even spontaneously. Patients with mild disease experience infrequent bleeding that is usually secondary to trauma. Among those with residual FVIII or FIX activity >25% of normal, the disease is discovered only by bleeding after major trauma or during routine presurgery laboratory tests. Typically, the global tests of coagulation show only an isolated prolongation of the aPTT assay. Patients with hemophilia have normal bleeding times and platelet counts. The diagnosis is made after specific determination of FVIII or FIX clotting activity.
Early in life, bleeding may present after circumcision or rarely as intracranial hemorrhages. The disease is more evident when children begin to walk or crawl. In the severe form, the most common bleeding manifestations are the recurrent hemarthroses, which can affect every joint but mainly affect knees, elbows, ankles, shoulders, and hips. Acute hemarthroses are painful, and clinical signs are local swelling and erythema. To avoid pain, the patient may adopt a fixed position, which leads eventually to muscle contractures. Very young children unable to communicate verbally show irritability and a lack of movement of the affected joint. Chronic hemarthroses are debilitating, with synovial thickening and synovitis in response to the intraarticular blood. After a joint has been damaged, recurrent bleeding episodes result in the clinically recognized "target joint," which then establishes a vicious cycle of bleeding, resulting in progressive joint deformity that in critical cases requires surgery as the only therapeutic option. Hematomas into the muscle of distal parts of the limbs may lead to external compression of arteries, veins, or nerves that can evolve to a compartment syndrome.
Bleeding into the oropharyngeal spaces, central nervous system (CNS), or the retroperitoneum is life threatening and requires immediate therapy. Retroperitoneal hemorrhages can accumulate large quantities of blood with formation of masses with calcification and inflammatory tissue reaction (pseudotumor syndrome) and also result in damage to the femoral nerve. Pseudotumors can also form in bones, especially long bones of the lower limbs. Hematuria is frequent among hemophilia patients, even in the absence of genitourinary pathology. It is often self-limited and may not require specific therapy.
Without treatment, severe hemophilia has a limited life expectancy. Advances in the blood fractionation industry during World War II resulted in the realization that plasma could be used to treat hemophilia, but the volumes required to achieve even modest elevation of circulating factor levels limit the utility of plasma infusion as an approach to disease management. The discovery in the 1960s that the cryoprecipitate fraction of plasma was enriched for FVIII, and the eventual purification of FVIII and FIX from plasma, led to the introduction of home infusion therapy with factor concentrates in the 1970s. The availability of factor concentrates resulted in a dramatic improvement in life expectancy and in quality of life for people with severe hemophilia. However, the contamination of the blood supply with hepatitis viruses and, subsequently HIV, resulted in widespread transmission of these bloodborne infections within the hemophilia population; complications of HIV and of hepatitis C are now the leading causes of death among U.S. adults with severe hemophilia. The introduction of viral inactivation steps in the preparation of plasma-derived products in the mid-1980s greatly reduced the risk of HIV and hepatitis, and the risks were further reduced by the successful production of recombinant FVIII and FIX proteins, both licensed in the 1990s. It is uncommon for hemophilic patients born after 1985 to have contracted either hepatitis or HIV, and for these individuals, life expectancy is in the range of age 65 years.
Factor replacement therapy for hemophilia can be provided either in response to a bleeding episode or as a prophylactic treatment. Primary prophylaxis is defined as a strategy for maintaining the missing clotting factor at levels ∼1% or higher on a regular basis in order to prevent bleeds, especially the onset of hemarthroses. Hemophilic boys receiving regular infusions of FVIII (3 days/week) or FIX (2 days/week) can reach puberty without detectable joint abnormalities.
Prophylaxis has become gradually more common in young patients. The Centers for Disease Control and Prevention reported that 51% of children with severe hemophilia who are younger than age 6 years receive prophylaxis, increasing considerably from 33% in 1995. Although highly recommended, the high cost and difficulties in accessing peripheral veins in young patients and the potential infectious and thrombotic risks of long-term central vein catheters are important limiting factors for many patients.
General considerations regarding the treatment of bleeds in hemophilia include (1) the need to begin the treatment as soon as possible because symptoms often precede objective evidence of bleeding; because of the superior efficacy of early therapeutic intervention, classic symptoms of bleeding into the joint in a reliable patient, headaches, or automobile or other accidents require prompt replacement and further laboratory investigation; and (2) the need to avoid drugs that hamper platelet function, such as aspirin or aspirin-containing drugs; to control pain, drugs such as ibuprofen or propoxyphene are preferred.
Factor VIII and FIX are dosed in units. One unit is defined as amount of FVIII (100 ng/mL) or FIX (5 μg/mL) in 1 mL of normal plasma. One unit of FVIII per kilogram of body weight increases the plasma FVIII level by 2%. One can calculate the dose needed to increase FVIII levels to 100% in a 70-kg severe hemophilia patient (<1%) using the simple formula below. Thus, 3500 units of FVIII will raise the circulating level to 100%.
FVIII dose (IU) = Target FVIII levels – FVIII baseline levels × body weight (kg) × 0.5 unit/kg
The doses for FIX replacement are different from those for FVIII, because FIX recovery postinfusion is usually only 50% of the predicted value. Therefore, the formula for FIX replacement is
FIX dose (IU) = Target FIX levels – FIX baseline levels × body weight (kg) × 1 unit/kg
The FVIII half-life of 8–12 h requires injections twice a day to maintain therapeutic levels, whereas FIX half-life is longer, ∼24 h, so that once-a-day injection is sufficient. In specific situations such as postsurgery, continuous infusion of factor may be desirable because of its safety in achieving sustained factor levels at a lower total cost.
Cryoprecipitate is enriched with FVIII protein (each bag contains ∼80 IU of FVIII) and was commonly used for the treatment of hemophilia A decades ago; it is still in use in some developing countries, but because of the risk of bloodborne diseases, this product should be avoided in hemophilia patients when factor concentrates are available.
Mild bleeds such as uncomplicated hemarthroses or superficial hematomas require initial therapy with factor levels of 30–50%. Additional doses to maintain levels of 15–25% for 2 or 3 days are indicated for severe hemarthroses, especially when these episodes affect the "target joint." Large hematomas, or bleeds into deep muscles, require factor levels of 50% or even higher if the clinical symptoms do not improve, and factor replacement may be required for a period of 1 week or longer. The control of serious bleeds including those that affect the oropharyngeal spaces, CNS, and the retroperitoneum require sustained protein levels of 50–100% for 7–10 days. Prophylactic replacement for surgery is aimed at achieving normal factor levels (100%) for a period of 7–10 days; replacement can then be tapered depending on the extent of the surgical wounds. Oral surgery is associated with extensive tissue damage that usually requires factor replacement for 1–3 days coupled with oral antifibrinolytic drugs.
Nontranfusion Therapy in Hemophilia
DDAVP (1-Amino-8-d-Arginine Vasopressin).
DDAVP is a synthetic vasopressin analog that causes a transient rise in FVIII and von Willebrand factor (vWF), but not FIX, through a mechanism involving release from endothelial cells. Patients with moderate or mild hemophilia A should be tested to determine if they respond to DDAVP before a therapeutic application. DDAVP at doses of 0.3 μg/kg body weight, over a 20-min period, is expected to raise FVIII levels by two- to threefold over baseline, peaking between 30 and 60 min postinfusion. DDAVP does not improve FVIII levels in severe hemophilia A patients, since there are no stores to release. Repeated dosing of DDAVP results in tachyphylaxis, since the mechanism is an increase in release rather than de novo synthesis of FVIII and vWF. More than three consecutive doses become ineffective and if further therapy is indicated, FVIII replacement is required to achieve hemostasis.
Bleeding in the gums, gastrointestinal tract, and during oral surgery requires the use of oral antifibrinolytic drugs such as ε-amino caproic acid (EACA) or tranexamic acid to control local hemostasis. The duration of the treatment depending on the clinical indication is 1 week or longer. Tranexamic acid is given at doses of 25 mg/kg three to four times a day. EACA treatment requires a loading dose of 200 mg/kg (maximum of 10 g) followed by 100 mg/kg per dose (maximum 30 g/d) every 6 h. These drugs are not indicated to control hematuria because of the risk of formation of an occlusive clot in the lumen of genitourinary tract structures.
The formation of alloantibodies to FVIII or FIX is currently the major complication of hemophilia treatment. The prevalence of inhibitors to FVIII is estimated to be between 5 and 10% of all cases and ∼20% of severe hemophilia A patients. Inhibitors to FIX are detected in only 3–5% of all hemophilia B patients. The high-risk group for inhibitor formation includes severe deficiency (>80% of all cases of inhibitors), familial history of inhibitor, African descent, mutations in the FVIII or FIX gene resulting in deletion of large coding regions, or gross gene rearrangements. Inhibitors usually appear early in life, at a median of 2 years of age, and after 10 cumulative days of exposure. However, intensive replacement therapy such as for major surgery, intracranial bleeding, or trauma increases the risk of inhibitor formation for patients of all ages that requires close laboratory monitoring in the following weeks.
The clinical diagnosis of an inhibitor is suspected when patients do not respond to factor replacement at therapeutic doses. Inhibitors increase both morbidity and mortality in hemophilia. Because early detection of an inhibitor is critical to a successful correction of the bleeding or to eradication of the antibody, most hemophilia centers perform annual screening for inhibitors. The laboratory test required to confirm the presence of an inhibitor is an aPTT with a mix (with normal plasma). In most hemophilia patients, a 1:1 mix with normal plasma completely corrects the aPTT. In inhibitor patients, the aPTT on a 1:1 mix is abnormally prolonged, because the inhibitor neutralizes the FVIII clotting activity of the normal plasma. The Bethesda assay uses a similar principle and defines the specificity of the inhibitor and its titer. The results are expressed in Bethesda units (BU), in which 1 BU is the amount of antibody that neutralizes 50% of the FVIII or FIX present in normal plasma after 2 h of incubation at 37°C. Clinically, inhibitor patients are classified as low responders or high responders, which provides guidelines for optimal therapy. Therapy for inhibitor patients has two goals, the control of acute bleeding episodes and the eradication of the inhibitor. For the control of bleeding episodes, low responders, those with titer <5 BU, respond well to high doses of human or porcine FVIII (50–100 U/kg), with minimal or no increase in the inhibitor titers. However, high-responder patients, those with initial inhibitor titer >10 BU or an anamnestic response in the antibody titer to >10 BU even if low titer initially, do not respond to FVIII or FIX concentrates. The control of bleeding episodes in high-responder patients can be achieved by using concentrates enriched for prothrombin, FVII, FIX, FX [prothrombin complex concentrates (PCCs) or activated PCCs], and more recently by recombinant activated factor VII (FVIIa) (Fig. 116-1). The rates of therapeutic success have been higher for FVIIa than for PCC or aPCC. For eradication of the inhibitory antibody, immunosuppression alone is not effective. The most effective strategy is the immune tolerance induction (ITI) based on daily infusion of missing protein until the inhibitor disappears, typically requiring periods longer than 1 year, with success rates in the range of 60%. The management of patients with severe hemophilia A and inhibitors resistant to ITI is challenging. The use of anti-CD20 monoclonal antibody (rituximab) combined with FVIII was thought to be effective. Although this therapy may reduce the inhibitor titers, sustained eradication is uncommon and may require two to three infusions weekly of FVIII concentrates.
Hepatitis C viral (HCV) infection is the major cause of morbidity and the second leading cause of death in hemophilia patients exposed to older clotting factor concentrates. The vast majority of young patients treated with plasma-derived products from 1970 to 1985 became infected with HCV. It has been estimated that >80% of patients older than 20 years of age are HCV antibody positive as of 2006. The comorbidity of the underlying liver disease in hemophilia patients is clear when these individuals require invasive procedures; correction of both genetic and acquired (secondary to liver disease) deficiencies may be needed. Infection with HIV also swept the population of patients using plasma-derived concentrates 2 decades ago. Co-infection of HCV and HIV, present in almost 50% of hemophilia patients, is an aggravating factor for the evolution of liver disease. The response to HCV antiviral therapy in hemophilia is restricted to <30% of patients and even poorer among those with both HCV and HIV infection. End-stage liver disease requiring organ transplantation may be curative for both the liver disease and for hemophilia.
Emerging Clinical Problems in Aging Hemophilia Patients.
There has been continuous improvement of the management of hemophilia since the increase in the population of adults living beyond middle age in the developing world. The life expectancy of a patient with severe hemophilia is only ∼10 years shorter than the general male population. In patients with mild or moderate hemophilia, life expectancy is approaching that of the male population without coagulopathy. Elderly hemophilia patients have different problems compared to the younger generation; they have more severe arthropathy and chronic pain due to suboptimal treatment, and high rates of HCV and/or HIV infections.
Early data indicate that mortality from coronary artery disease is lower in hemophilia patients than the general male population. The underlying hypocoagulability probably provides a protective effect against thrombus formation, but it does not prevent the development of atherogenesis. Similar to the general population, these patients are exposed to cardiovascular risk factors such as age, obesity, and smoking. Moreover, physical inactivity, hypertension, and chronic renal disease are commonly observed in hemophilia patients. In HIV patients on combined antiretroviral therapy, there may be a further increase in the risk of cardiovascular disease. Therefore, these patients should be carefully considered for preventive and therapeutic approaches to minimize the risk of cardiovascular disease.
Excessive replacement therapy should be avoided, and it is prudent to slowly infuse factor concentrates. Continuous infusion of clotting factor is preferable to bolus dosing in patients with cardiovascular risk factors undergoing invasive procedures. The management of an acute ischemic event and coronary revascularization should include the collaboration of hematologists and internists. The early assumption that hemophilia would protect against occlusive vascular disease may change in this aging population.
Cancer is a common cause of mortality in aging hemophilia patients as they are at risk for HIV- and HCV-related malignancies. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and a common cause of death in HIV-negative patients. The recommendations for cancer screening for the general population should be the same for age-matched hemophilia patients. Among those with high-risk HCV, a semiannual or annual ultrasound and α fetoprotein is recommended for HCC. Screening for urogenital neoplasm in the presence of hematuria or hematochezia may be delayed due to the underlying bleeding disease, thus preventing early intervention. Multidisciplinary interaction should facilitate the attempts to ensure optimal cancer prevention and treatment recommendations for those with hemophilia.
Management of Carriers of Hemophilia.
Usually hemophilia carriers, with factor levels of ∼50% of normal, have not been considered to be at risk for bleeding. However, a wide range of values (22–116%) have been reported due to random inactivation of the X chromosomes (lyonization). Therefore, it is important to measure the factor level of carriers to recognize those at risk of bleeding and to optimize preoperative and postoperative management. During pregnancy, both FVIII and FIX levels increase gradually until delivery. FVIII levels increase approximately two- to threefold compared to nonpregnant women, whereas a FIX increase is less pronounced. After delivery, there is a rapid fall in the pregnancy-induced rise of maternal clotting factor levels. This represents an imminent risk of bleeding that can be prevented by infusion of factor concentrate to levels of 50–70% for 3 days in the setting of vaginal delivery and up to 5 days for cesarean section. In mild cases, the use of DDAVP and/or antifibrinolytic drugs is recommended.
Factor XI is a zymogen of an active serine protease (FIXa) in the intrinsic pathway of blood coagulation that activates FIX (Fig. 116-1). There are two pathways for the formation of FXIa. In an aPTT-based assay, the protease is the result of activation by FXIIa in conjunction with high-molecular-weight kininogen and kallikrein. In vivo data suggest that thrombin is the physiologic activator of FXI. The generation of thrombin by the tissue-factor/factor VIIa pathway activates FXI on the platelet surface that contributes to additional thrombin generation after the clot has formed and thus augments resistance to fibrinolysis through a thrombin-activated fibrinolytic inhibitor (TAFI).
Factor XI deficiency is a rare bleeding disorder that occurs in the general population at a frequency of one in a million. However, the disease is highly prevalent among Ashkenazi and Iraqi Jewish populations, reaching a frequency of 6% as heterozygotes and 0.1 to 0.3% as homozygotes. More than 65 mutations in the FXI gene have been reported, whereas fewer mutations (two to three) are found among affected Jewish populations.
Normal FXI clotting activity levels range from 70 to 150 U/dL. In heterozygous patients with moderate deficiency, FXI ranges from 20 to 70 U/dL, whereas in homozygous or double heterozygote patients, FXI levels are <1–20 U/dL. Patients with FXI levels <10% of normal have a high risk of bleeding, but the disease phenotype does not always correlate with residual FXI clotting activity. A family history is indicative of the risk of bleeding in the propositus. Clinically, the presence of mucocutaneous hemorrhages such as bruises, gum bleeding, epistaxis, hematuria, and menorrhagia are common, especially following trauma. This hemorrhagic phenotype suggests that tissues rich in fibrinolytic activity are more susceptible to FXI deficiency. Postoperative bleeding is common but not always present, even among patients with very low FXI levels.
FXI replacement is indicated in patients with severe disease required to undergo a surgical procedure. A negative history of bleeding complications following invasive procedures does not exclude the possibility of an increased risk for hemorrhage.
Treatment: Factor XI Deficiency
The treatment of FXI deficiency is based on the infusion of FFP at doses of 15 to 20 mL/kg to maintain trough levels ranging from 10 to 20%. Because FXI has a half-life of 40–70 h, the replacement therapy can be given on alternate days. The use of antifibrinolytic drugs is beneficial to control bleeds, with the exception of hematuria or bleeds in the bladder. The development of an FXI inhibitor was observed in 10% of severely FXI-deficient patients who received replacement therapy. Patients with severe FXI deficiency who develop inhibitors usually do not bleed spontaneously. However, bleeding following a surgical procedure or trauma can be severe. In these patients, FFP and FXI concentrates should be avoided. The use of PCC/aPCC or recombinant activated FVII has been effective.