Anticoagulant therapy with recombinant hirudin in patients with thrombopenia induced by heparin

OBJECTIVES: Heparin-induced thrombocytopenia is an uncommon and severe complication of heparin therapy. Both venous and arterial thromboembolic events can occur, requiring withdrawal of the heparin therapy. When anticoagulant therapy is mandatory, recombinant hirudin can be used. METHODS: We used recombinant hirudin (HBW 023) in 6 patients with heparin induced thrombocytopenia. In case of venous thromboembolism, an initial intravenous bolus (0.07 mg/kg) was followed by continuous infusion (0.05 mg/kg/h); for arterial thromboembolism the initial bolus was 0.7 mg/kg and infusion rate 0.15 mg/kg/h. When possible oral anticoagulants were started and hirudin withdrawn when the INR ratio reached 3. RESULTS: The clinical course was uneventful in all 6 patients. There was no recurrent thromboembolism. Cephalin-activated coagulation time (patient/control) varied between 1.8 and 3.5 (median 2.4) during hirudin administration. Platelet count rose to the nadir (median 70 x 10(9)/l, range 15-90) reaching over 100 x 10(9)/l in all patients between the third and sixth day (median 5 days) after stopping heparin. CONCLUSION: Intravenous administration of hirudin provides effective immediate anticoagulation in patients with heparin-induced thrombocytopenia, thus allowing conversion to oral anticoagulants without risking recurrent thromboembolism.     

Recognition, diagnosis, and management of heparin-induced thrombocytopenia and thrombosis

This case report describes a post-coronary artery bypass graft patient who developed arterial thrombosis and loss of a dominant hand as a result of the common and serious immune complication of heparin anticoagulation, heparin-induced thrombocytopenia and thrombosis. This report underscores the need for all surgeons who use heparin in the course of their practice to be aware of heparin-induced thrombocytopenia and the spectrum of its clinical presentations and management. Thrombocytopenia or thrombosis that occurs in a patient receiving heparin should prompt a surgeon to stop all heparin as soon as possible and seek appropriate hematologic consultation. Because heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis are mainly clinical diagnoses, one should not wait for objective test confirmation of heparin-induced thrombocytopenia before stopping all heparin treatment. Alternative anticoagulation, other than low molecular weight heparin, must be considered for the patient who develops either condition. For surgeons who perform hand surgery, it is necessary to be aware of the significance of upper extremity thrombosis in a patient who is receiving heparin when consulted for surgical management.     

Increase in beta-galactosidase activity in a non-isothermal bioreactor utilizing immobilized cells of Kluyveromyces fragilis: fundamentals and applications

Heparin-induced thrombocytopenia is an increasingly common side effect associated with heparin usage. In the more severe manifestation of the syndrome, patients can develop thrombosis; a 10% mortality is associated with heparin induced thrombocytopenia. To date, the therapeutic options for patients with heparin-induced thrombocytopenia are limited. Glycoprotein IIb/IIIa inhibitors have been shown to block platelet aggregation induced by a wide variety of agonists. The ability of antibody and synthetic small molecule inhibitors of glycoprotein IIb/IIIa to block in vitro activation and aggregation of platelets in response to heparin-induced thrombocytopenia positive serum/heparin was examined using flow cytometry, platelet aggregometry, and luminescence aggregometry. Abciximab, YM 337, and SR 121566A were each found to inhibit platelet microparticle formation and P-selectin expression in whole blood, in response to heparin-induced thrombocytopenia positive serum/heparin. In a platelet rich plasma system, the platelet aggregation response was inhibited by all three agents. The IC50 for inhibition of heparin-induced thrombocytopenia positive serum/heparin induced platelet aggregation by SR 121566A was 18 nM, a concentration which was 4 to 8 fold lower than that observed for collagen and arachidonic acid induced aggregation. Adenosine triphosphate release from activated platelets, as measured by luminescence aggregometry, was concentration-dependently inhibited by SR 121566A. These results suggest that glycoprotein Ilb/IIIa inhibitors may be beneficial in the management of heparin-induced thrombocytopenia and warrant further investigation.     

Morphological changes in paraboloid glycogen of the accessory cone of the chick retina by exposure to light (author''s transl)

We studied five patients in whom severe thrombocytopenia developed during intermittent intravenous heparin treatment of arterial and venous thrombosis. Platelet aggregation was demonstrated when heparin (0.5 U per milliliter) was incubated with the patients' citrated platelet-rich plasma or with normal platelet-rich plasma in the presence of the patients' serum. Antiplatelet antibody was not detected in the patient globulin fractions prepared from serum collected within one week after heparin withdrawal by use of the platelet factor 3 availability technic. When the studies were repeated with modifications to detect heparin-dependent antiplatelet antibodies, positive results were obtained in four of five patients. The data suggest that a casual relation, mediated by an immune mechanism, existed between heparin therapy and thrombocytopenia, and that this syndrome may occur more often than has previously.     

Abciximab-induced thrombopenia during treatment of acute coronary syndromes by angioplasty

ReoPro (abciximab) is the Fab fragment of a chimeric monoclonal antibody directed against platelet glycoprotein IIb-IIIa. Its efficacy to prevent ischaemic complications after PTCA has been demonstrated in 3 studies: EPIC, EPILOG, UPTAKE. One hundred and sixty five cases of thrombocytopenia (< 100,000/microliter) were reported in a series of 5461 patients randomized in these 3 studies (i.e. 3.0%), including 46 (2.03%) with placebo and 119 (3.73% with abciximab. Among the 2270 patients randomized to receive placebo, 11 (0.48%) cases of severe thrombocytopenia (< 50,000/microliter) were observed versus 34 (1.07%) with abciximab. Major acute thrombocytopenia (< 20,000/microliter and < 24 hours) occurred in 0.60% (20 patients) of cases with abciximab. Their mechanism remains unknown. A therapeutic challenge did not modify either their incidence, or their severity. The development of thrombocytopenia did not worsen the patient's prognosis and course was always favourable. Twenty five cases of thrombocytopenia (0.60%), including 3 cases of acute major thrombocytopenia (0.08%) were spontaneously reported in France among the first 4000 patients treated with abciximab post-marketing. All patients treated with abciximab must be monitored by platelet count, 2 to 4 hours after the bolus administration, then 12 and 24 hours later. These platelet counts should be performed on 3 tubes (EDTA, citrate, heparin) in order to eliminate pseudothrombocytopenia and a differential diagnosis. In the case of true thrombocytopenia (< 10,000/l), treatment should be suspended and the platelet count should be repeated daily until return to normal. In the case of thrombocytopenia less than 60,000/microliter, heparin and aspirin should also be systematically discontinued and, below 50,000/microliter, platelet transfusion is justified.     

Heparin-induced thrombocytopenia and thrombosis: presentation after cardiopulmonary bypass

Heparin-induced thrombocytopenia and thrombosis syndrome was diagnosed in a 63-year-old woman 11 days after coronary artery bypass grafting. Her only presenting complaints were incisional leg pain and vague chest discomfort. The syndrome was suspected when her platelet count was found to be 37,000/microL. A subsequent ventilation-perfusion lung scan showed findings highly probable for pulmonary embolism. An inferior venacavogram obtained before a pulmonary angiogram revealed a large retrohepatic thrombus at the right atrial junction. The patient was successfully treated with the defibrinogenating agent ancrod (Arvin). A diagnosis of heparin-induced thrombocytopenia and thrombosis syndrome should be considered and heparin therapy should be avoided in patients with low platelet counts who have been previously treated with heparin.     

The thrombocytopenia syndrome caused by heparin

Heparin represents the basis for drug treatment and prevention of thrombosis. However, heparin itself may produce side effects, among others two types of heparin-induced thrombocytopenia (HIT). The more frequent type 1 occurs in about 10% of patients within the first days of the treatment and disappears spontaneously without sequelae. HIT type 2 represents a far more serious complication occurring in 0.1-1% of patients somewhat later, between days 4 and 10 of heparin therapy, and may provoke severe arterial and venous thrombosis. Apart from the differences in clinical picture, data regarding platelet count and platelet aggregation test are significant for the diagnosis. Heparin should be discontinued immediately and another anticoagulant therapy introduced. We are presenting the case of a patient with thrombosis of the left external iliac artery following surgery for ovarian cancer as a complication of HIT type 2, which was recanalized successfully and the leg was saved.     

Preventing the cardiotoxic effects of anthracyclines with Cardioxane]

An immune response to heparin, which is clinically manifested by the development of thrombocytopenia with or without thrombosis, is stimulated by a complex of heparin with platelet factor 4 (PF4). The primary thrombotic events in patients with heparin-induced thrombocytopenia (HIT) are more frequently venous than arterial. The development of antibodies, however, does not always result in thrombocytopenia or in catastrophic events. The antibodies, which are of the IgG, IgM, and IgA isotypes, can be easily measured by an ELISA that contains a complex of heparin-platelet factor 4 (PF4). Initial antibody formation can be greatly reduced by limiting the exposure to unfractionated heparin or by the use of low-molecular-weight heparin. For those patients who require anticoagulation and who have antibodies to heparin-PF4, danaparoid (Orgaran), a low-molecular weight heparinoid that does not react with the antibodies, is now commercially available; argatroban, a thrombin-specific inhibitor, can also be obtained for compassionate use. The use of these agents during anticoagulation with warfarin is preferable to the simple discontinuation of heparin and intitiation of warfarin, because the latter treatment can result in ongoing thrombosis.     

Thrombocytopenia due to heparin therapy. Use of danaparoid (Orgaran), 13 monocentric cases under authorization of temporary prescription (ATU)

Since September 1994, danaparoid (Orgaran), a heparinoid, has been used in our centre to treat patients with thrombocytopenia occurring during heparin therapy and who need continuing antithrombotic therapy. We carried out a retrospective study using clinical and biological data on the first 13 consecutive patients treated with danaparoid (for 1 to 18 consecutive days). The platelet count returned to normal for ten patients, but one patient died having contracted a severe sepsis and bleeding occurred in one patient with acute renal failure. In the three other cases, the diagnosis of heparin induced thrombocytopenia (HIT) was in retrospect unlikely and the death of these patients was related to severe underlying diseases which were held responsible for thrombocytopenia. We confirm that danaparoid appears to be an effective, well-tolerated substitute for heparin in HIT patients. The French regulation Temporary Authorization for Prescribing Medicines allowed the prompt use of this as yet unmarketed drug and collection of reliable and pertinent data.     

Bilateral femoro-popliteal acute recurrent arterial thrombosis in the course of heparin-induced thrombocytopenia (white thrombus syndrome)

Heparin induced thrombocytopenia with thrombosis, or the "white clot syndrome" is a rare but very important complication of heparin therapy. The syndrome is idiosyncrasic, immune-mediated and not dose dependent and therefore is equally likely to occur with prophylactic and therapeutic heparin dosage regimens. We report a typical case of HIT that occurs with prophylactic heparin therapy and results in bilateral amputation of the lower limbs. We discuss this important condition and some guidelines on its prevention and treatment.     

Danaparoid in the prevention of thromboembolic complications

OBJECTIVE: To review the therapies used to prevent postoperative thromboembolic complications with a focus on the role of danaparoid, a new low-molecular-weight glycosaminoglycan. DATA SOURCES: A MEDLINE search was performed to identify pertinent English-language literature including studies, abstracts, and review articles. Key search terms included danaparoid, heparinoid, lomoparin, heparin, prophylaxis, thrombosis, embolism, thromboembolism, and thromboembolic and postoperative complications. The manufacturer of danaparoid was contracted for additional information related to this compound. STUDY SELECTION AND DATA EXTRACTION: All identified articles were reviewed for possible inclusion in this review. Comparisons primarily focused on data obtained from prospective, randomized, controlled, blind clinical trials. Another important consideration was the use of venography to determine the presence of deep venous thrombosis. DATA SYNTHESIS: Various therapies are available for the prevention of postoperative thromboembolic complications. Effective pharmacologic treatments currently available include adjusted-dose heparin, warfarin, aspirin, dextran, and low-molecular-weight heparins (LMWHs). Until recently, warfarin was considered the drug of choice for thromboprophylaxis in high-risk patients, including patients undergoing orthopedic surgical procedures. Because of their comparable efficacy and greater ease of use, LMWHs are gaining favor over warfarin in this patient population. In well-designed clinical trials involving patients undergoing elective total hip replacement or fractured hip surgery, danaparoid has demonstrated greater efficacy than other active treatments, including warfarin, dextran, aspirin, and heparin plus dihydroergotamine. While studies comparing danaparoid with LMWHs have not yet been published, danaparoid may be more useful in patients with heparin-associated thrombocytopenia. CONCLUSIONS: Danaparoid is an antithrombotic agent with characteristics that distinguish it from heparin and LMWHs. Based on the efficacy and safety data reviewed, danaparoid should be considered one of the drugs of choice for the prevention of thromboembolic complications in patients undergoing orthopedic hip procedures and the drug of choice for the management of any patient with heparin-induced thrombocytopenia who requires anticoagulant therapy.     

The effect of N-alkyloxycarbonyl group on the anticonvulsant activities of N-alkyloxycarbonyl-alpha-aminoglutarimides

The aim of this study was to determine the effect of heparin therapy on the international normalized ratio (INR). In vitro heparin sensitivity curves were created using normal and warfarinized plasma samples from patients. The INR results were measured with each of two reagents. In addition, a comparison of INR values with these two reagents was performed on plasma from patients receiving therapeutic heparin and warfarin. The INR values were measured before and after heparin removal with a heparin adsorbent system. While one of the reagents was found to be sensitive to even low levels of therapeutic heparin, the other thromboplastin was resistant up to at least 0.9 U/mL. The INR values determined for patients with one of the reagents were found to be erroneously elevated by an average of 16%. The error ranged from 2% to 55% depending on the in vivo heparin concentration. With the other reagent, the INR values were not substantially affected by heparin. Previous studies have described the effect or lack thereof of heparin on the prothrombin time. The present study demonstrates that the degree to which INR results are prolonged by heparin therapy depends on the reagent formulation. As the therapeutic index for monitoring warfarin is relatively narrow (2.0-3.0), an INR value that is falsely elevated due to reagent sensitivity may precipitate premature cessation of heparin therapy and place certain patients at risk for recurrent thrombosis in the short term.     

Treatment of venous thromboembolism

This review provides meta-analytic data of studies aiming at improved treatment of deep vein thrombosis and pulmonary embolism. The introduction of low molecular weight heparin has considerably ameliorated the initial treatment of deep vein thrombosis, and should now be regarded as the treatment of choice for most patients with deep vein thrombosis. Oral anticoagulant treatment is presently considered safe and effective for the long-term treatment of venous thromboembolism, provided that the INR is maintained at 2.0-3.0. However, the optimal duration as well as the optimal intensity of anticoagulation have still to be determined. Patients with submassive pulmonary embolism should presently be treated with adjusted dose unfractionated heparin and coumarins. Studies determining the efficacy and safety of low molecular weight heparin in this condition deserve priority. Thrombolytic therapy should be restricted to patients with massive pulmonary embolism, unless safer methods of thrombolysis have been developed. Surgical embolectomy and catheter fragmentation of emboli seem alternative options but deserve further investigations.     

Enhanced expression of bcl-2 inhibits apoptosis in cultured human keratinocytes

Intravenous heparin followed by oral warfarin sodium is effective for preventing recurrent thromboembolism in patients who have pulmonary embolism or proximal vein thrombosis. The effectiveness of intravenous heparin depends on obtaining an adequate anticoagulant response early during therapy. A validated heparin protocol should be used to ensure that an adequate anticoagulant response is obtained as soon as possible. Low molecular weight heparin has the practical advantage that it does not require monitoring and dose finding. If thrombolytic therapy is indicated, it is safer for many patients to base management on the noninvasive diagnosis rather than performing pulmonary angiography. In patients suspected to have pulmonary embolism who have nondiagnostic lung scan and adequate cardiorespiratory reserve, serial noninvasive leg testing is a practical approach that avoids pulmonary angiography, identifies patients who have proximal vein thrombosis requiring treatment, and avoids the risks of anticoagulant treatment in the majority of patients.     

Heparin induced thrombocytopenia. Experiences in 12 heart surgery patients

A heparin induced thrombocytopenia Type II (HIT) is a dangerous complication of heparin therapy. Bleeding, but above all serious thromboembolic complications, which may result in crippling disabilities or even death, can develop. Twelve heart surgery patients who were diagnosed with a HIT Type II are reported. Seven of the patients were diagnosed post operatively, the other five pre-operatively. Two of these patients underwent heart surgery with r-Hirudin (Behringwerke AG, Marburg, Germany) on cardiopulmonary bypass and two on Orgaran (AKZO Organon, the Netherlands). Of the seven post operative HIT patients, four had had a bypass operation and each had received a mitral or aortic valve replacement. Another patient had received an artificial biventricular support system (Berlin Heart) and was diagnosed with HIT Type II post operatively. Because of his special condition, this patient underwent anticoagulation with Orgaran and heart transplantation with Orgaran on a heart lung machine. Upon suspicion of HIT Type II, heparin therapy was immediately halted and an alternative treatment of Orgaran or r-Hirudin was begun. One patient encountered bleeding of a gastric ulcer on Orgaran therapy. Heart surgery patients, especially patients with an artificial support system, are potentially lethally threatened by serious thromboembolic complications accompanying HIT Type II. Therefore, these patients must be diagnosed as early as possible. Orgaran along with r-Hirudin are effective heparin substitutes in patients with HIT Type II. These medications can be widely administered to heart surgery patients pre-, intra-, and post operatively without complication.     

Effects of intravenous immunoglobulins in thrombopenia related to septic shock

OBJECTIVES: Intravenous immunoglobulins have been shown to be effective in the treatment of immunologically mediated thrombocytopenia. Several articles have been published on the positive effect of immunoglobulins in sepsis-related death. We retrospectively studied the effects of intravenous immunoglobulins used during septic shock thrombocytopenia over a 5-year period in a polyvalent intensive care unit. PATIENTS AND METHODS: Inclusion criteria were development of acute thrombocytopenia under 75 G/l during septic shock, excluding all cases of disseminated intravascular coagulation. Thirty-five patients were included in the study; 18 were given polyvalent intravenous immunoglobulins (group IgIV) and 17 were not (controls). The two groups were comparable for SAPS and APACHE II gravity scores at admission and at day 0 (first day of septic shock with platelet count under 75 G/l), age, sex, platelet count at admission, OSF score, type of referral unit, McCabe score, and the presence of 4 parameters which might affect platelet count hemofiltration, ARDS, surgery, Swan-Ganz catheter. RESULTS: Platelet counts increased on day 8 in the treatment group (63.5 G/l, range 25-453 versus 105.7 G/l, range 38-355; p = 0.0505). The number of days with thrombocytopenia was the same in both groups. Overall mortality was high (60%) but there was a difference between the two groups in favor of the treated group (74.7% versus 44.4%; p = 0.053). The number of red cell units (214 vs. 164) and plasma units (175 vs. 54) transfused was higher in the control group. Platelet transfusion was equivalent in the two groups. DISCUSSION: Although we were unable to demonstrate a significant difference in the effects of immunoglobulins on platelet level and mortality, the trend during this evaluation was comparable with that reported in the literature. For transfusion, and although the results were not significant, a notion of reduced risk was evident. Prospective trials are needed to confirm these observations.     

Venous thromboembolism in multiple trauma patients

Thromboembolic complications are frequent in patients with multiple trauma. The efficacy of unfractionated heparin for venous thrombosis prophylaxis has not been established. Based on limited prospective data, low-molecular-weight heparin appears to be more effective than unfractionated heparin and at least as effective as compression devices for preventing thromboembolic complications in these patients. Vena cava filters should be considered in high-risk patients who cannot receive anticoagulant therapy, but long-term filter use without concomitant anticoagulant therapy is associated with a substantial risk of recurrent thromboembolism.     

The prevention of postoperative deep vein thrombosis and pulmonary embolism with low dose subcutaneous heparin and dextran

The standard low dose of heparin for the prevention of deep venous thrombosis in patients who are operated upon is 5,000 units administered subcutaneously two hours before operation and at eight or 12 hourly intervals for the next seven days. Heparin in low doses can at present be recommended as an effective agent in the prevention of deep venous thrombosis in patients over the age of 40 years who are undergoing a major abdominothoracic or gynecologic operation. There is reasonable evidence that heparin in low doses also offers a satisfactory protection against fatal pulmonary embolism for patients at high risk after general abdominothoracic operations. The evidence of the effectiveness of low doses of heparin in the prevention of deep venous thrombosis is less well established in other patients and particularly those at high risk, as after urologic and hip operations. This important distinction is to be made in terms of the population at risk and the efficacy of heparin in low doses. Considering the evidence so far available, it appears that the postoperative state in which dextran has been shown to reduce the incidence of phlebographically confirmed deep venous thrombosis most convincingly is after orthopedic operations. Major orthopedic operations are precisely the type in which the superiority of heparin in low doses is controversial. Unless proved otherwise, dextran 70 in an infusion of 500 to 1,000 milliliters of a 6 per cent solution started before operation and 500 milliliters the following and next three alternate days may be the agent of choice in preventing deep venous thrombosis in major orthopedic operations. Using this scheme, the prophylaxis of postoperative deep venous thrombosis appears equally effective with dextran 70 as with oral anticoagulants. Whether the protection offered by dextran 70 will also prevent fatal and nonfatal pulmonary embolism is still an open question. Low doses of heparin and dextran do not expose patients to serious risks of bleeding after operation, and with the recommended doses of the latter drug, other untoward effects are rare. At the doses recommended, neither of these two drugs requires laboratory monitoring.     

Brain-stem trigeminal and auditory evoked potentials in multiple sclerosis: physiological insights

Although suramin has long been used to treat human trypanosomiasis, recent clinical trials have tested its efficacy against the acquired immunodeficiency syndrome (AIDS) and various malignancies. Thromobocytopenia was observed in early trials with suramin in AIDS, but has been uncommon in patients treated for solid tumors. Here we describe 5 patients out of a total of 67 (7%) who developed severe thrombocytopenia while receiving suramin as part of a phase II clinical trial for metastatic prostate carcinoma refractory to hormonal therapy. IgG purified from one patient's plasma caused suramin-dependent platelet aggregation. There was also evidence of crossreactivity between suramin and heparin in this system. An immune mechanism, however, could not be documented in the other cases, suggesting that multiple mechanisms may be responsible for severe thrombocytopenia in this patient population.     

A fatal low-molecular-weight heparin-associated thrombocytopenia after hip surgery: possible usefulness of PF4-heparin ELISA test

In 37 patients undergoing total hip replacement, a prophylactic treatment by a low-molecular-weight heparin (LMWH) was conducted for 2 weeks. They belonged to a group of 499 patients included in a multicenter clinically controlled trial comparing two LMWHs. Blood was collected 1 day before surgery (D-1) and at D+1 or D+2 and D+5 or D+6 as well as D+10 through D+14 after surgery for determinations of platelets counts and anti-Xa. Bilateral venography was performed between D+10 and D+14. A fatal heparin-associated-thrombocytopenia (HAT) occurred on D+9 in one patient and was associated with a positive platelet aggregation test. This finding was confirmed with a recent ELISA test which evidenced a high concentration of PF4-heparin dependent antibodies 72 h before the detection of thrombocytopenia. This led us to study retrospectively PF4-heparin ELISA results by testing the plasma samples of 36 other surgical patients treated under the same conditions and during the same period (four measurements per patient). Among these patients, seven had a venous thrombotic event as a treatment failure. Although some authors claimed that some post-operative thromboses may be facilitated by the presence of heparin-dependent antibodies associated with or without thrombocytopenia, no thrombocytopenia and no positive PF4-heparin ELISA test was observed in this group. Out of the 144 tests performed in these 36 patients for the detection of PF4-heparin complexes dependent antibodies, 15 results were borderline in ten patients and three results in two patients were positive. No relation was evidenced between a positive ELISA test and the occurrence of venous thrombosis. This study points out the possible usefulness of the PF4-heparin ELISA test for HAT-antibodies detection. A daily platelet count in a postoperative patient under heparin therapy, showing thrombocytopenia associated with the detection of heparin-dependent antibodies could allow an earlier and more reliable diagnosis of HAT.