Venous thromboembolism prophylaxis in patients with multiple myeloma: where are we and where are we going?

Venous thromboembolism is a common complication of patients with hematologic malignancies, due both to release of procoagulant factors by tumor cells and to external factors, such us drugs. In multiple myeloma patients, the risk is increased by use of immunomodulants, especially when associated to multidrug therapy, during the induction phase. Prevention of venous thromboembolism in myeloma patients is highly recommended but specific guidelines are still lacking. The most common approach is to stratify the thrombotic risk according to individual, myeloma-related and therapy-related risk factors and to use aspirin for all patients, except those with two or more thrombotic risk factors who should be treated with traditional oral or parenteral anticoagulant. A more controversial approach indicates for prophylaxis either anticoagulant or aspirin, regardless of risk stratification. Recent trials investigate prophylaxis in myeloma patients with direct oral anticoagulants, based on studies showing efficacy and safety of this new class of drugs in the treatment and prophylaxis of thrombosis in patients with any malignancy. The results of these trials are encouraging but they need to be confirmed by larger studies. An international consensus about best prophylaxis to prevent venous thromboembolism in patients with multiple myeloma on treatment is still missing. Therefore, thrombosis in multiple myeloma remains an ongoing issue.

Isolated distal cutaneous thrombosis: an unusual presentation and an interesting etiology.

A middle-aged hypertensive male, with a fatty liver and chronic alcohol intake, relocated to a high altitude of 2100 m above sea level; in the first winter season, he developed bluish skin lesions over the tip of the nose, margins of both ear lobes, both knees, and subungual location. Systemic examination was unremarkable. Skin biopsy showed thrombi in dermal vessels without any evidence of vasculitis; immunofluorescence was negative. Investigations revealed mild elevation in plasma homocysteine levels, weakly positive antinuclear antibodies and elevated antiphospholipid antibodies, methylene tetrahydrofolate reductase C677T heterozygosity, and protein S deficiency. The patient received prednisolone for 2 weeks, aspirin and pentoxyphylline for 3 months, and continues to be on folic acid and vitamin B6. After 3 months, antiphospholipid antibodies and antinuclear antibody levels were normal. Isolated distal cutaneous thrombosis is an uncommon entity and precipitation by extreme cold in a hypertensive male with three thrombophilic states - one transient, one hereditary, and one acquired - is fascinating.

Antiphospholipid antibodies, antiphospholipid syndrome and infections.

Since the association between antiphospholipid antibodies (aPL) and syphilis was first described, many other viral, bacterial and parasitic infections have been shown to induce antiphospholipid antibodies, notably anticardiolipin antibodies (aCL). A review of the literature shows that while aCL occur frequently in viral infections, particularly in HIV (49.75%), HBV (24%) and HCV (20%), it is very rarely associated with anti-beta2 glycoprotein I antibodies (anti-beta2GPI) and is not correlated with thrombosis risk or hematological manifestations of the antiphospholipid syndrome (APS). Concerning bacterial infections, aCL is often present in leprosy (42.7%), where it is frequently associated with the presence of anti-beta2GPI (44.8%), and in syphilis infections (8 to 67%), though without correlation with thrombotic events. Though few individual patients with unequivocal infection-induced aPL satisfy criteria for APS, the lack of statistical association with thrombotic events strongly argues against the identification of a true APS subset in this context. However, physicians should keep in mind the fact that an infection, generally bacterial, in patients with confirmed APS, may lead to catastrophic antiphospholipid syndrome with a possible fatal outcome.

Tuberous sclerosis with portal vein thrombosis, protein C and S deficiency.

A 29-year-old lady with a bad obstetric history and portal vein thrombosis, presented to the Skin OPD for facial lesions. On examination, angiofibromas on face, shagreen patch and periungual fibromas were observed. She also had dental pits and a retinal hamartoma. Investigations revealed hamartomas in the brain and kidney. Hematological work-up showed protein C and S deficiency with Factor V Leiden positivity. Except for the cutaneous symptoms, the patient did not have any clinical manifestations in other organs affected by tuberous sclerosis. A similar association of tuberous sclerosis with protein C deficiency has been reported in only one case in literature.

[The revival of thalidomide: an old drug with new indications]. / Le renouveau du thalidomide. Un vieux médicament aux nouvelles indications.

Thalidomide has several mechanisms of action: several immuno-modulatory properties, an anti-angiogenic action and a hypnosedative effect. Thalidomide has been used in several cutaneous inflammatory disorders (such as erythema nodosum leprosum in lepromatous leprosy, cutaneous lupus erythematosus, severe aphtosis), cancers (relapsed/refractory multiple myeloma) and inflammatory conditions. Several side effects are associated with thalidomide; some are major: teratogenicity, peripheral neuropathy and deep venous thrombosis; some are minor, such as somnolence or abdominal pain and endocrinologic disturbances. Use of thalidomide is strictly controlled with close adherence to a birth control program and close monitoring for early development of peripheral neuropathy.

Distinguishing features of anti-beta2 glycoprotein I antibodies between patients with leprosy and the antiphospholipid syndrome.

Anticardiolipin (ACA), anti-beta2 glycoprotein I (beta2GPI), and antiprothrombin antibodies of IgG and IgM classes were quantitated by enzyme-linked immunosorbent assays in 176 untreated leprosy patients across the histopathological spectrum. Positivity rates ranged from 21% (IgG ACA) to 30% (IgM anti-prothrombin) versus 4% in healthy controls (p <10(-2) to 10(-3)). Levels of IgM anti-beta2GPI and IgG ACA were significantly higher in lepromatous leprosy and multibacillary patient subgroups. IgG3 was the most common subclass reactive to both beta2GPI and prothrombin in selected high-titer leprosy sera, unlike antibodies from patients with the antiphospholipid syndrome (APS) largely restricted to IgG2. In leprosy patients, but not in the APS control group, there was no statistical correlation between ACA and anti-beta2GPI antibody levels. Likewise, a large fraction of anti-beta2GPI positive sera (36/45 and 28/44 for IgG and IgM, respectively) were unreactive in the standard ACA assay. Most assayed anti-beta2GPI antibodies from leprosy patients showed (i) ability to recognize both human and bovine beta2GPI immobilized on non-irradiated polystyrene plates, (ii) concentration-dependent inhibition of binding by cardiolipin, and (iii) relatively high avidity binding to fluid-phase beta2GPI, thereby differing from those found in APS. Finally, the location of the major epitopic region on the beta2GPI molecule targeted by autoantibodies was different in leprosy and APS, as assessed by direct binding to domain I- and V-deleted mutants and competition with the mouse monoclonal antibody 8C3, directed at domain I. Thus, leprosy-related antiphospholipid antibodies comprise persistent IgG and IgM anti-beta2GPI that differ from APS-related ones with respect to IgG subclass, avidity and epitope specificity, possibly reflecting distinct pathophysiological significance.

Lucio's phenomenon: clinical and therapeutic aspects.

We report four cases of necrotizing reactions of the Lucio's phenomenon type, an entity rarely observed in Brazil despite the high prevalence of leprosy. Clinical, histopathological and therapeutic aspects are described and compared to those reported in the literature for cases classified as diffuse, non-nodular lepromatous leprosy with Lucio's phenomenon.

Anticardiolipin antibodies and dependence of a serum cofactor. A mechanism of thrombosis.

OBJECTIVE: To evaluate the dependence on the serum cofactor of anticardiolipin antibodies (aCL) in infectious and autoimmune diseases. We also studied their correlation with some clinical manifestations, specially thrombosis. METHODS: aCL were determined with a standard ELISA method, and a modified ELISA in which we substituted bovine serum albumin (BSA), gelatin and skim milk powder for fetal calf serum (FCS). Categorized variables were analyzed by means of the chi 2 test and Fisher's test. Four groups of patients were studied. Group 1. Patients with aCL and autoimmune disease (systemic lupus erythematosus [SLE] and the primary antiphospholipid syndrome [PAPS]). Group 2. Patients with aCL, no symptoms and no underlying infection or autoimmune disease. Group 3. Patients with aCL and infectious diseases (syphilis, leprosy, HIV infection and Q fever). Group 4. Control group. RESULTS: (a) 19 of 20 samples from patients in Group 1 disclosed cofactor dependence in aCL activity. (b) 17 of 19 samples from patients in Group 3 had aCL activity, that was independent of the presence of the cofactor. (c) 3 of 4 patients in Group 2 had cofactor independent aCL and one had cofactor dependent aCL activity. (d) no control group patient had aCL. (e) association of cofactor dependent aCL with the development of clinical manifestations (thrombosis) was statistically significant (p < 0.0001). (g) cofactor dependent aCL and cofactor independent aCL were, respectively, associated with autoimmune and infectious diseases (p < 0.0001). CONCLUSIONS: (a) Dependence or independence of the cofactor helps to differentiate "infectious" aCL from "autoimmune" aCL. (2) aCL related clinical manifestations (thrombosis) depends on the presence of cofactor dependent aCL and not on cofactor independent aCL.

[Myocardial disease, heart failure and reactional tuberculoid leprosy]. / Seção anátomo-clínica.

A 60-year-old woman was admitted with congestive heart failure, essential hypertension and abdominal distension. Her son reported that she appeared with red spots in the body and that she was under dapsone therapy. Seven months ago there was sudden increase of the skin lesions. In the 11th day after admission she underwent a stroke that progressed to decerebration and she expired on the fourth day. Autopsy confirmed CHF due to chronic myocarditis related to Chagas' disease. Aneurysm of the apical region of the left ventricular chamber was also observed leading to thrombosis and systemic embolism with brain and spleen hemorrhagic infarct. In the encephalous there was edema, uncus herniation and hemorrhagic infarct of the brain stem. The skin lesions were due to reactional tuberculoid hanseniasis (RHT) with focal lesions in axillary lymphnodes, nasopharyngeal mucosa and in the posterior tibial nerve. The pathogenesis of RHT is discussed as well as its differentiation with the BT group of Ridley and Jopling and its probably relationship with the secondary tuberculoid hanseniasis reported by Ridley. The focal lesions are also discussed with END to the involvement of a peripheral nerve trunk what is said to be uncommon in this form of Hansen's disease.

Miocardiopatia, insuficiência cardíaca e hanseníase tuberculóide reacional / Myocardial disease, heart failure and reactional tuberculoid leprosy (clinical conference)

Uma senhora de 60 anos de idade foi internada no Hospital com sinais e sintomas de insuficiência cardíaca congestiva (ICC), hipertensäo arterial e distençäo abdominal. Os familiares relatam que desde cerca de 14 meses a paciente vem apresentando manchas vermelhas pelo corpo, estando em tratamento com sulfona. Há 7 meses houve aumento súbito das lesöes. No 11§ de internaçäo desenvolveu acidente cerebral, que evoluiu com piora progressiva, descerebraçäo, tendo falecido no 4§ dia após o ictus. A autópsia confirmou ICC tendo como causa principal miocardite crônica, fortemente sugestiva de miocardite chagásica. Observou-se aneurisma de ponta do ventrículo esquerdo com trombose e embolizaçäo sistêmica levando à infartos esplênicos e cerebrais. No encéfalo havia intenso edema, hérnia de uncus e infarto hemorrágico do tronco cerebral. O diagnóstico das lesöes cutâneas foi de hanseníase tuberculóide reacional (HTR), observando-se também lesöes tuberculóides focais em linfonodos axilares, mucosa nasofaringea e nervo tibial posterior. Discute-se a patogenia da HTR, sua diferenciaçäo com o sub-grupo dimorfo-tuberculóide (BT da classificaçäo de Ridley e Jopling) e sua provável identidade com a hanseníase tuverculóide secundária referida por Ridley. Também säo analisadas as outras localizaçöes contendo lesöes especificas com ênfase ao comprometimento de tronco nervoso periférico, considerada uma manifestaçäo pouco comum na HTR

[Cryptococcus neoformans meningoencephalitis as a complication of arteriosclerotic vascular insufficiency in Virchowian leprosy]. / Meningoencefalite por Cryptococcus neoformans como complicação de insuficiência vascular arteriosclerótica em hanseníase virchowiana.

A 39 year old white man, with advanced Virchowian hanseniasis died with signs of extensive meningeal involvement. His medical background showed repeated episodes of Erythema nodosum hansenicum (ENH) in the last three years of his life, besides ischemic gangrena with amputation of the left leg and cerebral vascular ischemic attacks. The autopsy revealed an advanced stage of arteriosclerosis affecting mainly the brain and the distal segment of the aorta and its ramifications. A propagating thrombus was found along the left femoral and iliac arteries and in the terminal portion of the aorta extending to the renal arteries. Thrombosis was also found along the left femoral vein, left iliac vein and distal segment of the inferior cava. The brain showed anemic infarction in organization and a generalized meningoencephalic involvement with granulomatous reaction caused by Cryptococcus neoformans. It was suggested a possible relationship between Erythema nodosum reactions and thrombosis phenomena. Torulosis was considered as a final occurrence and the proliferative vasculitis due to the granulomatous process in the sub-arachnoidal space has certainly aggravated the cerebral ischemia.