Heparin-induced hyperkalemia

An 85-year-old lady with type 2 diabetes mellitus of 32 years duration with peripheral neuropathy was admitted under the vascular surgeons with extensive gangrene of her lower limb. She was on insulin for the last 7 years. Initial investigations showed normal serum electrolytes. She was started on antibiotics and unfractionated heparin, and her electrolytes showed hyperkalemia, which persisted on active treatment. Her short synacthen test showed good response, renin was normal with low aldosterone, urinary pH, sodium, potassium and osmolality was normal. On stopping heparin serum, potassium became normal. On restarting heparin (low molecular weight) during a suspected episode of pulmonary embolism, she developed hyperkalemia and heparin was stopped. Her potassium and aldosterone became normal on discontinuation of heparin. She developed hyperkalemia with both unfractionated and low molecular weight heparin.     

Heparin-induced thrombocytopenia

Opinion statement Treatment with heparin is associated with two types of thrombocytopenia. The most worrisome of these is the immune-mediated heparin-induced thrombocytopenia (HIT type II). Suspicion of HIT type II mandates immediate cessation of heparin adminis-tration and consideration of an alternative anticoagulation therapy. Hirudin and argatroban are approved alternative anticoagulants with no cross-reactivity with the HIT antibody. HIT type II is a clinicopathologic syndrome, and therefore diagnosis requires clinical and laboratory confirmation. The laboratory evaluation for HIT type II should also determine whether or not there is HIT-antibody cross-reactivity with danaparoid and low molecular weight heparin. Patients with HIT type II who require coronary artery bypass graft surgery present a particularly difficult situation, as there is no ideal alternative to heparin anticoagulation.     

Heparin-induced thrombocytopenia

Summary Thrombocytopenia is a frequent and sometimes insidious complication of anticoagulant therapy with heparin. Two types of heparin-induced thrombocytopenia with a distinct aetiology have been recognized. Type I is characterized by a mild thrombocytopenia of early onset which requires careful monitoring but usually not the cessation of heparin therapy. The mild thrombocytopenia is probably due to the mild pro-aggregatory properties of heparin and can be more severe in the presence of other predisposing factors, e.g. sepsis. Type II heparin-induced thrombocytopenia is more severe and usually occurs after a period of 7–10 days. Heparin therapy should be ceased immediately and other anticoagulant therapy initiated. The thrombocytopenia is believed to be due to the development of a heparin-dependent antibody that causes platelet aggregation and release. The precise mechanism of heparin-dependent antibody-platelet interaction is still not entirely clear but probably involves the binding of an antibody-heparin immune complex to the platelet Fc receptor.     

Heparin-induced thrombocytopenia

Hemorrhage is the most common and best-recognized complication of heparin treatment. However, a potentially more dangerous complication is the development of heparin-induced thrombocytopenia (HIT). All patients exposed to heparin, irrespective of the dose and route of administration, are at risk of developing HIT. It is due to the formation of antibodies against the heparin-platelet factor 4 complex, which cause secondary activation of platelets, coagulation and, finally, increased thrombin production. The main symptom is the sudden onset of thrombocytopenia involving a drop in the platelet count to less than 50% of the basal level, with or without the appearance of thrombotic complications some 5 to 14 days after the start of heparin therapy. Heparin-induced thrombocytopenia can be detected early in patients receiving heparin by monitoring the platelet count. Demonstration of heparin-dependent platelet activation using an antigen or functional assay confirms the clinical diagnosis. Once the diagnosis of HIT has been confirmed serologically or there is a high level of suspicion of HIT, heparin must be suspended and treatment with an alternative anticoagulant should be considered. This review contains a discussion of the diagnosis and treatment of this syndrome.     

Heparin-induced thrombocytopenia

Summary Heparin-induced thrombocytopenia (HIT), next to bleeding complications, is the most important side-effect of heparin therapy in cardiac patients and the most frequently found thrombocytopenia induced by medication. Two types of HIT are distinguished on the basis of both severity of disease, and pathophysiology: type I HIT is an early, transient, clinically harmless form of thrombocytopenia, due to direct heparin-induced platelet aggregation. Thromboembolic complications are usually not seen. No treatment is required. A normalization of platelet count even if heparin is continued is a usual observation. Type II HIT is more severe than type I HIT and is frequently complicated by extension of preexisting venous thromboembolism or new arterial thrombosis. The thrombocytopenia is caused by a pathogenic heparin-dependent IgG antibody (HIT-IgG) that recognizes as its target antigen a complex consisting of heparin and platelet factor IV. Type II HIT should be suspected when the platelet count falls to less than 100,000 per cubic millimeter or less than 50% of the base line value 5 to 15 days after heparin therapy is begun, or sooner in a patient who received heparin in the recent past. The clinical diagnosis of type II HIT can be confirmed by several sensitive assays. In cases of type II HIT, heparin must be stopped immediately. However, if the patient requires continued anticoagulant therapy for an acute event such as deep venous thrombosis, substitution of an alternative rapid-acting anticoagulant drug is often needed. In the authors experience Danaparoid sodium, a low-sulfated heparinoid with a low cross-reactivity (10%) to heparin, can be regarded as an effective anticoagulant in patients with type II HIT. Preliminary experiences with intravenous recombinant hirudin are also encouraging and suggest that this direct thrombin inhibitor will emerge as a valuable alternative treatment for patients who suffer from HIT.     

Heparin-induced thrombocytopenia

Thrombocytopenia is a common adverse effect of heparin therapy. Two types of heparin^linduced thrombocytopenia (HIT) are observed clinically - an early onset mild thrombocytopenia (Type I) in which the patients remain asymptomatic and a delayed onset severe thrombocytopenia (Type II). Patients with Type II HIT have an increased risk of thrombotic complications which frequently cause crippling disability e.g. limb amputation or even death. Type I HIT, the commoner of the two types, is believed to be due to the platelet proaggregating effect of heparin itself but Type II HIT is generally agreed to be caused by an immune mechanism, in which heparin-antibody complexes bind to platelets resulting in platelet activation, reduced platelet survival, thrombocytopenia and, in some cases, thrombosis. The diagnosis of HIT is made mainly on a clinical basis but in patients with suspected Type II HIT, laboratory test for the heparin-dependent antibody using platelet aggregometry or the two-point ¹⁴C-serotonin release method, allows confirmation of the diagnosis. In most Type I and all Type II patients, heparin should be stopped and warfarin commenced if there is a recent or new thrombosis requiring continuing anticoagulation. An alternative antithrombotic drug such as low molecular weight heparinoid (Org 10172) or dextran should be given at the same time until warfarin becomes therapeutic. The use of low molecular weight heparins (e.g. Fragmin) should be avoided unless it can be demonstrated that the HIT antibody does not cross-react with these drugs. (Aust NZ J Med 1992; 22: 145–152.)     

Heparin-induced thrombocytopenia

Two patients with underlying thromboembolic disorders developed severe thrombocytopenia while receiving heparin sodium; one of these patients developed recurrence of the thrombocytopenia and possible heparin-induced pulmonary emboli when heparin was restarted. In a prospective study of patients receiving heparin in a coronary care unit (CCU), nine of 37 patients developed transient mild thrombocytopenia (platelet counts ranging from 88,000 to 150,000/cu mm). Heparin added to citrated platelet-rich plasma caused platelet aggregation in the two original patients. In three of six CCU patients tested, and in 17 of 87 other subjects, with maximum aggregation at concentrations of heparin likely to be present in vivo during therapy. We herein discuss evidence that suggests that heparin may cause or aggravate thrombosis by causing platelet aggregation. The occurrence of severe heparin-induced thrombocytopenia is well documented, and mild transient thrombocytopenia may be more common than has been recognized. Studies of heparin efficacy should take these responses into account.     

Heparin-induced thrombocytopenia

BACKGROUND AND OBJECTIVE: There are two types of heparin-induced thrombocytopenia (HIT). HIT I is characterized by a transitory, slight and asymptomatic reduction in platelet count, occurring in the first 1-2 days of therapy, that resolves spontaneously; in contrast, HIT II, which has an immunologic origin, is characterized by a significant thrombocytopenia generally after the fifth day of therapy that usually resolves in 5-15 days only after therapy withdrawal. HIT II is the most frequent and dangerous side-effect of heparin therapy; in fact, in spite of thrombocytopenia, it can be complicated by venous and arterial thrombosis. Therefore, the recognition of HIT II may be difficult due to the underlying thrombotic symptoms for which heparin is administered. The aim of this article is to review the most recent advances in the field and to give critical guidelines for the clinical diagnosis and treatment of HIT II. STATE OF THE ART: The prevalence of HIT II, as confirmed by laboratory tests, seems to be about 2% in patients receiving unfractionated heparin (UH), while it is much lower in those receiving low molecular weight heparin (LMWH). The immunologic etiology of HIT II is largely accepted. Platelet factor 4 (PF4) displaced from endothelial heparan sulphate or directly from the platelets, binds to the heparin molecule to form an immunogenic complex. The anti-heparin/ PF4 IgG immunocomplexes activate platelets and provoke an immunologic endothelial lesion with thrombocytopenia and/or thrombosis. The IgG anti-heparin/PF4 immunocomplex activates platelets mainly through binding with the FcgRIIa (CD32) receptor. The onset of thrombocytopenia is independent of the dosage, schedule and route of administration of heparin. Orthopedic and cardiovascular surgery patients receiving post-surgical prophylaxis or treatment for deep venous thrombosis are at higher risk of HIT II. Besides thrombocytopenia, cutaneous allergic manifestations and skin necrosis may be present. Hemorrhagic events are not frequent, while the major clinical complications in 30% of patients are both arterial and venous thromboses which carry a 20% mortality. The diagnosis of HIT II should be formulated on the basis of clinical criteria and in vitro demonstration of heparin-dependent antibodies. Functional tests, such as platelet aggregation and (14)C-serotonin release assay and immunologic tests, such as the search for anti-PF4/heparin complex antibodies by an ELISA method are available. If HITT II is probable, heparin must be immediately suspended and an alternative anticoagulant therapy should be initiated before resolution of thrombocytopenia and the following treatment with a vitamin K antagonist. The general opinion is to administer low molecular weight heparin (in the absence of in vitro cross-reactivity with the antibodies), heparinoids such as Orgaran or direct thrombin inhibitors such as hirudin. PERSPECTIVES: Further studies are required to elucidate the pathogenesis of HIT II and especially to discover the clinical and immunologic factors that induce the occurrence of thrombotic complications. The best therapeutic strategy remains to be confirmed in larger clinical trials.     

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia with or without thrombosis has been recognized increasingly as a serious complication of heparin use. This article reviews type II heparin-induced thrombocytopenia, which is mediated by an antibody that in most cases has specificity for a complex between heparin and platelet factor 4, a secreted platelet alpha-granule protein. The antibody-heparin-platelet factor 4 complex can activate platelets and endothelial cells, thereby initiating thrombosis. Clinical thrombosis in this syndrome may be arterial or venous. Treatment of the syndrome requires discontinuation of heparin and institution of an alternative anticoagulant.     

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is the most frequent and the most important idiosyncratic haematological drug reaction. It is important for several reasons: first, because heparin is used so often, and the frequency of heparin-induced thrombocytopenia is high, the risk of a hospitalized patient developing heparin-induced thrombocytopenia is high. Second, heparin-induced thrombocytopenia poses a major therapeutic dilemma for the clinician - continue the heparin and risk a worsening of the thrombocytopenia, or stop the heparin and risk extension or embolism of the thrombus. Finally, a small subset of patients with heparin-induced thrombocytopenia develop the disastrous complication of heparin-induced thrombocytopenia plus arterial thrombosis. Some of these patients die. In this review, we will summarize some of the issues concerning heparin-induced thrombocytopenia, including its frequency, the various techniques used to diagnose the condition, its pathophysiology and approaches that can be used to manage patients with heparin-induced thrombocytopenia.     

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a syndrome of antibody-mediated activation of platelets and coagulation that confers increased risk for thrombosis. This article reviews recent studies of the pathogenesis, laboratory testing, frequency, and clinical presentation of HIT. Topics discussed include the nature of the neoepitopes on platelet factor 4 recognized by HIT antibodies, the nonspecific nature of the polyanions that support neoepitope formation, activation of monocytes and endothelium, and the development of new animal models. The transient "autoimmune" nature of HIT is highlighted in relation to new data concerning the rapid decline in HIT antibodies, as well as the recent recognition of a syndrome of "delayed-onset HIT" in which thrombocytopenia and thrombosis begin several days after stopping heparin. Detecting only HIT antibodies of the immunoglobulin G class is suggested as one way to increase diagnostic specificity of laboratory testing. Recent reports suggest that HIT could explain approximately 5% of cases of acute adrenal failure caused by bilateral adrenal hemorrhagic infarction.     

Heparin-induced thrombocytopenia

Thrombocytopenia is a common adverse effect of heparin therapy which may occur with bovine or porcine heparin when it is given either intravenously or subcutaneously. There are two main clinical types: a common, mild thrombocytopenia of early onset, probably due to the platelet proaggregating effect of heparin itself and a severe delayed-onset thrombocytopenia caused by an immune mechanism. Patients with mild thrombocytopenia due to heparin are usually asymptomatic. However, patients with severe thrombocytopenia may develop thromboembolic complications which often result in disastrous sequelae such as limb gangrene necessitating amputation or death. The thromboembolic complications may be attributed to an IgG heparin-dependent platelet antibody which induces thromboxane production and platelet aggregation. The diagnosis of heparin-induced thrombocytopenia is made clinically and may be confirmed by the demonstration of the heparin-dependent antibody in vitro by platelet aggregometry or [14C] serotonin release. In patients with delayed-onset severe thrombocytopenia, heparin should be stopped and warfarin commenced. Antiplatelet drugs and/or dextran may also be added. Recently low molecular weight heparin has been used with some success. Conversely, heparin may be continued in patients with asymptomatic mild thrombocytopenia provided the patients' condition and the platelet counts are closely monitored.     

Drug-induced hyperkalemia

After reviewing the available data on drug-induced hyperkalemia, we conclude that the situation has not improved since Lawson quantitatively documented the substantial risks of potassium chloride over a decade ago (90). As discussed, the risk of developing hyperkalemia in hospital remains at least at the range of 1 to 2% and can reach 10%, depending on the definition used (Table 2). Potassium chloride supplements and potassium-sparing diuretics remain the major culprits but they have been joined by a host of new actors, e.g., salt substitutes, beta-blockers, converting enzyme inhibitors, nonsteroidal antiinflammatory agents, and heparin, among others. Readily identifiable risk factors (other than drugs) for developing hyperkalemia are well-known but seem to be consistently ignored, even in teaching hospitals. The presence of diabetes mellitus, renal insufficiency, hypoaldosteronism, and age greater than 60 years results in a substantial increase in the risk of hyperkalemia from the use of any of the drugs we have reviewed. If prevention of hyperkalemia is the goal, as it should be, the current widespread and indiscriminate use of potassium supplements and potassium-sparing diuretics will need to end. We remain intrigued by Burchell's prescient pronouncement of over a decade ago that "more lives have been lost than saved by potassium therapy" (28).     

Heparin-induced hepatotoxicity.

Heparin-induced hepatotoxicity is well described in the literature, but rarely recognized clinically. Two cases were recently encountered. In the first case, elevated aminotransferase levels occurred after four days of heparin therapy. In the second case, enzyme levels increased after only 8 h of heparin treatment. To the authors' knowledge, this short time interval between the administration of heparin and liver enzyme elevations has not been described. The objective of this report is to increase the clinical awareness of this interesting and under-recognized biochemical observation.