Heparin-induced thrombocytopenia and warfarin-induced skin necrosis in a child with severe protein C deficiency: successful treatment with dermatan sulfate and protein C concentrate

Abstract

Dear Sir, Long trips, especially air flights, are considered a risk for venous thromboembolism [1][2][3][4][5]. The frequency of symptomatic thromboembolic events increases with the distance flown, but appears to be low [3]. In a recent study, however, Scurr et al. found symptomless calf vein thrombosis detected by ultrasonography in up to 10% of long-haul travelers [4]. Given the limited sensitivity of the method [6], the true incidence of travel-associated distal thrombi may even be higher. Taken together, these data suggest that subclinical thrombosis may be frequent during air travel but usually resolves once mobility is resumed. Accordingly, symptomatic thromboembolic events would reflect a rare situation where activation of coagulation escapes the natural control systems.The prolonged sitting position during an air trip is associated with venous stasis, decreased blood flow and hemoconcentration, and is widely assumed to be the main causal factor for thrombus formation in this setting. If this assumption is correct, prolonged immobility in a sitting position by itself would be sufficient to activate coagulation. Subclinical activation of coagulation À a so-called prethrombotic state [7] À can be assessed by sensitive biochemical markers of thrombin generation (prothrombin fragment 1 þ 2, F1 þ 2), of ongoing fibrin formation (fibrinopeptide A, FPA) and lysis (D-dimer, DD). The aim of this study was to test the hypothesis that prolonged immobility in a sitting position similar to the one occurring during air traveling activates coagulation.Forty healthy subjects of either sex (median age 29.5 years, range 19-58) with a negative personal and family history and no known risk factor for thromboembolism were kept seated for 6 h on normal chairs, with their knees bent; during this period they were allowed to drink, eat, read or watch television. At baseline and after 3 and 6 h of immobilization, blood was collected in CTADPPACK anticoagulant from sitting probands with a clean venepuncture from an antecubital vein under controlled venous stasis for measurement of F1 þ 2 (Enzygnost F1 þ 2 Behring), FPA (RIA reagents supplied by Imco), and DD (mini-VIDAS, BioMérieux). Hemoglobin concentration and hematocrit were determined as well. In order to control for the circadian variations of the hemostatic system [8], we used the same protocol for blood sampling in a subgroup of 18 volunteers who were allowed to move freely (control group).Statistical probability was assessed with repeated measures ANOVA on ranks followed by pairwise multiple comparison procedures (Student-Newman-Keuls method) for non-normally distributed data. A linear regression was done for correlation between data at baseline and after 6 h. A difference was considered significant when P <0.05.Over the 6 h of sitting position there was no change in the plasma levels of FPA and DD, whereas F1 þ 2 levels decreased from a median of 0.49 to 0.40 nmol L À1 (P < 0.0001, Table 1).The F1 þ 2 decrease was both relevant in quantitative terms (À20% of the baseline ...

Severe congenital protein C deficiency: the use of protein C concentrates (human) as replacement therapy for life-threatening blood-clotting complications

“…This concentrate was thereafter approved for the treatment of congenital protein C deficiency. Until now, several reports on the use of this concentrate in congenital protein C deficiency have been published (Auberger 1992; Conard et al 1993; DeStefano et al 1993; Alhenc-Gelas et al 1995; Baliga et al 1995; Dreyfus et al 1995; Muller et al 1996; Gatti et al 2003). In almost all treated children an impressive response with resolution of coagulopathy and skin lesions had been observed.…”

Heparin‐induced skin necrosis associated with thrombocytopenia and acquired protein C and protein S deficiency

“…It should be noted that HIT antibodies may also contribute to this process as most patients who receive warfarin have also received heparin. This is exemplified by recent case reports of skin necrosis in patients treated with warfarin who also have had HIT [14,17].Thus, ''anticoagulant-induced skin necrosis'' may be a better term for this entity.…”

“…Warfarin-induced skin necrosis is clinically similar to that caused by heparin and has been associated with congenital deficiencies of both proteins C [16,17] and S [18]. This phenomenon is usually attributed to an initial pro-thrombotic state resulting from the faster decrease of protein C owing to the shorter half-life of protein C (9 hr) as compared to that of prothrombin (60 hr) [1].…”

Case Report: Perioperative Use of Protein C Concentrate for Protein C Deficiency in THA

“…Protein C use also has been reported to prevent vascular thrombosis in a patient with familial protein C deficiency undergoing renal transplantation [28]. Ceprotin 1 has an excellent safety profile: no reported medication interactions, overdose, blood-borne infections, bleeding, or prothrombotic complications [6,9,14,23,25,26]. Given our patient's personal and family history of idiopathic PE, the presence of two thrombophilic mutations, and the substantial thrombotic and bleeding risks posed by THA [21], we decided the off-label use of protein C concentrate represented the most efficacious approach.…”