ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Plasma derivatives and recombinant DNA-produced coagulation factors

Plasma derivatives and recombinant DNA-produced coagulation factors
Literature review current through: Jan 2024.
This topic last updated: Jan 10, 2024.

INTRODUCTION — Plasma derivatives are products manufactured from human plasma by chromatographic and other fractionation techniques. Some proteins can also be purified from serum. (See 'Starting material' below.)

A number of plasma proteins (or their modified forms) are also produced using recombinant DNA technologies, in which the protein is produced from an expression system into which a gene has been introduced.

This topic review discusses selected plasma-derived, serum-derived, and recombinant proteins that are used in medical practice. Plasma products including Fresh Frozen Plasma (FFP), convalescent plasma for coronavirus disease 2019 (COVID-19), pathogen-inactivated plasma, Cryoprecipitate, and fibrin sealant (fibrin glue) are discussed in detail separately:

FFP and other plasma products – (See "Clinical use of plasma components", section on 'Plasma products'.)

COVID-19 convalescent plasma – (See "COVID-19: Convalescent plasma and hyperimmune globulin".)

Pathogen-inactivated plasma – (See "Pathogen inactivation of blood products", section on 'Plasma/FFP'.)

Cryoprecipitate – (See "Cryoprecipitate and fibrinogen concentrate".)

Fibrin sealant – (See "Fibrin sealants".)

BACKGROUND

Starting material — Plasma is the liquid portion of blood from which cellular elements have been removed. Serum is the remaining liquid portion after plasma has been allowed to clot and the clot removed. Serum does not contain coagulation factors; thus, plasma must be used to isolate coagulation factors.

Products derived from plasma or serum have a theoretical risk of exposing the recipient to an infectious organism(s) present in the donor's blood; however, viral inactivation steps are highly effective in reducing viral transmission. (See 'Purification methods' below.)

Products prepared from plasma or serum may contain trace amounts of IgA and as such, may trigger anaphylactic reactions in some individuals with selective IgA deficiency who make no IgA and thus see the IgA protein as foreign. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Selective IgA deficiency: Management and prognosis".)

Purification methods — The starting material for purification of clotting factors is plasma. For other derivatives such as immunoglobulins or albumin, plasma or serum can be used. Harvard biochemist Edwin J Cohn and a team of scientists developed the first plasma fractionation process using cold ethanol fractionation; this method became known as the Cohn fractionation process [1]. Additional methods for purifying these proteins involve ion exchange, immune affinity chromatography, and other separation techniques, but modifications of the original cold ethanol process remain the mainstay for the production of plasma derivatives. The Cohn fractionation process causes immune globulins (ie, antibodies, primarily immunoglobulin G [IgG]) and some coagulation factors to precipitate in fractions II and III, from which relatively pure preparations can be produced. (See 'Antibody products' below and 'Clotting factor products' below.)

Manufacturers of plasma derivatives perform various additional steps to inactivate viruses and other infectious agents [1]. Examples include chromatography, filtration, nanofiltration, solvent/detergent treatment, heat treatment, and pasteurization. (See "Pathogen inactivation of blood products", section on 'Technologies'.)

Often the proteins are purified from large pools of plasma donors (often thousands of donors). Many of these products can be stored as a lyophilized powder (ie, freeze-dried under a vacuum), which preserves biologic activity, increases shelf-life, and may eliminate the need for refrigeration.

Recombinant methods — In addition to purification, a recombinant system can be used to manufacture proteins [2]. Typically, a gene of interest is introduced into a cell line that is used to produce the protein in cell culture; other methods for recombinant expression are also available.

Recombinant proteins have advantages such as greater control over the source of starting material, easier ability to vary the quantity of protein produced (ie, to scale up or scale down production), and ability to reduce the risk of pathogen transmission from donors. However, recombinant proteins may differ in certain properties from proteins obtained from blood, such as the following:

Proteins made in bacteria or non-human cell lines could lack human-specific post-translational modifications or codon preferences that optimize protein function in humans. As an example, glycosylation, phosphorylation, proteolytic processing, and formation of disulfide bonds (which are crucial for biologic activity) do not occur in Escherichia coli, a deficit that has to be overcome when making insulin in E. coli.

Proteins made in non-human systems could vary from the endogenous protein antigenically, which could lead to development of antibodies. This may be a concern with some recombinant coagulation factor products. However, the concern is not specific to recombinant products, as individuals who produce no endogenous factor will have the potential to recognize any factor as foreign and mount an antibody (inhibitor) response. (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication".)

Multi-subunit proteins may be especially challenging to produce in cell culture, and as a result, recombinant proteins may lack certain subunits. Recombinant factor XIII, A subunit is an example. (See 'Factors XIII and X' below.)

Cell culture lines can carry viral or other pathogens; however, these can usually be characterized and/or their presence excluded. In some cases, albumin is added for stabilization. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Recombinant human factor VIII' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Recombinant factor IX'.)

Although the technique has not been used extensively, recombinant methods can also be used to create transgenic animals (or plants) that produce the desired product. One example is antithrombin produced in the milk of transgenic goats. (See 'Antithrombin' below.)

ALBUMIN — Albumin is the most abundant protein in blood (accounting for approximately 55 percent of serum protein) [3]. Albumin acts as a carrier protein for many circulating proteins that are present at very low concentrations; it also provides oncotic pressure to retain fluid in the intravascular space.

Albumin is purified from large pools of human plasma [4]. It can be prepared as a 5 percent solution, which is iso-osmotic with plasma, or a 25 percent solution, which is hyperosmotic. Sometimes, pharmacies or nursing staff may dilute the 25 percent solution from its original 50 mL volume to a volume of 250 mL. If done, the dilution fluid must be normal saline, in order to maintain the proper osmolarity. A number of cases of hemolysis have been reported in patients undergoing therapeutic plasmapheresis due to dilution of 25 percent albumin with sterile water. Albumin solutions are pasteurized and do not transmit any known infectious diseases [5].

There is also a less frequently used product ("plasma protein fraction") that contains primarily albumin (approximately 90 percent albumin, with some globulins) and is less expensive than albumin. It is available as a 5 percent solution.

The uses for human serum albumin include the following; details of indications and administration are discussed in the linked topic reviews:

As a replacement fluid for therapeutic plasmapheresis. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Replacement fluids'.)

As an adjunct to large volume paracentesis in the treatment of diuretic-resistant ascites in cirrhosis. (See "Ascites in adults with cirrhosis: Diuretic-resistant ascites", section on 'Colloid replacement'.)

For the treatment of the hepatorenal syndrome. (See "Hepatorenal syndrome", section on 'Treatment' and "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis", section on 'Albumin administration for patients with renal dysfunction'.)

Routine use of intravenous albumin for the prevention of ovarian hyperstimulation syndrome is not recommended, but it may be helpful with severe disease [6,7]. (See "Prevention of ovarian hyperstimulation syndrome" and "Prevention of ovarian hyperstimulation syndrome", section on 'Intravenous albumin'.)

In contrast, the use of parenteral albumin solutions for nutritional supplementation or volume replacement is not appropriate; the value of albumin administration in pancreatitis, burn injuries, edema related to nephrotic syndrome, acute respiratory distress syndrome (ARDS), traumatic brain injury, and pediatric patients with infection and hypoperfusion is either unproven or harmful. Evidence regarding lack of benefit and/or harm is presented separately. (See "Management of acute pancreatitis" and "Pathophysiology and treatment of edema in adults with the nephrotic syndrome" and "Evaluation and management of suspected sepsis and septic shock in adults".)

Albumin infusions are generally safe, but there have been reported cases of transfusion-associated circulatory overload, anaphylaxis and hypotension [8,9].

ANTIBODY PRODUCTS

Immune globulins — Immune globulins are directed against foreign antigens as part of the humoral immune response. Supratherapeutic levels of immune globulins can also be used to modify immune function. (See "The adaptive humoral immune response" and "Laboratory evaluation of the immune system", section on 'Antibody deficiency and defects'.)

Immune globulin products contain protective antibodies (predominantly IgG) to numerous infectious agents, including hepatitis A and B viruses. Thus, these products are used to treat individuals with immunodeficiency associated with low antibody levels. These can be administered using preparations intended for subcutaneous, intravenous, or intramuscular administration (SCIG, IVIG, and IMIG respectively). (See "Immune globulin therapy in inborn errors of immunity".)

Larger amounts of immune globulin, such as provided with IVIG, have immunosuppressive properties and are often used to treat autoimmune or inflammatory conditions (eg, immune thrombocytopenia [ITP], neonatal alloimmune thrombocytopenia [NAIT], Guillain-Barré syndrome [GBS], Kawasaki disease [KD], antibody-mediated solid organ transplant rejection, refractory heparin-induced thrombocytopenia, post-transfusion purpura, and others), as discussed separately. (See "Overview of intravenous immune globulin (IVIG) therapy".)

A number of immune globulin formulations are commercially available.

IVIG – IVIG is used when large doses of antibodies are needed. Comparison of the IVIG products, factors that influence the choice of product, administration, and complications are discussed in detail separately. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects".)

IMIG and SCIG – The IMIG and SCIG products are generally more concentrated (eg, 10 to 20 percent solutions, compared with 5 to 10 percent solutions for IVIG), allowing a larger amount of IgG to be administered in a smaller volume. SC products can be administered via an infusion pump, rapid-push, or with hyaluronidase, which facilitates absorption by increasing the dispersion space. However, the total dose given is generally insufficient for primary suppression of autoimmune disorders. Thus, SCIG is generally used to treat immunodeficiency. It can also be used for maintenance immunosuppressive therapy in some conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP). IMIG products have few advantages over SCIG and IVIG and are only used in selected settings such as postexposure prophylaxis or hepatitis A prophylaxis in unimmunized travelers. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Intramuscular'.)

Potential adverse effects include a small increased risk of thrombosis and possible nephrotoxicity. Adverse effects are generally lower with the SCIG products compared with the IVIG products. All of these plasma products undergo pathogen-reduction to reduce and/or eliminate virus transmission; the final products must test negative for a number of infectious agents including HIV and hepatitis B and C viruses (HBV and HCV) [10]. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Adverse reactions of SCIG' and "Intravenous immune globulin: Adverse effects".)

Since immunoglobulin products may be used to treat individuals with immunodeficiency, it is worth noting that one of the more important potential complications is an allergic or anaphylactic reaction to IgA present in the product; these reactions may occur in individuals with IgA deficiency who have developed an immune response directed against IgA. These reactions depend on host factors (eg, the severity of IgA deficiency) and product factors (eg, the concentration of IgA in the source plasma). Debate continues about the magnitude and severity of this risk despite years of experience [11,12]. The use of immunoglobulin products in IgA-deficient individuals is addressed in the topic reviews on IVIG, IMIG, and SCIG referenced above, and the general care of these individuals is discussed in more detail separately. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Selective IgA deficiency: Management and prognosis".)

Hyperimmune globulins — Hyperimmune globulins are preparations that are enriched for immunoglobulins directed against a specific antigen (eg, a pathogen or toxin). They are generated by selecting plasma from exposed individuals who have high titers of the desired antibody or by specifically immunizing donors to produce such antibodies.

Hyperimmune globulins can be used for passive immunization in individuals who require immunity more rapidly than can be achieved by immunization or for those exposed to substances for which immunizations are not available (eg, snake bite). Formulations are generally prepared for IM administration but in some instances, IV formulations are available.

Hyperimmune globulins can also be produced in animals. This is especially true for hyperimmune globulins directed against a normal blood or tissue protein or if human exposure is unusual or unsafe. Examples include horse- or rabbit-derived antithymocyte globulin (ATG) for the treatment of aplastic anemia, equine serum heptavalent botulism antitoxin, and some snake bite antivenoms.

While hyperimmune globulin can be used to treat or prevent a wide range of infectious diseases, the most common use of hyperimmune globulin is for non-infectious purposes. RhD immune globulin is used to reduce the risk (by >95 percent) of developing hemolytic disease of the fetus and newborn (HDFN) when an RhD-negative individual is potentially carrying an RhD-positive fetus [13-15]. (See "Red blood cell antigens and antibodies", section on 'Rh blood group system' and "RhD alloimmunization in pregnancy: Overview" and "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

Selected available products directed against infectious organisms or toxins include the following; information about their indications, dosing, and adverse effects is discussed in the linked topic reviews:

Rabies immune globulin (RIG) (see "Rabies immune globulin and vaccine", section on 'Rabies immune globulin')

Vaccinia virus immune globulin (see "Treatment and prevention of mpox (monkeypox)", section on 'Vaccinia immune globulin')

Botulinum toxin (botulism immune globulin from humans or equine serum heptavalent botulism antitoxin) (see "Botulism", section on 'Antitoxin therapies')

Snake bite antivenoms (see "Snakebites worldwide: Management", section on 'Antivenom')

Hepatitis B immune globulin (HBIG) (see "Prevention of hepatitis B virus and hepatitis C virus infection among health care providers", section on 'Hepatitis B Immune Globulin (HBIG)')

Cytomegalovirus immune globulin (CMV-IG; Cytogam) (see "Prevention of cytomegalovirus infection in lung transplant recipients", section on 'CMV immune globulin' and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients", section on 'Refractory or drug-resistant CMV')

Varicella (VariZIG; an investigational product available in Canada and available under an investigational new drug application expanded access protocol in the United States) (see "Post-exposure prophylaxis against varicella-zoster virus infection")

During the coronavirus disease 2019 (COVID-19) pandemic, convalescent plasma (CCP; plasma from individuals who have recovered from SARS-CoV-2 infection, also called "hyperimmune plasma") was widely used; hyperimmune globulin derived from CCP was evaluated. Over 500,000 units of CCP were transfused, without knowledge of which patient groups would benefit most [16-18]. During this time, >30 randomized trials involving >20,000 participants were conducted. Details of the trial results and current indications for CCP are discussed in separate topic reviews:

General information – (See "COVID-19: Convalescent plasma and hyperimmune globulin".)

Hospitalized patients – (See "COVID-19: Management in hospitalized adults", section on 'Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)'.)

Outpatients – (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'High-titer convalescent plasma'.)

CLOTTING FACTOR PRODUCTS — Numerous products have been developed to enhance hemostasis. In general, it is preferable to administer the most specific product available (eg, factor X for factor X deficiency; fibrinogen for fibrinogen deficiency) as this is least likely to cause adverse effects. The use of a specific factor product will reduce the need for administration of plasma or Cryoprecipitate, which exposes the patient to the risk of transfusion reactions and transfusion-transmitted infections.

Supporting evidence is provided in the associated topics. Examples include:

Rare coagulation factor deficiencies – The table summarizes the available concentrates and recombinant factor products for the rare coagulation disorders (table 1). (See "Rare inherited coagulation disorders", section on 'Products for treating bleeding'.)

Hemophilia – Clotting factor products for hemophilia A and B and factor XI deficiency (hemophilia C) are discussed in detail separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Available products' and "Factor XI (eleven) deficiency", section on 'Hemostatic therapies'.)

VWD – von Willebrand factor (VWF) products for von Willebrand disease (VWD) are discussed separately. (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'Plasma-derived VWF concentrates'.)

Most of the available products provide coagulation factors in their unactivated, zymogen form. The risk of thrombosis is thought to be lower with unactivated factors than with the activated factors because the unactivated factors will only be activated at sites of injury. In contrast, when activated factors are transfused, they will be present in the active form in the general circulation (instead of primarily at the site of injury). Mechanisms of clotting factor activation and roles of the factors in the clotting cascade are discussed in detail separately. (See "Overview of hemostasis", section on 'Clotting cascade and propagation of the clot'.)

Two products that contain clotting factors in the activated form are activated prothrombin complex concentrates (aPCCs; eg, factor eight inhibitor bypassing activity [FEIBA]) and recombinant activated factor VII (rFVIIa); in both of these, the activated factor is factor VII. (See 'PCCs' below and 'Recombinant factor VIIa' below.)

PCCs — Prothrombin complex concentrates (PCCs) contain vitamin K-dependent clotting factors. The 4-factor PCCs contain the procoagulant factors II, VII, IX, and X (as well as the anticoagulant proteins protein S, protein C, and antithrombin). The 3-factor PCCs contain factors II, IX, and X (and proteins S and C) but only small amounts of factor VII. Activated PCCs (aPCCs; eg, factor eight inhibitor bypassing activity [FEIBA]) contain factor VII in the activated form (factor VIIa); the other factors are the same as in 4-factor PCCs.

Available PCC products are summarized in the table (table 2). Clinical use is discussed in detail in UpToDate drug information and topics that cover bleeding in specific clinical circumstances:

Unactivated PCC products may be used in individuals with vitamin K deficiency or to urgently reverse anticoagulation in an individual with clinically serious bleeding due to a vitamin K antagonist (VKA) such as warfarin. As noted above, there are 3- and 4-factor products (which contain factors II, IX, and X or these three plus factor VII, respectively); the 4-factor products have better evidence of efficacy for VKA-associated major bleeding. These products are sometimes used for reversing other anticoagulants or for treating intractable bleeding, but the evidence to support these alternative uses is of low quality. Details and supporting evidence are presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Major bleeding'.)

These products may also be used to treat or prevent bleeding in individuals with rare factor deficiencies if a specific factor product is not available. (See "Rare inherited coagulation disorders", section on 'Management of specific deficiencies'.)

Activated PCC (aPCC) products are 4-factor PCCs in which factor VII is activated during purification. These products may be used for the prevention or treatment of bleeding in individuals with congenital hemophilia A complicated by an inhibitor, acquired hemophilia A (bleeding due to an autoantibody against factor VIII), other acquired factor inhibitors, or life-threatening bleeding associated with direct factor Xa inhibitor anticoagulants. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Bypassing products (rFVIIa products or FEIBA)' and "Fondaparinux: Dosing and adverse effects" and "Management of bleeding in patients receiving direct oral anticoagulants".)

PCCs carry a prothrombotic risk and should only be administered in situations where the benefit of therapy outweighs this risk. The risk of thrombosis appears to be especially high with aPCC in individuals receiving multiple doses and/or concomitant emicizumab (a bifunctional antibody that substitutes for the function of factor VIIIa). Generally, multiple doses of aPCC are not recommended. Risk may be increased in those with liver disease due to reduced clearance of these activated products from the circulation, although data are extremely limited. Details and supporting evidence are presented separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A' and "Hemostatic abnormalities in patients with liver disease", section on 'General approach to managing bleeding'.)

Other important caveats about PCC use include the following:

IgA deficiency – PCCs contain variable amounts of IgA. Caution must be used in selected patients with IgA deficiency who have anti-IgA antibodies and/or previously documented hypersensitivity reactions to IgA-containing products. The product information for the specific product can be consulted to determine whether IgA is present. (See "Selective IgA deficiency: Management and prognosis", section on 'Safe administration of blood products'.)

HIT – Some PCCs contain heparin and thus cannot be used in individuals with active heparin-induced thrombocytopenia (HIT) or a history of HIT. (See "Management of heparin-induced thrombocytopenia", section on 'Lifelong heparin avoidance (list of sources)'.)

DIC – We generally do not use PCCs in individuals with disseminated intravascular coagulation (DIC) due to the theoretical risk of triggering thrombotic complications, although there may be a role for selected patients with consumptive coagulopathy and severe bleeding. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Prevention/treatment of bleeding'.)

We also avoid concomitant use of PCCs with recombinant factor VIIa since both products are potentially prothrombotic. (See 'Recombinant factor VIIa' below.)

Recombinant factor VIIa — Two recombinant forms of activated factor VII (rFVIIa; NovoSeven and Sevenfact) are commercially available. NovoSeven is approved to prevent or treat bleeding in individuals with congenital or acquired factor VII deficiency, hemophilia A complicated by an inhibitor, Glanzmann thrombasthenia, acquired hemophilia A (autoantibody to factor VIII); it is also used for a number of off-label indications that are discussed separately. SevenFact is approved for hemophilia A complicated by an inhibitor. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Available products and their properties'.)

As with aPCCs, these products carry a prothrombotic risk that must be weighed against its potential benefit; they are generally avoided in patients with other prothrombotic risk factors such as DIC, coronary artery disease, cerebrovascular disease, or simultaneous use of other PCCs. Indications, mechanism of action, dosing, and adverse effects are discussed in depth separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Bypassing products (rFVIIa products or FEIBA)' and "Recombinant factor VIIa: Administration and adverse effects".)

Individual procoagulant factors — Individual clotting factors are typically used to treat specific clotting factor deficiencies such as hemophilia, von Willebrand disease (VWD), or one of the rare inherited coagulation factor disorders. The relationship among the clotting factors in the coagulation cascade are presented in detail separately. (See "Overview of hemostasis".)

Available products are summarized below. A factor V concentrate is under evaluation but is not yet commercially available [19].

von Willebrand factor — von Willebrand factor (VWF) promotes platelet adhesion to endothelial cells and stabilizes circulating factor VIII.

Available VWF products include the following:

Plasma-derived VWF concentrates – These products, which are purified from Cryoprecipitate, contain VWF plus factor VIII (which co-purifies with VWF). Some of the "intermediate purity" factor VIII concentrates purified from plasma also contain VWF. Plasma-derived VWF concentrates may rarely be used to treat factor VIII deficiency, if a factor VIII concentrate is not available. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Factor VIII concentrates from plasma'.)

Recombinant VWF – A recombinant VWF product can be used for individuals with VWD. Unlike the plasma-derived VWF concentrates, no factor VIII accompanies the VWF, and additional recombinant factor VIII should be given along with the recombinant VWF when the patient's measured factor VIII level is less than 40 percent of normal and there is insufficient time to determine whether the patient's factor VIII level will rise in response to desmopressin or the recombinant VWF product.

VWF products may be used to treat bleeding (or prevent surgical bleeding) in von Willebrand disease (VWD; inherited deficiency or dysfunction of VWF) or in acquired VWF deficiency (acquired von Willebrand syndrome [aVWS]). (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery" and "Acquired von Willebrand syndrome", section on 'Management'.)

Cryoprecipitate contains VWF but is only used if VWF replacement therapy is needed and the above products are not available. (See "Cryoprecipitate and fibrinogen concentrate", section on 'Differences between them'.)

Factors VIII and IX — The activated forms of factors VIII and IX (factors VIIIa and IXa) act together to form the intrinsic X-ase (ten-ase) complex responsible for cleaving factor X to Xa (figure 1). Deficiencies of factor VIII (F8; hemophilia A) and factor IX (F9; hemophilia B) are the two most common inherited factor deficiencies. De novo mutations account for up to one-third of hemophilia A cases, and autoantibodies can cause acquired hemophilia A. (See "Genetics of hemophilia A and B" and "Clinical manifestations and diagnosis of hemophilia" and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

The tables summarize factor VIII products (table 3) and factor IX products (table 4) available for prophylaxis and treatment of bleeding in individuals with hemophilia A and B, respectively. These include plasma-derived and recombinant products based on the human factor VIII and factor IX gene sequences, as well as a recombinant porcine (pig-derived) factor VIII product (Obizur) that can be used for acquired (and possibly hereditary) hemophilia A. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Management'.)

Some of the recombinant products have one or more modifications to extend their circulating half-life, potentially reducing the frequency of administration by a significant length of time (eg, three- to fivefold), especially for the factor IX products. Examples of the modifications include fusions with the Fc portion of IgG1 or addition of polyethylene glycol (PEGylation).

Available factor VIII and factor IX products are discussed in detail separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Available products'.)

A number of studies have addressed the risk of developing an antibody directed against a clotting factor that inhibits the function of that factor. This consideration is especially important for hemophilia A, which has a much higher rate of inhibitor development than hemophilia B. This subject and supporting evidence are discussed in detail separately. (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication".)

Fibrinogen — Fibrinogen (FBG, factor I) is the precursor to fibrin, the principal structural component of the fibrin clot. Fibrinogen is cleaved to fibrin at sites of vascular injury by thrombin. Typical fibrinogen levels in plasma range from approximately 200 to 400 mg/dL; these levels are significantly higher than any of the other coagulation factors. Concern for clinical bleeding increases with fibrinogen levels below 100 mg/dL; higher levels are often required during pregnancy. (See "Disorders of fibrinogen", section on 'Biology' and "Overview of hemostasis".)

Clinical situations where augmentation of fibrinogen levels might be considered include:

Treatment or prevention of bleeding in individuals with inherited fibrinogen disorders (afibrinogenemia, hypofibrinogenemia, or dysfibrinogenemia). (See "Disorders of fibrinogen", section on 'Management'.)

Treatment of DIC or dilutional coagulopathy with bleeding and a low fibrinogen level. (See "Disseminated intravascular coagulation in infants and children", section on 'Replacement therapy' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Prevention/treatment of bleeding' and "Disseminated intravascular coagulation (DIC) during pregnancy: Management and prognosis", section on 'Fibrinogen target'.)

Based on their strong safety profiles and ease of use, fibrinogen concentrates may be preferred over Cryoprecipitate as a source of fibrinogen. In the 2019 FIBRES (FIBrinogen Replenishment in Surgery) trial, which randomly assigned cardiac surgery patients with bleeding and hypofibrinogenemia to receive fibrinogen concentrate or Cryoprecipitate, transfusion rates were similar in both arms [20]. While fibrinogen concentrates have similar efficacy and lower adverse events than Cryoprecipitate, they are more expensive [21,22]. Most institutions stock only one of these products, so it is important to understand what is available at the specific facility.

Several fibrinogen concentrates derived from human plasma are available, including Fibryga, Haemocomplettan, and RiaSTAP. There are no recombinant fibrinogens, but products are under development. Dosing is discussed in detail separately. (See "Disorders of fibrinogen", section on 'Fibrinogen concentrate: Dosing and monitoring'.)

Cryoprecipitate may also be used as a concentrated source of fibrinogen. (See "Cryoprecipitate and fibrinogen concentrate", section on 'Differences between them'.)

Factors XIII and X — The activated form of factor XIII (factor XIIIa) stabilizes the fibrin clot by longitudinal and transverse crosslinking of fibrin; it also plays roles in wound healing and embryo implantation. The activated form of factor X (factor Xa), in combination with activated factor V, enzymatically cleaves prothrombin (factor II) to thrombin. (See "Overview of hemostasis", section on 'Continuation of the coagulation cascade' and "Overview of hemostasis", section on 'Multicomponent complexes'.)

Factor XIII or factor X products can be used to treat bleeding or prevent surgical bleeding in individuals with inherited deficiencies of factor XIII or factor X, respectively, both of which are rare. Factor XIII (and occasionally factor X) may also be administered in early pregnancy to prevent miscarriage. (See "Rare inherited coagulation disorders", section on 'Management of specific deficiencies'.)

Factor X is available as a plasma-derived concentrate that was approved by the US Food and Drug Administration (FDA) for the treatment of adults and children with hereditary factor X deficiency, on-demand and perioperatively. Unlike 4-factor PCC, which has a low percentage of factor X, the plasma-derived factor X concentrate has 94 percent factor X.

Importantly, andexanet alfa (which is labeled as "coagulation factor Xa [recombinant], inactivated zhzo") is not a factor X replacement product. Andexanet is a protein-based reversal agent for factor Xa inhibitor anticoagulants and has no role in treating other conditions. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Factor Xa inhibitors'.)

Factor XIII is available as a plasma-derived concentrate or a recombinant product. Factor XIII contains an A and a B subunit encoded by separate genes. The concentrate purified from human plasma contains both the A and B subunits, whereas the recombinant factor XIII produced from yeast cells only contains the A subunit (A subunit deficiency is the most common form of factor XIII deficiency, accounting for approximately 95 percent of cases). Genetics and prevalence of factor XIII deficiency are presented separately. (See "Rare inherited coagulation disorders", section on 'Factor XIII deficiency (F13D)'.)

Plasminogen — Plasminogen is a fibrinolytic factor that breaks down clots enzymatically. Plasminogen deficiency can cause a phenotype of excess thrombosis. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Plasminogen deficiency'.)

A plasma-derived plasminogen product was approved by the FDA in June 2021 for individuals with plasminogen deficiency [23]. This and the role of anticoagulation are presented separately. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Therapies for hypofibrinolytic states'.)

Topical thrombins — Thrombin (factor IIa, produced by cleavage of prothrombin) is the final procoagulant enzyme in the coagulation cascade; it cleaves fibrinogen to fibrin, which is then crosslinked to form a stable clot. Thrombin also activates platelets and factor VIII. (See "Overview of hemostasis".)

Topical thrombins are used in surgical patients to stop oozing and minor capillary and small-vein bleeding when standard surgical techniques are ineffective or impractical. These products are applied to surfaces of bleeding tissue and may be used along with an absorbable gelatin sponge. (See "Fibrin sealants", section on 'Thrombin'.)

There are three types of products: bovine thrombin, human thrombin, and a recombinant human thrombin; the human thrombins have largely replaced bovine thrombin, which was associated with a risk for autoantibodies to thrombin and/or factor V that could cause severe bleeding. Use of these products and clinical manifestations of the bleeding complication are discussed separately. (See "Overview of topical hemostatic agents and tissue adhesives", section on 'Topical thrombin' and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Factor II (prothrombin) and IIa (thrombin) inhibitors'.)

There is no plasma-derived or recombinant product containing prothrombin (factor II); individuals with prothrombin deficiency who require factor replacement may be treated with plasma or PCCs. (See 'PCCs' above and "Rare inherited coagulation disorders", section on 'Factor II (prothrombin) deficiency (F2D)'.)

Anticoagulant factors — Individuals with inherited or acquired deficiencies in one of the natural anticoagulants (protein S, protein C, antithrombin [AT]) may be at risk of thrombosis and thromboembolic complications. Anticoagulant replacement factors are available for AT and protein C. There is little high-quality evidence with which the relative risks and benefits (or the relative cost-effectiveness) of AT or protein C administration can be estimated. Details of treatment are discussed separately. (See "Antithrombin deficiency", section on 'Management' and "Protein C deficiency", section on 'Management'.)

Antithrombin — Antithrombin (AT, previously called antithrombin III) is an anticoagulant protein (a protease) that inhibits thrombin (factor IIa) and activated factor X (factor Xa); it also has effects on factors IXa and XIa. (See "Overview of hemostasis", section on 'Antithrombin, heparin, and heparan'.)

AT has a strong affinity for heparin and is required for heparins and fondaparinux to function effectively as anticoagulants (figure 2). (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Mechanisms of action' and "Fondaparinux: Dosing and adverse effects", section on 'Mechanism of action'.)

AT may be used for treatment or prophylaxis of thromboembolism in individuals with hereditary or acquired AT deficiency. Among individuals with hereditary or acquired AT deficiency, AT is also sometimes used during the perioperative and peripartum periods. AT is also prescribed for some individuals with heparin resistance, patients on extracorporeal membrane oxygenation (ECMO), and patients on a ventricular assist device (VAD) with low AT levels. (See "Antithrombin deficiency", section on 'Management' and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Heparin resistance/antithrombin deficiency' and "Extracorporeal life support in adults in the intensive care unit: The role of transesophageal echocardiography (TEE)" and "Anesthesia for placement of ventricular assist devices".)

Available AT products include plasma-derived AT concentrate and a recombinant AT (rhAT; ATryn) produced in the milk of transgenic goats that express the gene for human AT in mammary tissue.

Protein C — Protein C is proteolytically activated to the anticoagulant form, activated protein C (APC), by thrombin complexed with thrombomodulin. APC acts in a complex with its cofactor, protein S, to inhibit the functions of factors Va and VIIIa, in turn inactivating the prothrombinase and intrinsic ten-ase complexes, respectively. (See "Overview of hemostasis", section on 'Activated protein C and protein S'.)

The relatively common factor V Leiden (FVL) mutation is the most common cause of resistance to APC and may confer a prothrombotic risk in some individuals. Inherited protein C deficiency is less common and carries a greater prothrombotic risk than FVL, as shown in the table (table 5) and discussed in more detail separately. (See "Factor V Leiden and activated protein C resistance" and "Protein C deficiency".)

Protein C concentrate derived from human plasma is available for the treatment and prevention of venous thromboembolism and other severe complications of protein C deficiency such as warfarin-induced skin necrosis and neonatal purpura fulminans, as well as to treat purpura fulminans associated with DIC. (See "Protein C deficiency", section on 'Management' and "Neonatal thrombosis: Management and outcome", section on 'Neonatal purpura fulminans' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Purpura fulminans'.)

Importantly, protein C concentrate is not the same as recombinant APC, which has both anticoagulant and anti-inflammatory properties; this product was tested in the treatment of sepsis and subsequently removed from the market in 2011 when it failed to show a survival benefit.

PROTEIN THERAPIES FOR OTHER DISORDERS — Human plasma contains a variety of other proteins that can be purified and used to treat other protein deficiencies.

C1-esterase inhibitor — C1-esterase inhibitor (also called C1INH) limits the activity of the C1 component of complement, which cleaves C2 and C4 as part of the classical pathway of complement activation (figure 3). Deficiency of C1-esterase inhibitor can cause hereditary angioedema; autoantibodies against the protein can cause acquired angioedema. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" and "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)

Plasma-derived and recombinant C1INH products are available. Their use in treating inherited and acquired angioedema due to C1INH deficiency is discussed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis" and "Acquired C1 inhibitor deficiency: Management and prognosis".)

Alpha-1 antitrypsin — Alpha-1 antitrypsin (AAT, also called alpha-1-proteinase inhibitor) inhibits several proteases. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Background'.)

AAT can be used in individuals with alpha-1 antitrypsin deficiency, which carries increased risks for emphysema and less frequently for liver disease and panniculitis. In addition to a plasma-derived concentrate that is administered intravenously, studies are evaluating intravenous administration of a recombinant product and aerosolized therapy (direct delivery to the lung by inhalation). Details and supporting evidence are discussed separately. (See "Treatment of alpha-1 antitrypsin deficiency", section on 'Intravenous augmentation therapy' and "Treatment of alpha-1 antitrypsin deficiency", section on 'Emerging therapies'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemophilia A and B" and "Society guideline links: von Willebrand disease" and "Society guideline links: Acquired bleeding disorders" and "Society guideline links: Rare inherited bleeding disorders".)

SUMMARY AND RECOMMENDATIONS

Source of products – Proteins (or protein complexes) can be purified from human plasma or serum or produced through recombinant technology. These products have been developed in response to care for individuals with hemophilia or other less common protein deficiencies. (See 'Background' above.)

Albumin – Albumin is purified from human plasma. It can be used as a replacement fluid during therapeutic apheresis. However, the use of parenteral albumin solutions for nutritional supplementation or volume replacement is not appropriate. (See 'Albumin' above.)

Immune globulinsImmune globulin products are purified from plasma and can be used to treat immunodeficiency, for which subcutaneous or intravenous preparations (SCIG or IVIG, respectively) can be used; for treating inflammatory or autoimmune conditions (using IVIG); to treat antibody-mediated rejection of a transplanted solid organ; to provide passive immunity against pathogens (hyperimmune globulins); or to provide prophylaxis against hemolytic disease of the fetus and newborn (HDFN) related to RhD in RhD-negative individuals (RhD immune globulin). (See 'Antibody products' above and "Subcutaneous and intramuscular immune globulin therapy" and "Overview of intravenous immune globulin (IVIG) therapy".)

Coagulation factors – A number of procoagulant and anticoagulant proteins are available to optimize hemostasis, especially for patients who are deficient in specific clotting factors. In some cases, a single protein or a complex of proteins is purified from plasma; in others, a protein (or subunit of a protein) may be produced using recombinant methods. The procoagulant factor products are used to treat bleeding or prevent surgical bleeding in individuals with inherited or acquired factor deficiencies and, in some cases, in patients treated with an anticoagulant. (See 'Clotting factor products' above.)

Other proteins – Additional products are available for other conditions such as angioedema due to C1-esterase inhibitor deficiency or alpha-1 antitrypsin deficiency. (See 'Protein therapies for other disorders' above.)

Plasma and Cryoprecipitate – Separate topic reviews discuss the clinical use of plasma components, Cryoprecipitate, and topical hemostatic agents. (See "Clinical use of plasma components" and "Pathogen inactivation of blood products" and "Cryoprecipitate and fibrinogen concentrate" and "Overview of topical hemostatic agents and tissue adhesives".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Arthur J Silvergleid, MD, to earlier versions of this and many other topic reviews.

  1. Ofosu FA, Freedman J, Semple JW. Plasma-derived biological medicines used to promote haemostasis. Thromb Haemost 2008; 99:851.
  2. Swiech K, Picanço-Castro V, Covas DT. Production of recombinant coagulation factors: Are humans the best host cells? Bioengineered 2017; 8:462.
  3. Charoenphol P, Oswalt K, Bishop CJ. Therapeutics incorporating blood constituents. Acta Biomater 2018; 73:64.
  4. https://www.fda.gov/downloads/Biolog%E2%80%A6ionatedPlasmaProducts/ucm056844.pdf.
  5. Blümel J, Schmidt I, Willkommen H, Löwer J. Inactivation of parvovirus B19 during pasteurization of human serum albumin. Transfusion 2002; 42:1011.
  6. Venetis CA, Kolibianakis EM, Toulis KA, et al. Intravenous albumin administration for the prevention of severe ovarian hyperstimulation syndrome: a systematic review and metaanalysis. Fertil Steril 2011; 95:188.
  7. Jee BC, Suh CS, Kim YB, et al. Administration of intravenous albumin around the time of oocyte retrieval reduces pregnancy rate without preventing ovarian hyperstimulation syndrome: a systematic review and meta-analysis. Gynecol Obstet Invest 2010; 70:47.
  8. Shimode N, Yasuoka H, Kinoshita M, et al. Severe anaphylaxis after albumin infusion in a patient with ahaptoglobinemia. Anesthesiology 2006; 105:425.
  9. Howard G, Downward G, Bowie D. Human serum albumin induced hypotension in the postoperative phase of cardiac surgery. Anaesth Intensive Care 2001; 29:591.
  10. Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol 2017; 139:S1.
  11. Guo Y, Tian X, Wang X, Xiao Z. Adverse Effects of Immunoglobulin Therapy. Front Immunol 2018; 9:1299.
  12. Rachid R, Bonilla FA. The role of anti-IgA antibodies in causing adverse reactions to gamma globulin infusion in immunodeficient patients: a comprehensive review of the literature. J Allergy Clin Immunol 2012; 129:628.
  13. Bowman JM. Controversies in Rh prophylaxis. Who needs Rh immune globulin and when should it be given? Am J Obstet Gynecol 1985; 151:289.
  14. Bowman JM. The prevention of Rh immunization. Transfus Med Rev 1988; 2:129.
  15. Koelewijn JM, de Haas M, Vrijkotte TG, et al. One single dose of 200 microg of antenatal RhIG halves the risk of anti-D immunization and hemolytic disease of the fetus and newborn in the next pregnancy. Transfusion 2008; 48:1721.
  16. Bloch EM, Shoham S, Casadevall A, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest 2020; 130:2757.
  17. Budhai A, Wu AA, Hall L, et al. How did we rapidly implement a convalescent plasma program? Transfusion 2020; 60:1348.
  18. Tobian AAR, Cohn CS, Shaz BH. COVID-19 convalescent plasma. Blood 2022; 140:196.
  19. Bulato C, Novembrino C, Anzoletti MB, et al. "In vitro" correction of the severe factor V deficiency-related coagulopathy by a novel plasma-derived factor V concentrate. Haemophilia 2018; 24:648.
  20. Callum J, Farkouh ME, Scales DC, et al. Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery: The FIBRES Randomized Clinical Trial. JAMA 2019; 322:1966.
  21. Novak A, Stanworth SJ, Curry N. Do we still need cryoprecipitate? Cryoprecipitate and fibrinogen concentrate as treatments for major hemorrhage - how do they compare? Expert Rev Hematol 2018; 11:351.
  22. Cushing MM, Haas T, Karkouti K, Callum J. Which is the preferred blood product for fibrinogen replacement in the bleeding patient with acquired hypofibrinogenemia-cryoprecipitate or fibrinogen concentrate? Transfusion 2020; 60 Suppl 3:S17.
  23. https://www.fda.gov/media/149806/download (Accessed on December 21, 2023).
Topic 7925 Version 54.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟