A Compendium Of Drugs And Procedures

HEMATOLOGIC AGENTS
(To Stimulate Blood Cell Growth and Development)

For Red Blood Cells

  • Hematinics. Iron, folic acid, and vitamin B12 are essential nutrients for red blood cells.
  • Recombinant Erythropoietin (r-Hu-EPO). r-Hu-EPO is a biosynthetic form of a natural human hormone responsible for stimulation of red blood cell production.

For White Blood Cells

  • Recombinant Granulocyte-Colony Stimulating Factor (r-Hu-G-CSF). This medication is a biosynthetic form of a natural human hormone that stimulates production of neutrophils (a specific type of infection-fighting white blood cell) in the bone marrow. It is manufactured using recombinant DNA technology, and has the same biological effects as endogenous human granulocyte colony-stimulating factor.
  • Recombinant Granulocyte Macrophage-Colony Stimulating Factor (r-Hu-GM-CSF). This is a biotechnologically produced form of a naturally occurring human hematopoietic agent. It stimulates production of a variety of infection-fighting white blood cells (neutrophils/granulocytes and monocytes/macrophages).

For Platelets

  • Recombinant Interleukin-11 (r-Hu-IL-11). Interleukin-11 is a genetically produced form of a naturally occurring human hormone that stimulates the body's platelet production.
  • Recombinant Thrombopoietin (r-Hu-TPO), Megakaryocyte Growth and Development Factor (r-Hu-MGDF). These drugs stimulate platelet production. They are synthetic versions of a natural human hormone produced by recombinant DNA technology. The effect of r-Hu-TPO on platelet production is analogous to erythropoietin (r-Hu-EPO) in stimulating red blood cell production.

HEMOSTATIC AGENTS (To Promote Clotting)

  • Aminocaproic Acid. A medication that enhances clotting by slowing or stopping fibrinolysis (the breakdown of blood clots).
  • Tranexamic Acid. A drug that enhances clotting by slowing or stopping fibrinolysis (the breakdown of blood clots).
  • Aprotinin. A naturally occurring agent isolated from bovine lung tissue that reduces bleeding during and after surgery. The mechanism by which aprotinin minimizes bleeding is thought to involve effects on platelet function as well as on coagulation and fibrinolysis.
  • Desmopressin. A synthetic version of a naturally occurring hormone. Desmopressin causes a dose-dependent increase in plasma factor VIII, plasminogen activator, and to a lesser degree, factor VIII-related antigen and ristocetin cofactor activities. Large IV doses of desmopressin increase factor VIII activity in healthy individuals, in patients with mild to moderate hemophilia A and B or von Willebrands disease, and in patients with uremia.
  • Topical Hemostatic Agents. Pads, powders, pastes, sponges, solutions, meshes and special dressings that may be used before and during surgery to control blood loss from open wounds by promoting the clotting of whole blood, or plasma. In many types of surgery, several hemostatic agents may be combined for better hemostasis. Thrombin is a commercially available hemostatic agent of bovine origin.
  • Tissue Adhesives. These are products used to decrease blood loss. Fibrin glue is a human-derived tissue adhesive that may be used for hemostasis and sealing of tissues. This biological glue can be manufactured from clotting factors taken from donor plasma (fibrinogen and thrombin) or made intraoperatively out of fibrinogen coming from the patient's own blood. Tissue adhesives may be used topically or to seal wound surfaces to reduce postoperative bleeding, decrease or eliminate the need for sutures, as well as in treating thermal injuries.
  • Vitamin K (Phytonadione). A synthetic product identical to naturally occurring vitamin K. It is required for the production of certain blood-clotting factors (factors II, VII, IX, and X) in the liver.

RECOMBINANT ANTIHEMOPHILIC FACTORS

Recombinant antihemophilic (clotting) factors are biosynthetic forms of endogenous (naturally occurring) human blood coagulation factors. They are prepared using recombinant DNA technology (genetically engineered) and produce the same biological effects as the corresponding plasma-derived clotting products.

  • Recombinant Factor VIIa. Recombinant factor VIIa prevents or controls bleeding in patients with hemophilia.
  • Recombinant Factor VIII. Factor VIII is essential for blood clotting and the maintenance of effective hemostasis. Recombinant factor VIII provides a means of temporarily replacing missing or dysfunctional factor VIII in order to prevent or control bleeding episodes or to perform emergency or elective surgery in patients with hemophilia A.
  • Recombinant Factor IX. This recombinant product provides a means of temporarily replacing missing factor IX in order to prevent or control excessive bleeding in patients with hemophilia B.

NONBLOOD VOLUME EXPANDERS

  • Crystalloids. Intravenous fluids made up of water with various dissolved salts and sugars. These fluids are used to help maintain circulating blood volume in the body. Crystalloids include normal saline, Ringer's lactate, and hypertonic saline.
  • Colloids. Intravenous fluids composed of water mixed with very small particles of proteins or other material. These small particles do not dissolve in water. Colloids are used to maintain blood protein levels that stabilize fluid balances and circulation volume in the body. Colloids include pentastarch, hetastarch, gelatin, and dextran.

BLOOD CONSERVATION DEVICES AND EQUIPMENT

Hemostatic Surgical Instruments

  • Electrocautery. A device in which an electric current is used to heat a treatment instrument or probe. The heated probe cauterizes capillary vessels and small arteries, thus minimizing blood loss during surgery. Also called thermal cautery, this device does not transfer any electric current to the patient.
  • Lasers. Instruments similar in principle to electrocautery devices, but employing laser energy to cut, vaporize, and simultaneously coagulate a targeted area without disrupting adjacent tissue. Cutting is achieved hemostatically, making the systems suitable for endoscopic and open-surgical procedures. Lasers promote clotting by localizing heat in bleeding vessels, resulting in coagulation.
  • Microwave Scalpels. Microwaves are a form of electromagnetic energy that can be used to generate heat. The microwave scalpel is an instrument that concentrates a localized high-power microwave field around the leading edge of a scalpel blade. Because microwave energy is absorbed in tissue, the coagulating scalpel can provide in-depth coagulation during surgery on vascular organs such as the spleen or liver.
  • Argon-Beam Coagulator. A surgical instrument that uses a beam of ionized argon gas (argon "plasma") to conduct a high-frequency electric current to bleeding tissues with limited tissue contact. Argon-beam coagulation may be used for the hemostasis of surface, diffuse bleeding from parenchymatous tissues (e.g., of the liver, spleen).

MINIMALLY INVASIVE SURGERY

An approach to surgery whereby operations are performed with specialized instruments designed to be inserted into the patient through small incisions or natural body openings. This avoids the need for large incisions, minimizing the bleeding and trauma of surgery to the body. Miniaturized telescopelike devices allow surgeons to watch their actions on a television monitor, instead of looking directly at the part of the body being treated.

  • Endoscopy. Endoscopes allow visual examination of the interior of the stomach, intestines, and other body cavities. Bleeding or other problems can be located, diagnosed, and treated without conventional open surgery.
  • Laparoscopy. Using a small "keyhole" incision, a laparoscope may be used to visualize the abdomen. Specialized instruments and techniques adapted for minimally invasive surgery may be inserted through other nearby small unobtrusive incisions to perform surgical interventions.

BLOOD RECOVERY/SALVAGE DEVICES

Awareness of the need for blood conservation in the surgical patient and concerns about the risks of allogeneic blood transfusion have prompted clinicians to make wider use of the autologous blood recovery techniques. Modern intraoperative and postoperative autotransfusion is considered to be safe, well-tolerated, and cost-effective for a variety of patients with profuse bleeding.

  • Intraoperative Blood Salvage/Recycling Devices (Autotransfusion). Autologous blood cell salvage (autotransfusion) involves recovery of some portion of the patient's shed blood from a wound or body cavity, washing or filtering, and reinfusion of the blood into the patient. Reinfusion can be performed continuously during surgery.
  • Postoperative Blood Salvage/Recycling Devices. In some surgical procedures, postoperative blood loss exceeds intraoperative blood losses. Blood that is shed postoperatively can be collected from a drainage tube at the surgical site, processed and returned to the patient.

MINIMALLY AND NONINVASIVE BLOOD DIAGNOSTIC AND MONITORING SYSTEMS

Blood Microsampling. Microsample blood analysis devices use electrochemical, photometric and other technology to provide immediate critical diagnostic information at the point of care from only a few drops of blood (a fraction of the usual quantity). This reduces cumulative blood losses, as well as the time required to make decisions on patient management that are dependent on the results of blood tests.

CLINICAL OXYGEN DELIVERY SYSTEMS

Hyperbaric Oxygen (HBO). Hyperbaric oxygen therapy is used to manage severe anemia due to sudden blood loss in order to extend the physiologic limits of the cardiovascular system. HBO therapy is the medical use of intermittent doses of 100% oxygen at increased atmospheric pressure to a patient in a sealed environment in order to substantially increase the level of oxygen dissolved in the blood plasma.

MEDICAL AND SURGICAL TECHNIQUES

  • Preoperative Planning. Thorough patient evaluation is essential to formulating a comprehensive risk factor-based case management plan. This incorporates multiple blood conservation measures in an optimized, integrated, and algorithmic manner. A careful medical history, physical exam, and judicious laboratory testing will identify anemic conditions, clotting deficiencies or pre-existing complications (e.g., cardiopulmonary disease). This includes careful management of the patient's medications. Prophylactic treatment and perioperative management is determined for each individual patient. Consultation with senior specialists may be necessary.
  • Prompt Surgery. The timely arrest of bleeding by surgical repair or other means before blood levels fall to extremely low levels is imperative. Delayed action due to reliance on banked blood can result not only in increased blood loss, but also higher morbidity and mortality. Performing complex operative procedures in stages may minimize blood loss in some patients. In some trauma cases, emergency surgery may be performed to control bleeding and contamination followed by temporary packing of the wound and rapid closure to allow for adequate resuscitation and other care. Later, definitive surgery can be performed more safely. This "damage control" approach can avoid massive transfusions and the associated risks. It is vital to stop active bleeding before restoring normal blood pressure. Rapid restoration of normal blood pressure may inhibit clot formation, disrupt existing clots, and accelerate hemorrhage.
  • Meticulous Surgical Hemostasis. Meticulous surgical technique conserves red cells and contributes to avoidance of allogeneic blood. This includes atraumatic surgical techniques, expeditious and precise dissection along avascular anatomical planes, and meticulous occlusion and control of bleeding vessels encountered in the operating field. A drier surgical field provides better visibility, decreases tissue handling, reduces exposure of medical personnel to blood, and reportedly shorter operating times. Pharmacologic and mechanical blood conservation procedures are valuable adjuncts but cannot replace good surgical skills and appropriate use of hemostatic surgical devices. Preventive hemostasis is a fundamental aspect of blood conservation in surgery.
  • Mechanical Occlusion of Bleeding Vessels. A technique of using hemostatic clips, clamps, or similar devices to temporarily obstruct or close off blood vessels to minimize bleeding at the surgical site. This technique can be used to stop bleeding from small and large vessels. Vascular organs (e.g., liver, spleen) can be temporarily isolated in this way to minimize blood loss.
  • Arterial Embolization. Therapeutic introduction of either mechanical or chemical agents into blood vessels to occlude them. A catheter placed into an artery is used to inject various embolic materials. In elective surgery, it may be used preoperatively to limit blood loss from a surgical site (e.g., excision of a tumor). In emergencies, embolization can control active bleeding from a lacerated artery. This intervention avoids general anesthesia and major surgery.
  • Controlled Hypotension/Hypotensive Anesthesia. Intentional and controlled lowering of blood pressure reduces bleeding by decreasing pressure on injured blood vessels and causing less disruption of newly formed clots. It may minimize hemorrhage in orthopedic procedures, as well as during and after a wide range of other types of surgery. Hypertension must be avoided. Mild hypotension is desirable as long as cardiac output and oxygen delivery is adequate. Small volume resuscitation (using volume expanders) has the beneficial effect of decreasing ongoing blood loss by maintaining tissue perfusion without normalizing blood pressure.
  • Controlled Hyperthermia. Intentional and controlled lowering of an anemic patient's body temperature in order to decrease metabolic activity, heart rate, and oxygen consumption. Unless hypothermia is specifically indicated, maintenance of normothermia is reported to minimize bleeding.
  • Prompt Restoration of Normothermia. Prompt rewarming of patients after surgery minimizes bleeding and reduces the risk of infection. Coagulation proteins have been shown to be less effective at lowering temperatures.

AUTOLOGOUS TECHNIQUES

The broad categories of autologous techniques are (1) preoperative blood donation and storage (see Preoperative Techniques), (2) intraoperative and postoperative blood cell recovery (see Blood Recovery/Salvage Devices), and (3) intraoperative hemodilution.

Preoperative Autologous Blood Donation (PABD). Predonation and storage of a patient's own blood a few weeks before elective surgery for transfusion during or after surgery, if it is required. Many patients are reassured by the thought that they are using their own blood, rather than receiving the blood of another person.

Hemodilution. A technique whereby several units of blood are collected from a patient immediately before surgery and replaced with a nonblood volume expander. Despite this dilution, the patient has enough red blood cells to carry oxygen throughout the body. Although bleeding during surgery remains unchanged, any blood loss during the surgical procedure contains fewer red cells because the patient's blood has been diluted. (This shed blood optionally can be recovered and returned to the patient.) At the conclusion of surgery, collected blood may be returned to the patient.

Autologous Component Sequestration. Similar to hemodilution, except that the blood collected from a patient immediately before surgery (and replaced with a nonblood volume expander) is separated into components (red cells, concentrated platelets, and plasma). Red cells and plasma may be returned to the patient or held until required. This technique decreases the total plasma volume withheld from the patient compared with other platelet sequestration techniques. The sequestered platelets are fresh, autologous platelets, in a quantity reported to have an effect equivalent to approximately six to 10 units of allogeneic platelets. Furthermore, the plasma content sequestered within the concentrated platelets contains fresh autologous clotting factors in a quantity equivalent to one to two units of FFP (fresh frozen plasma).

LIST OF RECOMBINANT PRODUCTS

HEMATOPOIETIC GROWTH FACTORS (for Blood Cell Growth and Maturation)

Generic Names(s)
(Brand Name)		 Therapeutic
Category		 Manufacturer
/Distributor
EPO, Erythropoietin
Recombinant Human
Erythropoietin,
Glycosylated,
r-HuEPO,
Epoetin alfa

(Eprex®)		 Erythropenia
(red cell anemia);
stimulates
production of
red blood cells		 Janssen-Ortho
(Johnson &
Johnson)
(Amgen)
EPO, Recombinant
Human Erythropoietin,
Glycosylated,
r-HuEPO,
Epoetin beta

(Recorman®)		 As above Roche
Boehringer
Mannheim
Novel Erythropoiesis
Stimulating Protein,
NESP
 As above Amgen
G-CSF, Filgrastim,
Recombinant Human
Granulocyte Colony
Stimulating Factor,
Nonglycosylated,
r-HuG-CSF

(Neupogen®)		 Neutropenia and
PBSCT; stimulates
production of
granulocytes/
neutrophils
(white blood cells)		 Amgen
G-CSF, Lenograstim,
Recombinant Human
Granulocyte Colony
Stimulating Factor,
Glycosylated,
r-HuG-CSF

(Granocyte®;
Neutrogin®)

 As Above Chugai and
RhonePoulenc
Rorer
GM-CSF, Sargramostim,
Recombinant Human
Granulocyte
Macrophage Colony
Stimulating Factor,
Glycosylated,
RHuGMCSF

(Leukine®)		 Neutropenia and
PBSCT; stimulates
the production of
granulocytes/mono
phils and
macrophages/mono
cytes (white blood
cells) 		Schering-Plough
(Immunex)
TPO, Recombinant
Human Thrombopoietin,
r-Hu-TPO		 Thrombocytopenia;
stimulates production
of platelets		 Pharmacia &
Upjohn
(Genentech)
MGDF, Recombinant
Human Magakaryocyte
Growth and
Development Factor,
r-HuMGDF		 As above Amgen
IL-11, Oprelvekin;
Recombinant Human
Interleukin-11,
r-Hu-IL11

(Neumega®)		 As above Genetics
Institute

RECOMBINANT ANTIHEMOPHILIC (CLOTTING) FACTORS

Generic Names(s)
(Brand Name)		 Therapeutic
Category		 Manufacturer
/Distributor
Recombinant Factor VIIa

(Niastase®,
NovoSeven®)		 Coagulation factor
Replacement therapy		 Novo Nordisk
Recombinant Factor VIII

(Kogenate®, Helixate®
Recombinate™,
Bioclate®, ReFacto®)		 Coagulation factor
Replacement therapy		 Bayer
Baxter
Pharmacia &
Upjohn
(Genetics Institute)
Recombinant Factor IX

(Benefix™)		 Coagulation factor
replacement therapy 		Genetics
Institute

STATUS OF OXYGEN THERAPEUTICS (Updated 3/15/02)

SYNTHETIC OXYGEN-CARRYING BLOOD SUBSTITUTES

Product Description Manufacturer Status
Perflubron
Emulsion

(OxygentT)		 Perfluorochemical
(PFC)		 Alliance Pharmaceutical
(San Diego, CA)
Johnson & Johnson		 Awaiting approval to
resume Phase III
clinical trials
Perftoran Perfluorochemical
(PFC)		 Perftoran
(Russia)		 Approved for use
in Russia & Ukraine

HUMAN-DERIVED HEMOGLOBIN-BASED OXYGEN CARRIERS

Product Description Manufacturer Status
Hemolink™ Polymerized and
Cross-Linked
Human Hemoglobin		 Hemosol
(Etobicoke, Ontario		 Phase III clinical trials.
Awaiting regulatory
approval in Canada and
United Kingdom
PolyHeme&™ Polymerized Human
Hemoglobin		 Northfield Laboratories
(Chicago, IL)		 Phase III
clinical trials
HemoZyme Polynitroxyl-
Hemoglobin		 SynZyme Technologies
(Irvine, CA)		 Preclinical
Gelenpol Polymerized
Hemoglobin		 Institute of High-Molecular
Compounds & Center of
Hematology &
Transfusiology		 Approved for use
in Russia

ANIMAL-DERIVED HEMOGLOBIN-BASED OXYGEN CARRIERS

Product Description Manufacturer Status
HemoPure™
HBOC-201
Oxyglobin®		 Polymerized Purified
Bovine Hemoglobin		 Biopure
(Cambridge, MA)		 Phase III clinical trials
Approved for use in
South Africa
VTX-PHP Modified-Bovine
Hemoglobin		 Apex Bioscience
(Durham, NC)		 Phase III clinical trials

 

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