HEPARIN (Elkins-Sinn) Sodium Injection, USP
TUBEX Heparin Sodium Injection, USP is a sterile solution. Each mL contains 1,000, 2,500, 5,000, 7,500, 10,000, 15,000, or 20,000 USP units heparin sodium derived from porcine intestinal mucosa (standardized for use as an anticoagulant), in water for injection, and not more than 10 mg benzyl alcohol as a preservative.
The potency is determined by biological assay using a USP reference standard based upon units of heparin activity per milligram.
The pH range is 5.0 to 7.5.
Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) (alpha)-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-(alpha)-D-glucose 6-sulfate, (3) (beta)-D-glucuronic acid, (4) 2-acetamido-2-deoxy-(alpha)-D-glucose, and (5) (alpha)-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2) > (1) > (4) > (3) > (5), and are joined by glycosidic linkages forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxy-lic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions.
STRUCTURE OF HEPARIN SODIUM (representative subunits):
Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo . Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin-stabilizing factor.
Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin.
Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APPTs) compared with patients under 60 years of age.
Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear which suggests the absence of zero order processes. Liver and the reticulo-endothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t 1/2 = 10 min.), and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin.
Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.
Indications and Usage
Heparin sodium injection is indicated for anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension, in low-dose regimen for prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery who are at risk of developing thromboembolic disease (see DOSAGE AND ADMINISTRATION ), for prophylaxis and treatment of pulmonary embolism, in atrial fibrillation with embolization, for diagnosis and treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation), for prevention of clotting in arterial and cardiac surgery, and for prophylaxis and treatment of peripheral arterial embolism.
Heparin may also be employed as an anticoagulant in blood transfusions, extracorporeal circulation, dialysis procedures, and in blood samples for laboratory purposes.
Heparin sodium should not be used in patients:
with severe thrombocytopenia; in whom suitable blood-coagulation tests--e.g., the whole-blood clotting time, partial thromboplastin time, etc.--cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); with an uncontrollable active bleeding state (see WARNINGS ), except when this is due to disseminated intravascular coagulation.
Heparin is not intended for intramuscular use.
Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations.
Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event.
Heparin sodium should be used with extreme caution in disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are:
Cardiovascular --subacute bacterial endocarditis, severe hypertension.
Surgical --during and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye.
Hematologic --conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras.
Gastrointestinal --ulcerative lesions and continuous tube drainage of the stomach or small intestine.
Other --menstruation, liver disease with impaired hemostasis.
When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood-coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly (see OVERDOSAGE ).
Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%. Mild thrombocytopenia (count greater than 100,000/mm 3 ) may remain stable or reverse even if heparin is continued. However thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm 3 or if recurrent thrombosis develops (see PRECAUTIONS , General , White-clot Syndrome ), the heparin product should be discontinued. If continued heparin therapy is essential, administration of heparin from a different organ source can be reinstituted with caution.
This product contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature neonates.
It has been reported that patients on heparin may develop new thrombus formation in association with thrombocytopenia, resulting from irreversible aggregation of platelets induced by heparin, the so-called "white-clot syndrome." The process may lead to severe thromboembolic complications like skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. Therefore, heparin administration should be promptly discontinued if a patient develops new thrombosis in association with thrombocytopenia.
Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, and in postsurgical patients.
Increased Risk in Older Patients, Especially Women
A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age.
Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration (see DOSAGE AND ADMINISTRATION ).
Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained.
Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine, and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium.
Digitalis, tetracyclines, nicotine, or antihistamines may partially counteract the anticoagulant action of heparin sodium.
Drug/Laboratory Test Interactions
Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases that might be caused by drugs (like heparin) should be interpreted with caution.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin sodium. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.
Teratogenic effects--Pregnancy Category C
Animal reproduction studies have not been conducted with heparin sodium. It is also not known whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant woman only if clearly needed.
Heparin does not cross the placental barrier.
Heparin is not excreted in human milk.
A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS , General ). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).
Hemorrhage is the chief complication that may result from heparin therapy (see WARNINGS ). An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (see OVERDOSAGE ). It should be appreciated that gastrointestinal- or urinary-tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect:
- Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient's death.
- Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, may be fatal.
- Retroperitoneal hemorrhage.
Local irritation, erythema, mild pain, hematoma, or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended.
Generalized hypersensitivity reactions have been reported, with chills, fever, and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur.
Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%. While often mild and of no obvious clinical significance, such thrombocytopenia can be accompanied by severe thromboembolic complications such as skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. (See WARNINGS and PRECAUTIONS .)
Certain episodes of painful, ischemic and cyanosed limbs have been attributed, in the past, to allergic vasospastic reactions. Whether these are, in fact, identical to the thrombocytopenia- associated complications remains to be determined.
Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported.
Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin.
Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine, or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding.
Treatment --Neutralization of Heparin Effect
When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about Â½ hour after intravenous injection.
Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.
For additional information consult the labeling of Protamine Sulfate Injection, USP products.
Dosage and Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Slight discoloration does not alter potency.
When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to insure adequate mixing and prevent pooling of the heparin in the solution.
Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site.
The TUBEX BLUNT POINTEâ„¢ Sterile Cartridge Unit is suitable for substances to be administered intravenously. It is intended for use with injection sets specifically manufactured as "needle-less" injection systems. As of the date of this circular, TUBEX BLUNT POINTE is compatible with LifeShield Prepierced Reseal injection site, Interlink Injection Site, SafeLine Injection Site, User-Gard Intermittent Injection Cap, and SafSite reflux valve*. The dosage of heparin sodium should be adjusted according to the patient's coagulation-test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole-blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injections.
Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration.
Converting to Oral Anticoagulant
When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about 5 hours after the last IV bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time.
In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount, and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anti-coagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering.
Therapeutic Anticoagulant Effect with Full-Dose Heparin
Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:
Follow recommendations of appropriate pediatric reference texts. In general, the following dosage schedule may be used as a guideline:
Initial Dose: 50 units/kg (IV, drip).
Maintenance Dose: 100 units/kg (IV, drip) every four hours or 20,000 units/M 2 /24 hours continuously.
Patients over 60 years of age may require lower doses of heparin.
Surgery of the Heart and Blood Vessels
Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes or 400 units per kilogram for those estimated to last longer than 60 minutes.
Low-Dose Prophylaxis of Postoperative Thromboembolism
A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep-vein thrombosis in the legs, as measured by the I-125 fibrinogen technique and venography, and of clinical pulmonary embolism. The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over age 40 undergoing major surgery. Patients with bleeding disorders, those having neurosurgery, spinal anesthesia, eye surgery, or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS ). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate is advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation-test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters.
Extracorporeal Dialysis Use
Follow equipment manufacturer's operating directions carefully.
Addition of 400 to 600 USP units per 100 mL of whole blood
Usually, 7,500 USP units of heparin sodium are added to 100 mL of Sterile Sodium Chloride Injection (or 75,000 USP unit per 1,000 mL of Sterile Sodium Chloride Injection) and mixed, and from this sterile solution, 6 to 8 mL is added per 100 mL of whole blood.
Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, erythrocyte fragility tests, or platelet counts.
Heparin Sodium Injection, USP is available in TUBEX Sterile Cartridge-Needle Units. Each 1 mL size TUBEX contains one of the following concentrations of heparin sodium:
1,000 USP Units per mL
NDC 0008-0275-01, (22 gauge Ã— 1-1/4 inch needle), in packages of 10 TUBEX.
2,500 USP Units per mL
NDC 0008-0482-01, (25 gauge Ã— 5/8 inch needle), in packages of 10 TUBEX.
5,000 USP Units per 0.5 mL (10,000 USP Units per mL)
NDC 0008-0277-02, (25 gauge Ã— 5/8 inch needle), in packages of 10 TUBEX.
NDC 0008-0277-03, (25 gauge Ã— 5/8 inch needle), in packages of 50 TUBEX.
5,000 USP Units per mL
NDC 0008-0278-02, (25 gauge Ã— 5/8 inch needle), in packages of 10 TUBEX.
7,500 USP Units per mL
NDC 0008-0293-01, (25 gauge Ã— 5/8 inch needle), in packages of 10 TUBEX.
10,000 USP Units per mL
NDC 0008-0277-01, (25 gauge Ã— 5/8 inch needle), in packages of 10 TUBEX.
20,000 USP Units per mL
NDC 0008-0276-01, (25 gauge Ã— 5/8 inch needle), in packages of 10 TUBEX.
Heparin Sodium Injection, USP, 1,000 USP Units per mL, is also available in packages of 10 TUBEX BLUNT POINTEâ„¢ Sterile Cartridge Units, NDC 0008-0275-50.
Store at controlled room temperature, 20Â° to 25Â°C (68Â° to 77Â°F) [see USP].
Do not freeze.
Do not use if solution is discolored or contains a precipitate.
Wyeth Laboratories Inc.
A Wyeth-Ayerst Company
Philadelphia, PA 19101
CI 3465 - 9Â Â Â Â Â Â Â Â Revised January 12, 2000
PLEASE NOTE: THE WYETH-AYERST METAL TUBEX HYPODERMIC SYRINGE AND TUBEX FAST-TRAK SYRINGE HAVE BEEN DISCONTINUED AND REPLACED BY THE TUBEX INJECTOR. EXCHANGE OF THESE DISCONTINUED SYRINGES IS AVAILABLE, FREE OF CHARGE, FROM YOUR WYETH-AYERST SALES REPRESENTATIVE, OR FROM WYETH-AYERST DIRECTLY. FOR LOADING AND UNLOADING INFORMATION ON THESE DISCONTINUED SYRINGES, CONTACT THE MEDICAL AFFAIRS DEPARTMENT, AT WYETH-AYERST LABORATORIES, P.O. BOX 8299, PHILADELPHIA, PA 19101.
NOTE: The TUBEX Injector is reusable: do not discard.
TUBEX Sterile Cartridge-Needle Unit
DIRECTIONS FOR USE:
TUBEX BLUNT POINTEâ„¢ Sterile Cartridge Unit
DIRECTIONS FOR USE:
TUBEX BLUNT POINTE Sterile Cartridge Unit is intended for use with injection sets specifically manufactured as "needle-less" injection systems. As of the date of this circular, TUBEX BLUNT POINTE Sterile Cartridge Unit is compatible with Life-Shield Prepierced Reseal injection site, InterLink Injection Site, SafeLine Injection Site, User-Gard Intermittent Injection Cap, and SafSite reflux valve*. Consult manufacturer's recommendations regarding "Directions for Use" of the "needle-less" injection system.
|NOTE||USE ASEPTIC TECHNIQUE FOR ALL
MANIPULATIONS OF STERILE PARTS.
To load a TUBEX Sterile
Cartridge Unit into the
1. Turn the ribbed collar to
the "OPEN" position until it
TUBEX Sterile TUBEX BLUNT
Cartridge-Needle POINTE Sterile
2. Hold the Injector with the open end up and fully insert the TUBEX Sterile Cartridge Unit.
Firmly tighten the ribbed collar in the direction of the "CLOSE" arrow.
3. Thread the plunger rod into the plunger of the TUBEX Sterile Cartridge Unit until slight resistance is felt.
The Injector is now ready for use in the usual manner.
To administer TUBEX Sterile Cartridge-Needle Units
Method of administration is the same as with conventional syringe. Remove needle cover by grasping it securely; twist and pull. Introduce needle into patient, aspirate by pulling back slightly on the plunger and inject.
To administer TUBEX BLUNT POINTE Sterile Cartridge Units
"Needle-less" IV set administration is similar to administration with conventional syringes. Remove rubber cover by grasping it securely; twist and pull.
*For SafSite reflux valves, aseptically swab the Luer slip fitting of the TUBEX BLUNT POINTE sterile cartridge tip assembly with a sterile, individually wrapped, saturated 70% isopropyl alcohol swab. This action will remove the lubricant coating from the tip to facilitate a tight seal. Introduce TUBEX BLUNT POINTE Sterile Cartridge Unit into the "needle-less" IV set as per manufacturer's "Directions for Use."
To remove the empty
TUBEX Cartridge Unit and
dispose into a vertical
- Do not recap the needle/
point. Disengage the plunger
- Hold the Injector, needle/point down, over a vertical disposal container and loosen the ribbed collar. TUBEX Cartridge Unit will drop into the container.
- Discard the cover.
To remove the empty TUBEX Cartridge Unit and dispose into a horizontal (mailbox) disposal container
- Do not recap the needle/point. Disengage the plunger rod.
- Open the horizontal (mailbox) disposal container. Insert TUBEX Cartridge Unit, needle/point pointing down, halfway into container. Close the container lid on cartridge. Loosen ribbed collar; TUBEX Cartridge Unit will drop into the container.
- Discard the cover.
The TUBEX Injector is reusable and should not be discarded.
Used TUBEX Cartridge Units should not be employed for successive injections or as multiple-dose containers. They are intended to be used only once and discarded.
NOTE: Any graduated markings on TUBEX Sterile Cartridge Units are to be used only as a guide in administering doses.
Wyeth-Ayerst does not recommend and will not accept responsibility for the use of any cartridge-needle units or needle-less units other than TUBEX or E.S.I. DOSETTE Cartridge Units in the TUBEX Injector.
TUBEX is a registered trademark of Wyeth-Ayerst Laboratories.
BLUNT POINTE is a trademark of Wyeth-Ayerst Laboratories.
InterLink is a registered trademark of Baxter International, Inc.
LifeShield is a registered trademark of Abbott Laboratories.
SafeLine is a registered trademark of McGaw, Inc.
SafSite is a registered trademark of B. Braun Medical, Inc.
User-Gard is a registered trademark of Arrow International, Inc.
Kappa, Jeffrey R., M.D. et al.: Heparin-induced platelet activation in sixteen surgical patients: Diagnosis and Management. Journal of Vascular Surgery 5(1): 101-107, 1987.
King, Derek J. and Kelton, John G., M.D.: Heparin-associated thrombocytopenia. Annals of Internal Medicine 100: 535-540, 1984.
CI 3465 - 9Â Â Â Â Â Â Â Â Â Â Â Â Revised November 12, 2000