Pediatricians and orthopedists may see relatively few patients with hemophilia, depending on the geographic location and orientation of their practice. Nonetheless, factor VIII and IX deficiency are common enough to warrant a discussion of an approach to the management of the most common hemophilic disability - musculoskeletal bleeding.
In 1979, Margaret Hilgartner wrote an article for Pediatric Annals entitled, "Managing the Child with Hemophilia."1 Her overview of the treatment of hemophilia is excellent background. Because of the ready availability of therapeutic concentrates and the increasing acceptance of home infusion by the patient and his family, today's hemophiliac should be able to lead a more normal life than ever before. Braces, crutches and casts have become less necessary for most patients. Nonetheless, musculoskeletal bleeding in key areas requires aggressive and immediate treatment if serious sequelae are to be prevented. Operative treatment may now actually be the treatment of choice in some situations.2 Our rationale for the treatment of acute and chronic or recurrent bleeding in critical anatomic areas in the hemophilic child is presented here.
All too frequently, intramuscular bleeding is treated as a relatively innocuous process, with ice packs and compressive bandages. Unfortunately, it is not so simple. Severe deformity and permanent nerve or vascular damage can result if intramuscular bleeding is not treated quickly with adequate factor replacement. The active child with severe factor deficiency (less than 1 % plasma factor VIII or IX level) or moderate deficiency (1% to 5% level) is prone to develop not only traumatic bleeding but, also, apparently spontaneous intramuscular hemorrhages.
When bleeding occurs within a muscle, the muscle balloons up within its relatively nonelastic myofascial envelope. As this occurs, pressure builds within the muscle, which then can reach levels exceeding arteriolar pressure. Blood flow to the muscle fibers decreases dramatically, and muscle cells undergo ischemic necrosis.
The surrounding myofascia is relatively inelastic, and as hemorrhage expands the muscle's volume, the resting length of the muscle shortens. Since passive stretching of the swollen muscle is quite painful, the hemophilic child cannot prevent the joint spanned by the affected muscle from assuming an abnormal position.
If the hemorrhage has been severe enough to cause muscle necrosis, healing may occur in several ways. Most frequently, as the swelling subsides, the dead muscle is replaced by fibrosis and ultimately a scar. Since collagen, which makes up the scar, is inelastic, the muscle may remain in a shortened state, and the affected joint will therefore remain in an abnormal position. Occasionally, however, the hematoma and necrotic muscle may become walled off by a fibrous capsule before the effused blood has been completely removed by the reticuloendothelial system. When this happens, and the enclosed hematoma liquifies, the osmotic pressure within the hematoma increases and interstitial fluid is drawn into the blood-filled cyst. This precipitates further swelling and bleeding at the cyst margin. This process may be repeated many times until a large mass develops layer upon layer, forming a pseudocyst.
PSOAS MUSCLE HEMORRHAGE
Perhaps the muscle bleed most difficult to diagnose promptly and correctly is the psoas muscle hemorrhage. This muscle takes its origin from the transverse processes of the lumbar vertebrae and spans the hip joint to insert at the lesser trochanter of the proximal femur. The femoral nerve closely approximates the anterior myofascia of this muscle. When the psoas expands during a hemorrhage, the hip assumes a flexed position, and pain is referred to the hip joint. If the patient can walk, he does so bent forward with the hip flexed. He prefers pillows beneath his knee and thigh when he lies supine. The physician may erroneously believe his patient has an intra-articular hemorrhage into his hip joint, or if the psoas bleed is on the right side, that he has appendicitis.
To differentiate between a psoas hemorrhage and a bleed into the hip joint, it is only necessary for the physician to flex the hip passively to 90°, This will be painful if the bleeding is intra-articular, but will relieve the pain of a psoas bleed because it relaxes the muscle and reduces intramuscular pressure. Furthermore, rotating the hip slightly when it is flexed to 90° will be uncomfortable with a hip bleed, but not with psoas hemorrhage.
Differentiation of a right-sided psoas bleed from acute appendicitis with psoas irritation requires attention to the presenting symptoms. A psoas hemorrhage is not usually preceded by crampy abdominal pain, nausea and vomiting. Leukocytosis and mild leftward shift in the WBC differential may occur with psoas hemorrhage, but the white cell count usually does not continue to rise with the passage of time, as is the case with appendicitis.
Once a diagnosis of psoas hemorrhage has been established, it is important to evaluate femoral nerve function. This must be done by checking both sensory and motor activity of the nerve. Sensory function is evaluated by comparing sensation to light touch (not pinprick in the hemophiliac) in the anterior thigh above the patella in both lower extremities. If sensation is decreased on the side of hemorrhage, the femoral nerve is being stretched and compressed by the expanding psoas muscle. Motor function of the femoral nerve is evaluated by asking the patient to extend his knee fully. If he cannot do this, or if extension is weaker than on the opposite side, the femoral nerve, which supplies the quadriceps muscle, has been severely compromised. Approximately 10% of complete femoral neuropathies secondary to psoas bleeding never recover. When this is the case, the patient may be left with permanent quadriceps muscle weakness.
Bleeding within the gastrocnemius muscle causes the ankle to plantarflex, and the foot assumes an equinus or tiptoe position. The child cannot dorsiflex his foot to the neutral position because of pain. This intramuscular bleed is easy to recognize, but frequently is considered trivial. Permanent equinus contracture of the foot can result, necessitating a surgical procedure to lengthen the scarred muscle at a later date. Again, swift and adequate factor replacement will help prevent permanent disability.
TREATMENT OF MUSCLE HEMORRHAGE
As soon as a muscle hemorrhage is detected, the deficient clotting factor should be given to achieve an initial 50% level. Elastic bandages and casts should not be used acutely, since these can potentially increase intramuscular pressure and cause further damage. Patients with a psoas hemorrhage should be hospitalized until it can be determined that the femoral nerve is not in danger.
In most patients, the half-life of transfused factor VIII is approximately 10-12 hours and that of factor IX, 18-24 hours. A 50% dose should again be administered approximately 1 2 hours after the first dose in an attempt to maintain a 50% plasma level until the muscle swelling (if the muscle is palpable) begins to recede.
At that point, and only then, physical means may be used to stretch the contracted muscle. For the gastrocnemius, this may mean passive stretching of the muscle by the child, a family member, or a physical therapist. For psoas bleeding it will usually mean traction with gradual increase in hip extension. It is important to continuefactor replacement during therapy, usually at 50% levels daily, until the need for passive stretching of the muscle is over, and the joint spanned by the muscle has resumed its former range of motion.
Occasionally a muscle bleed will occur in a "closed compartment," such as the anterior compartment of the calf or the flexor compartment of the forearm. When this occurs, the danger of Volkmann's ischemic contracture may exist. Under these circumstances, and with adequate clotting factor supplementation, intramuscular pressure may be measured using a wick catheter.3 If the intramuscular pressure is 50 mm Hg or greater, fasciotomy should be urgently considered. In the hemophiliac without inhibitors to factor VIII or IX, an emergency operation to relieve the threat of severe muscle necrosis is far less risky than "waiting to see what happens" until it is too late for the muscle to recover. When dealing with a severe muscle bleed, your orthopedic colleague should be consulted promptly, rather than delaying until the severely damaged muscle can no longer benefit from decompressive fasciotomy.
STAGES OF HEMOPHILIC ARTHROPATHY
Aside from superficial bruising, joint hemorrhage is the most common disabling complication of hemophilia. The knee joints are most frequently affected, followed by elbows, ankles, hips and shoulders. More school and play time is lost by knee joint bleeding than by any other hemorrhage in the young hemophiliac. Knee bleeding with chronic arthropathy is also the leading cause of residual disability in adult hemophiliacs.
CLASSIFICATION OF HEMOPHILIC ARTHROPATHY
In their article on hemophilic arthropathy, Arnold and Hilgartner4 have developed a classification which is useful for planning treatment. This classification is summarized in Table I. Arthropathy is still a common feature of hemophilia, even with adequate home therapy programs. After a number of intra-articular hemorrhages, the joint synovium may become hyperplastic, much as it does in the child with juvenile rheumatoid arthritis. The synovium then begins to attack the articular cartilage by pannus formation. In addition, high concentrations of degradative enzymes capable of breaking down the matrix of articular cartilage may be found in the synovial fluid of the chronically swollen hemophilic joint.
When chronic arthropathy develops, the hyperplastic synovium becomes easily palpable as a rubbery mass, particularly in the suprapatellar region of the knee joint. Within the synovium in the Stage I or Stage II hemophilic joint are an extraordinary number of capillaries, arterioles and venules with extremely thin or deficient walls. Thus there is continual oozing of blood from the synovium into the joint cavity, which propagates the destructive process. In addition, because of the continued hyperemia and inflammation, epiphyseal growth is stimulated, and the epiphyseal centers of the distal femur, proximal tibia and patella grow more rapidly than normal, just as in rheumatoid arthritis. The shape of the bone ends at the joint then become altered and these structural changes produce a diminution in the joint's range of motion. The extremely irregular joint surfaces characteristic of adult stage IV and V arthropathy gradually develop. This process is identical for all joints affected by chronic hemophilic arthropathy.
TREATMENT OF EPISODIC JOINT BLEEDING
The object of home treatment programs is to prevent delay in factor replacement, in order to minimize the extent of hemorrhage occurring before hemostasis is achieved. Most hemophilia centers provide movies or videotapes which are shown repeatedly to parents and children in the waiting areas of the clinic. These films reinforce the concept of early recognition, particularly of intra-articular hemorrhage, and the importance of prompt, adequate factor infusion. We believe we have been able to reduce the incidence of chronic arthropathy in our children in this manner. In addition, we feel that in some cases we have postponed the onset of chronic arthropathy until the child is an early teenager, thereby decreasing the severity of growth disturbance for those who do develop hemophilic arthropathy. It is, however, still too early to have much more than an impression that this is so.
Figur· 1A. Stage III hemophilic arthropathy of left knee in a nineyear-old boy. Note the narrowing cartilage space and subchondral cysts. This x-ray was obtained just prior to surgical synovectomy.
Factor replacement for episodic hemarthroses should begin with a dosage calculated to increase the deficient factor to a 50% plasma level. This may need to be repeated every 12 hours for several days. A single infusion is rarely enough to prevent further bleeding. Here again, waiting to see if only one infusion is necessary frequently leads to recurrent hemorrhage and an increase in time lost from normal activities.
Joint aspiration is rarely necessary in episodic bleeding. The mixture of fresh blood and synovial fluid within the joint produces a very viscous fluid which is difficult to remove even with a 15-gauge needle. Occasionally a joint will become so swollen and tense that the pain is excruciating. Following adequate clotting factor coverage, a large bore needle may be used to remove some of the thick joint fluid. Even removing as little as 10 ml may reduce pain dramatically. When aspirating a knee joint, one should use careful sterile technique and should insert the needle just above and lateral to the patella. The needle point may then be advanced underneath the patella, which will prevent it from being obstructed by synovial tissue.
TREATMENT OF CHRONIC HEMOPHILIC ARTHROPATHY
When a joint has reached the stage of chronic synovitis, joint swelling is persistent. Frequently there is little discomfort, even though the joint may be quite tense and warm to the touch. Because the child's joint capsule is not yet scarred and contracted, range of joint motion is frequently nearly normal despite quite dramatic swelling.
Treatment of chronic synovitis is difficult, but if the problem is ignored, joint destruction is inevitable. Our routine is to attempt vigorous medical treatment for the joint that has remained chronically swollen for six months or more. This involves daily or alternate day factor replacement to achieve 40% factor levels, night splinting using a soft splint with stays, decreased activity during the day, and alternate day oral corticosteroid therapy using methy !prednisolone starting at a dosage of 2 mgm/kg. In approximately 30 to 50% of the cases treated in this manner, there has been significant improvement within three months, at which point both factor replacement and corticosteroids are gradually tapered and then discontinued.
If medical treatment is unsuccessful, surgical synovectomy may be recommended (Figures IA, B). Synovectomy should not be undertaken lightly, because the recovery period is prolonged and often involves a difficult, painful period of physical therapy required to regain range of motion. The child and parents should expect very slow progress during this process. Often a knee manipulation under anesthesia must be done approximately six weeks after synovectomy to prevent permanent loss of joint mobility from postoperative intra-articular scarring.
Figure 1B. The same patient four years later, at age 13, just prior to synovectomy of the right knee. Note the wider cartilage space of his left knee, and the absence of subchondral cysts, four years following synovectomy.
The emotional toll to all concerned is considerable in the weeks following synovectomy. There may be some slight residual loss of joint motion when maximum function has been regained, but we have observed very few subsequent joint hemorrhages. Also, the progress of the arthropathy seems to be aborted, although it is too early to be completely certain of this. Since most hemophilia treatment centers in this country have been performing synovectomy (usually of the knee) for only 10 years, longterm folio wup of significant numbers of patients is not yet available.
TREATMENT OF PSEUDOCYSTS AND PSEUDOTUMORS
The term pseudocyst refers to an expanding soft tissue hematoma, which can threaten adjacent structures such as nerves and blood vessels. The term pseudotumor is usually reserved for the same process which begins subperiosteally, and hence can destroy bone by pressure necrosis (Figure 2). Fractures in hemophiliacs, unless treated from their onset with appropriate hemostatic levels of factor, may progress to pseudotumors. Trauma which causes subperiosteal injury and hemorrhage, such as a sharp blow on the shin or ulnar aspect of the forearm, can also lead to this serious complication.
Figure 2. This 1 3-year-old had been struck on the lateral aspect of the calf with a softball bat six months ago, Note the expansile, destructive pseudotumor of the fibula.
Once a pseudocyst or pseudotumor has begun forming, it tends to progress relentlessly. Patients who develop this relatively uncommon complication should be referred promptly to a regional hemophilia treatment center.
TREATMENT OF MUSCULOSKELETAL BLEEDING IN PATIENTS WITH AN INHIBITOR
Perhaps the most feared complication of hemophilia is the development of IgG antibodies which neutralize the clotting factor activity of transfused factor viii or ix. these inhibitors appear for unknown reasons in 8- 14% of patients with severe factor viii deficiency and a similar proportion (12%) of those with severe factor ix deficiency.5
au hemophiliacs should be tested for inhibitors at regular intervals and at any time when bleeding is not controlled by what would be considered adequate factor concentrate therapy for a given bleeding episode. surgery, and even minor invasive procedures, should not be undertaken until an inhibitor screening test and factor survival study have been completed. as soon as an inhibitor is detected, the hemophiliac and his family should be referred to a regional hemophilia treatment center for continuing comprehensive care.
inhibitors do not alter the frequency or anatomical distribution of hemorrhage, but they obviously necessitate alternative management approaches. conventional factor replacement schedules are frequently ineffective in securing hemostasis and wound healing in these patients. special care must be exercised to avoid exposing the inhibitor patient to unnecessary trauma and invasive procedures.
factor viii deficient patients with inhibitor titers greater than 5 bethesda units may show little or no rise in their plasma factor vlii levels immediately following an infusion of large amounts of factor viii concentrate. there is, however, significant variability in antibody titer and response among inhibitor patients. massive doses of factor viil or ix with or without concomitant plasma exchange may stabilize bleeding in patients whose antibody can be temporarily overwhelmed. unfortunately, the anamnestic rise in inhibitor titer which can develop 5-7 days later may preclude treatment of another, possibly more serious, hemorrhage occurring at a later time. other treatment modalities, including immunosuppressive therapy, have been disappointing.
a promising approach to the treatment of hemorrhage in patients with factor viii inhibitors is the use of prothrombin complex concentrates (pcc) containing factors ii, vli, ix, x and other substances (including activated clotting factor intermediates). these concentrates apparently "bypass" or partially ameliorate tfte defect imposed by the factor viii antibody. it is clear that PCC are not as hemostatically effective as factor VIII concentrate used in the treatment of hemophiliacs lacking inhibitors. Nonetheless, two recent double blind clinical trials have demonstrated a significant beneficial effect of both "non-activated" and "activated" PCC on joint and muscle hemorrhage in hemophiliacs with factor VIlI inhibitors. Lusher et al6 showed symptomatic improvement in 52% of episodes of single joint hemarthroses treated with one infusion of non-activated PCC (Konyne or Proplex), compared with 25% improvement following albumin placebo. Sjamsoedin et al7 studied the efficacy of a single infusion of activated PCC (FEIBA) in the treatment of inhibitor patients with primarily joint and muscle hemorrhage. Using a nonactivated preparation as a control, they demonstrated a favorable clinical response in 64% of bleeding episodes treated with FEIBA and in 50% of those treated with non-activated PCC.
The management of hemophiliacs with inhibitors remains a topic of controversy, and the exact indications for the use of the costly "activated" forms of PCC have yet to be defined.8 This uncertainty underscores the need for early referral of the inhibitor patient to specialized regional hemophilia centers where he can benefit from the most current treatment strategies.
1. Hilgartncr MW; Managing the child with hemophilia. Pediatr Ann 8(8):393-4O0. 1979.
2. Greer RB: Operative management of hemophilic arthropathy: An overview. Orthopedics 3(3): 135-138, 1980.
3. Matsen FA, Winquist RA, Krugmire RB: Diagnosis and management of compartmental syndromes. J Bone Joint Surg 62A:286-29I, 1980.
4. Arnold WD, Hilgartner MW: Hemophilic arthropathy: Current concepts of pathogenesis and management. J Bone Joint Surg 59A: 287-305, 1977.
5. Shapiro SS. Hultin M: Acquired inhibitors to the blood coagulation factors. Semi Thromb Hemostas 1:336-385, 1975.
6. Lusher JM, Shapiro SS, Palascak JE, et al: Efficacy of prothrombin complex concentrates in hemophiliacs with antibodies to Factor VlIl: A mutticenter therapeutic trial. N Engl J Med 303:421-425, 1980.
7. Sjamsoedin LJM, Heijnen L, Mauser-Bunschoten EP, et al: The effect of activated prothrombin-complex concentrate (FElBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to Factor VIJI: A double-blind clinical trial. N Engl J Med 305:717-721, 1981.
8. Roberts H: Hemophiliacs with inhibitors: Therapeutic options. New Engl J Med 305:757-758, 1981.
STAGES OF HEMOPHILIC ARTHROPATHY