Familial Mediterranean Fever: Causes, Diagnosis, and Treatment
Gene Therapy For Hemophilia Becomes A Reality
Earlier this year we reported on FDA's approval of valoctocogene roxaparvovec (Roctavian) for adults with severe hemophilia A. In this story, we provide an update on what has happened since.
Two gene therapies have now been approved for the treatment of hemophilia following the FDA's June approval of valoctocogene roxaparvovec (Roctavian) as the first gene therapy for hemophilia A -- joining etranacogene dezaparvovec (Hemgenix) for hemophilia B, which was approved late last year. But uptake of these new therapies has been relatively slow.
Hemophilia A
Approval of valoctocogene roxaparvovec for adults with severe hemophilia A was based on data from the global phase III GENEr8-1 study, in which the therapy reduced the average annualized bleeding rate (ABR) by 52% compared with patients' baseline ABR on routine factor VIII prophylaxis. Mean ABR among the 112 patients for whom baseline data were prospectively collected decreased from 5.4 to 2.6 bleeds per year over a median 3 years of follow-up.
Following gene therapy, these patients also experienced a reduction in the rate of spontaneous bleeds (from 2.3 to 0.5 bleeds/year) and joint bleeds (from 3.1 to 0.6 bleeds/year) compared with their baseline rate while receiving routine factor VIII prophylaxis.
At the time of the approval, BioMarin, the drug's developer, said that it would begin educating physicians and patients about valoctocogene roxaparvovec in order to ensure that the hemophilia community was aware of this new treatment option.
Since most people with hemophilia are treated at hemophilia treatment centers, the company said it was working with leading centers in the U.S. To ensure that staff are prepared to administer the therapy, and that the centers will have readiness plans in place before the end of 2023.
In August, BioMarin announced that an individual in Germany with severe hemophilia A was treated with valoctocogene roxaparvovec, marking the first time that the gene therapy had been given commercially in Europe.
At the same time, the company said it was working with private and public payers in the U.S. To enable access to the drug, which is set at a list price of $2.9 million.
The company has not announced when the first patients in the U.S. Will start receiving the therapy.
Hemophilia B
Etranacogene dezaparvovec, the first gene therapy for treating hemophilia B, a genetic bleeding disorder resulting from missing or insufficient levels of factor IX, was approved by the FDA in late 2022. It is indicated for adults with the condition who currently use factor IX prophylaxis therapy for blood clotting, those who have or have had life-threatening hemorrhage, or those who have repeated serious spontaneous bleeding episodes.
CSL Behring, the therapy's developer, reported that as of May, payers covering roughly 60% of the U.S. Population have established clear medical policies covering etranacogene dezaparvovec, which is set at a list price of $3.5 million. In June, the company announced that the first patient had received treatment.
Meanwhile, this month, Steven Pipe, MD, of the University of Michigan, presented 3-year follow-up data from the HOPE-B study at the American Society of Hematology annual meeting, showing that among 54 individuals who received etranacogene dezaparvovec (52 of whom completed 3 years of follow-up), mean factor IX levels were 41.5 IU/dL at year 1, 36.7 IU/dL at year 2, and 38.6 IU/dL at year 3 post-treatment. In addition, 94% of patients remained free of continuous prophylactic therapy.
"The long-term follow-up data from the HOPE-B study reinforces that a one-time treatment with Hemgenix can produce elevated and sustained factor IX levels and reduce the rate of annual bleeds for years in people living with hemophilia B," said Pipe in a press release. "Most importantly, the data show that nearly all the phase III trial participants 3 years post-treatment with Hemgenix have remained free from the need for regular prophylactic infusions, which is groundbreaking for the hemophilia B community."
The FDA is also considering another hemophilia B gene therapy for approval in adults -- fidanacogene elaparvovec, which contains a bio-engineered adeno-associated virus capsid and a high-activity variant of the FIX gene.
The submission for fidanacogene elaparvovec was based on efficacy and safety data from the phase III BENEGENE-2 study, the results of which demonstrated superiority over a prophylaxis regimen with factor IX. Mean ABR was 1.3 for the 12 months from week 12 to month 15 compared with an ABR of 4.43 during the lead-in pretreatment period of at least 6 months, resulting in a 71% reduction in ABR after a single dose of fidanacogene elaparvovec.
Key secondary endpoints included a 78% reduction in treated ABR and a 92% reduction in annualized infusion rate. Mean factor IX activity was 27% at 15 months by one-stage SynthASil assay and 25% at 24 months.
The FDA has set a PDUFA goal date in the second quarter of 2024.
Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.
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Drugs For Treatment Of Hemophilia
List of drugs/medicine used for HemophiliaAdvertisement
Are you searching for medications to treat 'Hemophilia'? Welcome to this section, which serves as a repository for medications that are relevant to the treatment of Hemophilia. The page includes both the generic and brand names and can be an invaluable resource for healthcare professionals and individuals who wish to get an insight on different medication options. Click on a medication below to view details including brand names, prices, dosages, side effects, and administration guidelines. Additionally, a FAQs section is available for each medication, addressing popular inquiries and providing deeper insights into its use for Hemophilia management. We recommend consulting your doctor to verify the information presented on this page or for any additional clarifications.Advertisement
Brand Names and Generic Names of Drugs for Treatment of Hemophilia Anti-Inhibitor Coagulant Complex- Vapor HeatedAnti-Inhibitor Coagulant Complex- Vapor Heated is a freeze-dried sterile human plasma fraction with clotting factor, prescribed for bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients.
EmicizumabEmicizumab is a modified humanized monoclonal antibody which is prescribed to prevent or minimize the frequency of bleeding episodes in adults and children suffering from congenital factor VIII deficiency (known as hemophilia A), who have developed factor VIII inhibitors.
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Moroctocog AlphaMoroctocog Alpha is an antihemophilic factor, prescribed for preventing bleeding episodes in patients with hemophilia A.
Search for Drugs: For Related Medical Condition Suggested Readings on Hemophilia
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Management Of Bleeding
Hemorrhage and Coagulopathy Tests Used to Establish Presence of Coagulopathies Interpreting PT and PTT Results in Combination PTT Mixing Study Treating Multiple Factor Deficiencies with Fresh Frozen Plasma (FFP) Treating Fibrinogen and Factor XIII Deficiency with Cryoprecipitate (CRYO) Diagnosing Scurvy and Treating with Vitamin C Disseminated Intravascular Coagulation (DIC) Profile Von Willebrand Disease Primary vWD Laboratory Profile VWD Follow-up Testing VWD Treatment Options Congenital Single Factor Deficiencies (Hemophilias) Factor VIII Concentrates Factor IX Concentrates Activated Prothrombin Complex Products: FEIBA FHÒ, Autoplex TÒ Activated Recombinant Factor VII (NovoSevenÒ) Other Congenital Single Factor Deficiencies Prothrombin Complex Concentrates (PCCs) Steps in Dispensing Factor Concentrates (Summary) Hemorrhage and Coagulopathy Most bleeding episodes stem from local tissue injuries, not coagulopathies. A coagulopathy may be suspected when bleeds issue from multiple sites, are spontaneous, inappropriately excessive, or recurrent.Systemic (mucocutaneous) bleeding
Petechiae, easy bruising, epistaxis, hematemesis, or menorrhagia characterize systemic mucocutaneous bleeds. Systemic bleeds usually imply a defect in primary hemostasis: thrombocytopenia, a platelet qualitative abnormality, von Willebrand disease, or a vascular disease such as scurvy.
Anatomic (soft tissue) bleeding
Anatomic bleeds occur into joints, muscles, the peritoneum, or the central nervous system. Anatomic bleeds usually imply the impairment of secondary hemostasis: coagulation factor deficiencies.
Many patients have more than one defect or are taking medications that interfere with hemostasis. Most coagulopathies of primary or secondary hemostasis are acquired due to an underlying systemic disorder.
Acquired Vs. Congenital bleeding
Most coagulopathies are acquired, a few are congenital. Acquired bleeds are seen most often in adults, follow identifiable events or an underlying disorder, and show no familial pattern. Congenital bleeds, with the classic example of hemophilia, usually occur in children, may be spontaneous, recurrent, or have a positive family history.
When a coagulation disorder is suspected, treatment may include fresh frozen plasma, cryoprecipitate, platelet transfusion, or specific coagulation factor concentrates.
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Tests Used to Establish Presence of Coagulopathies
Perform these tests in the absence of anticoagulant therapy but when bleeding suggests a coagulopathy.Prothrombin time (PT)
If the PT is over 1.5 the mean of the reference interval, suspect single or multiple deficiencies of the "extrinsic" and "common" factors prothrombin, fibrinogen, V, VII, or X. The factor with the greatest impact on the PT is VII.
Partial thromboplastin time (PTT)
If the PTT is over 1.5 the mean of the reference interval, suspect single or multiple deficiencies of the "intrinsic" and "common" factors prothrombin, fibrinogen, V, VIII, IX, X, or XI. Deficiencies of the "contact" factors XII, Fletcher (prekallikrein), or Fitzgerald (high molecular weight kininogen, HMWK) also prolong the PTT but are not associated with bleeding. Very prolonged PTT results (> 200 s) are due to heparin until proven otherwise.
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Interpreting PT and PTT Results in Combination
Useful when anticoagulant therapy has been ruled out and when bleeding suggests a coagulopathy. Unreported heparin may be ruled out in the laboratory using the thrombin time, which is prolonged to > 21 seconds when heparin is present.PT PTT Acquired Disorder Congenital Disorder Long Normal Liver disease or vitamin K deficiency Factor VII deficiency Normal Long Acquired factor VIII inhibitor Factor VIII, IX, or XI deficiency Long Long DIC, liver disease, Lupus anticoagulant (LA) Fibrinogen, prothrombin, factor V or X deficiency Normal Normal Thrombocytopenia, qualitative platelet disorder Mild factor deficiency, mild von Willebrand disease, factor XIII deficiencyPTT Mixing Study
When the PTT is prolonged at least 5 seconds beyond the upper limit of the refer-ence interval, the patient's plasma is mixed 1:1 with normal plasma and the PTT is repeated:[top]
Donor Blood Components
Treating multiple factor deficiencies with fresh frozen plasma (FFP)FFP is the plasma from a unit of whole blood separated by centrifugation and frozen within 8 hours of collection. It is stored at -18ºC or colder for up to 12 months, thawed at 30-37ºC and kept at 1-6ºC for no longer than 24 hours after thawing. FFP contains an average of 1 IU/mL of each coagulation factor, including the labile factors V and VIII.
FFP is primarily used to treat bleeding due to acquired multiple factor deficiencies that occur in liver disease, vitamin K deficiency, disseminated intravascular coagulation (DIC), and massive transfusion. Less frequently, it may be used to treat the rare congenital single factor deficiencies of II, V, VII, X, or XI, or deficiencies of proteins C or S.
FFP may be used for immediate short-term reversal of over-anticoagulation with Coumadin . However, because of its short half-life of 3-5 hours, factor VII is difficult to replace with FFP without volume overload. Thus, vitamin K and FFP are indicated in patients who have a high INR and are bleeding.
FFP is the replacement fluid of choice in therapeutic plasma exchange for thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).
A dose of 10-20 mL of FFP/kg of body weight will increases any factor level by 20-30%. Frequency of transfusion depends on the half-life of the deficient factor(s). FFP is not indicated unless the PT or PTT is >1.5 x the mean of the normal range. FFP should not be used as a volume expander, or to "correct" a mildly prolonged PT or PTT. A patient may have a mildly prolonged PT or PTT and yet have hemostatically stable levels of coagulation factors.
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Treating Fibrinogen and Factor XIII deficiency with Cryoprecipitate (CRYO)
CRYO is the protein precipitate left after FFP is thawed at 4oC and the supernatant liquid plasma is removed. CRYO is refrozen and stored at -18oC or lower for up to 12 months. After thawing at 30-37oC, it is kept at 20-24oC for no longer than 6 hours, or if pooled, no longer than 4 hours. A unit contains at least 80 IU of factor VIII, 150-250 mg of fibrinogen, 50-75 IU of factor XIII, and vWF.
CRYO is most commonly transfused to replace fibrinogen due to acquired deficien-cies either due to DIC or thrombolytic therapy, or for congenital hypofibrinogenemia or dysfibrinogenemia. CRYO is the only source of concentrated fibrinogen available. A fibrinogen level of 50-100mg/dL is considered hemostatically effective, and can be achieved using a general guideline of infusing one unit CRYO/7 kg of body weight. Fibrinogen has a half-life of 100-150 hours. CRYO is also used to treat the rare congenital or acquired deficiency of factor XIII. Factor XIII has a long half-life, 7-12 days, so the recommended treatment for factor XIII deficiency is one unit of CRYO/10 kg every 7 days.
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DiagnosingScurvy and Treating with Vitamin C
The diagnosis of scurvy requires a high index of suspicion. In western countries, the incidence appears to be on the rise. Populations at least include the elderly, chronic alcoholics, diet faddists, the mentally ill, and patients with cancer, malabsorption, or who are on renal dialysis.
The symptoms of scurvy are weakness, lassitude, depression, arthralgias, petechiae, perifollicular hemorrhage (corkscrew hairs), follicular hyperkeratosis, purpura, ecchymoses, gingival swelling, hemorrhage, halitosis, poor wound healing, and loss of teeth. Typical plaque-like ecchymoses of the lower extremities may also be present.
Adults should receive 100 mg of vitamin C 3-5 x a day up to 4 grams followed by 100 mg/day. Infants and children should receive 10-25 mg 3 x a day. Symptoms disappear within 3-5 days.
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Disseminated Intravascular Coagulation (DIC) Profile
DIC is generalized activation of coagulation secondary to systemic conditions such as septicemia, carcinoma, and severe inflammation or pregnancy complications. The presence of high concentrations of D-dimer, often > 20,000 ng/ml, is the sine qua non criterion of DIC, as it reflects increased fibrin production and breakdown. In acute DIC, activation of the tissue factor (intrinsic) pathway results in a decrease in factors II, VII, IX and X, prolonging the PT and PTT. However, an increase in factor VIII production coupled with von Willebrand factor released from the endothelium may make the PTT less useful than the PT in laboratory diagnosis of DIC. The PT is also expected to be abnormal before the PTT because it is highly dependent on factor VII level, which has a very short half-life of 3-5 hours.Assay Expected Results in DIC PT Usually prolonged (even before PTT becomes prolonged) PTT Usually prolonged above upper limit of reference interval Fibrinogen Low; but may be normal or high due to acute phase reaction; sequential measurements are helpful Quantitative D-dimer Significantly above the limit of reference interval· Single most important assay to establish DIC
· In compensated DIC, D-dimer may be the only abnormal test
Complete blood count with platelet count Anemia with schistocytesLow platelet count reflects significant consumption but count may be near normal due to marrow response
DIC treatment issues
The most important aspect of treating DIC is to remove the underlying cause of the syndrome. Secondly, it is key to maintain the blood pressure and to correct electrolyte imbalances to improve tissue oxygenation. Transfuse FFP, CRYO and platelets if there are signs of ineffective hemostasis, such as profuse oozing or frank bleeding. The PT, PTT, fibrinogen and or platelet count suggest the cause of the abnormal coagulation. High D-dimer levels suppress platelet function.
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Von Willebrand Disease
Von Willebrand disease (vWD) is a deficiency or abnormality of plasma von Wille-brand factor (vWF), a 5-20 million Dalton multimeric protein essential to platelet adhesion. VWF is also the plasma carrier of coagulation factor VIII. VWD affects 1 to 2 % of the general population. Clinicians must differentiate the various types and subtypes of vWD before establishing treatment.VWD type 1
Type 1 vWD is a mild to moderate quantitative vWF deficiency in 80% of vWD patients. It varies in severity among patients and over time in individual patients, and may cause systemic mucocutaneous (platelet-type) bleeding.
VWD type 3
Type 3 vWD is caused by the homozygous absence of vWF. Type 3 is rare but causes severe systemic and anatomic bleeding because factor VIII is also low.
VWD type 2
Type 2 vWD is a moderate to severe qualitative vWF deficiency in 15 to 20% of vWD patients. There are four subtypes.
Acquired vWD is multifactorial and may arise as a consequence of an anti-vWF autoantibody, reduced vWF production, or increased turnover. It is associated with monoclonal gammopathy of unknown significance (MGUS), non-Hodgkin lymphoma, multiple myeloma, solid tumors, hypothyroidism, and sodium valproate and ciprofloxacin.
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Primary VWD Laboratory Profile
or normal
Mildly decreasedor normal
2B Lower than antigen Mildly decreasedor normal
Mildly decreasedor normal
2N Normal Normal Decreased 2M Lower than antigen Mildly decreased NormalVWD primary profile limitations
VWD Follow-up Testing
VWD Treatment Options
Desmopressin (DDAVP)The normal level of vWF is roughly 50-150%, or 0.5 to 1.5 IU (see effect of blood type above). A level of 50% is regarded as effectively hemostatic under normal conditions, although for major surgery one may aim for a higher level. The formula for computing the first, or loading dose, is:
Dose in IU = (desired activity – current activity) x PV
Where…
· IU is international units, defined as amount per mL of plasma. 1 IU= 100%
· Desired activity is therapeutic level to be achieved
· Current activity is measured using the vWF activity assay
· PV is plasma volume in mL computed as follows:
PV = Blood volume x (1-hematocrit)
Where…
· Blood volume based upon patient weight in kilograms (1 lb. = 0.453 kg)
Blood Volume Multiplier Body Type 70 mL/kg Slim 60 mL/kg Obese 50 mL/kg Morbidly obeseThe maintenance dosage is 50% of the loading or initial dosage and is administered 12 hours after the first dosage. Subsequent dosages are administered at 12-hour intervals and are monitored by repeat vWF antigen assays collected just prior to the next dose (through level).
Example for calculating factor concentrate dosage
A woman with type 3 vWD arrives with an acute abdominal bleed. Her initial laboratory results are:
vWF activity <1% vWF antigen <1% Factor VIII activity <1% HCT 30%She weighs 132 lbs and is 4'11" tall, moderately obese, blood volume multiplier is 60 mg/kg.
1. Compute blood volume:
132 lb x 0.453 lb/kg = 60 kg
BV = 60 kg x 60 mL/kg = 3600 mL
2. Compute plasma volume:
PV = 3600 mL x (1-.30) = 2520 mL
3. Compute dosage:
Dose in IU = (0.5 IU – 0 IU) x 2520 Dose = 1260 IU
4. She is given an initial dose of 1260 IU of vWF in the form of Humate-PÒ and subsequent maintenance doses of 630 IU every twelve hours. VWF activity should remain between 25% and 50% and dosage adjustments should follow factor levels.
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Congenital Single Factor Deficiencies (Hemophilias)
Calculating factor VIII concentrate dosageThe normal level of factor VIII is 50-186% (or 0.5 to 1.86 IU/ml). Effective therapeutic levels vary from 30% to 100% depending on clinical condition of the patient. The formula for computing the first or loading dose of factor is the same as that for vWF:
Dose in IU = (desired activity – current activity) x PV
Where…
· IU is international units, defined as amount per mL of plasma. 1 IU= 100%
· Desired activity is therapeutic level to be achieved
· Current activity is measured using the vWF activity assay
· PV is plasma volume in mL computed as follows:
PV = Blood volume x (1-hematocrit)
Where…
· Blood volume based upon patient weight in kilograms (1 lb. = 0.453 kg)
Blood Volume Multiplier Body Type 70 mL/kg Slim 60 mL/kg Obese 50 mL/kg Morbidly obeseIt is advisable to check the peak factor VIII level after the loading dose by collecting a sample approximately 15 minutes after the infusion of the factor. If the desired activity was achieved, 50% of the initial dose should be administered 8-12 hours later. Immediately prior to the second dose another factor level will be helpful to estimate the in vivo half-life of factor VIII and will guide calculation of subsequent doses. A bleeding patient is likely to require larger doses than someone who is clinically stable. Changes in hematocrit will also affect the appropriate dose at any given time.
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Factor VIII Concentrates
Plasma-derived productsFactor IX Concentrates
Plasma-derived products[top]
Activated Prothombin Complex Products (APCCs): FEIBA FHÒ, Autoplex TÒ
FEIBA dosages in IU/kg (per manufacturer recommendations)Activated Recombinant Factor VII (NovoSevenÒ)
Steps in Dispensing Factor Concentrates (Summary)
Confirm coagulopathy diagnosis Confirm current indication for factor replacement Select product:· Plasma-derived factors VIII or IX
· Recombinant factors VIII or IX
· Bypass products for patients with factor VIII inhibitors
· von Willebrand factor
Assess availability of product in inventory Calculate dosage based on clinical indication Establish treatment frequency (dosing interval) Establish expected number of repeat treatments required Establish laboratory monitoring by plasma factor level· Precise time interval
· Frequency of testing
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