Hemophilia A is an X-linked, recessive bleeding disorder attributable to decreased blood levels of properly functioning procoagulant factor VIII (VIII:C, antihemophilic factor, or AHF). Hemophilia B is also an Xlinked, recessive disorder and is indistinguishable from hemophilia A with respect to its clinical manifestations. In hemophilia B, the defect is a decreased level of functional procoagulant factor IX (IX:C, plasma thromboplastin component, PTC, or Christmas factor).
The incidence of hemophilia is probably 20 per 100,000 males; 1 per 10,000 of the whole population. Factor VIII deficiency accounts for 80% to 85% of cases of hemophilia with factor IX deficiency accounting for the remainder.1 Both types of hemophilia occur with similar incidence among all races and in all parts of the world.
INHERITANCE AND CARRIER DETECTION
Hemophilia is transmitted as an X-linked recessive disorder and always affects males who are hemizygous. As a result, all of the sons of a hemophiliac male are normal but al! of his daughters are obligatory carriers, having inherited the abnormal X chromosome from their father. The daughters of these carriers then have a 50% chance of transmitting the disease to their sons, and a 50% chance that their daughters will also be carriers. From a careful history, family trees should be constructed. More than 60% of patients will have a positive family history.2 Because of the high mutation rate for this disease, as many as one-third of hemophiliacs have no family members with demonstrable evidence or history of hemophilia.3
Using assays of VJILC activity, it is known that the levels of VIIIiC are lower in obligatory carriers than control population. However, given the large range of normal for factor VIII:C assays and the increase in VIII:C levels, the error associated with factor VIII=C assays, and the increase in VIII:C with pregnancy, exercise, and various disease states, measurement of VIII:C alone does not permit an accurate diagnosis of the carrier state.4
The carrier detection has been improved greatly by the production of an antibody to factor VIII which is prepared in the rabbit (factor VIIIR:ag is normal or increased despite low levels of factor VIII:C). In obligatory carriers of hemophilia the factor VIIIR:ag levels are normal or slightly higher than normal, with relatively less factor VIII:C. In normal control women, the levels of factor VIII:C measured by a clotting assay are proportional to the concentration of factor VIIIR:ag. It is thus possible to distinguish obligatory carriers from normal women. The accuracy of the methodology is about 90% in centers performing such studies frequently.5,6
Hemophilia B is inherited the same way as classical hemophilia as an X-linked disorder. Several varieties of Christmas disease have been described. In most patients, the coagulant deficiency of factor IX is paralleled by a deficiency of antigens recognized by antiserum against this agent, that is, the defect is cross-reacting material negative-CRM( - ). In others, disproportionately high titers of factor IX-like antigens can be detected, that is, the defect is CRM( + ). Such individuals synthesize one or another abnormal variant of factor IX. Detection of carriers is much less satisfactory than in classic hemophilia, since in most families the disorder is CRM( - ), that is, the titer of coagulant factor IX and of proteins detected by specific antibodies against this factor are proportionately reduced. Obligate carriers of Christmas disease may be distinguished from normal women by the coagulant assay of factor IX since 60% of those women have less than 50% of factor IX activity.9-13
In a minority of families with Christmas disease the defect is CRMf+) (ie, the plasma contains a nonfunctional variant of factor IX). Unlike classic hemophilia, in most series relatively few obligate carriers of CRM( + ) Christmas disease could be identified by the relative excess of factor IX, as measured immunologically (factor IXR:Ag) compared to coagulant factor IX (factor IX:C).
When carrier status has been confirmed, several options are possible aside from risk-taking or electing to have no children. Fetal sex determination is possible by amniocentesis at the 12th to 14th Weeks of pregnancy, followed by termination of pregnancy if the fetus is a male. If facilities are available, however, it is now possible to recognize classic hemophilia in utero, through the fetoscopy and fetal sampling, and measuring the antigen of the VIIhC (VIII:Cag) by immunoradiometric assay (IRMA). l2,13 !n one study, 47 fetuses were examined in total of 46 pregnancies, of these, 32 were shown to have normal assay values, using bioassay of factor VIIhC and IRMA for factor VHI:Cag." The results were confirmed at birth, giving a 100% success rate for the technique. Classical hemophilia was diagnosed in 14 of 47 fetuses at risk, and the diagnosis was confirmed in 10 available aborted fetuses.
RELATION OF FACTOR LEVELS TO SEVERfTY OF CLINICAL MANIFESTATIONS OF HEMOPHILIA A AND B
The prenatal detection of hemophilia B has also been established by using IRMA assay for factor IX:Cag. l4 The sensitivity is, however, limited in CRM( + ) subjects in whom the test cannot be applied.15
The efficacy of carrier testing, prenatal diagnosis of hemophilia, or other technologic advances as measured by changes in genetic outcomes will depend upon the genetic counseling that goes with such advances.16
CLINICAL SEVERITY AND CLINICAL MANIFESTATIONS
The frequency and severity of bleeding in hemophilia is usually associated with factor VIII or factor IX procoagulant levels (Table 1).
In the patient with severe hemophilia, concentrations of factor VIII or IX are less than 1% of those found in normal plasma (Table 1). Such patients constitute approximately 60% to 70% of patients with hemophilia A and 50% of those with hemophilia B. Severe hemophilia is characterized by recurrent hemorrhages occurring spontaneously or following extremely minor degrees of trauma. In the neonatal period, central nervous system (CNS) hemorrhage is not common, but it definitely may occur.17 We encountered 3 newborn infants with severe hemophilia A and CNS hemorrhage during the last 10 years. Two had subdural hematomas and one intracerebral hemorrhage. Commonly severe hemophilia is diagnosed when prolonged bleeding occurs after circumcision. 18 Presently, a number of neonates with severe hemophilia still are not detected despite family histories for hemophilia and early signs of bleeding tendency. In infants with severe hemophilia, palpable subcutaneous ecchymoses begin to develop at 3 or 4 months of age. This becomes more evident by 1 year of age with the onset of walking. Large hematomas may follow deep intramuscular injections. Another frequent presenting symptom in the first 2 years of life is oral mucosal membrane bleeding. Small lacerations of frenulum, tongue, gingiva, or buccal mucosa are followed by oozing from the site for days. At about 3 to 4 years of age, bleeding into the muscles and joints usually begins to present problems. Most of the severe hemophiliacs are usually diagnosed by this time. Major musculoskeletal hemorrhages are commonly seen during mid-childhood and adolescence (Table 2).
COMMON SITES OF HEMORRHAGES IN HEMOPHILIA
Patients with moderately severe hemophilia A or B (concentrations of factor VIII or IX between 1% and 5%) occasionally have spontaneous hemorrhages, but more often bleeding occurs following a trauma. Most bleeding signs and symptoms are similar to those of the severe hemophiliac. The child with mild hemophilia, levels of factor VlII or IX between 5% and 25% of normal, must sustain moderate or severe trauma to develop hemorrhage. Mild hemophilia often may not be diagnosed until late childhood or even adulthood. Mild hemophiliacs are often recognized following excessive postoperative hemorrhage or traumatic joint or muscle bleeding. More commonly, they are now identified at the time of elective surgery when they are found to have a prolonged partial thromboplastin time.
A detailed and careful history taking is of significant value in the diagnosis of hemophilia. In general, the history is more important and usually provides more valuable information than laboratory tests when evaluating children with suspected coagulation disorders. When the history suggests hemophilia it is necessary to perform screening tests of the blood coagulation mechanism (including platelet count, prothiombin time, partial thromboplastin time, and bleeding time). In hemophilia only the partial thromboplastin time is increased. Functional assays of factor VIII and IX are required in order to confirm the diagnosis of hemophilia.
PRODUCTS FOR FACTORS VIII AND IX REPLACEMENT
I. FACTOR REPLACEMENT THERAPY
Prompt support of hemostatis is best achieved by correction of coagulation defect. The available products for replacement therapy are listed in Table 3.
Fresh Frozen Plasma
Fresh frozen plasma (FFP) contains all of the clotting factors in a concentration of approximately 1 unit of clotting factor activity per milliliter and can be used when only small amounts of clotting factor need to be delivered to the patient. Its use, however, is limited by the volume, since only 10 to 15 ml/kg FFP may be given with safety in one dose. That is unlikely to achieve a level of more than 20% to 30% of factor VIII and 15% to 20% rise in factor IX. Such levels are insufficient for serious bleedings and presurgical preparation in a patient with deficiency of factor VIII or factor IX. FFP is harvested from single-donor units and therefore carries less risk of hepatitis and AIDS than the pooled concentrates. For this reason, it should be considered for use in those patients with factor IX deficiencies who have mild deficiencies and who are treated infrequently.
One of the most widely used concentrated forms of factor VIIl is cryoprecipitate. Cryoprecipitate, the protein that precipitates in FFP thawed at 40C, is rich in factor VIII1 fibrinogen, and factor XIII. It is easily prepared in most blood banks capable of component fractionation, and is stored frozen at - 20°C. Single units can concentrate the factor VIII approximately tenfold in 10 ml of plasma, and 50% to 150% of the factor VIII can be recovered from the donor plasma. The fibrinogen content may therefore be 3.0 to 4-5 g/dl. It also carries less hepatitis and AIDS risk, since it is a single-donor component. There are some disadvantages to the use of cryoprecipitate. It must be stored at - 2O0C, and even a small patient, an adequate dose for replacement therapy requires pooling several bags of material. Since the level of factor VIII may vary 50% to 200%, there is significant variation in the factor VIII content. An average content of 100 units of factor VIII activity per bag by cryoprecipitate probably represents a useful guide calculating dose for treatment.
Several commercial factor VIII and factor IX concentrates are currently produced in the US (Table 3) and similar products are available in other countries. These lyophilized concentrates are made from pooled plasma obtained by plasmapheresis or as part of a blood bank's program of total donor unit fractionation. The factor VIII concentrates are prepared from cryoprecipitates and purified further by a variety of methods, with some removal of fibrinogen. Those more highly purified concentrates with low fibrinogen concentrations are extremely desirable at the time of a surgical procedure, or for a patient on high-dose therapy for an extended period. Factor VIII concentrates can be stored at 4°C in a refrigerator and reconstituted with sterile water warmed to body temperature, drawn up into a syringe through a filter needle and then infused slowly into the patient. The amount of clotting activity is stated on the bottle label, and this information facilitates dosage calculations. Transfusion reactions are virtually eliminated by the removal of white cells and platelets. The convenience of storage, the safety and ease of administration, and the standardization of the product have made these concentrates highly acceptable to both physician and patient.
Hemophiliacs receiving plasma concentrate therapy are at risk to be exposed to hepatitis B, non A, non B hepatitis, and other unknown viral challenges including, perhaps, association with the newly identified acquired immune deficiency syndrome, AIDS.
Despite screening of individual blood donors for HBsAg, hemophiliacs are still at high risk of infection by hepatitis B virus because even third-generation tests are not sensitive enough to detect all infective units.19·20 The other viral agents that may cause hepatitis, such as hepatitis A, or "nonA, non-B, " are not detected. Recently, heat treated factor VIIl and factor IX concentrates have been produced by various companies (Table 3). These concentrates have undergone extensive animal and human resting for safety and efficacy. Product characterizations for diese concentrates demonstrate that the heat-treatment process does not alter the biological activity of the product and conserves about 85% of factor activity.21 The heat treatment employed has been shown to be capable of modifying the hepatitis B virus altering its pathogenic ity. Further, non-?, non-B hepatitis developed in the control animals in the chimpanzee study while the animals administered antihemophilic factor showed no clinical signs of disease, indicates that the process lowers the risk of infection due to non- A, non-B virus as well as hepatitis B virus. 22 The ability of infectious retroviruses to withstand the procedures used for factor VIII concentration was investigated. Mouse retroviruses added to human plasma survived diese procedures and remained infectious in lyophilized samples of factor VlII. Lyophilized material had to be heated at 680C for several hours before substantial quantities of infectious virus became inactivated. These findings support the possible role of retroviruses in AIDS, and indicate that factor VIII concentrates must be heated to inactivate these infectious viruses.23
These results are encouraging. Heat treated products offer a reduced hepatitis threat for hemophiliac patients. Longterm studies involving previous untreated patients will give us the accurate answer regarding this matter.
The lyophilized concentrates of factor IX also contain factors II, VII, IX, and X (prothrombin complex). Again, the advantages and disadvantages of these concentrates are similar in those factor VI[I concentrates. In addition, these concentrates contain increased amounts of thrombogenic material (variable amounts of activated factors IX8 and X^sub a^).M It is suggested, therefore, that these products be administered with great caution in patients with pre-existing liver disease or vascular disease who may require long-term replacement therapy.
The proper dose of factor VIII or factor IX for replacement therapy is an amount of the appropriate clotting factor that will provide adequate hemostasis to control the individual bleeding episode. By definition, International Unit (U) of factor VIII or IX is that amount of clotting activity found in 1 ml of fresh normal pooled plasma, and 1 U is equal to 100% clotting factor activity. Each unit of factor VIII per kilogram of body weight infused will result in vivo rise of approximately 2%. In vivo response to factor IX per kilogram of body weight is about 1% to 1.5%. The difference in plasma level attained is related to the greater amount of factor IX that goes into the extravascular space and may be related to molecular size.
Subsequent dosage is based on the desired plasma level, severity of the bleeding episode, and utilization of the infused factor (the half-disappearance time and biologic halfdisappearance time of the infused factor), as well as the length of time desired for replacement therapy. The initial half-disappearance time of factor VIIl is 4 to 8 hours and the biologic half-life is 12 to 15 hours. Factor IX has an initial half-disappearance time of 4 to 6 hours but a longer biological half life of about 30 hours.
TREATMENT OF BLEEDING EPISODES
II. DRUG THERAPY
Several drugs have proved useful as adjunct forms of therapy in hemophilia.
Analgesics have always been an important part of therapy for hemophiliacs. It is imperative that the physician know the effect of these drugs on the clotting mechanism (ie, platelet function).
Many analgesics contain aspirin. Antihistamines and certain cough syrups contain glyceral guaiacholate (Robitussin). These are known to inhibit platelet aggregation and cause prolonged bleeding time. Patients should be cautioned against the use of any medication containing an aspirin compound. Acetaminophen, or codeine may be used as alternatives. Meperidine (Demerol), dolophine (methadone), and morphine are very seldom prescribed narcotics in the pediatrie hemophiliac population.
The most widely used and best of the an ti- inflammatory drugs are the corticosteroids. They have been used in the dose of 1 to 2 mg/kg/day for 5 days for hematuria and acute hemarthrosis (Table 4), Indomediacin (Indocin) or phenylbutazone (Butazolidine) should not be used. These drugs inhibit platelet function. Ibuprofen (Motrin) is a known prostaglandin inhibitor, with anti-platelet aggregation effect in vitro has been shown as a safe and effective ant i- inflammatory agent in hemophiliacs.25
Epsiksvaminocaproic acid-EACA (AMICAR) and tranexaminic acid ate antinbrinolytic agents that have been used in several trials to prevent spontaneous bleeding. The results were not impressive.26
EACA is not indicated in the treatment of hemarthrosis since a clot formed with EACA absorbed to the fibrin strands may not dissolve for many months and may contribute to fibrosis and further joint destruction. It has proved beneficial to specific circumstances in hemophilia. Traumatic oral mucous membrane bleeding can be difficult to control or may require prolonged replacement therapy. This frequent problem in a child and the persistent bleeding may be enhanced by the excess fibrinolytic activity in saliva. EACA, a potent fibrinolytic agent, is a useful drug in conjunction with replacement therapy during the period of healing such mucosa! lesions (Table 5). Secondly, EACA is useful for dental extractions. Some recommend using EACA alone, others with conjunction of replacement therapy,27,28 A recent study clearly indicates that dental extractions can be carried out in hemophiliacs using less replacement therapy.29 EACA should not be used in the presence of hematuria, since internal fibrin deposition with renal function may occur.30
The author's recommendations for dental extraction are:
* In mild hemophiliacs, EACA is started 24 hours prior to the procedure as 50 mg/kg Q6h and continue the dose for seven days.
* In moderate to severe hemophiliacs, an initial dose of factor VIII or factor IX of 25 u/kg is infused and EACA is given 50 mg/kg, Q6h for seven days.
Danazol is an attenuated androgen derivative (17 alphapregna-2, 4-then-20-yno [2, 3-d] isoxazol-17-ol) and has been used in the treatment of patients with hemophilia A and B.31,32 The results are conflicting regarding the mild increase in FVIII and FIX with Danazol treatment (600 mg/ day orally for 14 days). The side effects of Danazol are prominent; irritability, drowsiness, muscle cramps, pruritic rash and transient hepatic dysfunction.32 The author feels that the risks of Danazol treatment far outweigh the benefits, therefore, it should not be used to treat hemophilia.
DESMOPRESSIN (DDAVP, STIMATE®)
DDAVP (1-desamino-8-D-arginine-vasopressin acetate trihydrate) is a synthetic analog of 8-arginine vasopressin, the natural antidiuretic hormone secreted by the posterior pituitary. DCMVP infusions cause a marked increase in factor VIII related properties (FVIII:C, FVHJrVAg) in patients with mild to moderate hemophilia and von Willebrand's disease.34'*' Its mechanism of action is not known with certainty; it has been postulated that DDAVP acts through the release of a second messenger, probably from the central nervous system, which results in release of F VIII from its endothelial storage sites.33 The DDAVP molecule differs from the natural hormone by two changes: 1) at the Nterminal of position 1, the amino group has been removed, 2) L-arginine in position 8 has been replaced by D'arginine. These structural changes have resulted in a molecule with antidiuretic effect, about 80 to 100 times that of natural vasopressin, but decreased pressor effect, only 0.25% to 1% that of natural vasopressin.
TREATMENT OF MUCOUS MEMBRANE HEMORRHAGES
The half-life after intravenous administration is biphasic, with a first phase Tl/2 of 7.8 minutes and a second phase of 75.5 minutes, on the average. DDAVP has a low order of toxicity. In animal studies, it had little or no effect on sodium and potassium excretion, the cardiovascular system, blood glucose, serum lipids, or ACTH release, and it had low oxytocic activity. All mice survived single doses which were 25,000 times the clinical dose for humans. Long-term studies in rats and dogs given the drug showed no toxic effects. No teratogenic or embryonic effects were found in rat and rabbit studies.
In human recipients, infusions of recommended doses may provoke trivial transient symptoms, such as facial flushing or mild headache or rniid nausea, which disappear when the infusion ends. Despite the strong antidiuretic action of DDAVP1 water retention is not a problem when a normal fluid intake is maintained. Careful intake-and-output measurements should be obtained in patients undergoing anesthesia and therefore receiving intravenous fluids, and in any patient with a tendency to retain water. Most patients require no supervision of water balance.
Intravenous preparations of DDAVP (Stimate®desmopresstn acetate) injection by Armour currently is available as a sterile solution in 10 ml multiple dose vials, each containing 4.0 meg desmopressin acetate per ml. The recommended dosage is 0.3 to 0.4 meg/kg DDAVP is mixed with 50 ml isotonic saline solution immediately prior to use and is infused slowly over a period of 15 minutes.39 In normal subjects, VIII:C rises to levels two to five times the baseline value, peaking in 30 minutes to 3 hours, according to various studies. VIIIR;Ag rises to two to three times the baseline value, a response less marked than that of VIIIiC.
In patients with mild classic hemophilia, the response of VIII:C is marked. There may be an average seven-fold increase in VIII:C plasma levels.39 Patients with very severe hemophilia A do not respond at all. Those with mild hemophilia A (factor VIlI coagulant activity levels of 10% or more) usually respond adequately and those with levels of 4% to 9% may have useful responses, sufficient for minor hemorrhages.
Patients with very severe von Willebrand's disease (type III) also are unresponsive. 4l DDAVP usually is quite effective in type I variant of von Willebrand's disease, with correction of both the bleeding time and the plasma factor VIfI complex components. In the type UA variant, the correction of the bleeding time may be only partial but the levels of VIII:C improve and clinical benefit usually is seen. Some patients with the type UB variant rapidly develop severe, transient thrombocytopenia after administration of DDAVP;42 thus, DDAVP is contraindicated in type HB.
Desmopressin acetate can be used most effectively in the management of acute hemorrhages and minor surgery, requiring only one dose. Repeated closely spaced infusions of desmopressin acetate induce lower responses of factor VIII. If the interval between infusions is about 48 hours, allowing stores to be replenished, full responses usually are obtained. Thus, infusions of desmopressin acetate alone may not sustain a patient recovering from major surgery in whom elevated levels of VIII:C may be desirable for a couple of weeks. For such cases, desmopressin acetate infusions may be alternated with infusions of plasma or cryoprecipitate. When elective surgery is scheduled in an adolescent or adult with good venous access, the patient's own desmopressin acetatestimulated factor Vlll-rich plasma may be harvested by plasmapheresis on several occasions to stockpile for autologous plasma transfusions.43
The treatment regimens have been outlined in Tables 4 to 7. The following will emphasize some of the bleeding episodes and their special care and therapy.
TREATMENT OF HIGH-RISK HEMORRHAGES
REPLACEMENT THERAPY FOR SURGICAL PROCEDURES IN PATIENTS WITH HEMOPHILIA 52
The joints most frequently involved are, in descending order of frequency, the knees, elbows, ankles, shoulders, hips, and wrists. The first episode of acute hemarthrosis usually occurs when the child begins to walk. It is usually either spontaneous or associated with some trauma. The onset of hemorrhage causes warmth, tingling sensation and stiffness of joint and slight limitation of joint motion occurs next followed (after 1 to several hours) by pain, joint swelling, and eventual severe limitation of motion follows within a few hours- Each episode of major hemarthrosis results in inflammatory and hypertrophie changes in the synovial tissue. Like rheumatoid arthritis, the inflamed and enzymeproducing synovia! tissue, erythrocyte debris, and leukocytes all eventually contribute to the erosion of cartilage and bone. Proliferative chronic synovitis also leads to the presence of highly vascular tissue at or near articulating surfaces, thus increasing the frequency of repeated hemorrhages. This vicious cycle leads to the destruction of cartilage, résorption of bone, and formation of bone cysts which communicate with joint space. Anatomic instability of joints will also lead to more frequent hemorrhages within the joint itself as well as in neighboring joints and muscles. Finally, chronic pain with subsequent atrophy of local muscle groups will accelerate the worsening of joint instability. The final stage of hémophilie arthropathy includes fibrous and bony ankylosis of large joints. In the smaller joints, such as the elbow, complete joint destruction may occur because of the thinner cortices of the smaller bones. Radiographie findings will illustrate vividly the progression of hemophilie arthropathy. Treatment is difficult, however, it appears that the following regimen is useful: 1) prophylactic infusion two to three times weekly sufficient to maintain the patient above 25% factor level for 6 to IZ weeks; 2) prednisone 1 mg/kg daily for 2 to 3 weeks; and 3) intensive physical therapy if the lower extremity is involved. This regimen may need to be repeated for two or three courses before complete healing occurs. If the joint continues to be chronically enlarged after 6 months of therapy, a surgical synovectomy should be considered.
As an adjuvant therapy, ice and ace bandages are often helpful for hemarthrosis. Additional support to the ankles may be given with firm, high-laced boots. Should a bleeding episode progress sufficiently to cause severe distension of the joint (especially knee hemarthrosis), aspiration of the blood may be necessary. Replacement therapy should be given just before the procedure and a firm ace bandage, Jones' splint, applied afterward.
Intracraneal bleeding remains one of the most common causes of death in patients with bleeding disorders. With the availability of the factor concentrates, the mortality rate is about 35% to 50%. 44,45 Associated complications such as seizures, impaired intellectual function and motor impairment can be expected to occur in approximately 50% of survivors.46 Subdural hematomas occur in hemophilic infartes as a result of foils, but some episodes appear to be spontaneous especially in severely affected patients. A diagnostic problem, however, arises in the hémophilie patient who has received a blow to the head but has no neurological signs. We studied 26 children who had 6? hospital admissions for head trauma, 18 had Factor VIII, 7 Factor IX deficiency and l von Willebrand's Disease.4? Of the 26 children, 17 had severe hemophilia and 2 had Factor VIII inhibitors. All patients had scalp hematoma; 3 had lacerations at the site of the hematoma; 1 had severe cerebral concussion; 3 had a history of possible loss of consciousness; 12 had headache; 1 had vomiting and 4 had dizziness on admission. All patients received factor replacement therapy within 12 hours of trauma and factor levels were maintained over 50% for 2 to 9 days (mean 2.7 ± I.I); all recovered without sequelae. Eighteen patients had skull x-rays on 38 occasions, all of which were negative. Six patients had EEGs, all of which were normal. Of 20 patients who had CT scans on 25 occasions, all were negative. Hemophilic patients treated with adequate factor replacement following head trauma have an excellent prognosis and in the absence of persistent neurological signs or symptoms probably do not require extensive radiological studies. All patients with neurologic sigrw and symptomatology should have CT scanning to ensure early diagnosis of small intracerebral bleeds. By using this routine, the number of patients requiring neurosurgery has been significantly reduced.
In the event that intracerebral bleeding is diagnosed, a massive infusion of concentrates should be given urgently to maintain a plasma factor level of 80 to 100 percent, and the patient should undergo neurosurgical management. Therapy must be continued until healing is complete. This may require several weeks of intensive therapy.
Bleeding into the Vertebral Canal
This is a rare complication of hemophilia and tends to present without any history of trauma. The signs are usually dramatic, with acute onset of pain in the neck or back and progressive onset of paralysis. Seventy five percent of hemorrhages are extramedullary and only 25% are intramedullary.48 Symptoms of acute back pain or neck pain of increasing severity should suggest the diagnosis even before ascending sensory motor paralysis develops. Replacement therapy should begin immediately. Prompt recognition of the problem and institution of medical and surgical therapy before the neurologic deficit has become complete is mandatory if permanent paralysis is to be avoided. Such patients require urgent plasma concentrate replacement, and myelography should be carried out once hemostasis is secured. If the hematoma is large, no cerebrospinal fluid may be obtained and cistemal puncture may be required to localize the lesion. In most cases surgery has had little effect and is associated with high mortality and morbidity. For the patients with complete or partial residual neurologic deficits, intensive physical therapy and rehabilitation measures must be undertaken, often over a prolonged period.
This frequently accompanies pharyngitis and should be suspected when a patient complains that he cannot swallow his saliva. With such a complaint, a lateral x-ray of the neck will help to determine the presence of a retropharyngeal mass and the extent of airway obstruction. Retropharyngeal bleeding may be lethal if not treated immediately and adequately. With adequate replacement therapy, tracheostomy should not be necessary.
This is potentially a life- threatening event because of the large volume of blood which can be lost in the soft tissues of the retroperitoneal space. Spontaneous or traumatically induced bleeding into the retroperitoneal tissues may occur, and because of tracking of blood between tissue planes, a volume sufficient to produce severe hypotension may be lost. Diagnosis may be made by CT scanning or ultrasonography. The pain due to retroperitoneal hemorrhage is treated with bedrest in a position of comfort, factor replacement therapy to a level of 100% for 48 to 72 hours and 50% until complete resolution of the hematoma.
Peripheral Nerve Lesions
Hemorrhage involving peripheral nerves is probably more frequent than is generally recognized. The femoral nerve is the most frequently affected in all series.49·50 Less commonly, the ulnar and median nerves are affected, each accounting for approximately 15% of peripheral nerve lesions in the combined series. Sciatic, radial, and perineal nerves have also been reported to be affected but less commonly. The peripheral nerve lesions in hemophilia are due to external compression or traction on the nerve. Intramuscular hemorrhage is almost always the basis for the subsequent neurologic complications.
In about 25% of patients, documented trauma may be a causative factor. Spontaneous iliopsoas bleeding may cause pain and/or stiffness in the leg, hip, or groin area without any visible signs of swelling. The differential diagnosis of this symptom complex includes hemarthrosis of the hip joint, pulled muscle, gastroenteritis, renal colic, and even appendicitis.
Although plain films of the abdomen may demonstrate asymmetry of the iltopsoas shadows with enlargement of the affected muscle in iliopsoas bleeding, this is a late finding. Similarly, deviation of the ureter and/or bladder as demonstrated by intravenous urography is also a late finding. Until the advent of ultrasonography, there had been no single diagnostic tool capable of detecting early iliopsoas bleeding with accuracy.51
Clinical management of an iliopsoas hematoma differs from that of hip hemarthrosis and superficial hematomas. Treatment for iliopsoas hematomas consists of 1 week of bed rest and replacement with the appropriate clotting factor concentrate. Plasma concentrate is given intravenously twice daily to maintain clotting factor levels between 50% and 100% of normal. Inadequate hemostasis can lead to serious complications such as hip flexion contractures and entrapment of the femoral nerve with attendant loss of quadriceps function, patellar reflex, and anesthesia along the medial aspect of the thigh.13-19 Early mobilization of the limb should be encouraged.
Replacement Therapy for Surgical Procedures
Elective surgery in patients with hemophilia now may be undertaken with effective factor replacement as indicated in Table 7. All patients should have presurgical inhibitor screening and factor recovery should be established since every patient will have different levels of recovery and first half-life and biological half-lives of the factor according to the dosage of replacement factor. Intervals of factor infusions should be established for every patient, especially before major surgical procedures.
Management of Inhibitors in Hemophilia
Approximately 5% to 10% of patients with hemophilia A develop antibodies directed against the functional activity of factor VIII. Incidence of inhibitors in hemophilia B is about 3%. Most of these antibodies are IgG immunoglobulins and will destroy the factor VIII or IX coagulant activity of infused concentrates. There are two distinct patterns of behavior of these antibodies. In about 65% of factor VIII deficient hemophiliacs with inhibitors the antibody level rises after exposure to the factor infusion and falls off over a period of weeks or months in accordance with the 3-week half-life of IgG. Re-exposure to even minute amounts of the factor produces an anamnestic response, with a rapid rise in antibody titer which reaches a peak about 2 weeks later. These patients are "high responders." The antibody titer is usually greater than 10 Bethesda U/ml. In 30% to 35% of patients, the antibody circulates at low levels with little or no rise in titer after the factor infusion. These patients are the "low responders." The antibody titer tends to be low and to remain below 5 Bethesda U/ml. Even if repeated doses of the factor are given, the antibody titer rises only slightly and it may remain below 5 Bethesda U/ml.
Several clinical studies have shown the usefulness of "Prothrombin Complex Concentrates" (PCC) in hemophilic patients with inhibitors.53,54 PCC includes significant levels of prothrombin, factor VH, factor IX and factor X as well as activated forms of factor (Vila, IXa and Xa). The factor VHI by passing activity of PCC is thought to be, in part, related to the factor Xa content of the product. It is additionally hypothesized that the elevated factor Vila content of this product is also a contributing factor in the in vivo re-establishment of normal hemostasis by way of factor X activation in conjunction with tissue factor, phospholipid, and ionic calcium.
The commercially available US products are Konyne (Cutter) and Proplex (Hyland). The US inhibitor study group has evaluated the efficacy of single doses of Konyne and Proplex in the treatment of early hemarthroses in patients with inhibitors in a double blind study using albumin as a control material. Both nonactivated prothiombin complex concentrates resulted in better response than albumin.54
Presently, there are activated PCC (APCC) products in the US Autoplex (Hyland) and in Europe FEIBA (Immuno, Austria). Clinical experience with Autoplex, mild to moderate bleeding episodes usually respond to infusion of 50 units/ kg, and more serious hemorrhages are treated with an initial infusion of 100 units/kg with repeat doses at 6- to 24-hour intervals as needed to maintain hemostasis. Laboratory or clinical evidence of thrombosis or disseminated intravascular coagulation is not usually observed following the use of Autoplex. Significant hypofibrinogenemia, not associated with evidence of disseminated inrravascular coagulation or fibrinolysis has been observed in 2 children who received repeated doses of Autoplex.55 In view of this, regular measurement of fibrinogen is advisable in children who are receiving repeated doses of Autoplex.
RECOMMENDATIONS FOR REPLACEMENT THERAPY FOR TREATMENT OF BLEEDING IN PATIENTS WITH FACTOR VIII INHIBITOR54
However, there have been numerous reports of thrombotic complications occurring in patients receiving PCC, nearly all of these have occurred in patients with liver disease or in factor IX deficient patients receiving repeated doses of PCC. There have now been several reports of young men with inhibitor who have developed myocardial infarcts after receiving large and repeated doses of nonactivated PCC- 56, 57 Therefore, repeated doses of nonactivated PCC are not recommended.58 Though nonactivated PCC (Konyne, Proplex) may be effective in some limited bleeding episodes, their use should be restricted to no more than one or two doses in an effort to avoid thrombotic complications.
Since only limited data are available on the administration of PCC or APCC products together with antifibronolytic agents such as EACA, the concomitant use of Konyne, Proplex or Autoplex with such agents is not recommended. Following recommendations for replacement therapy for various type of bleeding in patients with inhibitors are offered (Table 8).
1) Known "low responder" patients (<5BU) can be treated with higher doses of factor VlIl (50 to 200 u/kg) to achieve hemostasis in minor and major bleedings.
2) "High responders" with low inhibitor levels (<5BU) should be treated for minor bleedings with non-activated PCC at a dose of 100 u/kg, daily, up to 4 days. Patients with high inhibitor levels (>5BU) should be given APCC (50 u/ kg, daily).
3) "High responder" and low inhibitor level (<5BU) patients with major bleedings may be treated with high doses of factor VIII infusions (50 to 200 u/kg) until amnestic response occurs (post infusion recovery and survival should be measured).
4) For major to life-threatening bleedings, "high responder" and high level inhibitor (>5BU) patients APCC should be initiated immediately at a dose of 50 to 100 u/kg. If the patient improves clinically in the next 4 to 6 hours, a second dose of unactivated concentrate can be given in 6 to 12 hours and then q 12 to 24 hours.
5) Plasmapheresis and factor VIII replacement is the preferred method of management for semi-urgent surgery (where delay is possible to have 1 to 3 plasmapheresis) in patients with high titers (>5BU). One to three plasmapheresis are usually sufficient to decrease the titer to low levels (<1-2BU) such that large doses of factor VIII infusions will achieve a circulating level of factor VIII sufficient for hemostasis. This approach, more predictably allows a factor VIII level >50% during surgery and the first few postoperative days. In an anamnestic rise in titer at 3 to 5 days prevents further factor VIII therapy, factor IX concentrate can be substituted, or further daily plasmapheresis performed.
6) High responder patients with morbidity from chronic recurrent bleeding in one site that has not responded to regular prophylactic therapy with unactivated PCC can be given a trial of activated PCC.
7) Elective surgery should be avoided in all inhibitor patients except those well-known to be low responders and with an obvious indication for surgery. (Dental extractions can generally be performed with EACA therapy alone. )
Home Treatment Program
The early and prompt therapy for the hemophiliac is very important. Home treatment programs were developed to provide this type of care. It has been a great success and ideal for the vast majority of severely affected hemophiliacs.59,60 Parents of affected children over 3 to 4 years of age and the patients themselves when they reach 10 or 12 years can easily be taught the technique of venipuncture and be familiarized with the indications for treatment. They are supplied with factor concentrates to be stored at home in the freezer or refrigerator. Close telephone contact and careful recordkeeping by the patient and primary physician or nurse coordinator of the "Hemophilia Comprehensive Care" center are required. Continued regular clinic follow-up is necessary in order to monitor the results of home therapy. At some centers, all patients attend biannual or annual comprehensive evaluation sessions as a requirement for continuation of the program. During the course of each visit, the patient is evaluated by a hematologist and an orthopedic surgeon, a nurse practitioner, a medical social worker, an oral surgeon, a physical therapist, a vocational counselor, a genetic counselor and/or a psychologist or psychiatrist.
Despite some existing difficulties, home treatment is greatly accepted by patients and their families. There are many benefits from such care. There is less disruption of family life in that lengthy and intermittent emergency room or hemophilia clinic visits are no longer necessary. With immediate tretament, there is more rapid recovery from acute bleeding symptoms. Therefore, less number of days are missed from school. Psychological benefits are remarkable as the patient established self-sufficiency. Home treatment programs resulted in an increase in the quantity of clotting factor materials utilized, but the total costs are actually much less than conventional therapy in the clinic or emergency room.60
Active Immunization Against Hepatitis B Virus
Hemophilie children who are HBsAg and anti-HBs antibody negative should be immunized with hepatitis B vaccine. Plasma-derived vaccines against hepatitis B have proven to be highly effective in several recent trials in highrisk populations. Two double-blind trials conducted in the US demonstrated 80% to 90% efficacy.6'-64 These studies used a hepatitis B vaccine (Heptavax-B*, Merck Sharp and Dohme, West Point, PA). Heptavax-B is a non-infectious formalin-inactivated subunit viral vaccine derived from surface antigen (HBsAg or Australia antigen) of hepatitis B virus. The antigen is harvested and purified from the plasma of human carriers of hepatitis B. About 22% to 23% of individuals may experience side effects during the 5 days after their injections (local pain, mild fever).65 The immunization regimen consists of three doses of vaccine given according to the following schedule: 1st dose: at elected date; 2nd dose: 1 month later; 3rd dose; 6 months after the first dose. The volume of vaccine to be given on each occasion is from birth to 10 years of age 0. 5ml, and in older children and adults 1.0ml.
Acquired Immune Deficiency Syndrome (AIDS) and Hemophilia
As of December 17, 1984, physicians and health departments in the US have reported a total of 51 AIDS cases among hemophilia patients (47 adult/adolescent and 4 children).
The following recommendations have been given for physicians treating patients with hemophilia by the National Hemophilia Foundation, Medical and Scientific Advisory Council:
A. For patients with factor VlII deficiency, it is recommended that cryoprecipitate be used to treat patients in the following groups (with the recognition that there are some circumstances where viral attenuated-heat treated factor VIII concentrate may be appropriate therapy):
* newborn infants and children under 4;
* newly identified patients never treated with factor VIII concentrates. (Similar guidelines should be applied to factor IX deficiency patients where fresh frozen plasma can be used. )
B. Desmopressin ( DDAVP) should be used whenever possible in patients with mild or moderate hemophilia A.
C. There are not sufficient data of scientific nature to know with certainty that viral attenuated (heat-treated) coagulation factor concentrates should now be adopted. However, very preliminary data suggest that HTLV-III have been exposed to living virus capable of causing AIDS or have developed effective immunity against AIDS.
VARIANTS OF VON WILLEBRAND1S DISEASE
D. AH elective surgical procedures should be evaluated with respect to the possible advantages or disadvantages of a delay.
E. The patients should continue treating bleeding episodes with clotting factor as prescribed by their physician as the risk of withholding treatment far outweighs the risk of treatment. Therefore, it is important that patient education and psychological support be provided.
MANAGEMENT OF VON WILLEBRAND'S DISEASE
Von Willebrand described a group of patients with an inherited hemorrhagic disorder characterized by defective primary hemostasis and a prolonged bleeding time.66 Later, it became apparent that it is also associated with low levels of VIIIrC.67 One of the characteristic features of the disease is its variable nature both in clinical presentation and laboratory manifestations. This variation occurs not only from family to family but also from affected individual to individual within a family and even if to a lesser extent, as individual patients at different times. Most patients aie heterozygous and some, therefore, tend to be clinically mildly affected, although bleeding may occur from specific sites such as the gastrointestinal tract. There is an uncommon severe form of the disease in which hémophilie-type lesions such as hemarthroses occur; this may represent a homozygous genotype. Because of this variable it is difficult to estimate accurately the incidence of the disease. It is reported in one center that the incidence is about one-half that of hemophilia A, ie, about 3 to 4 per 100,000 of the population.68
Von Willebrand's disease is due to an abnormality of the large multimene glycoprotein, Willebrand factor (VWF). Variants are defined according to the type of abnormality, which may be quantitative, qualitative, or both (Table 9). VWF supports adhesion of platelets to the subendothelial tissues.69 Platelets have receptor sites for the factor.70 VWF is found in the plasma, platelets, megakaryocytes and endothelial cells and is under the control of autosomal genes. VWF subunits, MW about 200,000, bond together to form multimers of various sizes, up to 12,000,000 MW.71-72 The larger multimers are more effective in supporting platelet adhesion. Deficiency in the total amount of Willebrand factor, or in larger multimers, or other structural abnormalities may lead to a bleeding time. When measured in an immunologie test, VWF is known as factor VIH-related antigen (VIIIR:Ag). 73
RECOMMENDED TREATMENT IN VON WILLEBRAND S DISEASE
VWF also circulates complexed with factor VlII procoagulant activity ( VIIIiC), the plasma factor, under control of a gene on the X-chromosome, that is deficient in classic hemophilia. VWF appears to have a stabilizing effect on VlIIiC, and thus facilitates its survival in circulation. VWF is deficient or defective, the amount of circulating VIII:C may be low. VWF function is reflected by the bleeding time and by the ristocetin cofactor (VIIIR:RCo) test. The latter measures the ability of patient plasma to support the agglutination of normal washed platelets in the presence of die reagent, ristocetin, thus, permitting the development of a quantitative assay. 7J Studies of the muttimeric structure of VWF are made by electropheresis in gels of agarose or acrylamide or both.75'76 The total amount of VWF can be measured as VIIIR:Ag by electropheresis with rabbit antihuman-factor VIII antibody by the Laureti technique,73 or by radioimmunoassay.77
Descriptions of Variants in von WUlebrand's Disease (Table 9)
Type 1: The most common form, is autosomal dominant with variability of the degree of phenotypic expression. The total amount of VWF is decreased but multimers of all sizes, including the very large, are present both in plasma and in platelets. Administration of DCAVP increased levels of VIIIRiRCo of all multimene sizes and levels of VIII:C and VIIIRiAg, thus leading to temporary restoration of normal hemos tasis.
Type II: The larger multimers of VWF are absent from the plasma. This type is subdivided further.
Type IIA: Large and medium-large multimers are absent from the plasma and platelets. Administration of DDAVP leads to release of more small multimers of VWF, but no increase in large multimers. The bleeding time may improve substantially but usually is not completely corrected.
Type IIB: The larger multimers are absent from the plasma but present in platelets. After DDAVP, the multimene structure of VWF may be corrected transiently; large multimers may be released from platelets and endothelial cells. These large multimers released by DDAVP are cleared from the plasma more rapidly than are large multimers of Willebrand factor infused as cryoprecipitate. Thus, type IIB large multimers may have enhanced affinity for cellular bind' ing sites. After DDAVP, the bleeding time may be improved but usually is not corrected fully. However, in some patients DDAVP causes a temporary but precipitous drop in the platelet count, probably due to the formation of platelet aggregates.42
In Type 11C, the rare inherited in an autosomal recessive pattern, larger multimers are missing from both plasma and platelets, but the amount of small multimers is increased. DDAVP increased plasma levels of VWF and VHI:C, some improvement of the bleeding time may be seen. This variant is due to a structural abnormality of VWF.
Type II is a very severe type of von Willebrand's disease, which is inherited in an autosomat recessive fashion. VIIIB:RCo cannot be detected. There is no agglutination of platelet-rich plasma with ristocetin. VIIIR:Ag may be absent in both plasma, platelets and endothelial cells. Type III is not responsive to DDAVP.
Epistaxis is the most common symptom.78'79 Gingival bleeding, easy bruising and menorrhagia in females are the next most common symptoms. Bleeding after tonsillectomy and gastrointestinal hemorrhage also occurs. Prolonged bleeding after dental extraction is also common. Similarly, prolonged bleeding from cuts and trauma is a fairly common complaint among affected patients. There is a tendency for symptoms to decrease significantly after adolescence, especially in females. Postpartum hemorrhage is variable and even may vary in different deliveries in the same women.
Spontaneous hemarthroses are rare and occur only in patients with very low VIII:C level (type-Ill). Only a small fraction of affected patients have severe bleeding symptoms, and death as a result of bleeding is extremely rare. However, uncontrollable gastrointestinal hemorrhage may be the lethal event. Recommendations for the treatment of VWD are offered in Table 10.
DDAVP infusions cause a marked increase in factor VIII related properties in patients with mild hemophilia or VWD.34-40 The structure, usage and dosage of DDAVP were discussed earlier. Patients with very severe VWD-type-lII are unresponsive to DDAVP.41 It is quite effective in type-I variant of VWD (probably most common type), with correction of both the bleeding time and the plasma factor VIII complex components. In the type UA variant, the correction of the bleeding time may be only partial, but the levels of VIII:C improve and clinical benefit is usually seen. Some patients with type-IIB variant rapidly develop severe, transient thrombocytopenia after administration of DDAVP;42 thus, DDAVP is contraindicated in type-IIB.
CRYOPRECIPITATE TREATMENT IN VON WIUEBRANO1S DISEASE
Cryoprecipitate therapy is essential in patients with VWD for monitoring surgical procedures and managing severe hemorrhages (Table II). In severe type of VWD (type-Ill), bleeding may be treated with cryoprecipitate. Sufficient cryoprecipitate is given to raise the plasma factor VIII activity (VHI:C) adequately, and to supply VIIIR:WF to correct the platelet dysfunction. The improvement in the plasma VIIhC level usually lasts for several days because of the "secondary rise" in VIH:C. The correction of the platelet dysfunction lasts only a few hours. The bieeding time may not improve although the other platelet function tests improve and the patient's bleeding stops.
Patients with levels of factor VIII activity ( VIII:C) in the normal range may still need infusions of cryoprecipitate to permit normal platelet plug formation to stop hemorrhaging, or to prevent hemorrhaging during surgery. For dental extraction, the plasma factor activity is raised to 20% to 30% by either DDAVP or cryoprecipitate infusions and EACA (Amicar) is given 50mg/kg, Q6h for 7 days. Use of EACA was discussed earlier. The same principles for mild hemophiliacs are applicable to patients with VWD regarding usage, the dosage, and the duration of EACA.
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RELATION OF FACTOR LEVELS TO SEVERfTY OF CLINICAL MANIFESTATIONS OF HEMOPHILIA A AND B
COMMON SITES OF HEMORRHAGES IN HEMOPHILIA
PRODUCTS FOR FACTORS VIII AND IX REPLACEMENT
TREATMENT OF BLEEDING EPISODES
TREATMENT OF MUCOUS MEMBRANE HEMORRHAGES
TREATMENT OF HIGH-RISK HEMORRHAGES
REPLACEMENT THERAPY FOR SURGICAL PROCEDURES IN PATIENTS WITH HEMOPHILIA 52
RECOMMENDATIONS FOR REPLACEMENT THERAPY FOR TREATMENT OF BLEEDING IN PATIENTS WITH FACTOR VIII INHIBITOR54
VARIANTS OF VON WILLEBRAND1S DISEASE
RECOMMENDED TREATMENT IN VON WILLEBRAND S DISEASE
CRYOPRECIPITATE TREATMENT IN VON WIUEBRANO1S DISEASE