Heparin-induced thrombocytopenia

Seen from a societal perspective, the health gains that might result from prostate screening are too uncertain to justify the substantial associated costs and adverse health effects. Clinicians who rely on observational screening studies to justify current screening practices should be aware of the potential biases that render conclusions suspect. Medical history documents numerous cases of medical interventions that appeared reasonable at the time, but ultimately proved worthless and even harmful. Before embarking on an ambitious screening program for prostate cancer, clinicians should demand that five basic criteria are satisfied: (1) that prostate cancer is a significant health burden, (2) that screening can identify localized disease, (3) that tests used in screening programs have acceptable performance among the population being tested, (4) that the potential for cure is greater among patients with screen-detected disease, and (5) that screen-detected patients have improved health outcomes compared with those who are not screened. Randomized trials provide the best methodology for determining the efficacy of screening and treatment. Clinicians are often too quick to credit medical intervention for successful outcomes and blame tumor biology for disease progression. Furthermore, when faced with a decision of administering or withholding therapy, physicians generally wish to err on the side of having done everything possible. Data modeling can provide critical insights concerning these issues using currently available information. Three recently published models suggest that the overall benefit to a population of men screened for prostate cancer can be measured in days of additional time of life gained, not months or years. Furthermore, models suggest that a substantial number of men need to undergo treatment in order to avert a single cancer death. The costs of implementing a screening program are enormous and deflect resources away from alternative uses, such as increased basic science funding to identify a cure for this disease. Therefore, based on the evidence presented, I believe that without more substantial data supporting the efficacy of screening programs, screening for prostate cancer is neither appropriate nor cost-effective.     

Heparin-induced thrombocytopenia and thrombosis

The effect of antisense oligodeoxynucleotide to rat troponin T (TnT) mRNA on its expression in differentiated rat L6 myotubes in culture was examined. The target sequence following the initiation codon was between nucleotides 83 and 97 and is found in all mRNAs produced from the f-TNT gene. Our studies showed that chimeric oligomer with one phosphorothioate linkage at the 3'-end was considerably more resistant to nucleases than was a phosphodiester oligomer. The chimeric oligomer produced >50% inhibition of TnT polypeptide synthesis. Synthesis of myosin heavy chain (MHC), troponin I (TnI), and alpha and beta tropomyosins (Tm) was not inhibited by the anti-TnT oligomer. However, synthesis of alpha-actin and troponin C (TnC) was somewhat affected by this treatment. Furthermore, compared with the untreated control myotubes, the steady-state level of TnT mRNA was reduced by approximately 40%-50% in anti-TnT oligomer-treated myotubes. Cellular levels of three other muscle mRNAs, alpha-Tm, s-TnI, and alpha-actin were also reduced by approximately 30%-40%. In contrast, fast TnI, beta-Tm, and TnC mRNA levels were not significantly affected by this treatment. Therefore, inhibition of TnT synthesis in differentiated myotubes uncoupled the coordinated expression of muscle proteins.     

Heparin-induced thrombocytopenia and thrombosis

Although heparin is widely used as the injectable anticoagulant of choice, it has several potential shortcomings. These include heparin resistance, excessive bleeding, allergic reactions, and, with longterm use, occasional osteoporosis or alopecia. Perhaps the most notorious complication is heparin-induced thrombocytopenia and thrombosis (HITT); although unusual, it often results in major morbidity or death. Until recently, reliable diagnostic tests and anticoagulation alternatives have not been widely available. After a review of the pharmacology of heparin and related drugs, advances in the prevention, diagnosis, and treatment of this problem are discussed.     

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.     

Heparin-induced thrombocytopenia: new insights into the impact of the FcgammaRIIa-R-H131 polymorphism

Heparin-induced thrombocytopenia (HIT), a severe complication of heparin treatment, can be associated with new thrombotic complications. HIT antibodies activate platelets via the platelet Fcgamma-receptor (FcgammaRIIa), which carries a functionally relevant polymorphism (FcgammaRIIa-R-H131). The effect of this polymorphism on the clinical manifestations of HIT is controversial. We determined prospectively the FcgammaRIIa-R-H131 genotypes in 389 HIT patients, in 351 patients with thrombocytopenia or thrombosis due to causes other than HIT and without detectable HIT antibodies, and in 256 healthy blood donors. For this purpose, a novel nested sequence-specific primer-polymerase chain reaction (SSP-PCR) was developed. FcgammaRIIa-R/R131 was found to be overrepresented in the HIT patients (27%) compared with the control groups (non-HIT patients [21%] and blood donors [20%]). In a subgroup of 122 well-characterized HIT patients, the genotype distribution in patients presenting with thrombocytopenia only was compared with that of patients who developed thromboembolic complications. The frequency of FcgammaRIIa-R/R131 among patients with thrombotic events was significantly elevated (37% v 17%; P = .036). Our results indicate that genotype distribution can be correlated to the clinical outcome of patients with HIT. We speculate that the reduced clearance of immune complexes in patients with the FcgammaRIIa-R/R131 allotype causes prolonged activation of endothelial cells and platelets, thus increasing the risk for thrombotic complications.     

Heparin-induced thrombocytopenia with thrombotic complications during prophylactic treatment with low-molecular-weight heparin

Heparin-induced thrombocytopenia is very uncommon with low-molecular-weight heparin, especially when given for prophylaxis of venous thromboembolism. In two of the four published cases, with thrombotic complications, thrombocytopenia may have been related to cross-reactivity between unfractionated heparin and low-molecular-weight heparin. We report one patient who received low-molecular-weight heparin for prophylaxis against venous thromboembolism without any previous injection of unfractionated heparin, and experienced thrombocytopenia with thrombotic complications. Heparin-induced thrombocytopenia was confirmed by several laboratory assays. This observation emphasizes the need for platelet count monitoring during low-molecular-weight heparin therapy.     

Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy

Although several new anticoagulant drugs are in development, heparin remains the drug of choice for most anticoagulation needs. The clinical effects of heparin are meritorious, but side effects do exist. Important untoward effects of heparin therapy including heparin-induced thrombocytopenia, heparin-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia and alopecia will be discussed in this article.     

Heparin-induced thrombocytopenia: IgG-mediated platelet activation, platelet microparticle generation, and altered procoagulant/anticoagulant balance in the pathogenesis of thrombosis and venous limb gangrene complicating heparin-induced thrombocytopenia

Until recently, the confusing clinical profile of HIT and the widespread unavailability of reliable diagnostic assays have conspired to produce under-recognition-if not frank skepticism-of the clinical importance of HIT. However, during the 1990s, HIT has emerged as one of the major-if not the most important-immunohematologic problems in clinical medicine. The clinical and laboratory investigations summarized here have contributed to a greater understanding of the frequency, clinical spectrum, pathogenesis, laboratory diagnosis, and-potentially-the prevention of this important drug allergy. Further, the demonstration of increased platelet procoagulant activity and, thrombin generation in HIT, together with insights into the pathogenesis of a new clinicopathologic syndrome (venous limb gangrene), help explain how a disorder characterized by IgG-mediated platelet activation can lead to such diverse clinical sequelae as venous thrombosis, pulmonary embolism, disseminated intravascular coagulation, and venous limb gangrene. These studies should lead to improved treatment of HIT (new emphasis on suppression of thrombin generation, eg, hirudin and its analogs), future avoidance of HIT (preparation of low-molecular-weight heparins and heparinoids that are less immunogenic), and a greater understanding of the interaction between platelet activation and procoagulant/anticoagulant processes.     

Gallstone pancreatitis: pathophysiology

The stools of 45 patients with proven gallstones pancreatitis were screened for gallstones. An equal number of peripheral with gallstones but without pancreatitis served as the control group. Gallstones were found in the stools of 38 of the 45 patients (84 percent) with gallstone pancreatitis and in only five (11 percent) patients of the control group. The patients with gallstone pancreatitis experienced a relief of symptoms and a decrease in the levels of serum amylase and bilirubin prior to rectal passage of the stones. Operative cholangiography revealed reflux of contrast material into the pancreatic duct of 67 percent of the patients with gallstone pancreatitis and in only 18 percent of the controls. Of the 38 patients that passed stones, 30 cholangiograms (79 percent) demonstrated a functioning common channel. it would appear that a functioning common channel is necessary for reflux and in addition favors stone passage. This study suggests that the pathophysiology of gallstone pancreatitis relates to the temporary impaction of migrating stones at the ampulla of Vater.     

Pouchitis: pathophysiology and treatment

Pouchitis is a potential complication after proctocolectomy and restorative ileoanal anastomosis. It is more frequent in UC than in familial polyposis. Little is known about the etiopathology of pouchitis. Risk factors include the presence of extraintestinal manifestations, primary sclerosing cholangitis, cessation of smoking, and previous course of disease. A host of pathophysiological pathways have been identified as potential mechanisms of pouchitis, which include inflammatory mediators, adhesion molecules, oxygen radical species, p-ANCA, and short-chain fatty acids. The microflora in the pouch may also be an important factor in causing inflammation. The risk of developing cancer in cases of pouchitis has not been established as clearly as in those of UC. Particular attention should be paid to patients who have remaining anorectal mucosa after pouch construction. Experience in the treatment of chronic relapsing and chronic refractory pouchitis is limited. The continuation of conventional anti-inflammatory treatment is successful only in a small percentage of patients. New biological response-modifying therapies which target novel immunoregulatory molecules in IBD will also have impact on the systemic and topical treatment of pouchitis.     

Cor pulmonale: pathophysiology and management

Pulmonary disease may set in motion a chain of events that ultimately leads to hypertrophy--or even failure--of the heart's right ventricle. The most common cause is chronic obstructive disease, which deprives the lungs of oxygen and produces pulmonary hypertension. But other disorders that raise pulmonary artery pressure also may be responsible. The thin right ventricle, which must work harder to overcome this increased resistance, ends up resembling the thick left ventricle. Comprehensive treatment of the primary lung condition at home usually enables the patient with chronic cor pulmonale to be more active and prevents frequent hospitalizations. Controlled-dose supplemental oxygen therapy is particularly effective, according to recent studies. Bronchospasm or bronchial infection super-imposed on the chronic lung condition may prove too much for the already strained right ventricle. Right ventricular failure calls for hospitalization and vigorous treatment, which may include mechanical ventilation, phlebotomy, antibiotics, steroids, digitalis, diuretics, and correction of electrolyte disturbances.     

Hypertrophic cardiomyopathy: presentation and pathophysiology

HCM is a heterogeneous disease with various clinical presentations. Recent advances in understanding the genetic abnormalities responsible for ventricular hypertrophy promise to improve our ability to diagnose this condition and to identify subgroups who are at the highest risk of cardiovascular mortality. Numerous difficulties remain in treating patients with HCM, including obtaining relief of symptoms and preventing SCD, but several new treatment options are currently being evaluated. In the future, randomized trials comparing the major treatment options (eg, pharmacologic therapy, myotomy/myectomy, mitral valve replacement, pacemaker implantation, and nonsurgical septal reduction) will be needed to provide guidance concerning the optimal treatment of patients with HCM.     

Atrial fibrillation: a review of pathophysiology

Atrial fibrillation is the most common sustained tachyarrhythmia and, as such, has become the recent focus of intense clinical and experimental interest. Because of its associated morbidity and mortality, there is a multidisciplinary effort to understand the pathophysiology that may ultimately lead to improved therapeutic options.     

Malignant bone pain: pathophysiology and treatment

2-acetyl aminofluorene (AAF) reacts in acidic conditions with nitrous fume yielding N-nitroso-AAF (N-NO-AAF), as previously described, that exerts more toxic and mutagenic effects than its parental compound. In this study, the effect of sodium nitrite (NaNO2) on the tumorigenicity of AAF in rats fed with AAF and NaNO2 was observed. Wistar rats were divided into five groups: group I served as control; group II were treated with NaNO2 (0.3%); group III was given 0.02% AAF alone; groups IV and V received both AAF and NaNO2 (0.2 and 0.3% respectively) in their diet for 12 weeks. At the end of the experiment, all rats in groups III, IV and V developed early stage phenomena of hepatocellular carcinoma, including hepatomegaly with variable-sized foci and neoplastic nodules. Severe damage was observed in the rats treated with AAF and NaNO2. Feeding of AAF (0.02%) for 3 months elevated the levels of c-Fos, c-Jun and c-Myc proteins in the rat livers. The AAF-induced c-Jun, c-Fos and c-Myc expressions were significantly magnified (P < 0.001) by NaNO2. These data confirmed that the strengthening of AAF-induced hepatocarcinogenesis by NaNO2 should be associated with its enhancing effect on the AAF-induced increases in the expressions of c-Jun, c-Fos and c-Myc.     

Congenital release thrombocytopathy: pathophysiology and management

Congenital release thrombocytopathy must be included in the differential diagnosis of bleeding diatheses in women. A review of the coagulation profiles of 7 patients with congenital release thrombocytopathy suggests that more sophisticated platelet aggregation studies must be performed when routine screening procedures fail to determine the cause of a clinically suspected bleeding disorder. Establishing the diagnosis helps to avoid the use of medications which cause an acquired platelet dysfunction, and contributes to adequate prophylaxis against surgical and obstetric hemorrhage.