Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies.

Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk) that has proven to be an effective therapeutic agent for multiple B-cell-mediated lymphoproliferative disorders. Ibrutinib, however, carries an increased bleeding risk compared with standard chemotherapy. Bleeding events range from minor mucocutaneous bleeding to life-threatening hemorrhage, due in large part to the effects of ibrutinib on several distinct platelet signaling pathways. There is currently a minimal amount of data to guide clinicians regarding the use of ibrutinib in patients at high risk of bleeding or on anticoagulant or antiplatelet therapy. In addition, the potential cardiovascular protective effects of ibrutinib monotherapy in patients at risk of vascular disease are unknown. Patients should be cautioned against using non-steroidal anti-inflammatory drugs, fish oils, vitamin E and aspirin-containing products, and consider replacing ibrutinib with a different agent if dual antiplatelet therapy is indicated. Patients should not take vitamin K antagonists concurrently with ibrutinib; direct oral anticoagulants should be used if extended anticoagulation is strongly indicated. In this review, we describe the pathophysiology of ibrutinib-mediated bleeding and suggest risk reduction strategies for common clinical scenarios associated with ibrutinib.

Between Scylla and Charybdis: antithrombotic therapy in hematopoietic progenitor cell transplant patients.

Patients who undergo hematopoietic progenitor cell transplant may require antithrombotic therapy for a variety of reasons--history of vascular events or developing new ones during therapy. For patients with arterial disease, use of antiplatelet therapy is based on acuity. For primary prevention of an arterial event, aspirin can be withheld at the start of transplant. On the other hand, in the face of a patient experiencing an acute myocardial infarction, aspirin should be given, no matter what the degree of thrombocytopenia is. Patients with cardiac 'hardware'-stents and mechanical valves-pose difficult issues because as higher risk patients (especially patients with recent implantation of a drug eluting stent) they require more aggressive anticoagulation, even in the face of severe thrombocytopenia. Anticoagulation with heparin is dependent on the platelet count with full dose recommended for a platelet count over 50 × 10(9)/L and prophylactic dosing with platelets in the 20-50 × 10(9)/L range. If the patient develops a distal venous thrombosis, then simple observation can be used, but more proximal thrombosis or pulmonary embolism requires consideration of anticoagulation. Central venous catheter thrombosis is best treated by line removal, as the risk of bleeding is high if the device is left in. The advent of new anticoagulants with minimal drug and food interactions may offer better choices for therapy for these difficult patients. This is also an area in which clinical trials would be helpful to clarify the treatment choices.

Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model.

Modulation of thiol levels may alter both the efficacy and toxicity of chemotherapeutic agents. We investigated cytoenhancement, using L-buthionine-[S,R]-sulfoximine (BSO) to reduce cellular glutathione levels prior to intracarotid alkylator administration. We also evaluated chemoprotection against chemotherapy-induced systemic toxicity when the thiol agents N-acetylcysteine (NAC) and sodium thiosulfate were administered into the descending aorta to limit brain delivery. BSO treatment reduced rat brain and intracerebral tumor glutathione levels by 50-65%, equivalent to the reduction in liver and s.c. tumor. BSO treatment significantly enhanced the toxicity of chemotherapy with carboplatin, melphalan, and etoposide phosphate against granulocytes, total white cells, and platelets. Intracarotid administration of NAC resulted in high delivery to the brain, whereas infusion via the descending aorta minimized brain delivery. When NAC, with or without sodium thiosulfate, was administered via aortic infusion prior to chemotherapy, the magnitude of the bone marrow toxicity nadir was minimized, even with BSO-enhanced myelosuppression. Thus, BSO depleted brain and brain tumor glutathione but thereby increased chemotherapy-induced myelosuppression. Surprisingly, although NAC was found to readily cross the blood-brain barrier when given into the carotid artery, aortic infusion of NAC resulted in minimal exposure to the central nervous system (CNS) vasculature because of rapid clearance. As a result, aortic infusion of NAC to perfuse bone marrow and minimize myelosuppression and toxicity to visceral organs could be performed without interfering with the CNS cytotoxicity of intracarotid alkylators, even after BSO depletion of CNS glutathione.

Recurrent thromboembolic disease following splenectomy for pyruvate kinase deficiency.

We report a case of recurrent thromboembolic disease and chronic pulmonary hypertension in an adult patient with pyruvate kinase deficiency who underwent splenectomy as a child. Thromboembolism has been reported as a complication following splenectomy for various hereditary chronic hemolytic anemias. To our knowledge, this association has not been described in patients specifically with pyruvate kinase deficiency. Our patient presented at age 37 with recurrent pulmonary emboli, 36 years after splenectomy for severe hemolytic anemia. Work-up for other hypercoagulable states was negative. The mechanism for hypercoagulability in this condition is unclear but may involve a quantitative or qualitative change in disrupted thrombogenic red blood cell membranes that would normally be removed by the spleen. Clinicians should have a high index of suspicion for thrombotic events in these patients, as early diagnosis and treatment can reduce morbidity and mortality, and chronic anticoagulation may help prevent the sequelae of repeated thromboembolic events.

Anticoagulant therapy in special circumstances.

Situations often occur in anticoagulated patients that require adjustment of anticoagulation therapy. These situations often place the patient at risk of bleeding, and often there is little clinical data to guide the clinician. This paper reviews several of these situations and offers guidance for the management of patients. The problems reviewed concern the patient on anticoagulants who is or desires to get pregnant, peri-operative management of anticoagulated patients, anticoagulated patients with intracranial bleeding or endocarditis, and the "warfarin refractory" patient.

Pulmonary hemorrhage in a hemophiliac simulating a lung neoplasm.

We report an elderly, male smoker with moderate hemophilia B who presented with hemoptysis. Chest imaging revealed a well-circumscribed, pulmonary, mass lesion. Repeated bronchoscopy failed to make a diagnosis, and the patient ultimately underwent open thoracotomy with resection of the mass. Pathologic examination revealed hemorrhagic changes in association with bullous lung disease. This is the first report of symptomatic pulmonary hemorrhage in a patient with hemophilia B. Hemorrhage into a pre-existing bulla can simulate a primary lung neoplasm.

Fatal cerebroembolism from nonbacterial thrombotic endocarditis in a trauma patient: case report and review.

Nonbacterial thrombotic endocarditis (NBTE) is a rare condition that may result in an unexpected and usually fatal cerebroembolism. It occurs in a variety of clinical situations, including malignancy, immune disorders, and sepsis, but it has rarely been reported after trauma. The formation of NBTE appears to require a hypercoagulable state and changes in valvular morphology, e.g., during a hyperdynamic state. Patients with disseminated intravascular coagulation have a 21% incidence of NBTE. Although NBTE is usually found at autopsy, premorbid detection by echocardiography is currently possible and feasible. Untreated patients have a high incidence of embolic events, but anticoagulation with heparin may be life-saving. A lethal case of NBTE in a severely injured patient is reported here with the purpose of increasing awareness among medical personnel caring for trauma patients. Recommendations have been made for surveillance echocardiography in high-risk patients, e.g., critically ill patients with sepsis or disseminated intravascular coagulation.

Coagulation abnormalities and cardiovascular disease.

In patients with excessive venous thrombosis, genetic defects predisposing to thrombosis can be found in 60-80%. Increased plasma levels of coagulation proteins such as fibrinogen and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of myocardial infarction. However, despite the presence of polymorphisms that regulate plasma levels of factor VIII, PAI-1, and fibrinogen the association between common polymorphisms of these coagulation protein and ischemic cardiac disease remains ambiguous. Up to 10% of the population have defects that predispose them to excessive venous thrombosis. In spite of the essential role of thrombosis in coronary ischemic syndrome, no convincing evidence has implicated the two most common venous hypercoagulable states in ischemic heart disease. Pathogenic polymorphisms in the platelet fibrinogen and collagen receptors remains an area of intense research interest. Finally, it has been shown that lipoproteins can act as mediators of coagulation processes.

Management of bleeding with uremia and liver disease.

Bleeding can complicate the clinical course of both liver disease and uremia. The pathogenesis of bleeding in both syndromes is complex. A variety of options are available for treatment of uremic bleeding including desmopressin, erythropoietin, and estrogens. Bleeding complications of liver disease reflect the importance of this organ for the production of both coagulation factors and thrombopoietin. Careful assessment of both the patient's clinical situation and laboratory findings is important for tailoring therapy of the bleeding patient.

Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke.

A common mutation in methylenetetrahydrofolate reductase (MTHFR), a homocysteine metabolic pathway enzyme, has been associated with increased homocysteine levels and increased risk for premature cardiovascular disease. The purpose of this study was to assess the association between the prevalence of the MTHFR mutation, hyperhomocysteinemia, and subtypes of ischemic stroke in an elderly population comprised of three age-balanced groups of patients. The presence of the C677T MTHFR mutation was determined by a direct polymerase chain reaction-based assay performed on blood samples from 136 patients with acute ischemic stroke, 95 patients with atherosclerotic risk factors for stroke (including some with a history of previous stroke or transient ischemic attack), and 52 healthy control subjects. The prevalence of the homozygous C677T mutation was not significantly higher in the elderly stroke patients (7%) than in the atherosclerotic risk (8%) or healthy elderly control (2%) groups. Plasma homocysteine levels were higher in the acute stroke patient group (14.5+/-4.5 micromol/L) and atherosclerotic risk patient group (14.6+/-6.2 micromol/L) compared with the control subjects (10.3+/-3.1 micromol/ L, P < 0.03). Homozygotes for the C677T MTHFR mutation did not have significantly higher homocysteine levels than non-homozygotes. Moderate hyperhomocysteinemia, though common in older patients with ischemic cerebrovascular disease, is not attributable, at least in this patient group, to a higher prevalence of the C677T MTHFR mutation.

Higher total homocysteine concentrations and lower folate concentrations in premenopausal black women than in premenopausal white women.

BACKGROUND: Premenopausal black women have a greater rate of coronary artery disease (CAD) than do premenopausal white women. Plasma total homocysteine concentrations, a risk factor for CAD, have not been reported in premenopausal black women. OBJECTIVE: The purpose of this study was to compare plasma total homocysteine, folate, and vitamin B-12 concentrations in premenopausal black and white women. DESIGN: Eighty-nine black and 90 white, healthy, premenopausal women living in Portland, OR, were recruited. Dietary histories were obtained by using the Diet Habit Survey, a 40-item eating-behavior questionnaire. Plasma concentrations of total homocysteine, folate, and vitamin B-12 were measured. RESULTS: Black women had higher plasma total homocysteine (8.32 compared with 7.60 micromol/L;P = 0. 013), lower plasma folate (6.62 compared with 9.88 nmol/L;P < 0. 0001), and higher vitamin B-12 (355 compared with 283 pmol/L;P < 0. 001) concentrations than white women. White women had a greater rate of daily multivitamin supplement use (42.4% compared with 24.7%;P = 0.019) and ate more ready-to-eat cereal than did black women. After adjustment for multivitamin use and intake of ready-to-eat cereal, plasma total homocysteine concentrations did not differ significantly, but plasma folate remained significantly lower in the black women. None of the black women but 12.3% of the white women (P = 0.013) were homozygous for the cytosine to thymidine mutation at nucleotide 677 in the methylenetetrahydrofolate reductase gene. CONCLUSIONS: Black women had higher plasma total homocysteine and lower plasma folate concentrations than white women, largely because of lifestyle factors, which may contribute to the greater rate of CAD in premenopausal black than in white women.

Homozygous hereditary resistance to activated protein C presenting as cerebral venous thrombosis.

The factor V Leiden mutation is a specific point mutation in the gene coding for factor V. It renders activated factor V resistant to degradation by activated protein C (APC). This hereditary resistance to APC (HRAPC) is a known risk factor for systemic venous thrombosis. We present a case of homozygous HRAPC presenting as cerebral venous thrombosis (CVT). A 24-year-old woman presented with a dense left hemiplegia and papiledema. A computed tomography scan showed a high ritht parieto-occipital infarct with hemorrhagic conversion. Angiography confirmed the diagnosis of extensive CVT. Treatment included heparin and direct intrathrombus thrombolysis initially as a bolus and then as an infusion for 21 hours. Repeat angiography showed partial recanalization. After 9 days, the patient was discharged on warfarin with minimal residual left weakness but persistent papilledema. Homozygous HRAPC appears to be a risk factor for CVT and should be considered in the evaluation of CVT.

Clinical one-year outcomes after stenting in acute myocardial infarction.

We retrospectively review our results of 96 stent placements in 64 patients identified from our data base who received stents acutely and within 48 hr of acute myocardial infarction. The average age was 60 years; 77% were male. The average length of stay was 6.75 days. Three patients needed coronary artery bypass grafting (CABG) before discharge: 2 for stent occlusion and 1 for papillary muscle rupture. Need for CABG, further percutaneous transluminal coronary angioplasty (PTCA), myocardial infarction, and death defined outcome. Mean patient follow-up was 10.3 (+/-5.3) months. Seventy-two percent of patients were free of outcome events at 1 year, 17% needed CABG, and 11% required further PTCA. There were 2 myocardial infarctions and 1 death. Presence of left bundle branch block on admission electrocardiogram and angina in hospital after stent placement predicted worse outcome (P < 0.01).

International normalized ratio in anticoagulant therapy: understanding the issues.

Recently, a change in anticoagulation therapy occurred that is still partially ignored by the healthcare community. Understanding the controversy over the use of the internal normalized ratio in monitoring patients receiving warfarin therapy is important for nurses who provide care to these patients. Five questions related to current monitoring of patients treated with anticoagulants are addressed. Nurses must recognize the importance to their practice of changes in laboratory methods and move toward using the most useful measures available to influence patients' outcomes. The international normalized ratio is the most appropriate way to evaluate the effects of warfarin therapy. All healthcare providers should use this ratio as the standard in evaluating the effects of anticoagulation therapy.

Abnormal phospholipid molecular species of erythrocytes in sickle cell anemia.

As the lipid composition of cell membranes has significant effects upon cellular function, we hypothesized that the membranes of sickle cells might have a distorted lipid composition. Accordingly, we analyzed the molecular species of the choline and ethanolamine glycerophospholipids, the fatty acid composition of the total phospholipids and of the five major individual phospholipids of erythrocytes from 8 patients with sickle cell anemia and from 14 normal subjects. Of the 31 molecular species identified for each subclass of the glycerophospholipids, 12 were found to be distinctly abnormal. Sickle cells contained more molecular species with saturated and monounsaturated fatty acid at the sn-2 position and fewer molecular species with polyunsaturated fatty acids at the sn-2 position. The values ranged from 20 to 60% above or below normal values. In diacyl choline glycerophospholipids (outer membrane leaflet), sickle erythrocytes contained lower amounts of the 16:0-18:2 species and higher 16:0-18:1 and 16:0-16:0 species. In diacyl ethanolamine glycerophospholipid (inner membrane leaflet), sickle erythrocytes had lower amounts of 18:0-22:6; 16:0-22:4; 18:0-18:2; 18:1-18:2; and 18:1-20:3. In phosphatidylcholine and phosphatidylethanolamine, sickle erythrocytes contained less linoleic acid, less docosahexaenoic acid (30-40%) and more oleic and palmitic acids (20-30%) compared to normal erythrocytes. These same differences were seen also in the total phospholipids. Our data demonstrated distinct abnormalities of the phospholipid molecular species composition in the membrane lipids of sickle erythrocytes. These defects might have a role in one or more known metabolic abnormalities of sickle cell disease including cation imbalance, dehydration, disturbed membrane phospholipid asymmetry, and hypercoagulability. Furthermore, detailed information of the phospholipid molecular species composition of normal erythrocytes was provided.

Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease.

BACKGROUND: Increased homocysteine levels are a risk factor for atherosclerosis and its sequelae. A common genetic mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile enzyme with reduced activity. We determined the prevalence of this mutation in many subjects with and without vascular disease and related it to homocysteine and folate levels. METHODS AND RESULTS: DNA from 247 older subjects with vascular disease and 594 healthy subjects without vascular disease (in three different control groups) was screened for the MTHFR 677 C-to-T mutation. Within each group, 9% to 17% of the subjects were homozygous for this mutation, and the mutant allele frequency was 31% to 39%. The genotype distributions, homozygote frequencies, and allele frequencies did not differ significantly between the study groups. In the vascular disease subjects, despite significantly lower folate levels in MTHFR homozygotes, there was no significant difference in homocysteine levels among the MTHFR genotype groups. The negative slope of the regression line relating homocysteine and folate was significantly steeper for those with a homozygous MTHFR mutation compared with those without this mutation. CONCLUSIONS: Although the thermolabile MTHFR mutation is very common, it does not appear to be a significant genetic risk factor for typical late-onset vascular disease. Because MTHFR homozygotes have increased homocysteine with low folate levels, this mutation may contribute to early-onset or familial vascular disease. The genotype dependence of the folate-homocysteine correlation further suggests that homozygotes for this mutation may have both an exaggerated hyperhomocysteinemic response to folic acid depletion and a better response to folic acid therapy.