Hypercoagulable states, as a general term, refer to a broad spectrum of constitutional and acquired conditions that are known to be associated with increased intravascular coagulation and/or development of thromboembolic events. The etiology of hypercoagulable states includes genetic predisposition, certain clinically acquired conditions, and environmental factors. 1
A previously healthy 19-month-old boy was referred from another hospital with left lower extremity ischemia. The ischemic event developed 1 week after inguinal hernia repair, which was complicated by development of measles and pneumonia during the postoperative period. Intravenous antibiotic treatment was initiated, which necessitated the use of lower extremity superficial veins in addition to upper extremity veins for intravenous catheterization. Within a few days, decreased movement and coldness in the left lower limb was noted, and symptoms progressed to more proximal regions. One week later, the same symptoms developed on the right side. On physical examination, both of the lower extremities were cyanotic, cold, tender to touch, and edematous. Discoloration of the toes of both feet—an indicator of circulatory failure–was apparent (Fig). Dorsalis pedis and popliteal pulses could not be detected, and femoral pulses were weak. Lower extremity Doppler ultrasonographic examination demonstrated intra-arterial thrombus in the right external iliac artery, and no flow could be visualized in the main femoral, superficial femoral, and popliteal arteries on both sides. Blood biochemical analysis, complete blood count, and other routine hematological tests (prothrombin time, partial thrombin time, internationalized normal ratio) revealed normal findings. Protein C, protein S, modified active protein C, and antithrombin III levels were 69% (range, 70–130%), 45% (range, 65–140%), 0.98 (>0.80), and 13% (range, 80–120%) respectively. Protein S levels of his mother and father were found to be 89% and 94% respectively. Anticoagulant therapy with intravenous heparin infusion and antiaggregant therapy with low-dose salicylic acid were initiated as soon as arterial thrombosis was diagnosed via Doppler ultrasonography. Initial intravenous heparin infusion therapy was shifted to intermittent, subcutaneous, low-molecular weight heparin injection therapy after a few days. During surgical reconstruction, only minimal debridement of the lesions was required, and partial-thickness skin grafting was sufficient to close the resultant tissue defects. The initial preoperative anticoagulant and antiaggregant therapies were continued during the postoperative period without any complications. The patient was discharged on prophylactic, low-dose antiaggregant therapy without any functional deficit.
The sequence of the coagulation reactions resulting in fibrin generation, and antithrombin and protein C–protein S anticoagulant pathways are interlocked. Although thrombin plays an important role in the coagulation pathway and has a biofeedback effect on previous steps of the coagulation cascade, it also behaves as an initiator of anticoagulation, acting through the protein C pathway. Protein S is a vitamin K-dependent cofactor for protein C, which is also a vitamin K-dependent serine proteinase, functioning in the inactivation of factors Va and VIIIa. Thus, they contribute to regulating clotting activity. 2 As a result, deficiencies of either protein S or protein C, or the resistance of the target proteins to the proteinase action of activated protein C (as in the case of factor V Laiden) result in recurrent or atypical patterns of thrombosis.
Protein S deficiency was once thought to be transmitted as an autosomal dominant trait; however, today it is more evident that both protein S and protein C deficiencies are transmitted autosomally with variable penetrance. 3,4 In some families, heterozygous individuals experience recurrent venous thrombosis and pulmonary embolism, with an onset at adolescence or early adulthood, and 50% have a vascular occlusion by the age of 30 to 40 years (clinically dominant trait with an estimated prevalence of 1 in 16,000–36 000 individuals).5,6 In other families, heterozygous individuals are asymptomatic, and homozygotes develop fetal thrombotic complications such as severe recurrent purpura fulminans, cerebral thrombosis, ophthalmic vascular occlusion, or disseminated intravascular coagulation (clinically recessive trait with a prevalence of 1 in 200–300 individuals). 4,7–9 Parents and all siblings of a patient in this group must have partial deficit of free protein S. In addition to these clinically evident genetic forms, molecular studies demonstrated two copies of protein S gene in the genome, one being an untranslated pseudogene, which has complicated the search for mutations. 10 In addition to these hereditary protein S deficiencies, several clinical conditions leading to acquired protein S deficiency, such as use of oral contraceptives or coumarin, pregnancy, disseminated intravascular coagulation, hepatic disease, nephrotic syndrome, or type I diabetes, have been described with variable change in total and free protein S levels. 11 Finally, in some patients, other hereditary conditions of hypercoagulable states may be associated with protein S deficiency, 12 or certain environmental influences may trigger thrombosis in genetically predisposed individuals.
Although the exact etiological factor for protein S deficiency could not be determined in our patient, it can be speculated that either operation for inguinal hernia repair under general anesthesia, the septic condition of the patient resulting from measles with lung complications and intravenous catheterization for antibiotic therapy during the postoperative period, or the overall effects of all these factors disturbed the balance between coagulation and anticoagulation systems in the favor of the development of intravascular clotting in a genetically predisposed individual.
In the treatment of protein S/protein C deficiencies, besides anticoagulant and thrombolytic therapies, fresh frozen plasma and/or protein C concentrate (if possible) are advised in infants with acute purpura fulminans. 8,13 Because the thrombolytic therapy was not initiated within the first few hours after the development of arterial thrombosis, there was no rationale to start it after development of end-stage lesions with well-demarcated, necrotic margins. Although the use of vitamin K antagonists are recommended for long-term treatment of protein S and protein C deficiencies, we did not prefer to use vitamin K antagonists, not only because coumarin is one of the agents that leads to acquired protein S deficiency, but because there have been cases of coumarin-induced skin necrosis reported 2 when initiating this therapy, resulting from the fact that vitamin K-dependent protein S and protein C have shorter half-lives than the vitamin K-dependent coagulation proteins. Additionally, we preferred to use intermittent subcutaneous injection of low-molecular weight heparin therapy than either intravenous infusion or subcutaneous injection of heparin because of its similar efficacy and wider safety margin. 15
In the literature, protein S deficiency is associated primarily with venous thrombosis. However, in homozygous individuals of the second group in which the heterozygotes are asymptomatic, in clinically recessive traits, severe arterial occlusions may develop early in life. There are a few reports of bilateral lower extremity arterial thrombosis resulting from protein S deficiency. 16,17 In all of these reported cases, clinical outcomes were relatively poor, and amputation of the digits was usually inevitable. In our patient, although both of the lower extremities of the patient were involved grossly at the time of presentation, he responded well to the applied treatment and only required minimal debridement and grafting to close the resultant tissue defects. No residual functional deficit was noted after treatment. One should consider hypercoagulable states and their treatment modalities in patients with atypical or recurrent intravascular thromboembolisms. This case emphasizes that with appropriate medical treatment and surgical reconstruction, outcomes of patients with hypercoagulable states can be improved dramatically.
Ibrahim Vargel, MD
Emre Aksu, MD
Halil Ibrahim Canter, MD
Abdullah Keçik, MD
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