Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency

A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.     

Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin III

Summary Two patients with familial antithrombin III deficiency developed deep venous thrombosis of the lower limb. The diagnosis of venous thrombosis was made by the indium labelled platelet technique which also allowed for the daily assessment of thrombus size. Each patient received treatment with Warfarin, subcutaneous heparin, and infusions of antithrombin III concentrates. The authors conclude that infusions of antithrombin III concentrates may be of value in limiting the extent of acute thrombosis in patients with a severe deficiency of this protein and may help prevent pulmonary embolism. The haemorrhagic risk of continuing modest doses of heparin with high dose ATIII therapy appears small. In addition to its value in the diagnosis of venous thrombosis the indium platelet technique may give an early indication of thrombus extension and may thus indicate the effectiveness of treatment.     

Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin III

Summary Two patients with familial antithrombin III deficiency developed deep venous thrombosis of the lower limb. The diagnosis of venous thrombosis was made by the indium labelled platelet technique which also allowed for the daily assessment of thrombus size. Each patient received treatment with Warfarin, subcutaneous heparin, and infusions of antithrombin III concentrates. The authors conclude that infusions of antithrombin III concentrates may be of value in limiting the extent of acute thrombosis in patients with a severe deficiency of this protein and may help prevent pulmonary embolism. The haemorrhagic risk of continuing modest doses of heparin with high dose ATIII therapy appears small. In addition to its value in the diagnosis of venous thrombosis the indium platelet technique may give an early indication of thrombus extension and may thus indicate the effectiveness of treatment.     

Cerebral thrombosis in a newborn with a congenital deficiency of antithrombin III

An Israeli Arab family with type I antithrombin III (AT-III) deficiency with several affected symptomatic members in three generations is reported. The propositus presented with deep vein thrombosis and pulmonary emboli associated with gestation. The propositus infant presented at the age of 2 weeks with superior sagittal and rectus sinus thrombosis. Hereditary AT-III deficiency should be considered in infants with cerebral thrombosis, especially if they have a family history of thromboembolism. The role of prophylactic therapy by AT-III concentrates in these infants should be further assessed.     

Evaluation of a new immunoturbidimetric test (Liatest® antithrombin III) for determination of antithrombin antigen

Antithrombin (AT) is a glycoprotein mainly synthesised in the liver, and is one of the most important inhibitors of coagulation. Although AT activity determination is more important in clinical practice and anti‐IIa and anti‐Xa chromogenic tests are widely available, sometimes AT antigen measurement is preferred. Immunoradiometric and enzyme linked immunoabsorbent assay (ELISA) tests have been the only methods available so far for AT antigen determination, but both of them are relatively complicated, time consuming, and the ELISA test cannot be used for single sample assessment. A new immunoturbidimetric test (Liatest® antithrombin III) is now available. We have adapted it for the Cobas Mira® biomedical analyser. The intra‐ and inter‐assay and total coefficients of variation for normal and low control plasma, as well as for normal pool plasma were low (< 3%). Blood samples from 32 patients with different clinical conditions were assessed both by the standard ELISA method and by the immunoturbidimetric method. The correlation coefficient was 0.95. According to our findings it seems that the immunoturbidimetric test (Liatest® antithrombin III) for determination of AT antigen automated for the Cobas Mira® biochemical analyser is easy to perform, time sparing and precise, with good comparability to other assays. It is suitable for measuring of AT antigen in routine laboratory work.     

Recurrent leg ulcers and arterial thrombosis in a 33-year-old homozygous variant of antithrombin

We report here a homozygous variant case of antithrombin (AT) associated with arterial thrombosis and recurrent leg ulcers. The deep vein thrombosis was recognized by the venogram of his pelvic veins. His leg ulcers were scattered around his left ankle and accompanied by lipodermatosclerosis, which was evident in venous insufficiency. The propositus had developed cerebral infarction 12 years prior to his leg ulcers. Coagulation study showed low heparin cofactor activity of his AT with a normal level of immunoreactive AT. Nucleotide sequence analysis of the exon 2 of his AT gene showed Arg47-Cys mutation, leading to the lack of affinity of AT for heparin. The propositus is a homozygote for this abnormality.     

Abnormal proteolysis (DIC)--successful treatment with antithrombin III concentrate and a concentrate containing F XIII and native von Willebrand factor

Two patients with life-threatening disseminated intravascular coagulation (DIC) syndrome, one caused by Gram-negative bacteria and one by premature separation of the placenta, are described. Specific substitution was given by antithrombin III concentrate and AHF-Kabi, a low purity factor VIII concentrate containing native von Willebrand factor and factor XIII. The treatment quickly returned the extremely low levels of antithrombin III, factor VIII:C, fibrinogen and factor XIII, initially found, to normal, and also returned the multimeric pattern of von Willebrand factor to normal. This resulted in diminished bleeding, enabling surgical treatment of the underlying disease.     

Impaired high-shear-stress-induced platelet aggregation in patients with chronic renal failure undergoing haemodialysis

We investigated shear-induced platelet aggregation (SIPA) in 30 patients with chronic renal failure (CRF) undergoing haemodialysis. 26 patients showed a significant decrease in SIPA at high shear stress but no change in SIPA at low shear stress. The former reaction reflects the interaction between plasma von Willebrand factor (vWF) and its platelet receptors, glycoprotein (GP) Ib-IX and lIb/ IlIa complex, whereas the latter is assumed to involve the binding of plasma fibrinogen to GP IIb/IIIa complex. These SIPA profiles in CRF patients after haemodialysis showed almost no change compared to those before haemodialysis.
The ratio of ristocetin cofactor/vWF antigen in plasma was slightly lower in CRF patients than in controls (P<0.01). However, the level of GPIb antigen in the platelets of these patients was significantly reduced (42.1±20-3% of normal platelets), with partial destruction of GPIb antigen. The number of vWF receptors on the GPIb molecule was quantitated using the GPIb-binding protein alboaggregin-B (AL-B), purified from the snake venom of Trimeresurus albolabris. AL-B bound to GPIb at a total of 48 760±9944 molecules per normal platelet and a K_d of 85.44±15.70 nM at saturation. In contrast, binding in CRF platelets was 22 980±6395 molecules per platelet and K_d was 50.08±13.83 nM. Taking these results together, we conclude that the impaired SIPA found in CRF patients is due to both abnormalities in plasma vWF and in its platelet GPIb receptor.     

Management of planned pregnancy in a patient with congenital antithrombin III deficiency

Long-term warfarin therapy was changed to subcutaneous heparin to cover a planned pregnancy in a patient with congenital antithrombin III (AT III) deficiency. Satisfactory anticoagulation was easily maintained in spite of low levels of biologically active AT III. Delivery and the puerperium were covered by a reduced dose of heparin and alternate day infusions of AT III concentrate. A mean dose of 0.77 U/kg of AT III concentrate produced a rise of 1% in AT III and the half-life was of the order of 24 h, with no evidence of increased consumption during labour and delivery. Pregnancy and labour were uncomplicated and resulted in delivery of a healthy female infant. The importance of early and adequate anticoagulation during pregnancy is emphasized.     

Inferior vena cava thrombosis in a child with nephroblastoma and combined deficiency of antithrombin III and free protein S

Summary A 31/2-year-old girl developed thrombosis of the inferior caval and renal veins several weeks after complete resection of a nephroblastoma. Her mother had suffered from pulmonary embolism at the age of 18 years. Familial antithrombin III deficiency and persistently lowered free protein S levels in the proposita were found. It is assumed that the combination of these two regulatory defects of hemostasis contributed to the early occurrence of this severe thrombotic event.     

Transient ischemic attack in a patient with congenital protein-C deficiency during treatment with stanozolol

A patient with congenital protein-C deficiency was treated with stanozolol for 8 weeks to increase circulating levels of protein C. A rise in protein C was achieved, accompanied by an increase in factor II, factor X, antithrombin III, and protein S; but at the 8th week the patient suffered a transient ischemia attack.     

Ambiguous genitalia and hypertension in a patient with congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is an uncommon condition. Its clinical presentation with hypertension is rare. Deficiency of the steroid 11‐beta‐hydroxylase accounts for less than 10% of CAH. We report a case of a 19‐year‐old patient who presents with hypertension with ambiguous genitalia secondary to adrenal steroidogenesis dysfunction. We also discuss the defects in adrenal steroidogenesis and clinical phenotypes of CAH.     

A case of Poncet's disease (tuberculous rheumatism) in a patient with chronic renal failure undergoing hemodialysis therapy]

A 78-year-old man who was undergoing hemodialysis therapy was admitted to our hospital because of sore throat, remittent cervical lymphadenopathy, and polyarthritis over the preceding 4 weeks. On admission, he had bilateral cervical lymphadenopathy. He complained of arthralgia associated with tenderness, warmth and swelling of both elbows, left side wrist and left shoulder joint. The C-reactive protein level on admission was 15.3 mg/dl. Rheumatoid factor, antinuclear antibodies, tuberculin skin test and blood culture were negative. Joint fluid was not aspirated. Radiographs of the joints did not reveal any abnormalities. Acid-fast bacilli were demonstrated in the smear of the cervical lymph node with a fluorochrome rhodamine-auramine stain. Mycobacterium tuberculosis DNA was identified by polymerase chain reaction. We found the presence of caseating granuloma on the biopsy specimens and M.tuberculosis was detected from culture. At that point, we diagnosed this patient as having tuberculous lymphadenitis. His general symptoms resolved rapidly after starting with a three-drug regimen consisting of isoniazid, rifampin and pyrazinamide. His polyarthritis also improved dramatically. Finally we considered that his polyarthritis was tuberculous rheumatism, also called Poncet's disease. Poncet's disease is characterized by sterile polyarthritis during active tuberculosis infection. It is considered a reactive arthritis, which is a different entity from tuberculous arthritis. Although this is a rare disease, we should be aware of it in hemodialysis patient clinics, because the incidence of tuberculosis infection has been reported to be increasing in patients with end-stage renal failure.     

Antithrombin-TRI (Ala 382 to Thr) causing severe thromboembolic tendency undergoes the S-to-R transition and is associated with a plasma-inactive high-molecular-weight complex of aggregated antithrombin

An antithrombin (AT) variant Ala382 to Thr (AT-TRI) was identified by mass spectrometric techniques. The variant behaved as a substrate rather than a thrombin inhibitor, but, contrary to previously described P12 AT variants, AT-TRI, expressed as a heterozygous dominant trait, caused severe thromboembolic tendency beginning in their teens in affected members of an English family. In addition, it underwent the S-to-R conformational state transition as evidenced by an increased resistance to thermal denaturation on active centre cleavage, but did not react with a monoclonal antibody, 4C9, directed against a neoepitope that is present on complexed and cleaved normal AT. Antithrombin-TRI, in plasma, was also associated with an abnormal high molecular weight (M_r 194000) component composed of non-covalently-linked antithrombin molecules. This component (D194) showed low affinity for heparin and was devoid of antithrombin progressive activity. D194, isolated by ammonium sulphate precipitation and three chromatographic steps (heparin Sepharose, ion exchange and immunoaffinity), migrated as a single band of M_r 60000 on SDS-PAGE under both reducing and non-reducing conditions and was recognized by monospecific anti-human antithrombin antibodies, but did not immunoreact with antibodies raised against a number of proteins including albumin and thrombin. The above data and the fact that the 15 N-terminal amino acids of this M_r 60 000 band were identical to that of normal antithrombin indicated that the inactive D194 component was composed of aggregated antithrombin molecules, possibly antithrombin trimers.
In conclusion, early adulthood severe thromboembolic tendency, failure to expose the 4C9 epitope, and presence of aggregated AT molecules in the plasma are characteristic features of AT-TRI not previously described in other ALA-382 THR mutations.     

Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with L-asparaginase: an in vitro study

Thrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an L-asparaginase-induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0.53 U/ml). LMWH 0.3 and 0.7 U/ml or melagatran 0.3 and 0.5 micromol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno-depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66-88% decrease in ETGC in AT-normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT-depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.     

Associated von Willebrand disease as a possible cause of lack of thrombosis in an AT III abnormality (AT III Trento)

Summary In a family with a known antithrombin III abnormality (AT III Trento) an associated von Willebrand defect (Type I) was found. The two defects seem to segregate independently. In fact four types of individuals were present, namely: subjects with isolated AT III abnormality, subjects with isolated von Willebrand defect, patients with double defect and normal subjects. Only one of the two patients with isolated AT III abnormality showed a thrombotic tendency. None of the patients with double defect showed thrombotic disease, indicating a possible protective action of the von Willebrand defect against thrombotic manifestations. Patients with isolated von Willebrand defect showed neither thrombotic nor bleeding manifestations. The study emphasizes the need for a careful evaluation of the hemostatic balance of patients with AT III abnormalities before concluding that they are symptomatic or asymptomatic.This study was supported by Grants from the CNR (Grant 84.02363.56 II 5.01677), from the M. P. I. Rome (Grant 1592–1984) and from the Veneto Region, Venice, Italy