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.     

Loss of extremities caused by heparin-induced thrombocytopenia

We report the cases of two patients who last lims as a result of heparin-induced thrombocytopenia (HIT). On the basis of these cases, the incidence, pathophysiology and the diagnosis of HIT are reviewed. For the diagnosis of HIT, the platelet aggregation test and ELISA are used. For HIT prophylaxis and treatment of thromboembolic complications is recommended Orgaran. Exact dosage schedules are provided.     

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

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.     

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.     

Reduced morbidity and mortality rates of the heparin-induced thrombocytopenia syndrome

PURPOSE: We reported a 61% morbidity rate and a 23% mortality rate for the heparin-induced thrombocytopenia (HIT) syndrome in 1983. We subsequently reported in 1987 that with early recognition, immediate cessation of the administration of heparin, and platelet function inhibition, the morbidity rate could be reduced to 23% and the mortality rate to 12%. One hundred recent cases of patients with heparin-associated antiplatelet antibodies (HAAb) have been reviewed to determine whether aggressive screening, early diagnosis, and alternate management could further reduce morbidity and mortality rates. METHODS: The consecutive records of 100 patients with positive platelet aggregation tests were reviewed. Sixty-six patients were male. The patients' ages ranged from 23 days to 92 years. The patients were from vascular (28), cardiothoracic (42), and other (30) services. HIT was suspected in patients who received heparin and had falling platelet counts, platelet counts less than 100,000/mm3, or new thromboembolic or hemorrhagic events. RESULTS: Heparin was not offered to six patients with known HAAb. Twelve patients were successfully treated with antiplatelet therapy and limited reexposure to heparin, and 75 patients were successfully treated with early diagnosis and prompt cessation of heparin. Alternate forms of anticoagulation therapy were used selectively. Seven patients had 11 complications. Three of the seven patients were treated successfully with warfarin anticoagulation and aspirin (2) or with aspirin alone (1). A fourth patient was treated with thrombectomy, hematoma evacuation, and aspirin. A fifth patient underwent thrombolysis and coronary angioplasty in addition to receiving warfarin and aspirin. The sixth patient required two thrombectomies and warfarin. A seventh patient required two thrombectomies and aspirin. HIT was responsible for one of 17 deaths. CONCLUSION: A 7.4% morbidity rate and a 1.1% mortality rate have been achieved in patients with HAAb by aggressive screening, early recognition of HIT, and prompt cessation of the administration of heparin. Platelet function inhibitors and other anticoagulants, including nonreacting low molecular weight heparin, are important adjuncts in the management of the thromboembolic disorders associated with HIT.     

Cardiopulmonary bypass with danaparoid sodium and ancrod in heparin-induced thrombocytopenia

Heparin is the standard anticoagulant for patients undergoing cardiopulmonary bypass. There are some patients for whom heparin is unsuitable and ancrod (a defibrinogenating enzyme) has been used as an alternative. We present a patient with heparin-induced thrombocytopenia in whom treatment ancrod was ineffective. The addition of danaparoid sodium (a heparinoid) allowed safe cardiopulmonary bypass. We discuss the reasons for this and suggest that the combination of ancrod and danaparoid sodium is a logical one in such cases.     

Comparison of PF4/heparin ELISA assay with the 14C-serotonin release assay in the diagnosis of heparin-induced thrombocytopenia

The diagnosis of heparin-induced thrombocytopenia (HIT) may be affirmed by demonstrating heparin-dependent anti-platelet antibodies using the 14C-serotonin release assay (SRA). In this study, results of the SRA was compared with the recently described platelet factor 4 (PF4)/heparin enzyme-linked immunosorbent assay (ELISA). Compared with the SRA, the sensitivity and specificity of a PF4/heparin ELISA was 87% and 92%, respectively, using an assay developed in our laboratory; and 90% and 98%, respectively, using a commercially developed kit (Diagnostica Stago, Asnieres, France). However, antibodies to PF4/heparin were also detected in up to 8% of patients whose plasma was negative by SRA, and 23% of patients receiving heparin who were not thrombocytopenic. These data indicate that results obtained with the PF4/heparin ELISA and the SRA are generally in accord in patients with a clinical diagnosis of HIT. However, discrepant results occur in approximately 20% of cases because of the greater sensitivity of ELISA and the possible involvement of other heparin-binding proteins. The fact that each assay contributes independent information in some cases must be considered in the sequence of test performance and in providing consultation to the practicing hematologist.     

Defining an antigenic epitope on platelet factor 4 associated with heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin therapy. Antibodies to platelet factor 4 (PF4)/heparin complexes have been implicated in the pathogenesis of this disorder, but the antigenic epitope(s) on the protein have not been defined. To address this issue, we studied the binding of HIT antibodies to a series of recombinant proteins containing either point mutations in PF4 or chimeras containing various domains of PF4 and the related protein, neutrophil activating peptide-2 (NAP-2). Serum samples from 50 patients with a positive 14C-serotonin release assay (14C-SRA) and a clinical diagnosis of HIT and 20 normal controls were studied. HIT antibodies reacted strongly with wild-type (WT) PF4/heparin complexes, but reacted little, if at all, with NAP-2/heparin complexes (optical density [OD]405 = 2.5 and 0.2, respectively). Alanine substitutions at three of the four lysine residues implicated in heparin binding, K62, K65, and K66, had little effect on recognition by HIT antibodies (OD405 = 2.2, 2.8, and 2.0, respectively), whereas an alanine substitution at position K61 led to reduced, but still significant binding (OD405 = 1.0). Similar studies involving chimeras between PF4 and NAP-2 localized a major antigenic site to the region between the third and fourth cysteine residues for more than half of the sera tested. This site appears to involve a series of amino acids immediately after the third cysteine residue beginning with P37. Thus our studies suggest that whereas the C-terminal lysine residues of PF4 are important for heparin binding, they do not comprise a critical antigenic site for most HIT antibodies. Rather, we propose that maintaining a region near the third cysteine residue of PF4, distal from the proposed heparin-binding domain, is required to form the epitope recognized by many HIT antibodies.     

Recognition, management and prophylaxis of endocarditis

Infective endocarditis (IE) remains a disease with high morbidity and mortality. In recent years, a higher frequency of IE has been observed in the elderly, in intravenous drug users and in patients with prosthetic valves. The diverse manifestations of this disease demand a high degree of suspicion from the practitioner, in order to make an early diagnosis. Advances in and increasing use of echocardiography (especially transoesophageal) allow us to identify valvular changes earlier and more precisely. The use of the new Duke's diagnostic criteria, based on clinical manifestations and microbiological and echocardiographic findings, facilitates the diagnosis and categorisation of IE. An increase in staphylococci and other problem pathogens, such as penicillin-resistant streptococci, enterococci resistant to beta-lactams, aminoglycosides and methicillin-resistant staphylococci has been observed. Important changes have also taken place in the management of IE. There is a clear trend towards the use of shorter treatment courses, oral and once-daily regimens and outpatient programmes, all of which aim to reduce costs and provide patients with improved quality of life. Antibiotic prophylaxis for the prevention of IE is still controversial. In the past few years more rational regimens have been used, and indications are now more precise. In spite of all this, however, few cases are prevented and patient compliance to the prophylaxis regimens remains low.     

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.     

Spontaneous arterial thrombosis in association with pancreatic carcinoma: diagnosis and interventional management

BACKGROUND: Soft tissue sarcomas of the hands and feet present a challenge for limb-preserving resections. METHODS: A retrospective review of 19 patients with sarcomas of the hand or foot was done. Wide or local excision was performed in 14 patients (74%), and amputation in 5 patients (26%). Of the latter group, three amputations involved a digit or toe, and two (10%) were major amputations (one Syme amputation and one below-knee amputation). When the minimum surgical margin was narrow (1 to 2 mm), adjuvant radiation was given postoperatively (n = 4). RESULTS: Local recurrence was observed in four patients (21%). Two of these required an amputation for local control. Local recurrence was observed in one of four patients (25%) treated with marginal resection and radiation and three of 15 (20%) of those with resection alone. CONCLUSIONS: A sizable percentage (37%) of patients with soft tissue sarcomas of the hand and foot ultimately required an amputation, although often the amputation was a minor one involving only a toe or a digit. Limb preservation was successful in the majority of patients (63%). The local recurrence rate was 21%, which may be improved with more frequent use of adjuvant therapy. The 5-year survival rate was 82%, which is better than that usually quoted for overall extremity soft tissue sarcomas.     

Prenatal diagnosis of fetal thrombocytopenia]

A case of maternal idiopathic thrombocytopenic purpura complicated by severe fetal thrombocytopenia is reported. Fetal thrombocytopenia was diagnosed by scalp blood-sampling during labour. With discussion of the relevant literature, the authors recommend the use of their method in thrombocytopenic patients in labour. In cases of fetal thrombocytopenia Caesarean section in recommended to prevent trauma and subsequent neonatal haemorrhagic complications.     

The syndrome of thrombosis, thrombocytopenia, and recurrent spontaneous abortions associated with antiphospholipid antibodies: Hughes syndrome

aPL-associated thrombosis (Hughes syndrome) is widely recognized as a major cause of organ damage in autoimmune diseases. Beginning with the first symposium in 1984, international aPL symposia have facilitated research on aPL antibodies, and the clinical standardization of aPL tests. It is hoped that the present symposium will continue this tradition, because much remains to be learnt about the origin and pathogenicity of aPL antibodies. In addition, new insights are needed for more effective therapies to be developed.