Medication Guide App

Antihemophilic Factor (Systemic)


VA CLASSIFICATION
Primary: BL116

Commonly used brand name(s): Alphanate; Bioclate; Helixate; Helixate FS; Hemofil M; Humate-P; Hyate:C; Koate-HP; Kogenate; Kogenate FS; Kogenate FS, Helixate FS; Kogenate FS,Helixate FS; Monarc-M; Monoclate-P; Recombinate.

Other commonly used names are
AHF and factor VIII .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihemorrhagic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hemophilia A, hemorrhagic complications of (prophylaxis and treatment) —Antihemophilic factor (AHF) is indicated for the control and prevention of bleeding {01} {02} {03} {10} {16} {41} {44} {45} {46}, including bleeding during and following surgical procedures {16} {45}, in patients with hemophilia A (classical hemophilia). Human AHF is not likely to be effective in patients with acquired inhibitor antibodies to human AHF when the antibody concentration exceeds 5 {69} to 10 Bethesda Units (BU) per mL. Alternative treatment modalities available to these patients include anti-inhibitor coagulant complex concentrates {50} {57} {68}, factor IX complex concentrates {19} {50} {57} {68}, and porcine AHF {19} {43} {50} {57} {68}.

Hemorrhagic complications in patients with factor VIII inhibitors (prophylaxis and treatment)—AHF (Porcine) is indicated for the control and prevention of bleeding, including bleeding during and following surgical procedures, in hemophilic patients with antibodies to human factor VIII, {43} {50} {57} and in previously non-hemophilic patients with spontaneously acquired antibodies to human factor VIII {43}. AHF (Porcine) is used in patients with anti–human factor VIII antibody concentrations between 10 and 50 BU per mL, or more than 50 BU per mL if the anti–porcine factor VIII antibody concentration is less than 15 to 20 BU per mL, provided that in vitro testing has demonstrated lack of cross-reactivity with the factor VIII antibody {69}. Patients with antibody concentrations beyond these ranges are not likely to receive any therapeutic benefit from this product {43}.

von Willebrand disease (treatment)Cryoprecipitated AHF and human AHF, dried, pasteurized are indicated in the treatment of type I{18}{19} type II{19}and type III (severe) {81}von Willebrand disease.{115}
Hypofibrinogenemia (treatment) or
Factor XIII deficiency (treatment)—Cryoprecipitated AHF is indicated for the replacement of fibrinogen and factor XIII {61} {65}.

[Coagulation, disseminated intravascular (treatment adjunct)]1or
[Kasabach-Merritt syndrome (treatment adjunct)]1—Cryoprecipitated AHF may be used as a source of fibrinogen in the treatment of disseminated intravascular coagulation {19} {21} {27} {75}. It may be given in conjunction with fresh frozen plasma and platelet concentrates, which replace other clotting factors and platelets, respectively. Heparin may be added to this regimen, although such use is controversial, to inhibit the formation of thrombin and microthrombi and to reduce the inappropriate activation and consumption of clotting factors and platelets. {27} {75}
—Cryoprecipitated AHF may be used as a source of fibrinogen in the treatment of Kasabach-Merritt syndrome. It may be used in conjunction with aminocaproic acid and thrombin, which inhibit fibrinolysis and promote thrombosis in, and subsequent shrinkage of, the tumor. {77} {78}

Unaccepted
AHF products other than the cryoprecipitated AHF do not contain sufficient quantities of von Willebrand factor, and therefore are not indicated, in the treatment of von Willebrand disease {01} {02} {03} {10} {16} {41} {44} {45} {46}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Antihemophilic factor (AHF) is obtained from pooled human plasma {01} {02} {03} {41} or purified porcine plasma {43}, or produced by recombinant DNA technology {16} {45}.
    Almost all of the plasma-derived AHF products currently available are sterile, nonpyrogenic, high-purity concentrates purified by gel permeation chromatography {02}, ion exchange chromatography, or immunoaffinity chromatography utilizing murine monoclonal antibodies to factor VIII {01} {12} {41} {55} or von Willebrand factor (vWf) {03} {55}. However, to date, no procedure has been shown to be totally effective in removing the risk of viral infection from coagulant factor concentrates. The purified concentrates contain 50 to 150 {02} {03} times as much AHF as an equal volume of fresh plasma. Some products contain albumin as a stabilizer {03} {06} {07} {10} {13}, and monoclonal purified products contain trace amounts of mouse protein {01} {03} {30} {41}. Humate-Pis purified from the cold insoluble fraction of pooled human fresh-frozen plasma. It contains highly purified and concentrated AHF and the labeled amount of von Willebrand factor activity: Ristocetin Cofactor (vWF:RCof) expressed in international units (IU). It has a high degree of purity with a low amount of non-factor proteins {44}{115}.
    AHF (Porcine) is a sterile, high-purity, freeze-dried concentrate that also contains platelet aggregating factor, the equivalent of porcine vWf, at a concentration of 1 porcine vWf unit for at least 5 units of porcine factor VIII {43} {70}.
    Human recombinant AHF (rAHF) is a sterile, nonpyrogenic concentrate with biologic activity comparable to that of plasma-derived AHF {07} {16} {45} {56}. rAHF contains albumin as a stabilizer {10} {13} {16} {45} and trace amounts of mouse, hamster, {10} {16} {45} and bovine {16} proteins. vWf is co-expressed with rAHF in the production of Recombinate, and helps to stabilize it {10} {16}; however, it is present in such minute quantities that it offers no therapeutic benefit to patients with von Willebrand disease {16}.
    Cryoprecipitated AHF is a sterile, frozen concentrate of human AHF obtained from the plasma of 1 unit of whole blood or from 1 or more units of single-donor fresh frozen plasma {42} {60} {61}.

Mechanism of action/Effect:

Antihemophilic Factor (AHF), or factor VIII, is an endogenous glycoprotein necessary for blood clotting and hemostasis. It is a cofactor necessary for factor IX to activate factor X in the intrinsic pathway. {03} {47} {48} {56} In hemophilia A (classical hemophilia), there is a deficiency of this clotting factor. The average normal plasma activity of factor VIII is designated as 100% {69} {80} {81} {82} {83}, and a factor VIII concentration of 25% of normal is required for hemostasis. Patients with severe hemophilia have a factor VIII concentration of less than 1% of normal and frequently experience bleeding even in the absence of trauma. Patients with a factor VIII concentration between 1 and 5% (moderate hemophilia) experience less bleeding, and patients with a factor VIII concentration greater than 5% (mild hemophilia) usually experience bleeding only after obvious trauma. {47} The administration of AHF temporarily replaces the missing clotting factor to correct or prevent bleeding episodes {01} {16} {41}.

Half-life:

Distribution—2.4 {09} to 8 hours {09} {60}.

Elimination—8.4 to 19.3 hours {01} {02} {03} {04} {06} {10} {13} {16} {31} {32} {38} {41} {44} {45} {56}. However, the half-life may be significantly reduced in the presence of inhibitor antibodies, or during active consumption of clotting factors {73}.

Time to peak concentration:

There is conflicting information regarding the time to achieve peak concentration; values have ranged from 10 minutes {09} {32} to 2 hours {32} after intravenous administration.

Time to peak effect:

1 to 2 hours after intravenous administration {04}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients with a history of allergies, especially those who are allergic to pork or pork products, may be allergic to this medication also {33} {69} {71} {73} {76} {79}.

Carcinogenicity

The carcinogenic potential of antihemophilic factor has not been investigated {16}.

Mutagenicity

Recombinant antihemophilic factor (rAHF) does not induce reverse mutations, chromosomal aberrations, or an increase in micronuclei in bone marrow polychromatic erythrocytes at doses considerably exceeding plasma concentrations of rAHF in vitro , and at doses 10 {16} {45} to 40 {45} times the maximum clinical dose in vivo .

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans.

Studies have not been done in animals. {01} {02} {03} {16} {41} {43} {45} {46}

FDA Pregnancy Category C {01} {02} {03} {16} {41} {43} {44} {45} {46}.

Breast-feeding

It is not known whether antihemophilic factor is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of antihemophilic factor in children {16} {45}.


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of antihemophilic factor in the elderly {29} {37} {50} {69}.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Sensitivity to mouse {01} {03} {16} {41} {45} , hamster {16} {45} , or bovine {16} protein    (risk of allergic reaction to these proteins, which may be present in monoclonal antibody–derived and recombinant AHF products)


Sensitivity to antihemophilic factor

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Antibody determinations    (recommended periodically to detect the development and concentration of antibodies to factor VIII {01} {11} {16} {41} {43} {45} {46} {57}, and to predict whether or not a patient is likely to respond to AHF therapy. Patients with antibody concentrations lower than 10 Bethesda Units [BU] per mL may be given larger amounts of AHF to complex with and thereby inactivate the antibodies. However, patients with antibody concentrations greater than 10 BU per mL are not likely to respond, even to very large amounts of AHF, and therefore must be treated with alternative modalities {57}; (See the Hemophilia therapeutic monograph for information about the treatment of patients with inhibitor antibodies.))


Direct Coombs' test and
Hematocrit determinations    (recommended when large volumes and/or frequent doses are administered, to detect the onset of progressive anemia {01} {02} {03} {41}; some products contain red blood cell anti-A and anti-B isoantibodies, which may precipitate intravascular hemolysis in patients with blood types A, B, or AB {02} {43} {46} {53})


» Plasma factor VIII determinations    (recommended periodically to assure that adequate factor VIII concentrations have been achieved and are maintained {01} {16} {32} {41} {61} {65})


Platelet count    (recommended during the administration of AHF [Porcine] to detect thrombocytopenia {43} {49} {50})


Pulse rate determinations    (recommended before and during administration; if a significant increase in pulse rate occurs, the infusion should be slowed or halted until the pulse rate returns to normal {01} {41})




Side/Adverse Effects

Note: To reduce the risk of transmission of viruses by blood and blood components, potential blood donors are screened {05} {35} {37} {42} {44} {46} {55} {61}, and donor blood is tested and must be found negative for antibodies to human immunodeficiency virus (HIV), hepatitis B surface antigen, antibody to hepatitis B core antigen, and antibody to hepatitis C (non-A, non-B) virus. The concentration of alanine aminotransferase (ALT) also must be within normal limits {61}. However, these precautions are not totally effective in eliminating viral infectivity. To further reduce the risk, plasma-derived AHF concentrates, with the exception of the cryoprecipitated product, undergo viral inactivation procedures. The inactivation methods currently employed are treatment with an organic solvent/detergent combination (tri- n-butyl-phosphate [TNBP] and polysorbate-80 [Tween-80], sodium cholate, or Triton X-100) with or without heat treatment, vapor treatment, or nanofiltration; {01} {02} {05} {06} {07} {12} {23} {41} {55} pasteurization by heating at 60 °C (140 °F) for 10 hours in an aqueous solution {03} {04} {05} {24} {31} {35} {36} {37} {44} {55}; vapor heating; dry heating at 80 °C (176 °F) for 72 hours; sodium thiocyanate plus ultrafiltration; and immunoaffinity purification {39} {55}. These processes effectively inactivate lipid-enveloped viruses such as HIV {01} {02} {03} {05} {06} {15} {25} {35} {36} {37} {41} {44} {53} {55}; hepatitis B virus {01} {02} {35} {36} {41} {44}; and hepatitis C virus {02} {05} {06} {23} {31} {35} {36} {44} {55}. Hepatitis A and human parvovirus B19 are nonlipid-enveloped viruses and have been reported in patients receiving solvent/detergent-treated AHF {84} {85}. However, it is not known if these cases were caused by the concentrate, the water used in processing, or by other sources. {40} {54} {55} {58} {59} {64} Also, unknown viruses and prions, such as the agent that causes Creutzfeldt-Jakob disease (CJD), may not be eliminated by current inactivation and purification methods and could be transmitted {86}. There is no evidence, however, of CJD transmission through any transfused blood component, and it remains only a theoretical concern {87}. AHF (Porcine) is screened for porcine viruses; there have been no reports of transmission of hepatitis or HIV associated with its use {43}. Recombinant AHF carries a very slight risk of transmission of viruses {69}; however, there have been no cases of viral infection attributed to this product {05} {51} {56}.
Unlike the intermediate-purity AHF concentrates, the high-purity concentrates currently available contain virtually no contaminating proteins {05} {07}. The many foreign proteins and alloantigens contained in the intermediate-purity concentrates {29} {38} have been reported to cause downmodulation of immune function, primarily by inhibiting phagocytic function of monocytes {22} {28} {53} and macrophages {28} and by inhibiting secretion of interleukin-2 {07} {28} {52} {53}. Studies have not shown downmodulation of immune function with high-purity concentrates; there is minimal evidence that the highly purified concentrates may stabilize the immune function of HIV-positive hemophiliacs {28} {29} {38}. However, other studies have shown conflicting results {88} {89}.
The development of inhibitor antibodies, which neutralize the procoagulant activity of factor VIII, is a complication associated with the use of AHF. The incidence of antibody development is between 15 and 35% in patients with hemophilia A {87} {90}. Inhibitor antibodies have been reported after treatment with both plasma-derived factor VIII concentrates and recombinant factor VIII, but it is unclear if the incidence differs among the various AHF products {91} {92}. The antibody concentration begins to increase 4 to 7 days after AHF exposure and peaks in 2 to 3 weeks {57}. The risk of developing an antibody is greatest in patients with severe disease, and most often in those younger than 5 years of age {08} {20} {33} {90}. Antibodies also may develop spontaneously in postpartum women, patients with autoimmune disorders or cancer, or otherwise healthy older adults {57}. [See the Hemophilia therapeutic monograph for information about the treatment of patients with inhibitor antibodies.]

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Anaphylaxis or other allergic reaction to AHF, or to mouse, hamster, or bovine protein (changes in facial skin color; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; skin rash, hives, and/or itching)—may include anaphylactic shock with sudden, severe decrease in blood pressure and collapse{01}{02}{03}{16}{41}{44}{45}{46}{53}{60}{61}
    
hemolytic anemia ( unusual tiredness or weakness)— primarily associated with the use of large volumes of low- or intermediate-purity factor VIII preparations in patients with group A, B, or AB red blood cell antigens{01}{02}{03}{41}{46}{53}{61}
    
thrombosis (tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over affected area){14}{34}

Incidence rare
    
Allergic reaction to albumin ( chills; fever; hives; nausea){01}{16}{41}
    
hyperfibrinogenemia {46}{61}
    
thrombocytopenia (unusual bleeding or bruising)—for AHF (Porcine) only{43}{49}{50}
    
paresthesias ( sensation of burning, warmth, heat, numbness, tightness, or tingling)

Note: Chills {03} {43} {46} {50} {60} and fever {06} {43} {44} {45} {46} {49} {50} {60} also may occur independently of an allergic reaction to albumin (incidence less frequent).




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Burning, stinging, or inflammation at injection site (swelling ){03}{06}{10}{45}{46}
    
dizziness or lightheadedness {06}{10}{41}{45}
    
dry mouth {10}
    
fatigue (unusual tiredness or weakness){16}{46}{60}
    
flushing (redness of face){16}{45}{49}{51}
    
headache {06}{31}{43}{46}
    
nausea or vomiting {03}{16}{43}{45}{46}
    
nosebleed {16}
    
skin rash {10}{44}{45}{46}{49}{50}{51}{60}
    
unpleasant taste {06}{10}{41}{45}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antihemophilic Factor (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to antihemophilic factor or to mouse, hamster, or bovine protein

Proper use of this medication
» Proper preparation of medication: bringing dry concentrate and diluent to room temperature before reconstitution; wiping rubber surface with alcohol swab and allowing to dry, when reconstituting, directing stream of diluent against side of vial of concentrate to avoid foaming of contents; gently swirling vial to dissolve contents; not shaking hard

» Inspecting solution visually for discoloration or particulate matter before administration.

» Administering within 3 hours of reconstitution, according to the individual manufacturer's instructions

» Use of plastic disposable syringe and filter needle; safe handling and disposal of syringe and needle

Proper dosing
Missed dose: Contacting physician as soon as possible for instructions; if physician is unavailable, using usual dose as soon as it is remembered

» Proper storage

Precautions while using this medication
Need for patients newly diagnosed with hemophilia to receive hepatitis A and hepatitis B vaccines

» Need to carry identification stating condition and treatment

» Notifying physician if medication seems less effective than usual; this may indicate the development of antibodies to factor VIII


Side/adverse effects
Signs of potential side effects, especially allergic reactions, hemolytic anemia, thrombosis, hyperfibrinogenemia, thrombocytopenia, or paresthesias


General Dosing Information

Choice of product


• The types of factor VIII products currently available include {96}:    • recombinant factor VIII (rFVIII), produced in cultured hamster cell lines that have been transfected with a gene for human FVIII, and stabilized in human albumin ( Bioclate, Helixate, Kogenate, Recombinate );
   • recombinant factor VIII (rFVIII), produced in cultured hamster cell lines that have been transfected with a gene for human FVIII, and stabilized without the addition of human albumin, formulated with sucrose. ( Kogenate FS, Helixate FS{118}){117}
   • immunoaffinity-purified (ultrahigh purity) FVIII, derived from human plasma ( Hemofil M; Monarc-M;Monoclate P; Antihemophilic Factor, Method M);
   • intermediate- and high-purity FVIII, derived from human plasma ( Alphanate, Humate-P, Koate-HP);
   • porcine FVIII ( Hyate:C), reserved for patients with inhibitors to human factor VIII.



• In general, it is recommended that previously untreated patients and those who are HIV-negative receive recombinant factor VIII {86} {94} {95}. For HIV-positive patients, some studies have shown that the use of immunoaffinity-purified or recombinant products may preserve cellular immunity better than products of intermediate purity {28} {29} {38}. However, other studies have shown conflicting results {88} {89}.


• Random-donor cryoprecipitated antihemophilic factor is not recommended as a treatment alternative for hemophilia A because the product does not undergo a viral attenuation process {96} {97}. Appropriately screened, single-donor cryoprecipitate (such as from desmopressin-treated fathers of hemophilic children) has been used as an inexpensive alternative to the use of factor VIII concentrates for the management of hemophilia in small children {98} {99}.

It is important to verify the existence of a factor VIII deficiency before administering antihemophilic factor (AHF) {01} {16} {41} {44} {45} {61}.

AHF is recommended for intravenous use only {01} {02} {03} {41} {42} {43} {44} {45} {46}.

AHF should be administered via plastic disposable syringes because it tends to adhere to the ground-glass surface of all glass syringes {01} {03} {16} {41} {44}.

AHF should be filtered before administration {01} {02} {03} {41} {42} {44} {45} {46}.

AHF may be administered as a continuous intravenous infusion via a minipump or syringe pump for severe, life-threatening bleeding, or following surgery {103} {104} {109} {110}. When administered this way, the addition of heparin, 1 to 5 USP Units per mL of concentrate, may be considered if problems with local thrombophlebitis occur at the injection site {109}.

Long-term prophylactic therapy for severe hemophilia, in which factor replacement is given several times a week to maintain the factor level above 1%, has been used extensively in Europe {17} {100} {101}. The goal is to convert severe hemophilia to a mild or moderate form of the disease to prevent spontaneous bleeding and preserve joint function {26} {103}.

Because AHF (Porcine) is a foreign-species protein, there is a slight risk of an anaphylactic or other allergic reaction {43}. Pretreatment with hydrocortisone and/or an antihistamine may minimize or prevent these reactions {50} {113} {114}.

Antifibrinolytic therapy is useful adjunctive therapy in hemophilic patients with oral or mucous membrane bleeding, particularly that which occurs during dental and oral surgery {87}. It prevents or controls bleeding, thus reducing the need for replacement therapy. Aminocaproic acid may be given orally or intravenously at a dose of 75 mg per kg of body weight (up to 6 grams) immediately after surgery, then every six hours for seven to ten days {87}. Or, tranexamic acid may be given as a single dose of 25 mg per kg of body weight orally or 10 mg per kg of body weight intravenously two hours before surgery, followed, after surgery, by 25 mg per kg of body weight orally every six to eight hours for seven to ten days {87}. When antifibrinolytic agents are used in this manner, a single factor VIII infusion of 40 International Units per kg of body weight prior to surgery is often enough for normal hemostasis {26} {72}. These agents can also be given as an oral rinse (5 mL of aminocaproic acid syrup, or 10 mL of a 5% tranexamic acid solution four times a day for seven to ten days). {93}


Parenteral Dosage Forms

ANTIHEMOPHILIC FACTOR (HUMAN)

Note: Each vial of AHF is labeled with the AHF activity expressed in International Units (IU) per vial. This potency assignment is referenced to the World Health Organization International Standard. One IU of factor VIII activity and 1 IU vWF:RCof is approximately equal to the AHF and vWF:RCof activity of 1 mL of fresh plasma.{01} {03} {41}{53} {115} One IU of AHF also increases the plasma concentration of factor VIII by 2% {01} {03} {41}{53} . The specific factor VIII activity ranges from 2 to over 3000 AHF IU per mg of total protein, after discounting the human albumin used to stabilize these products {96}.
Although the dose of AHF must be individualized for each patient based on patient weight, circulating antibody concentration, type of hemorrhage, and desired plasma factor VIII concentration, the following formulas may be used as guides in determining dosage {03} {46} {53}:
Desired AHF increase (% of normal) = ([Dose AHF(IU)]/[Body weight (kg)]) × 2
Dose AHF (IU) = Body weight (kg) × Desired AHF increase × 0.5
Hemofil M and Alphanate may be administered at a rate not exceeding 10 mL per minute; Monoclate-P and Humate-P may be administered at a rate of 2 or 4 mL per minute, respectively; and the entire dose of Koate-HP may be administered over five to ten minutes. However, the rate at which AHF is administered should be guided by the comfort of the patient.


Usual adult and adolescent dose
Prophylaxis of spontaneous hemorrhage
Intravenous, 25 to 40 IU per kg of body weight, administered three times per week, maintaining the trough factor level above 1% between doses {17}.

Treatment of hemorrhage
Schedules for administration of clotting factor concentrates are based on the severity of the bleeding diathesis. Currently, there is no consensus among practitioners regarding the optimal dose of factor replacement therapy for the treatment of the various types of bleeding, and the optimal therapeutic level for control of such bleeding remains debatable {90}. The doses in Table 1 should be considered only as a guideline, since recommendations may vary from one hemophilia center to another {26} {87} {94} {102} {103} {104}. Doses and duration of treatment may be adjusted according to the patient's condition.

Table 1. General Factor Replacement Guidelines for the Treatment of Bleeding in Hemophilia {103} {104} {105} {106}



Indication  Initial minimum desired factor level (%)  Factor VIII dose * (IU/kg)  Duration (days) 
Severe epistaxis  20–30  10–15   1–2 
Oral mucosal bleeding   20–30  10–15  1–2  
Hemarthrosis   30–50  15–25  1–2 
Hematoma  30–50  15–25  1–2 
Persistent hematuria   30–50  15–25  1–2  
Gastrointestinal bleeding   30–50  15–25  at least 1–2 days after bleeding stops 
Retroperitoneal bleeding  30–50  15–25  at least 3 
Trauma without signs of bleeding  40–50  20–25  2–3  
Tongue/retropharyngeal bleeding   40–50  20–25  3–4  
Trauma with bleeding §  100  50  10–14 
Intracranial bleeding §  100  50  10–14 
* Dosing intervals are based on a half-life for Factor VIII of 8 to 12 hours (2 to 3 doses/day). Maintenance doses of one half the initial dose may be given at these intervals. The frequency depends on the severity of bleeding, with more frequent dosing for serious bleeding.
 In addition to antifibrinolytics {105}.
 Painless spontaneous hematuria usually requires no treatment. Increased oral or intravenous fluids are necessary to maintain renal output.
{105}{107} § Continuous factor infusion may be administered. Following the initial loading dose, a continuous infusion at a dose of 3 IU/kg per hour is given {104} {108}. Subsequent doses are adjusted according to the plasma factor levels.


Treatment of von Willebrand Disease
Intravenous, 40 to 80 IU vWF:RCof (corresponding to 16 to 32 IU factor VIII in Humate-P) per kg of body weight is given every 8 to 12 hours. Repeat doses are administered for as long as needed based on repeat monitoring of appropriate clinical and laboratory measures. Dosages should be adjusted according to the extent and location of bleeding. The administration of 1 IU of Factor VIII per kg of body weight can be expected to lead to a rise in circulating vWF:RCof of approximately 3.5 to 4 IU per dL. Table 2 shows dosing recommendations for pediatric and adult patients.

Table 2. Dosing Guidelines for the Treatment of von Willebrand Disease (treatment).



Classification of vWD  Hemorrhage  Dosage (IU vWF:RCof per kg body weight 
Type 1   • mild, if desmopressin is inappropriate (Baseline vWF:RCof activity typically >30%)
 
Major (e.g. severe or refractory epistaxis, GI bleeding, CNS trauma, or traumatic hemorrhage)   Loading dose 40 to 60 IU/kg, then 40 to 50 IU/kg every 8 to 12 hours for 3 days to keep the nadir level of vWF: RCof >50%; then 40 to 50 IU/kg daily for total of up to 7 days of treatment  
Type 1   • moderate or severe (Baseline vWF:RCof activity typically <30%)
 
Minor (e.g. epistaxis, oral bleeding, menorrhagia) Major (clinical indications above)  40 to 50 IU/kg (1 or 2 doses) Loading dose 50 to 75 IU/kg, then 40 to 60 IU/kg every 8 to 12 hours for 3 days to keep the nadir level of vWF: RCof >50%; then 40 to 60 IU/kg daily for total of up to 7 days of treatment. Factor VIII-C levels should be monitored and maintained according to the guidelines for hemophilia A therapy  
Types 2 (all variants) and Type 3   Minor (clinical indications above) Major (clinical indications above)  40 to 50 IU/kg (1 or 2 doses) Loading dose 60 to 80 IU/kg, then 40 to 60 IU/kg every 8 to 12 hours for 3 days to keep the nadir level of vWF: RCof >50%; then 40 to 60 IU/kg daily for total of up to 7 days of treatment. Factor VIII-C levels should be monitored and maintained according to the guidelines for hemophilia A therapy  
{115}

Control of perisurgical hemostasis


Dental and oral surgery:
Intravenous, 40 IU per kg of body weight prior to surgery. A single dose is often sufficient for normal hemostasis when an antifibrinolytic agent, such as aminocaproic acid or tranexamic acid, is used as adjunctive treatment. {26}



Other surgical procedures:
Intravenous, 50 IU per kg of body weight to obtain a plasma factor VIII level of 100%, which must be confirmed prior to surgery {103} {104}. Subsequent doses equal to half the initial dose are given every eight to twelve hours to maintain that plasma level for the first few days after surgery {102} {103} {104}. As an alternative to the intermittent dosing of replacement factor, continuous infusion of factor VIII may be given following surgery at a dose of 3 IU per kg of body weight per hour via a minipump or syringe pump {103} {104} {108} {109} {110}. The dose can then be tapered to maintain a plasma factor level > 30% for the following one to two weeks {26} {104}. Major orthopedic surgery may require several weeks of replacement therapy {102} {103}.



Usual pediatric dose
See Usual adult and adolescent dose .

Size(s) usually available:
U.S.—


250 IU with 2.5 mL sterile water for injection provided as diluent (Rx) [Monoclate-P (sodium ion 300 to 450 mmol per liter) (calcium chloride 2 to 5 mmol per liter) ( albumin human 1 to 2%) (mouse protein < 50 nanograms per 100 IU)]


250 IU with 5 mL sterile water for injection provided as diluent (Rx) [Koate-HP (heparin £ 5 units per mL) (calcium chloride £ 3 mmol) (aluminum £ 1 part per million (ppm)) (albumin human £ 10 mg per mL )]


250 IU with 10 mL sterile water for injection provided as diluent (Rx) [Alphanate (albumin human 0.05 to 1 gram per 100 mL) (calcium £ 10 mmol per L) (heparin £ 2 Units per mL) (sodium £ 10 mEq)] [Hemofil M ( albumin human 12.5 mg per mL) (mouse protein £ 0.1 nanogram)] [Humate-P (sodium citrate 14 to 28 mg per 100 IU) (sodium chloride 8 to 16 mg per 100 IU) (albumin human 16 to 24 mg per 100 IU) (other proteins 4 to 20 mg per 100 IU )][Generic]


500 IU with 5 mL sterile water for injection provided as diluent (Rx) [Koate-HP (heparin £ 5 units per mL) (calcium chloride £ 3 mmol) (aluminum £ 1 ppm) (albumin human £ 10 mg per mL)] [Monoclate-P (sodium ion 300 to 450 mmol per liter) (calcium chloride 2 to 5 mmol per liter) (albumin human 1 to 2%) (mouse protein < 50 nanograms per 100 IU)]


500 IU with 10 mL sterile water for injection provided as diluent (Rx) [Alphanate (albumin human 0.05 to 1 gram per 100 mL) (calcium £ 10 mmol per L) (heparin £ 2 Units per mL) (sodium £ 10 mEq)] [Hemofil M ( albumin human 12.5 mg per mL) (mouse protein £ 0.1 nanogram)] [Monarc-M (albumin human 12.5 mg/mL) (polyethylene glycol 3350 1.5 mg/mL) (histidine 55 mmol) ( glycine 30 mmol) (mouse protein £ 0.1 nanogram )][Generic]


500 IU with 20 mL sterile water for injection provided as diluent (Rx) [Humate-P (sodium citrate 14 to 28 mg per 100 IU) (sodium chloride 8 to 16 mg per 100 IU) ( albumin human 16 to 24 mg per 100 IU) (other proteins 4 to 20 mg per 100 IU)]


1000 IU with 10 mL sterile water for injection provided as diluent (Rx) [Alphanate (albumin human 0.05 to 1 gram per 100 mL) (calcium £ 10 mmol per L) (heparin £ 2 Units per mL) (sodium £ 10 mEq)] [Hemofil M ( albumin human 12.5 mg per mL) (mouse protein £ 0.1 nanogram)] [Koate-HP (heparin £ 5 units per mL) (calcium chloride £ 3 mmol) (aluminum £ 1 ppm) (albumin human £ 10 mg per mL)] [Monarc-M (albumin human 12.5 mg/mL) (polyethylene glycol 3350 1.5 mg/mL) (histidine 55 mmol) ( glycine 30 mmol) (mouse protein £ 0.1 nanogram )] [Monoclate-P (sodium ion 300 to 450 mmol per liter) ( calcium chloride 2 to 5 mmol per liter) (albumin human 1 to 2%) (mouse protein < 50 nanograms per 100 IU)][Generic]


1000 IU with 30 mL sterile water for injection provided as diluent (Rx) [Humate-P (sodium citrate 14 to 28 mg per 100 IU) (sodium chloride 8 to 16 mg per 100 IU) ( albumin human 16 to 24 mg per 100 IU) (other proteins 4 to 20 mg per 100 IU)]


1500 IU with 10 mL sterile water for injection provided as diluent (Rx) [Alphanate (albumin human 0.05 to 1 gram per 100 mL) (calcium £ 10 mmol per L) (heparin £ 2 Units per mL) (sodium £ 10 mEq)] [Koate-HP (heparin £ 5 units per mL) (calcium chloride £ 3 mmol) (aluminum £ 1 ppm) (albumin human £ 10 mg per mL)]

Canada—


250 IU with 5 mL sterile water for injection provided as diluent (Rx) [Koate-HP (heparin £ 5 units per mL) (calcium chloride £ 3 mmol) (aluminum £ 1 ppm) (albumin human £ 10 mg per mL)][Generic]


250 IU with 10 mL sterile water for injection provided as diluent (Rx) [Hemofil M (albumin human 12.5 mg per mL) ( mouse protein £ 0.1 nanogram)]


500 IU with 5 mL sterile water for injection provided as diluent (Rx) [Koate-HP (heparin £ 5 units per mL) (calcium chloride £ 3 mmol) (aluminum £ 1 ppm) (albumin human £ 10 mg per mL)][Generic]


500 IU with 10 mL sterile water for injection provided as diluent (Rx) [Hemofil M (albumin human 12.5 mg per mL) ( mouse protein £ 0.1 nanogram)]


1000 IU with 10 mL sterile water for injection provided as diluent (Rx) [Hemofil M (albumin human 12.5 mg per mL) ( mouse protein £ 0.1 nanogram)] [Koate-HP (heparin £ 5 units per mL) (calcium chloride £ 3 mmol) (aluminum £ 1 ppm) (albumin human £ 10 mg per mL)][Generic]


1500 IU with 10 mL sterile water for injection provided as diluent (Rx) [Koate-HP (heparin £ 5 units per mL) ( calcium chloride £ 3 mmol) (aluminum £ 1 ppm ) (albumin human £ 10 mg per mL)][Generic]

Packaging and storage:
The dry concentrates are preferably stored between 2 and 8 °C (36 and 46 °F) {01} {02} {03} {41} {44} {46}. However, some products may be stored at temperatures not exceeding 30 °C (86 °F) for 2 months ( Alphanate ) {46} or 25 °C (77 °F) for 6 months ( Koate-HP, Monoclate-P, Humate-P) {02} {03} {42} {44}, according to the individual manufacturer's instructions. The solutions should not be refrigerated after reconstitution {01} {02} {41} {46}. The diluent should be protected from freezing {01} {41} {44}.

Preparation of dosage form:
The diluent and dry concentrate should be brought to room temperature, approximately 25 °C (77 °F), prior to reconstitution {01} {02} {03} {41} {44} {46}. They may be removed from the refrigerator and allowed to sit just until they reach room temperature, or in an urgent situation, they may be placed in a warm water bath, 30 to 37 °C (86 to 96 °F) {69} {74} {76} {79} {80} {81} {83}. The reconstituted solution should not be shaken, since excessive shaking will cause foaming {02}. The reconstituted solution should be at approximately room temperature at the time of administration {01} {02} {03} {41} {46}.

Stability:
Administration should begin within 1 {01} {41} or 3 {02} {03} {44} {46} hours after reconstitution, according to the individual manufacturer's instructions. Partially used vials should be discarded {44} {46}. For use as a continuous infusion, studies have shown reconstituted AHF remains stable for extended periods {111}.

Incompatibilities:
It is recommended that AHF, after reconstitution with the provided diluent, be administered through a separate line, by itself, and without mixing with other intravenous fluids or medications {66} {69} {70} {73} {74} {76} {79} {80} {82} {83}. However, when administered as a continuous intravenous infusion, the addition of heparin, 1 to 5 USP Units per mL of concentrate, may be considered if problems with local thrombophlebitis occur at the injection site, without affecting stability {109}.


ANTIHEMOPHILIC FACTOR (PORCINE)

Note: The specific activity of AHF (Porcine) is more than 15 porcine units per mg of protein.
Hyate:C must be tested in vitro , prior to administration, to demonstrate that it will not cross-react with anti-human factor VIII antibodies {69}.
The dose of AHF (Porcine) must be individualized for each patient based on patient weight, circulating antibody concentration, type of hemorrhage, and desired plasma factor VIII concentration {43}.
Hyate:C should be administered at a rate of not more than 2 to 5 mL per minute {43}.


Usual adult and adolescent dose
Hemorrhagic complications in patients with factor VIII inhibitors (prophylaxis and treatment)
Intravenous, initially, 50 to 100 International Units (IU) per kg of body weight {103} {113} {114}. Further doses are titrated according to the patient's clinical response and by monitoring the patient's factor VIII response {43} {50} {114}.


Usual pediatric dose
See Usual adult and adolescent dose .

Size(s) usually available:
U.S.—


400 to 700 Porcine Units (Rx) [Hyate:C (sodium ion £ 200 mmol per liter) (citrate ion £ 55 mmol per liter)]

Canada—


400 to 700 Porcine Units (Rx) [Hyate:C (sodium ion £ 200 mmol per liter) (citrate ion £ 55 mmol per liter)]

Packaging and storage:
The dry concentrate should be stored between -20 and -15 °C (-4 and +5 °F) {43}.

Preparation of dosage form:
The dry concentrate should be warmed to 20 to 37 °C (68 to 96 °F) {43} prior to reconstitution. It may be removed from the refrigerator and allowed to sit just until it reaches room temperature or, in an urgent situation, it may be placed in a warm water bath, 20 to 37 °C (68 to 96 °F) {70}. The dry concentrate should then be dissolved with 20 mL of sterile water for injection. The vial should be shaken gently until the concentrate is dissolved, taking care to prevent foaming. {43}

Stability:
Administration should begin within 3 hours after reconstitution. Partially used vials should be discarded. {43}

Incompatibilities:
It is recommended that AHF (Porcine), after reconstitution, be administered through a separate line, by itself, and without mixing with other intravenous fluids or medications {66} {69} {70} {73} {74} {76} {79} {80} {83}.


ANTIHEMOPHILIC FACTOR (RECOMBINANT)

Note: Each vial of AHF is labeled with the AHF activity expressed in International Units (IU) per vial. This potency assignment is referenced to the World Health Organization International Standard. One IU of factor VIII activity is approximately equal to the AHF activity of 1 mL of fresh plasma, and increases the plasma concentration of factor VIII by 2%. {16} {45} {53} The following formulas may be used as guides in determining dosage: {45} {53}
Desired AHF increase (% of normal) = ([Dose AHF(IU)]/[Body weight (kg)]) × 2
Dose AHF (IU) = Body weight (kg) × Desired AHF increase × 0.5
Kogenate,Helixate FS and Kogenate FS may be administered over five to ten minutes {45}{117}{118}, and Recombinate at a rate of up to 10 mL per minute {16}. However, the rate at which recombinant AHF is administered should be guided by the comfort of the patient.{117}{118}


Usual adult and adolescent dose
See Antihemophilic Factor USP (Human) .

Usual pediatric dose
See Antihemophilic Factor USP (Human) .

Size(s) usually available:
U.S.—


250 IU with 2.5 mL sterile water for injection provided as diluent (Rx) [Helixate] [Kogenate ( calcium chloride 2 to 5 mmol) (sodium 100 to 130 mEq per liter) (chloride 100 to 130 mEq per liter ) (albumin human 4 to 10 mg per mL) (mouse protein £ 0.03 nanogram per IU) ( hamster protein £ 0.04 nanogram per IU)]


250 IU with 2.5 mL sterile water for injection provided as diluent (Rx) [Kogenate FS,Helixate FS (no human albumin) (sucrose 28 mg [0.9 to 1.3%]) (glycine 21 to 25 mg per mL) (histidine 18 to 23 mmol)]{117}{118}


250 IU with 10 mL sterile water for injection provided as diluent (Rx) [Bioclate] [Recombinate (albumin human 12.5 mg per mL) (sodium 180 mEq per liter) (calcium 200 mcg per mL) (von Willebrand factor £ 2 nanograms per IU) (mouse protein £ 0.1 nanogram per IU) ( hamster and bovine proteins £ 1 nanogram per IU)]


500 IU with 2.5 mL sterile water for injection provided as diluent (Rx) [Kogenate FS, Helixate FS (no human albumin) (sucrose 28 mg [0.9 to 1.3%]) (glycine 21 to 25 mg per mL) (histidine 18 to 23 mmol)]{117}{118}


500 IU with 5 mL sterile water for injection provided as diluent (Rx) [Helixate] [Kogenate (calcium chloride 2 to 5 mmol) (sodium 100 to 130 mEq per liter) (chloride 100 to 130 mEq per liter) (albumin human 4 to 10 mg per mL) ( mouse protein £ 0.03 nanogram per IU) (hamster protein £ 0.04 nanogram per IU)]


500 IU with 10 mL sterile water for injection provided as diluent (Rx) [Bioclate] [Recombinate (albumin human 12.5 mg per mL) (sodium 180 mEq per liter) (calcium 200 mcg per mL) (von Willebrand factor £ 2 nanograms per IU) (mouse protein £ 0.1 nanogram per IU) ( hamster and bovine proteins £ 1 nanogram per IU)]


1000 IU with 2.5 mL sterile water for injection provided as diluent (Rx) [Kogenate FS (no human albumin) ( sucrose 28 mg [0.9 to 1.3%]) (glycine 21 to 25 mg per mL) (histidine 18 to 23 mmol)]{117}


1000 IU with 2.5 mL sterile water for injection provided as diluent (Rx) [Helixate FS (no human albumin) ( sucrose 28 mg [0.9 to 1.3%]) (glycine 21 to 25 mg per mL) (histidine 18 to 23 mmol)]{118}


1000 IU with 10 mL sterile water for injection provided as diluent (Rx) [Helixate] [Kogenate ( calcium chloride 2 to 5 mmol) (sodium 100 to 130 mEq per liter) (chloride 100 to 130 mEq per liter ) (albumin human 4 to 10 mg per mL) (mouse protein £ 0.03 nanogram per IU) ( hamster protein £ 0.04 nanogram per IU)] [Bioclate] [Recombinate (albumin human 12.5 mg per mL) (sodium 180 mEq per liter) (calcium 200 mcg per mL) (von Willebrand factor £ 2 nanograms per IU) (mouse protein £ 0.1 nanogram per IU) ( hamster and bovine proteins £ 1 nanogram per IU)]

Note: The amount of sucrose contained in Kogenate FS and Helixate FS is not expected to affect blood glucose concentrations.{117}{118}


Canada—


250 IU with 2.5 mL sterile water for injection provided as diluent (Rx) [Kogenate (calcium chloride 2 to 5 mmol) ( sodium 100 to 130 mEq per liter) (chloride 100 to 130 mEq per liter) (albumin human 4 to 10 mg per mL) (mouse protein £ 0.03 nanogram per IU) (hamster protein £ 0.04 nanogram per IU)]


250 IU with 10 mL sterile water for injection provided as diluent (Rx) [Recombinate (albumin human 12.5 mg per mL) ( sodium 180 mEq per liter) (calcium 200 mcg per mL ) (von Willebrand factor £ 2 nanograms per IU ) (mouse protein £ 0.1 nanogram per IU) (hamster and bovine proteins £ 1 nanogram per IU)]


500 IU with 5 mL sterile water for injection provided as diluent (Rx) [Kogenate (calcium chloride 2 to 5 mmol) (sodium 100 to 130 mEq per liter) (chloride 100 to 130 mEq per liter) (albumin human 4 to 10 mg per mL) (mouse protein £ 0.03 nanogram per IU) ( hamster protein £ 0.04 nanogram per IU)]


500 IU with 10 mL sterile water for injection provided as diluent (Rx) [Recombinate (albumin human 12.5 mg per mL) ( sodium 180 mEq per liter) (calcium 200 mcg per mL ) (von Willebrand factor £ 2 nanograms per IU ) (mouse protein £ 0.1 nanogram per IU) (hamster and bovine proteins £ 1 nanogram per IU)]


1000 IU with 10 mL sterile water for injection provided as diluent (Rx) [Kogenate (calcium chloride 2 to 5 mmol) ( sodium 100 to 130 mEq per liter) (chloride 100 to 130 mEq per liter) (albumin human 4 to 10 mg per mL) (mouse protein £ 0.03 nanogram per IU) (hamster protein £ 0.04 nanogram per IU)] [Recombinate (albumin human 12.5 mg per mL) (sodium 180 mEq per liter) ( calcium 200 mcg per mL) (von Willebrand factor £ 2 nanograms per IU) (mouse protein £ 0.1 nanogram per IU) (hamster and bovine proteins £ 1 nanogram per IU)]

Packaging and storage:
The dry concentrates are preferably stored between 2 and 8 °C (36 and 46 °F) {16} {45}. However, Kogenate may be stored at temperatures not exceeding 25 °C (77 °F) for 3 months{45}. Helixate FSandKogenate FS may be stored at temperatures not exceeding 25 °C (77 °F) for 2 months, protected from light, and stored in the carton prior to use{117}{118}

. The solution should not be refrigerated after reconstitution {16}. The diluent should be protected from freezing {16} {45}.

Preparation of dosage form:
The diluent and dry concentrate should be brought to room temperature, approximately 25 °C (77 °F), prior to reconstitution {16} {45}. They may be removed from the refrigerator and allowed to sit just until they reach room temperature or, in an urgent situation, they may be placed in a warm water bath, 30 to 37 °C (86 to 96 °F) {69} {74} {76} {79} {80} {81}. The reconstituted solution should not be shaken, since excessive shaking will cause foaming {45}. The reconstituted solution should be at approximately room temperature at the time of administration {16}.

Stability:
Administration should begin within 3 hours after reconstitution {16} {45}. Partially used vials should be discarded. For use as a continuous infusion, studies have shown reconstituted recombinant AHF remains stable for extended periods {111}.

Incompatibilities:
It is recommended that recombinant AHF, after reconstitution with the provided diluent, be administered through a separate line, by itself, and without mixing with other intravenous fluids or medications {76} {79}. However, when administered as a continuous intravenous infusion, the addition of heparin, 1 to 5 USP Units per mL of concentrate, may be considered if problems with local thrombophlebitis occur at the injection site, without affecting stability {112}.


CRYOPRECIPITATED ANTIHEMOPHILIC FACTOR USP

Note: Random-donor cryoprecipitated antihemophilic factor is not recommended as a treatment alternative for hemophilia A because the product does not undergo a viral attenuation process {96} {97}. Appropriately screened, single-donor cryoprecipitate (such as from desmopressin-treated fathers of hemophilic children) has been used as an inexpensive alternative to the use of factor VIII concentrates for the management of hemophilia in small children {98} {99}.
Cryoprecipitated AHF is blood group–specific {42}; ABO-compatible material is preferred {61} when large amounts of this component are infused, to avoid hemolysis {60} {61}.
Each bag of cryoprecipitated AHF contains a minimum of 80 IU of factor VIII {19} {42} {61} {62} {63} {65}. The following formula may be used as a guide in determining dosage: {65}
Number of bags required = [Body weight (kg) × Desired AHF increase (% normal) × 0.5]/[Average IU cryoprecipitate per bag (minimum 80)]


Usual adult and adolescent dose
Hemophilia A
Intravenous, initially, a loading dose to achieve the desired plasma factor VIII concentration, administered at a rate of 10 mL per minute, followed by a smaller maintenance dose every eight to twelve hours. To maintain hemostasis after surgery, it may be necessary to continue therapy for ten days or more. {61}

von Willebrand disease
Intravenous, 1 bag per 10 kg of body weight, administered every eight to twelve hours for several days {19}.

Hypofibrinogenemia
Intravenous, a quantity sufficient to raise the plasma fibrinogen concentration to 50 mg per 100 mL for minor bleeding, or to 100 mg per 100 mL for surgery {21} {76} {80}. Each bag of cryoprecipitated AHF can be expected to raise the fibrinogen concentration 4 to 7 mg per 100 mL {69} {71}.

Disseminated intravascular coagulation
Intravenous, 1 to 2 bags of cryoprecipitate per liter of patient's plasma {76} {80}.

Kasabach-Merritt syndrome
Intravenous, a quantity sufficient to raise the plasma fibrinogen concentration to 100 mg per 100 mL {76} {80}.


Usual pediatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


80 IU (Rx)[Generic] ( Available only through approved blood banks)( fibrinogen ³ 150 mg per 15 mL plasma)(von Willebrand factor)(factor XIII)( fibronectin)

Canada—


80 IU (Rx)[Generic] ( Available only through approved blood banks)( fibrinogen ³ 150 mg)(von Willebrand factor)

Packaging and storage:
The concentrate should be stored at -18 °C (-0.4 °F) {42} {53} {60} {62} {63}. It may be stored for up to 1 year from the date of collection of source material {42} {60} {62}. The solution should not be refrozen after thawing {61}.

Preparation of dosage form:
The frozen concentrate should be thawed in a water bath at 30 to 37 °C (86 to 98.6 °F) {42} {60} {61} {62} for up to 15 minutes. The reconstituted solution should be maintained at room temperature and administered as soon as possible, but no more than 6 hours after thawing {42} {61} {62}, or 4 hours after the container is entered {42} {61}. For pooling, the precipitate in each concentrate may be mixed with 10 to 15 mL of 0.9% sodium chloride injection {19} {61}. Cryoprecipitated AHF, Pooled, usually requires no extra diluent {61}.

Stability:
Should not be used if container shows evidence of breakage or if thawing occurred during storage {42} {60} {61}.

Incompatibilities:
It is recommended that cryoprecipitated AHF be administered through a separate line, by itself, and without mixing with other intravenous fluids (with the exception of 0.9% sodium chloride injection) or medications {61}.



Revised: 07/08/2001



References
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  1. Mannucci PM. Outbreak of hepatitis A among Italian patients with haemophilia [letter]. Lancet 1992; 339: 819.
  1. Gerritzen A, Schneweis KE, Brackmann HH, et al. Acute hepatitis A in haemophiliacs. Lancet 1992; 340: 1231-2.
  1. Gennaro AR, editor. Remington's pharmaceutical sciences. 18th ed. Easton, PA: Mack Publishing; 1990. p. 809.
  1. American Red Cross circular of information for the use of human blood and blood components. Washington, DC: American Red Cross; 1992. p. 2-3, 21-2.
  1. Holland PV, Schmidt PJ, editors. Standards for blood banks and transfusion services. 12th ed. Arlington, VA: American Association of Blood Banks; 1987. p. 20, 35.
  1. Code of federal regulations food and drugs. Washington, DC: Office of the Federal Register, National Archives and Records Administration 1992; 21 Parts 600 to 799.
  1. Nowicki MJ, Mosley JW, Koerper MA, et al. Passive antibody to hepatitis A virus in US haemophiliacs. Lancet 1993; 341: 562.
  1. Personal communication, Dale Rosborough, Canadian Red Cross, 3/24/93.
  1. Panel comment, 5/93.
  1. Panel comment, 7/93.
  1. Aznar JA, Jorquera JI, Peiró A, et al. The importance of corticoids added to continued treatment with factor VIII concentrates in the suppression of inhibitors in haemophilia A. Thromb Haemost 1984; 51: 217-21.
  1. Panel comment, 5/93.
  1. Manufacturer comment, 6/93.
  1. Panel comment, 5/93.
  1. Djulbegovic B, Goldsmith GH. Guidelines for management of hemophilia A and B [letter]. Blood 1995; 85: 598.
  1. Panel comment, 5/93.
  1. Panel comment, 5/93.
  1. Consider disseminated intravascular coagulation in any seriously ill patient. Drugs Ther Perspect 1993 Apr; 1(6): 9-11.
  1. Panel comment, 6/93.
  1. Stahl RL, Henderson JM, Hooks MA, et al. Therapy of the Kasabach-Merritt syndrome with cryoprecipitate plus intra-arterial thrombin and aminocaproic acid. Am J Hematol 1991; 36: 272-4.
  1. Warrell RP, Kempin SJ. Treatment of severe coagulopathy in the Kasabach-Merritt syndrome with aminocaproic acid and cryoprecipitate. N Engl J Med 1985; 313: 309-12.
  1. Panel comment, 6/93.
  1. Panel comment, 6/93.
  1. Panel comment, 6/93.
  1. Manufacturer comment, 5/93.
  1. Panel comment, 5/93.
  1. Azzi A, Ciappi S, Zakvrzewska K, et al. Human parvovirus B19 infection in hemophiliacs first infused with two high-purity, virally attenuated factor VIII concentrates. Am J Hematol 1992; 39: 228-30.
  1. Mannucci PM, Gdovin S, Gringeri A, et al. Transmission of hepatitis A to patients with hemophilia by factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. Ann Intern Med 1994; 120: 1-7.
  1. National Hemophilia Foundation. Medical and Scientific Advisory Council (MASAC) recommendation regarding the use of recombinant factor VIII in the treatment of hemophilia A. New York: The National Hemophilia Foundation; 1995. Medical Bulletin No. 232, Chapter Advisory No. 234.
  1. Reviewers' consensus on Hemophilia monograph developed 4/29/97.
  1. Gjerset GF, Pike MC, Mosley JW, et al. Effect of low- and intermediate-purity clotting factor therapy on progression of human immunodeficiency virus infection in congenital clotting disorders. Blood 1994; 84: 1666-71.
  1. Mannucci PM, Gringeri A, de Biasi R, et al. Immune status of asymptomatic HIV-infected hemophiliacs: randomized, prospective, two-year comparison of treatment with a high-purity or an intermediate-purity factor VIII concentrate. Thromb Haemost 1992; 67: 310-3.
  1. Lusher JM. Considerations for current and future management of haemophilia and its complications. Haemophilia 1995; 1: 2-10.
  1. Aledort L. Inhibitors in hemophilia patients: current status and management. Am J Hematol 1994; 47: 208-17.
  1. Panel comment on Hemophilia monograph, 1/97.
  1. Casdorph DL. Topical aminocaproic acid in hemophilic patients undergoing dental extraction. DICP 1990; 24: 160-1.
  1. Furie B, Limentani SA, Rosenfield CG. A practical guide to the evaluation and treatment of hemophilia. Blood 1994; 84: 3-9.
  1. Menitove JE, Gill JC, Montgomery RR. Preparation and clinical use of plasma and plasma fractions. In: Beutler E, Lichtman MA, Coller BS, et al., editors. Williams hematology. 5th ed. New York: McGraw-Hill; 1995. p. 1649-63.
  1. National Hemophilia Foundation. Medical and Scientific Advisory Council (MASAC) recommendations concerning HIV infection, hepatitis, and other transmissible agents in the treatment of hemophilia. New York: The National Hemophilia Foundation; 1995. Medical Bulletin No. 226, Chapter Advisory No. 227.
  1. DiMichele D. Hemophilia 1996: new approaches to an old disease. Pediatr Clin North Am 1996; 43: 709-36.
  1. McLeod BC, Sassetti RJ, Cole ER, et al. A high-potency, single-donor cryoprecipitate of known factor VIII content dispensed in vials. Ann Intern Med 1987; 106: 35-40.
  1. Panel comment on Hemophilia monograph, 3/97.
  1. Brackmann HH, Eickhoff HJ, Oldenburg J, et al. Long-term therapy and on-demand treatment of children and adolescents with severe haemophilia A: 12 years of experience. Haemostasis 1992; 22: 251-8.
  1. Petrini P, Lindvall N, Egberg N, et al. Prophylaxis with factor concentrates in preventing hemophilic arthropathy. Am J Pediatr Hematol Oncol 1991; 13: 280-7.
  1. Roberts HR, Hoffman M. Hemophilia and related conditions–inherited deficiencies of prothrombin (factor II), factor V, and factors VII to XII. In: Beutler E, Lichtman MA, Coller BS, et al., editors. Williams hematology. 5th ed. New York: McGraw-Hill; 1995. p. 1413-39.
  1. Association of Hemophilia Clinic Directors of Canada. Hemophilia and von Willebrand's disease: 2. Management. Can Med Assoc J 1995; 153: 147-57.
  1. Rickard KA. Guidelines for therapy and optimal dosages of coagulation factors for treatment of bleeding and surgery in haemophilia. Haemophilia 1995; 1 Suppl 1: 8-13.
  1. Panel comment on Hemophilia monograph, 1/97
  1. Panel comment on Hemophilia monograph, 1/97.
  1. Jandl JH. Chapter 32: Disorders of coagulation. In: Blood: textbook of hematology. 2nd ed. Boston: Little, Brown; 1996. p. 1361-1414.
  1. Panel comment on Hemophilia monograph, 1/97.
  1. Schulman S, Varon D, Keller N, et al. Monoclonal purified F VIII for continuous infusion: stability, microbiological safety and clinical experience. Thromb Haemost 1994; 72: 403-7.
  1. Martinowitz U, Schulman S, Gitel S, et al. Adjusted dose continuous infusion of factor VIII in patients with haemophilia A. Br J Haematol 1992; 82: 729-34.
  1. Schulman S, Gitel S, Martinowitz U. Stability of factor VIII concentrates after reconstitution. Am J Hematol 1994; 45: 217-23.
  1. DiMichele DM, Lasak ME, Miller CH. In vitro factor VIII recovery during the delivery of ultrapure factor VIII concentrate by continuous infusion. Am J Hematol 1996; 51: 99-103.
  1. Lusher JM. Transfusion therapy in congenital coagulopathies. Hematol Oncol Clin North Am 1994; 8: 1167-80.
  1. Kernoff PBA, Thomas ND, Lilley PA, et al. Clinical experience with polyelectrolyte-fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII. Blood 1984; 63: 31-41.
  1. Product Information: Humate-P®, antihemophilic factor/ von Willebrand factor complex, dried, pasteurized. Centeon, Kankakee, IL, USA, 1998.
  1. Product Information: Monarc-M™, antihemophilic factor (human), method M, monoclonal purified. American Red Cross, Washington, DC, USA, 1998.
  1. Product Information: Kogenate® FS, antihemophilic factor (recombinant). Bayer Corporation, Elkhart, IN. (PI Issued 06/2000) PI Reviewed 01/2001
  1. Product Information: Helixate® FS, antihemophilic factor (recombinant). Aventis– Behring, King of Prussia, PA. (PI Issued 06/2000) PI Reviewed 07/2001
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