Pharmacological Correction of Cisplatin-Induced Hemostatic Disorders.

A single intraperitoneal administration of cisplatin in the MTD to outbred female mice disturbed hemostasis and formed the procoagulant phenotype of hemostatic potential on days 7-10 culminating in a pronounced hypocoagulation on day 15. Hemostasis was corrected with warfarin and an extract containing furocoumarins composed of isopimpinellin (42.97%), bergapten (35.18%), and xanthotoxin (15.41%). The extract was standardized with gas chromatography-mass spectrometry, thin-layer chromatography, and HPLC. Furocoumarins and reference drug warfarin were administered intragastrically during 4 days starting on day 6 after the administration of cisplatin. Both furocoumarins and warfarin corrected hypercoagulation on days 7-10. On day 10, furocoumarins normalized coagulation, whereas warfarin resulted in hypocoagulation. On days 15-30, no effects of warfarin were observed. furocoumarins corrected hypocoagulation on days 15-20 with prolongation of this effect up to experimental day 30.

Rectal bleeding and hemostatic disorders induced by dabigatran etexilate in 2 elderly patients.

OBJECTIVE: To report rectal bleeding associated with hemostatic disorders in 2 elderly patients treated with dabigatran etexilate. CASE SUMMARY: A 79-year-old woman (weight, 69 kg) was hospitalized in a gastroenterology unit for severe rectal bleeding. She had been treated for 2 months with dabigatran etexilate 110 mg twice daily for chronic atrial fibrillation. On admission, her creatinine clearance (CrCl) was 20.7 mL/min/1.73 m(2), prothrombin time (PT) less than 10% (reference range 70-130%), and international normalized ratio (INR) 14.5 (venous blood). Eleven days after admission, hematologic and renal function were normalized and rectal bleeding stopped. An 84-year-old man (weight, 71 kg) was admitted for rectal bleeding with acute renal failure and dehydration that began while he was treated with dabigatran etexilate 110 mg twice daily for atrial fibrillation. On admission, CrCl was 33.5 mL/min/1.73 m(2), PT 13%, and INR 7.53 (venous blood). Dabigatran etexilate was stopped on admission. At the end of the hospitalization, CrCl was 66.5 mL/min/1.73 m(2), PT 54%, and INR 1.53. In both cases, an objective causality assessment revealed that those adverse reactions were probably related to dabigatran etexilate. DISCUSSION: In these 2 cases of rectal bleeding during dabigatran etexilate therapy, coagulation monitoring showed elevated PT and INR; neither patient had been exposed to vitamin K antagonists. These cases indicate the importance of PT and INR monitoring when using dabigatran etexilate, mainly in patients with a high risk of overdose, such as elderly patients or those with renal function impairment. CONCLUSIONS: It is critical to identify and subsequently manage dabigatran etexilate toxicity because there is no specific antidote to reverse the drug's anticoagulant effects.

Estrogen and thrombosis: controversies and common sense.

Soon after the introduction of hormonal oral contraceptive agents reports of thrombotic complications appeared. In the past several decades, large epidemiological studies helped defined these risks for both arterial and venous complications. Clinicians can assess a patient's risk of thrombosis by both composition of the agent and patients' personal risk factors. For women with bleeding disorders these prothrombotic changes can help decrease bleeding complications. There is now also abundant data on future management of patients with estrogen related thrombosis.

Anesthetic concerns for patients with coagulopathy.

PURPOSE OF REVIEW: Patients often receive preoperative therapies that interfere with hemostasis, and can present for surgery with underlying hemostatic disorders because of pre-existing preoperative anticoagulation or antiplatelet therapy. Perioperative bleeding can occur following surgery due to multiple causes; however, the addition of pharmacologic agents creates an acquired defect that complicates the surgical injury and may result in increased blood loss. An understanding of the potential impact of anticoagulation therapies on hemostasis is critical in managing these patients. Further, newer agents are evolving in clinical practice that clinicians should be aware of. RECENT FINDINGS: The anticoagulants and antiplatelet agents that patients are receiving preoperatively apart from unfractionated heparin include low-molecular-weight heparins (LMWHs); a pentasaccharide (fondaparinux); oral anticoagulants: vitamin K antagonists (warfarin), new oral Xa inhibitors (rivaroxaban, apixiban), or the oral direct thrombin inhibitor (DTI) dabigatran; platelet inhibitors: thienopyridines (clopidogrel, ticlopidine, prasugrel) or IIb/IIIa receptor antagonists (tirofiban, abciximab, eptifibatide); or DTIs (r-hirudin, bivalirudin, argatroban). SUMMARY: There are multiple pharmacologic therapies that surgical patients may be exposed to preoperatively, although there are currently few available methods to antagonize their effects. Often therapeutic prohemostatic pharmacologic approaches are used to treat or prevent bleeding, in addition to transfusional therapies.

[Hemostatic disorders caused by chronic use of valproic acid in neurosurgical patients. Thromboelastographic monitoring].

The paper gives the results of analyzing the hemostatic system in 26 patients with various neurosurgical diseases on the basis of routine laboratory biochemical tests and thromboelastographic indicators. In all the patients, the pattern of the disease contained an epilepsy syndrome that required mono- or combination therapy with valproic acid. Laboratory indicators of clinical hypocoagulation were found to develop during the use of valproic acid, and its monotherapy in particular. Hemorrhagic complications were also analyzed in not only the immediate, but also late postoperative period (for as long as 6 months after surgery). Two cases of severe late complications, such as formation of chronic subdural hematomas requiring surgical intervention, were diagnosed in the valproate monotherapy group. A tactic using a thromboelastographic technique is proposed to prepare these patients for further neurosurgical intervention.

[Acquired platelet function disorders: pathogenesis, classification, frequency, diagnosis, clinical management]. / Erworbene Plättchenfunktionsstörungen: Pathogenese, Klassifikation, Häufigkeit, Diagnostik und Behandlung.

Given the high consumption of pharmacological agents in western societies, it is not surprising at all that drugs represent the most common cause of acquired platelet dysfunction. While acetylsalicylic acid, clopigogrel and integrin alphaIIbbeta3 (GPIIb-IIIa) receptor antagonists are well-known as prototypes of antiplatelet drugs, other widely used agents including non-steroidal anti-inflammatory drugs, antibiotics, serotonin reuptake inhibitors, and volume expanders can also impair platelet function and cause or aggravate haemorrhages. Besides pharmacological agents, certain clinical conditions are often associated with qualitative platelet disorders and bleeding diathesis. Consequently, in contrast to inherited platelet disorders, acquired platelet function defects are much more frequent in clinical practice and deserve special attention. Their pathogenesis is widespread and heterogeneous with various, sometimes overlapping abnormalities. Moreover, acquired platelet dysfunctions can occur at any age and range in severity from mild to life-threatening haemorrhages. Due to their heterogeneity, acquired platelet function disorders will be classified and discussed according to the underlying clinical setting or disease.

Hemostatic disorders induced by skin contact with Lonomia obliqua (Lepidoptera, Saturniidae) caterpillars.

Patients envenomed by Lonomia sp caterpillars initially experience a mild burning pain, headache, nausea, vomiting, and skin and mucosal hemorrhages. Some patients can rapidly progress to a severe coagulopathy that presents as visceral or intracerebral hemorrhaging. We studied the hemostatic alterations that occurred in 14 patients who were envenomed by Lonomia obliqua in Southern Brazil and presented at the Hospital São Vicente de Paulo (Passo Fundo, RS), Brazil during the summers of 1993 and 1994 when Lonomia antivenom was not yet available for treatment. The patients were classified into to 4 clinical groups: 0 (two patients), I (eight patients), II (two patients), and III (two patients). The patients were admitted to the hospital between 4 hours and five days after contact with the caterpillars. In this study, the coagulation parameters of the patients were followed up for up to 172 hours after the accidents. The patients received no treatment with the exceptions of two patients who received blood transfusions and antifibrinolytic treatment. The observed abnormalities related to blood coagulation and fibrinolytic factors were similar regardless of the severity of the bleeding symptoms. These findings suggest that alterations in hemostatic parameters without thrombocytopenia are not predictors of the seriousness of such accidents. Thus, consumptive disorder and reactive fibrinolysis are not proportional to mild coagulopathy. Furthermore, these patients recovered. The hemostatic parameters of most of the patients normalized between 96 and 120 h after the accident.

Hemostasis disorders caused by polymer coated iron oxide nanoparticles.

BACKGROUND: Superparamagnetic iron oxide nanoparticles (SPIONs) are inorganic nanomaterials gaining strong clinical interest due to their increasing number of biological and medical applications. The stabilization of SPIONs in a biocompatible stable suspension (bioferrofluid) is generally achieved by an adequate polymeric coating. As many applications using these materials are intended for clinical use through intravenous injection, it is of outmost importance to evaluate their hemostatic behaviour. OBJECTIVES: The aim of this work is to evaluate the hemocompatibility of selected polymer coated bioferrofluids and of their separated components by observing the effects of the bioferrofluid on: the coagulation process--by measuring the prothrombin time (PT) and activated partial thromboplastin time (aPTT)--, the complete blood count (CBC)--Erythrocytes, Leucocytes, Platelets, Hemoglobin and hematocrit--and the hemolysis. METHODS: A SPIONs/bioferrofluid model consisting of a magnetic core of iron oxide nanoparticles embedded within poly(4-vinyl pyridine) (P4VP) and all coated with polyethylene glycol (PEG) has been selected. RESULTS AND CONCLUSIONS: By increasing the concentration of the bioferrofluids an inhibitory effect on the intrinsic pathway of blood coagulation is observed, as indicated by significant increase in aPTT in vitro while PT values stay normal. The effect of the coating components on the inhibition of blood coagulation process shows that PEG has no effect on the process while the P4VP-g-PEG copolymer coating has a strong anticoagulant effect indicating that P4VP is at the origin of such effects. The studied bioferrofluids have no effect on the CBC neither they show in vitro hemolytic effect on blood.

Hemostatic disorders induced by skin contact with Lonomia obliqua (Lepidoptera, Saturniidae) caterpillars

ABSTRACT Patients envenomed by Lonomia sp caterpillars initially experience a mild burning pain, headache, nausea, vomiting, and skin and mucosal hemorrhages. Some patients can rapidly progress to a severe coagulopathy that presents as visceral or intracerebral hemorrhaging. We studied the hemostatic alterations that occurred in 14 patients who were envenomed by Lonomia obliqua in Southern Brazil and presented at the Hospital São Vicente de Paulo (Passo Fundo, RS), Brazil during the summers of 1993 and 1994 when Lonomia antivenom was not yet available for treatment. The patients were classified into to 4 clinical groups: 0 (two patients), I (eight patients), II (two patients), and III (two patients). The patients were admitted to the hospital between 4 hours and five days after contact with the caterpillars. In this study, the coagulation parameters of the patients were followed up for up to 172 hours after the accidents. The patients received no treatment with the exceptions of two patients who received blood transfusions and antifibrinolytic treatment. The observed abnormalities related to blood coagulation and fibrinolytic factors were similar regardless of the severity of the bleeding symptoms. These findings suggest that alterations in hemostatic parameters without thrombocytopenia are not predictors of the seriousness of such accidents. Thus, consumptive disorder and reactive fibrinolysis are not proportional to mild coagulopathy. Furthermore, these patients recovered. The hemostatic parameters of most of the patients normalized between 96 and 120 h after the accident.

Effects of heating on the immunogenicity and biological toxicity of Deinagkistrodon acutus venom and its fractions.

To improve toxoid preparation, the effects of selective heat denaturation were assessed on Deinagkistrodon acutus venom. The venom and its fractions (peak 1 and peak 2 separated by gel filtration chromatography) were heated to various temperatures (45-70 degrees C) for 30 min, after which protein concentration, immunoreactivity, lethality, myotoxicity and hemorrhagic and membrane lysis activities of the samples were determined. In addition, the synergistic effects of the venom fractions were evaluated by separate or simultaneous intramuscular injection in mice. The results showed that the peak 1 fraction consisted primarily of proteins in the range of 18 to 105 kDa, while the peak 2 fraction consisted primarily of proteins smaller than 21 kDa. The hemorrhagic activity, immunoreactivity, and protein concentration of heated samples were gradually reduced as the temperature increased from 25 degrees C to 70 degrees C. Bioactivities significantly decreased but immunoreactivity was retained when the crude venom, peak 1 fraction, or peak 2 fraction were heated to the critical temperatures of 60 degrees C, 55 degrees C, or 60 degrees C, respectively. Synergistic effects of two kinds of heated fractions were observed in toxicity and antibody production after the peak 1 and peak 2 injected simultaneously or respectively. The results suggest that venom fractions heated and injected separately could significantly reduce their toxicity and enhance the neutralization of antiserum induced by them.

Ceruloplasmin prevents hemostatic disorders during experimental hyperammonemia.

Experimental hyperammonemia in rats was accompanied by hemostatic disorders manifesting in coagulopathy (activation of the intrinsic pathway of blood coagulation) and suppression of platelet function. Ceruloplasmin in a total dose of 60 mg/kg effectively normalized coagulation hemostasis and functional activity of platelets by improving secretory processes in platelets and increasing aggregation rate.