Management of hemophilia in colon and rectal surgery

With the introduction of Factor VIII concentrates, surgery on patients with hemophilia has become possible. The mortality in recent large series is zero. The morbidity has been variable, with postoperative hemorhage the most common complication. There is a dramatic change in therapeutic strategy with the development of Factor VIII inhibitors. In reviewing the literature, there are no reports discussing this patient population with respect to the subspecialty of colon and rectal surgery. The authors present a report of a patient with hemophilia who, after hemorroidectomy, developed Factor VIII inhibitors and continued hemorrhage. This article also reviews the literature and centralizes the management of colon and rectal surgery patients with hemophilia.     

Prophylaxis in haemophilia patients with inhibitors

Summary.   The presence of high titre inhibitors makes the treatment of bleeding episodes in haemophilia patients difficult and increases the risk of uncontrollable bleeding and disability, despite optimum on-demand treatment with bypassing agents. The inability to effectively control joint bleeding leads to progressive joint disease in many patients with inhibitors. Significant mobility impairments are far more prevalent in patients with inhibitors than in those without inhibitors. Emerging data suggest that prophylaxis using bypassing agents may be effective and safe in reducing the incidence of joint bleeding during immune tolerance induction (ITI), and for patients who failed ITI or who were never candidates for ITI. Only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors. This article will review the published data on the use of bypassing agents in the prevention of bleeding, and will discuss ongoing clinical prophylaxis trials in inhibitor patients.     

Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors

Prothrombin complex concentrates (PCCs) and, more recently, activated prothrombin complex concentrates (APCCs), are widely used for the treatment of active bleeding in haemophiliacs with inhibitors. Myocardial infarction (MI), associated with the use of these concentrates, is a well-recognized, but uncommon, complication. We review the 14 previous cases published in the literature and describe two additional patients. MI related to the use of activated and non-activated PCCs predominantly affects young patients who often have no preceding history of, or risk factors for, MI and tends to be associated with large cumulative doses of concentrate. The most frequent pathological finding is myocardial haemorrhage, with no evidence of coronary artery atheroma or thrombosis. The management of further bleeding in these patients is difficult. We have safely used recombinant factor VIIa to treat bleeding in the immediate and long-term period following PCC-related MI.     

Prevention of bleeds in hemophilia patients with inhibitors: emerging data and clinical direction

In patients with hemophilia, the development of high-responding inhibitors to factor VIII prevents adequate replacement therapy and results in increased risk of serious bleeding episodes, poor control of joint bleeding, and progressive, debilitating joint disease. Immune tolerance therapy can eradicate inhibitors, but it is not uniformly successful. Emerging data suggest that prophylaxis using activated prothrombin complex concentrates may be effective and safe in reducing the incidence of joint bleeding during immune tolerance therapy and for patients in whom immune tolerance induction fails. However, only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors.     

Successful medical management of a neonate with spontaneous splenic rupture and severe hemophilia A

Splenic rupture in neonates is a rare event, usually occurring in the setting of underlying predisposing conditions. Here, we present the case of a term neonate who presented with worsening anemia in the setting of known hemolytic disease during the newborn period and was later found to have a spontaneous splenic rupture. He was subsequently diagnosed with severe hemophilia A, and was managed medically with recombinant factor VIII replacement therapy without any surgical intervention. This is the first reported case of a neonate who had spontaneous splenic rupture and severe hemophilia A, and underwent successful medical treatment without any surgical intervention.     

Surgery in haemophilic patients with inhibitor: 20 years of experience

Summary.  Surgery in haemophilic patients with inhibitor against factor (F)VIII or FIX is high risk. Surgery may be performed with the administration of sufficiently high dose of FVIII in patients with low-response inhibitor or who, despite having a high response, present a low inhibitor titre at the time of surgery. The use of high doses of FX is more complicated in patients with a low-titre FIX inhibitor, as there is a high risk of anaphylactic reactions. In the case of patients with high-titre inhibitors, several treatments have been proposed, such as porcine FVIII, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrate (APCC). We present our 20 years' experience in the treatment and subsequent management of haemophilic patients with inhibitor in surgery and evaluate the results obtained with the products available for haemostatic control in 64 surgical procedures. The efficacy we obtained with FVIII is good in 100% of the cases described; we had no haemorrhagic complication (HC) in the 18 procedures in which it was used (three major and 15 minor surgery). With APCC we obtained excellent results with only one HC in a synoviorthesis in the form of bleeding and haematomas out of 32 procedures. Good results were obtained with rFVIIa with few haemorrhagic episodes. Thus, in major surgery there was one HC out of three cases. In minor surgery, greater efficacy was observed using extremely large doses of rFVIIa (≥ 120 mg kg⁻¹ 2h⁻¹) because of the shorter half-life of this factor in this type of patients.     

Home treatment with bypassing products in inhibitor patients: a 7.5-year experience

Summary.  The advantages of early treatment of bleeds include minimizing the damage caused by the haemorrhage as well as offering increased convenience and time saved for the patient. The objectives of this prospective, single-centre study were to evaluate the efficacy, safety and feasibility of long-term home treatment with bypassing product in inhibitor patients. Since May 2000, 10 haemophilia A patients with high-titre inhibitors have been included in the study. Nine patients were treated with activated prothrombin complex concentrate (aPCC; factor eight inhibitor bypassing activity, FEIBA™; Baxter AG, Vienna, Austria) and one patient with both aPCC and recombinant activated factor VII (rFVIIa; NovoSeven^®; NovoNordisk A/S, Bagsvaerd, Denmark). A total of 1008 infusions of aPCC and 17 infusions of rFVIIa were given in a home treatment setting. The numbers include 448 infusions of aPCC and 10 infusions of rFVIIa given as prophylactic treatment. During the 7.5 years of follow-up, the patients experienced 431 bleeds. Five hundred and sixty infusions of aPCC and seven infusions of rFVIIa were given to treat these bleeds. Haemostasis was rated as effective in 88% (372/424) and partially effective in 10% (43/424) of the bleeds after a mean number of 1.3 injections. The number of treatments rated as effective was comparable for muscle (90%), joint (85%) and mucocutaneous (86%) bleeds. The safety of the treatment was very good. Only two mild adverse events were reported in total. No thrombotic adverse event has been observed. In conclusion, home treatment with bypassing agents in inhibitor patients is feasible, effective and safe in a long-term perspective.     

Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors

Haemophilia patients with inhibitors are treated for acute bleeding with prothrombin complex concentrates (PCCs) or activated prothrombin complex concentrates (aPCCs). Despite this therapy, patients with high-level inhibitors are at increased risk of developing devastating joint disease. This paper examines available information that supports the study of PCCs and/or aPCCs as prophylactic therapy for haemophilia patients with inhibitors. This strategy would require that PCCs or aPCCs be administered repetitively in a dose that is sufficient to prevent haemarthrosis without causing thrombogenic events, or causing anamnestic response in inhibitor titre. PCC doses ranging from 30 to 50 U kg⁻¹ every other day for up to 8 months have resulted in subjective improvement both in bleeding associated with target joints and in the management of chronic joint inflammation. aPCC doses as low as 50–100 U kg⁻¹ every other day have been useful in postsurgical prophylaxis. The risk of developing a myocardial infarction or clinically relevant disseminated intravascular coagulation is linked to total dosages of either PCCs or aPCCs greater than 200 U kg⁻¹ day⁻¹. It is uncertain what anamnestic response would result from prophylaxis, but with typical therapy the aPCCs cause such a response in only a small percentage of patients. Based on these findings, a clinical trial of these products used in doses of 50–100 U kg⁻¹ every other day would appear to be warranted in patients who have permanent inhibitors and frequent joint bleeding.     

A cost minimization model for the treatment of minor bleeding episodes in patients with haemophilia A and high-titre inhibitors

Treatment of acute bleeding episodes in patients with haemophilia A and inhibitory antibodies to factor VIII (FVIII) most often involves the use of bypassing haemostatic agents, such as activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa). We constructed a cost minimization model to compare the costs of initial treatment with aPCC vs. rFVIIa in the home treatment of minor bleeding episodes. We developed a clinical scenario describing such a case and presented it to a panel of US haemophilia specialists. For each product class, we asked panellists to provide dosing regimens required to achieve complete resolution of a minor haemarthrosis in a child with high-titre inhibitors, and for the probabilities of success at two time points (8-12 and 24 h). Consensus among the panellists was refined by a second round of the process, and the median values resulting were used as inputs to a decision analysis model. Sensitivity analyses were conducted to determine threshold values for key variables. The base case model found that initial treatment with aPCC would result in a mean cost per episode of 21 000 dollars, compared with 33 400 dollars for initial treatment with rFVIIa. Sensitivity analyses over a range of clinically plausible values for cost, dosing, and efficacy did not change the selection of aPCC as the dominant strategy.     

The future of plasma-derived clotting factor concentrates

In developed countries, preferred treatments for both haemophilia A and B have moved toward recombinant clotting factor concentrates, while plasma-derived replacement therapies are still required by many patients. Great improvements have been made in producing relatively pathogen-free clotting factor replacements from pooled plasma. The fluidity and complexity of the worldwide plasma product market are discussed in the context of the 'yin and yang' of plasma therapeutics, showing how multiple issues can influence the safety and availability of clotting factor concentrates. Use of plasma-derived products will likely continue for the next decade for patients with inhibitors, patients with von Willebrand disease, those requiring bypassing agents, in immune tolerance induction, and for treatment of rare inherited deficiencies of procoagulant or anticoagulant proteins. Furthermore, in developing countries many of the most advanced therapies are not available for the majority of haemophilia patients, and thus plasma-derived replacement concentrates will continue to be used even for noninhibitor patients.     

Factors affecting choice of hemostatic agent for the hemophilia patient with an inhibitor antibody

Achieving adequate hemostasis in patients with hemophilia and high-titer inhibitor antibodies remains a challenge despite the development of plasma-derived and recombinant therapies to bypass the inhibitory effect. A group of hemophilia treaters met to examine the factors that influence physician choices among the very costly and cumbersome available therapies. Specific knowledge deficits in need of prospective research were identified with respect to the rational treatment of inhibitor patients.     

The management of hemophilia in elderly patients

After the increasing rate of deaths observed during the 1980s due to human immunodeficiency virus (HIV) infection, the health-related quality of life and life expectancy of persons with hemophilia have improved, mainly due to the progresses of replacement therapy and antiviral drugs and to the improvement of the global comprehensive care provided by specialized centers. As a consequence, an increasing number of hemophiliacs have reached an older age and nowadays physicians in hemophilia centers find that they must handle age-related clinical problems never previously observed in this population. The management of elderly persons with congenital hemophilia is discussed in the first part of this review. The second part describes the general aspects of acquired hemophilia due to anti-factor VIII autoantibodies, focusing on the clinical management of elderly patients, one of the groups most frequently affected by this acquired bleeding disorder.     

Therapeutic choices for patients with hemophilia and high-titer inhibitors.

Effective treatment of bleeding episodes in hemophilia with high titer inhibitors (HTI) remains a challenge, despite the fact that the therapeutic armamentarium has expanded considerably over the past few years. Treatment safety has improved with the availability of porcine factor VIII (FVIII) and bypassing products such as recombinant factor VIIa (rFVIIa), and plasma‐derived activated Prothrombin Complex Concentrates (aPCCs) that are virally inactivated. The major drawbacks of rFVIIa and aPCCs are their unpredictable hemostatic effect, lack of laboratory assays to monitor efficacy and dosing frequency, and the risk of thrombosis. The proceedings of a one‐day workshop of physicians who specialized in treating patients with hemophilia held in Vienna on May 13, 2000 have been summarized. In making a decision regarding the choice of product, physicians often consider the type of bleeding episode (life or limb threatening), age of the patient, volume of the reconstituted product, previous exposure to plasma derived products, cost, efficacy, and safety. For plasma naïve patients, to achieve rapid hemostasis a majority of the panelists used porcine FVIII (for patients who lack porcine inhibitory antibodies) or rFVIIa. For patients previously treated with plasma derived factors, in addition to the above concentrates, aPCCs were recommended. Although no data exists regarding safety and efficacy, switching products was routinely practiced either because of availability or cost. Furthermore, the panelists were uncertain about the efficacy of bypassing agents in the prevention of joint disease in inhibitor patients. The workshop participants felt that future research offers the best solution to resolve some of the dilemmas faced by clinicians and may help individualise treatment in a hemophilia patient with a high titer inhibitor. Am. J. Hematol. 67:240–246, 2001. © 2001 Wiley‐Liss, Inc.     

Cost minimization analysis to compare activated prothrombin complex concentrate (APCC) and recombinant factor VIIa for haemophilia patients with inhibitors undergoing major orthopaedic surgeries

Summary. Benefits of bypassing agents for maintaining haemostasis in major surgeries have been described in the literature; however, their use has a substantial economic impact. This study assessed the cost of FEIBA, an activated prothrombin complex concentrate and recombinant factor VIIa (rFVIIa) when used in inhibitor patients undergoing major surgeries. After reviewing published literature, a cost minimization model was developed describing dosing regimens recommended and used during major surgeries for FEIBA (pre‐operative: 75–100 U kg⁻¹; postoperative: 75–100 U kg⁻¹ q 8–12 h days 1–5 and 75–100 U kg⁻¹ q 12 h days 6–14) and rFVIIa (pre‐operative: 90 μg kg⁻¹; intra‐operative: 90 μg kg⁻¹ q 2 h; postoperative: 90 μg kg⁻¹ q 2–4 h days 1–5 and 90 μg kg⁻¹ q 6 h days 6–14). Using a 75 kg patient and US prices, total drug cost was calculated for three scenarios: use of FEIBA or rFVIIa alone and a third case combining rFVIIa pre‐ and intra‐operative and FEIBA throughout a 14‐day postoperative period. Dosage amounts of modelled bypassing agents were similar to cases in the literature. Using FEIBA instead of rFVIIa would decrease total drug cost by >50% and save over $400 000 per surgery. Sequential use of both bypassing agents would increase total drug cost by 9% when compared with FEIBA alone, but would remain >40% lower than rFVIIa alone. Univariate sensitivity analyses confirmed robustness of results. As large amounts of bypassing agents are necessary for patients with inhibitors to undergo major surgeries, cost is a major consideration. Use of FEIBA alone or in combination with rFVIIa has emerged as a cost‐saving approach.     

Zero incidence of inhibitor development in previously treated Haemophilia A, HIV-negative patients upon exposure to a plasma-derived high-purity and double viral inactivated factor VIII concentrate

Thirty-six Haemophilia A, HIV-negative, previously treated patients were changed therapy to a high-purity and double-inactivated (solvent/detergent and dry-heating) previously unused factor VIII concentrate. The mean age of these patients was 27 years at the time of the change. Twenty-three patients were severe Haemophiliacs (FVIII:C < 0.02 IU mL⁻¹), seven moderate (FVIII:C between 0.02 and 0.05 IU mL⁻¹) and six mild (FVIII:C > 0.05 IU mL⁻¹). The mean follow-up with this single product was 16 months, with 82 accumulated exposure days and the mean consumption was 117 300 IU of FVIII corresponding to a mean of six batches per patient. No patient developed FVIII inhibitors (upper limit of the CI95: 7.98%), resulting in an incidence rate of 0/48 patient-years (upper limit of the CI95: 77/1000 patient-years). The change in therapy to this new factor VIII concentrate was not associated with the appearance of inhibitors.     

Activated prothrombin complex concentrate (FEIBA®) treatment during surgery in patients with inhibitors to FVIII/IX: the updated Norwegian experience

Summary.  Non-activated and activated prothrombin complex concentrates have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 15 minor and six major surgical and invasive diagnostic or therapeutic procedures in eight inhibitor patients with congenital haemophilia A and in two patients with acquired haemophilia. Administration of a loading dose of 100 U kg⁻¹ of FEIBA^® followed by 200 U kg ⁻¹ day ⁻¹ in three doses every 8 h for 3 days and then tapering the daily dose to 150–100 U kg⁻¹, resulted in no severe or unexpected bleeding complications. One adverse event was observed. A 69-year-old man suffered a myocardial infarction the third postoperative day following sigmoidectomy. He was managed safely with opiate analgesia, nitrates and diuretics and the continued use of FEIBA^®.     

Activated prothrombin complex concentrate (FEIBA®) treatment during surgery in patients with inhibitors to FVIII/IX

Non-activated and activated prothrombin complex concentrates (PCC/aPCC) have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX (FVIII/IX) concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 14 minor and five major surgical and invasive diagnostic procedures in eight patients with congenital haemophilia A and inhibitors and in two patients with acquired haemophilia. When a loading dose of 100 U kg-1 of FEIBA was given followed by 200 U kg-1 day-1 in three divided doses every 8 h for 3 days, and then, when the daily dose was tapered to 100-150 U kg-1, no severe or unexpected bleeding complications were observed. However, one adverse event was observed. A 69-year-old man who suffered a myocardial infarction the third postoperative day following sigmoidectomy was managed safely with opiate analgesia, nitrates and diuretics, and the continued use of FEIBA(R).     

IgG subclasses of anti-FVIII antibodies during immune tolerance induction in patients with hemophilia A

The eradication of inhibitory antibodies in patients with haemophilia A can be accomplished by frequent administration of high or intermediate doses of factor VIII (FVIII), so-called immune tolerance induction (ITI). This study monitored the distribution of IgG subclasses of anti-FVIII antibodies during ITI. FVIII-specific antibodies of subclass IgG1 were detected in all inhibitor patients tested, anti-FVIII IgG4 in 16, IgG2 in 10 and IgG3 in one of 20 patients analysed. Levels of anti-FVIII IgG1 and IgG4 correlated well with inhibitor titres as measured by Bethesda assay. In low-titre inhibitor patients, anti-FVIII antibodies consisted primarily of subclass IgG1 whereas, anti-FVIII antibodies of subclass IgG4 were more prominent in patients with high titre inhibitors who needed prolonged treatment or who failed ITI. Longitudinal analysis of 14 patients undergoing ITI revealed that the relative contribution of IgG subclasses was constant for most of the patients analysed. In two patients, the relative contribution of IgG4 increased during ITI. Overall, our findings document the distribution and dynamics of anti-FVIII IgG subclasses during ITI. Future studies will need to address whether monitoring the relative contribution of anti-FVIII subclasses IgG1 and IgG4 may be useful for the identification of patients who are at risk of failing ITI.     

Recurrent Intramural Hematoma of the Small Intestine in a Severe Hemophilia A Patient with a High Titer of Factor VIII Inhibitor: A Case Report and Review of the Literature

A 17-year-old man with severe hemophilia A (factor VIII <1%) developed intermittent left upper quadrant pain. He had a high titer of factor VIII inhibitor (1024 Bethesda units/mL) and was diagnosed with intramural hematoma of the jejunum. He was managed conservatively with activated prothrombin complex concentrate (APCC), resulting in the resolution of symptoms. He developed recurrent intramural hematoma of the small intestine over the next 54 months, and was successfully treated with APCC. This case highlights a rare clinical manifestation in hemophilia patients, and also indicates the effectiveness of APCC instead of exploratory surgery for intramural hematoma. Cases of intramural hematoma of the gastrointestinal tract among hemophilia patients are also reviewed.     

Successful use of recombinant factor VIIa for hemostasis during total knee replacement in a severe hemophiliac with high-titer factor VIII inhibitor

A 32-year-old male patient with severe factor VIII (FVIII) deficiency had developed a high-titer FVIII inhibitor at age 13. Recurrent hemarthroses caused bony destruction in both knees, significantly impairing his ability to walk. Knee examination revealed 20 degrees of varus, destruction of the medial joint line, and flexion contracture. Total knee arthroplasty was performed using recombinant factor VIIa (rFVIIa, NovoSeven) for hemostatic control. rFVIIa (85 microg/kg given intravenously over 3-5 minutes) was given just prior to surgery. The dose was repeated every 2 hours during and for the first 48 hours after surgery. When the tourniquet was removed, rFVIIa had not been infused for 1.5 hours, and significant hemorrhage was noted. The hemorrhage responded promptly to rFVIIa infusion. The infusion interval was extended to every 4 hours for an additional 48 hours, and subsequent doses were given every 6 hours until the patient returned to the clinic 2 days postdischarge. Hemoglobin levels dropped from 16.9 gm/dL on admission to 9.1 gm/dL at discharge. After 2 months, the patient returned to work. We recommend that tourniquet release be performed immediately after rFVIIa administration and that aggressive physical therapy be considered in the early postoperative period when rFVIIa infusions are frequent.