Coumarin induced acral skin necrosis associated with hereditary protein C deficiency

Hemorrhagic skin necrosis of the toes was observed in a patient with heterozygous protein C deficiency (protein C:Ag 32% and protein C activity 30%) on the 4th day of coumarin treatment overlapping with effective intravenous anticoagulation with heparin. Family studies revealed protein C deficiency in two sisters of the proposita without a history of thromboembolic disease. Immunologic studies in the proposita at the time of coumarin necrosis revealed slight depression of complement factor C4 and the presence of immune complexes. The present case and review of the literature show that the pathogenetic mechanism leading to coumarin necrosis in patients with protein C deficiency seems not yet to be fully understood.     

Clinical relevance of protein C

Protein C is, after activation by thrombin, a potent inhibitor of blood coagulation. An isolated deficiency of protein C increases the risk of thrombosis. The two forms of protein C deficiency, the heterozygous and the homozygous deficiency state, have different clinical features. Patients with heterozygous protein C deficiency are at a high risk to develop venous thrombosis and pulmonary embolism. In newborns with homozygous protein C deficiency with very low protein C levels (1%) a purpura fulminans like syndrome was observed. Heparin and coumarin derivatives are effective drugs in heterozygous protein C deficiency, homozygous patients may be treated either by replacement of protein C or coumarin derivatives. Decreased protein C levels were observed in various other diseases: Chronic and acute liver disease, disseminated intravascular coagulation, malignancy, postoperatively and during treatment with asparaginase. The role of protein C in these diseases to trigger thrombosis is not yet established.     

Congenital protein C deficiency and thrombotic disease in nine French families.

Investigation of 118 patients for protein C deficiency using an immunological and a functional assay, and subsequent investigation of those (nine) found to be deficient, identified 22 patients (14 women, eight men) with protein C deficiency, of whom six were asymptomatic, 15 had histories of venous thromboembolism, and one had a history of arterial thromboembolism. Protein C deficiency was associated in the nine probands with young age at first episode of thromboembolic disease (mean 24.1 (SD 11.9) years), absence of a precipitating condition (five (56%], and a family history of thromboembolic disease (six (66%]. Investigation of the nine families suggested autosomal dominant transmission of the defect. Thromboembolic episodes were seen in patients with protein C antigen concentrations below 0.6 U/ml. Mean (SD) protein C antigen concentrations were 0.48 (0.12) U/ml in 18 patients not receiving oral anticoagulant treatment and 0.28 (0.05) U/ml in four receiving such treatment. One patient with severe protein C deficiency (0.16 U/ml) developed skin necrosis soon after starting oral anticoagulant treatment.     

Decreased thrombotic mortality and morbidity after valvular cardiac surgery as a consequence of adequate coumarin anticoagulation. A retrospective study in 516 patients.

Two almost identical groups of 258 patients each who underwent surgery for the substitution of one or more than one cardiac valve were taken into consideration. After surgery all patients, with the exception of those who received a porcine allograph, were given coumarin drugs for 1 year for thrombosis prophylaxis. In the first group of patients operated in 1972 and 1973 the laboratory follow-up and the therapeutic range were neither constant nor uniform. In the case of the second group, which included patients operated in 1974 and 1975, adequate laboratory follow-up and constantly adequate therapeutic ranges were always kept. This retrospective study has shown a statistically significant decrease in mortality due to thromboembolism and to unknown causes in the second group of patients (x2 = 8,313, "p" less than 0,0025). A decrease of the non-lethal embolic complications was also noted in the second group of patients (x2 = 6,813, "p" less than 0,0025). On the other hand, bleeding complications were greater in the second group of patients (x2 = 3,485, "p" less than 0,05) and this was interpreted as secondary to the higher anticoagulation administered to the latter patients. The results indicate that an adequate coumarin anticoagulation seems able to decrease the incidence of lethal or non-lethal thromboembolic complications after cardiac valve replacement significantly.     

An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency.

We used two-locus segregation analysis to test whether an unknown genetic defect interacts with protein C deficiency to increase susceptibility to venous thromboembolic disease in a single large pedigree. Sixty-seven pedigree members carry a His107Pro mutation in the protein C gene, which reduces protein C levels to a mean of 46% of normal. Twenty-one carriers of the mutation and five other pedigree members had verified thromboembolic disease. We inferred the presence in this pedigree of a thrombosis-susceptibility gene interacting with protein C deficiency, by rejecting the hypothesis that the cases of thromboembolic disease resulted from protein C deficiency alone and by not rejecting Mendelian transmission of the interacting gene. When coinherited with protein C deficiency, the interacting gene conferred a probability of a thrombotic episode of approximately 79% for men and approximately 99% for women, before age 60 years.     

Cerebral haemorrhagic infarction in young patients with hereditary protein C deficiency: evidence for "spontaneous" cerebral venous thrombosis.

Among 53 patients with hereditary protein C deficiency belonging to 20 families three women were encountered who, aged 27, 34, and 38 respectively, had had cerebral haemorrhagic infarction, probably due to intracranial venous thrombosis. All three had also had venous thrombosis of the leg and pulmonary embolism either before or after their cerebral infarction. One patient sustained cerebral infarction while receiving an oral contraceptive, but infarction in the two others occurred "spontaneously." One patient also had an intraventricular and subarachnoid haemorrhage during the induction phase of coumarin treatment, which was assumed to have resulted from haemorrhagic infarction of the chorioid plexus, analogous to coumarin provoked haemorrhagic skin necrosis in protein C deficiency. Hereditary protein C deficiency should be considered in young patients with acute or subacute cerebral symptoms, especially if they have a family or personal history of venous thromboembolism.     

Heart valve prosthesis, anticoagulants and pregnancy

Patients with artificial valve prostheses require lifelong anticoagulation treatment. The risk of thrombotic complications increases greatly in pregnancy. Anticoagulant treatment in pregnant women with artificial heart valve prostheses in one of the most controversial problems in medical practice as anticoagulants which are beneficial and safe for the mother may by hazardous for the fetus. Recommended procedure is to administer heparin subcutaneously at last during the first 14 weeks and the last 2 weeks of gestation and coumarin derivates throughout the second and third trimesters. In asymptomatic or mildly symptomatic women who are willing to follow a strict regimen of antithrombotic prophylaxis in pregnancy the risk is not associated with an increased morbidity or mortality in the mother or fetus. Hence, recommendations against pregnancy in women with artificial heart valves are not always justified.     

Erythraemia in Renal Transplantation

Seven cases of erythraemia following successful renal transplantation are described. This complication was not necessarily associated with clinical evidence of rejection of the transplant, and the prognosis so far as rejection was concerned was excellent. Four patients, however, developed thromboembolic pulmonary complications, and two other patients had thrombotic episodes. Hence it is suggested that treatment either by anticoagulation or by venesection is indicated.     

Antithrombotic therapy in patients with known risk factors for thromboembolism

In about 50% of the cases of spontaneous deep vein thrombosis a congenital deficiency of an inhibitor of coagulation or an insufficient fibrinolytic mechanism can be detected. In arterial thromboembolism a connection with hyperactive platelets or with a diminished availability of tissue plasminogen activator can be found in about 70%. However, in these cases the defect which provokes thrombosis is mostly acquired and is connected with hyperlipidemia and/or with atherosclerotic alterations of the vessel wall. A study on patients with thromboembolic tendency and detectable risk factors was carried out. A total of 470 patients could be observed for 2 years under an adequate antithrombotic prophylaxis. The occurrence of thromboembolic episodes 2 years prior to prophylaxis and 2 years under prophylaxis was compared. In venous cases thrombosis could be controlled almost completely by coumarins when the underlying cause was a deficient plasmatic inhibitor. In patients with diminished fibrinolysis there was only a partial effect of oral anticoagulants. A better result could be obtained when pentosan polysulfate was administered. In arterial thromboembolism the results of prophylaxis were less convincing. The efficacy of ASA in patients with an increased platelet function was only moderate. In addition, ASA hat to be discontinued in about 20% of the patients because of gastrointestinal problems. Pentosan polysulfate in patients with a diminished fibrinolytic capacity had a fairly good effect and resulted in a 60% reduction of thromboembolic manifestations. It is shown that an exact diagnosis of the underlying deficiency which is likely to cause thrombosis can also improve the efficacy and the specificity of prophylaxis.     

Thyrotoxic atrial fibrillation

Atrial fibrillation is the most common cardiac complication of hyperthyroidism and occurs in 15% of patients with hyperthyroidism. It is associated with a higher risk of thromboembolism that often involves the central nervous system. Oral anticoagulation is important in the majority of these patients to prevent thromboembolic complications. These patients require adjustment in the dose of various rate-controlling agents because of increased clearance associated with hyperthyroidism and a decrease in warfarin dosage because of increased clearance of vitamin K-dependent clotting factors. The management of thyrotoxic atrial fibrillation is summarized in this clinical review.     

Continuation of vitamin K antagonists as acceptable anticoagulation regimen in patients undergoing pulmonary vein isolation

Background

Recent studies have demonstrated that radiofrequency isolation of the pulmonary veins (PVI) is an effective treatment for symptomatic atrial fibrillation. Based on these positive results, non- pharmacological therapy has been incorporated in the guidelines for drug refractory atrial fibrillation, resulting in an increased popularity. The prevention of thromboembolic complications remains an important issue.

Methods

In January 2010, we adopted an anticoagulation strategy based on continuation of vitamin K antagonists (VKAs) and selective use of transoesophageal echocardiogram (TEE). We retrospectively analysed the results of this strategy in all patients referred for PVI treatment. VKAs were started for all patients 2 months prior to treatment. Discontinuation of oral anticoagulation was considered 3 months after treatment based on thromboembolic and bleeding risk profile. Bleeding and thromboembolic complications were registered during outpatient clinic follow-up up until 3 months.

Results

We performed 151 PVI procedures from January 2010 to March 2011. All patients were seen 6 weeks after discharge. No transient ischaemic accidents or ischaemic cerebrovascular incidents occurred pre-, peri- or postprocedure. Four (2.7%) procedures were complicated by tamponade requiring pericardiocentesis.

Conclusions

Our data support the increasing evidence for continuation of periprocedural administration of VKAs complemented by a selective TEE approach as a safe therapy for thromboembolic complications.     

Primary care management for optimized antithrombotic treatment [PICANT]: study protocol for a cluster-randomized controlled trial

ABSTRACT: BACKGROUND: Antithrombotic treatment is a continuous therapy that is often performed in general practice and requires careful safety management. The aim of this study is to investigate whether a best practice model that applies major elements of case management, including patient education, can improve antithrombotic management in primary health care in terms of reducing major thromboembolic and bleeding events. METHODS: This 24-month cluster-randomized trial will be performed in 690 adult patients from 46 practices. The trial intervention will be a complex intervention involving general practitioners, health care assistants and patients with an indication for oral anticoagulation. To assess adherence to medication and symptoms in patients, as well as to detect complications early, health care assistants will be trained in case management and will use the Coagulation-Monitoring-List (Co-MoL) to regularly monitor patients. Patients will receive information (leaflets and a video), treatment monitoring via the Co-MoL and be motivated to perform self-management. Patients in the control group will continue to receive treatment-as-usual from their general practitioners. The primary endpoint is the combined endpoint of all thromboembolic events requiring hospitalization, and all major bleeding complications. Secondary endpoints are mortality, hospitalization, strokes, major bleeding and thromboembolic complications, severe treatment interactions, the number of adverse events, quality of anticoagulation, health-related quality of life and costs. Further secondary objectives will be investigated to explain the mechanism by which the intervention is effective: patients' assessment of chronic illness care, self-reported adherence to medication, general practitioners' and health care assistants' knowledge, patients' knowledge and satisfaction with shared decision making. Practice recruitment is expected to take place between July and December 2012. Recruitment of eligible patients will start in July 2012. Assessment will occur at three time points: baseline (T0), follow-up after 12 (T1) and after 24 months (T2). DISCUSSION: The efficacy and effectiveness of individual elements of the intervention, such as antithrombotic interventions, self-management concepts in orally anticoagulated patients and the methodological tool, case-management, have already been extensively demonstrated. This project foresees the combination of several proven instruments, as a result of which we expect to profit from a reduction in the major complications associated with antithrombotic treatment.     

‘Ins’ and ‘outs’ of triple therapy

Chronic oral anticoagulant treatment is obligatory in patients (class I) with mechanical heart valves and in patients with atrial fibrillation with CHADS2 score >1. When these patients undergo percutaneous coronary intervention with placement of a stent, there is also an indication for treatment with aspirin and clopidogrel. Unfortunately, triple therapy is known to increase the bleeding risk. For this group of patients, the bottom line is to find the ideal therapy in patients with indications for both chronic anticoagulation therapy and percutaneous intervention to prevent thromboembolic complications such as stent thrombosis without increasing the risk of bleeding. (Neth Heart J 2010;18:444-50.)     

Paroxysmal nocturnal hemoglobinuria. Enhanced stimulation of platelets by the terminal complement components is related to the lack of C8bp in the membrane

Recently, a protein isolated from the membrane of human E, the so-called C8 binding protein (C8bp), has been described. C8bp is characterized as a 65-kDa protein that binds to C8 and inhibits the C5b-9-mediated lysis in a homologous system. In the present study, membranes of peripheral blood cells were tested for the presence of C8bp by SDS-PAGE and immunoblotting. In all cells a protein band reacting with anti-C8bp was seen, the Mr, however, was only about 50 kDa. To further analyze the 50-kDa protein, we isolated the protein by phenol-water extraction and isoelectric focusing from papain-treated platelets. The isolated protein behaved similar to the E-derived C8bp: it inhibited the lysis of model target cells by C5b-9. To examine the function of C8bp in platelets, we tested platelets from patients suffering from paroxysmal nocturnal hemoglobinuria (PNH). These platelets were deficient in C8bp, being in accordance with their higher lytic susceptibility in vitro. In response to sublytic C5b-9 doses, the PNH platelets released considerably more serotonin and thromboxane B2 than normal platelets. By addition of purified C8bp, the thromboxane B2 release was suppressed, indicating that C8bp not only restricts the lytic complement attack, but also regulates the C5b-9-mediated stimulation of target cells. Thus, lack of C8bp might not only result in enhanced hemolysis, but also in enhanced stimulation of platelets, which in turn might contribute to the thrombotic complications seen in some PNH-type III patients.     

Clinical significance of protein C

The coagulation inhibitors are important components of control mechanisms which ensure the haemocoagulation equilibrium. One of them is protein C, whose level was followed in patients with DIC. and IM. In DIC. cases a significant decrease was noted with regard to the MI groups and healthy donors. EID and ELISA methods were used for testing. The patients exhibiting the protein C defect require a corresponding treatment which should suppress the thromboembolic complications.     

Monogenetische Risikofaktoren einer Thrombophilie

Inherited thrombophilias are a group of hereditary conditions that predispose to thrombotic events. The most important monogenetic causes of the venous thromboembolic (VTE) phenotype are mutations in the genes for the coagulation inhibitors antithrombin (AT), protein C (PC), and protein S (PS). Their mutation profiles show high heterogeneity in loss-of-function defects. The frequencies of AT, PC, and PS deficiencies in VTE patients are estimated at 1.9%, 2.3%, 3.7%, respectively. The rate of recurrence in that group is 48.4%. The composite risk of recurrence for VTE patients with AT, PC or PS deficiency is estimated at 1.5 times that for VTE patients without inhibitor deficiency, for those with AT deficiency alone up to 1.9 times. The detection rates for inhibitor deficiency and symptomatic VTE are about 70% for AT, 60% for PC, and 30% for PS. These results demonstrate the problems with the varying accuracy of phenotype diagnostics and differential diagnosis of inherited and intrinsic inhibitor deficiencies.     

Heparin binds to lipopolysaccharide (LPS)-binding protein, facilitates the transfer of LPS to CD14, and enhances LPS-induced activation of peripheral blood monocytes

Heparin is one of the most effective drugs for preventing and treating thromboembolic complications in surgical patients. Recent evidence suggests that heparin enhances the proinflammatory responses of human peripheral blood monocytes to Gram-negative endotoxin (LPS). We have identified LPS-binding protein (LBP) as a novel heparin-binding plasma protein. The affinity of LPB to heparin was KD = 55 +/- 8 nM, as measured by surface plasmon resonance. Using a fluorescence-based assay, we showed that clinically used heparin preparations significantly enhance the ability of LBP to catalytically disaggregate and transfer LPS to CD14, the LPS receptor. The presence of clinically relevant heparin concentrations in human whole blood increased LPS-induced production of the proinflammatory cytokine IL-8. Fondaparinux, which is identical with the antithrombin III-binding pentasaccharide in heparin, did not bind to LBP or alter LBP function. Thus, this novel anticoagulant drug is a potential candidate for safe administration to patients who have endotoxemia and require anticoagulation.     

Changes of antithrombin III (AT III) in AT III deficient patients during long-term anticoagulant treatment

Antithrombin III deficient patients with manifest thromboembolic diseases need long term coumarin treatment. There are contradictory data on the change of AT III during this therapy. The authors observed 5 patients with severe AT III decrease type I, 3 with functional abnormality and 2 with a pathological heparin binding. AT III function was determined by the Gerendás-Rák method and with chromogenic substrate. AT III antigen was measured with Behring M-Partigen and Laurell rocket electrophoresis. Crossed immunoelectrophoresis was carried out in all patients. In patients with type I AT III decrease, AT III hasn't changed even in a long period of more than 10 years. In the other types AT III became normal. The pathological heparin binding wasn't changed.     

Acceptor splice site mutation in the invariant AG of intron 5 of the protein C gene,causing type I protein C deficiency

An acceptor splice-site mutation (3318, AG) in the invariant AG of intron 5 of the human protein C gene has been identified in a Spanish family with heterozygous type I protein C (PC) deficiency and thromboembolic disease. Family studies confirmed cosegregation of the mutation with type I PC deficiency. Computer analysis of the mutated sequence predicted the normal splicing site to be abolished by this mutation, whereas a cryptic splice site located two nucleotides downstream, in exon 6, is probably activated. According to this, 3318, AG should result in a frameshift with a stop at codon 119, in agreement with the presence of a type I or quantitative PC deficient phenotype in the affected members of the family.     

Recurrent fracture of a recovery inferior vena cava filter with pulmonary migration

Inferior vena cava (IVC) filters are indicated in patients with venous thromboembolic disease in whom standard anticoagulation therapy is contraindicated or ineffective. A 32-year-old female presented to our hospital with chest pain 5 years after IVC filter placement. Imaging revealed sequential fracturing and embolization of two of the IVC filter arms to the pulmonary arteries. IVC filter fracture and subsequent migration to the lung is a rare complication. Systematic long-term follow-up in patients with IVC filters and, if possible, filter removal should be considered to prevent possible complications.