Vasculitic neuropathy in a patient with hereditary C1 inhibitor deficiency

OBJECTIVE: To report the clinical, pathological, and mutational features of hereditary C1 inhibitor (C1INH) deficiency as a cause of isolated vasculitic neuropathy. PATIENT: A 35-year-old woman with sensorimotor mononeuritis multiplex and facial palsy. RESULTS: The sural nerve biopsy results showed a decrease of myelinated fibers with axonal degeneration and severe hypersensitivity vasculitis, with deposition of C1q on vessel walls. Mutational analysis of the C1INH gene found a new mutation, a heterozygous 2-base pair deletion in exon 8. The patient was treated with plasmapheresis and intravenous methylprednisolone, followed by oral prednisolone, which resulted in marked improvement. CONCLUSION: Hereditary C1INH deficiency should be included in the differential diagnosis of nonsystemic vasculitis neuropathy.     

Genetic and phenotypic variability between families with hereditary protein S deficiency

While many mutations thought to result in protein S (PS) deficiency are known, there have been few attempts to relate genotype expression with plasma phenotype. We have investigated the nature and consequence of PS gene (PROS1) mutations in 17 PS-deficient families who presented with mixed type I and type III phenotypes. Seven different mutations were found in nine families: delG-34 (STOP codon at -24), Val-24Glu, Arg49Cys, Asn217Ser, Gly295Val, +5 G to A intron j and His623Pro. PS wild type (PSWT) and the five missense mutants were transiently expressed in COS-1 cells. All mutants expressed lower (p<0.05) PS antigen compared to PSWT (100%). The mutants Val-24Glu, Gly295Val and His623Pro expressed very low/undetectable PS levels. The mutant Asn217Ser produced around 30% of PSWT, while the mutant Arg49Cys had the highest PS levels (around 50%). Metabolic labelling and pulse-chase experiments showed that all of the mutants had impaired secretion, but this was of variable severity. Also, enhanced intracellular degradation of unsecreted material was found for all mutants. There was a strong correspondence between plasma free PS levels in carriers of the mutations, secreted PS from transfected COS-1 cells and labelled PS from 24 h conditioned medium in pulse-chase experiment. We conclude that the magnitude of secretion defect depends on the nature of the PROS1 mutation and influences the level of free PS in plasma. It is likely that the severity of the secretion defect will determine the risk for venous thrombosis.     

Application of two neutral MspI DNA polymorphisms in the analysis of hereditary protein C deficiency.

Screening of restriction enzyme digested DNA from normal and protein C deficient individuals with a variety of probes derived from the protein C locus has revealed the existence of two neutral MspI polymorphism. One polymorphism (MI), which is located approximately 7 kb upstream of the protein C gene, has allelic frequencies of 69 and 31%, and was used to exclude extensive gene deletions as a likely cause of type I protein C deficiency in 50% of cases in a panel of 22 families. Furthermore, the same polymorphism has been used in 5 doubly affected individuals establishing compound heterozygosity in 3 of these. The second, intragenic, polymorphism (MII) has allelic frequencies of 99 and 1% in the normal population. The frequency of the rare allele of this RFLP was with 7% much higher in a panel of 22 Dutch families with protein C deficiency. Interestingly, in all three probands that were heterozygous for MII the rare allele of MII coincided with a point mutation that leads to a stop codon in amino acid position 306 of the protein C coding sequence. This mutation may account for 14% of the protein C deficient individuals in The Netherlands.     

Treatment with stanozolol before thrombolysis in patients with arterial occlusions

The administration of the anabolic steroid stanozolol during 7, 8 days as pretreatment before thrombolytic therapy of acute or subacute arterial occlusions enhances the fibrinolytic potential significantly. On average the plasminogen increased from 101% to 133%, the euglobulin lysis time after venous stasis was shortened and the alpha 2-antiplasmin remained constant. This effect could be favourable to prepare patients undergoing thrombolytic treatment.     

A new hereditary abnormal protein C (protein C Yonago) with a dysfunctional Gla-domain.

A familial abnormal protein C most probably with the dysfunctional Gla domain was found in a 60-year-old man with recurrent thrombosis. Namely, the anticoagulant activity as measured by the APTT method and the antigen level by an ELISA utilizing a calcium-dependent antibody were reduced to nearly half of normal, 43.5% and 2.1 micrograms/ml (normal range: 2.8-5.0 micrograms/ml), respectively. On the other hand, the amidolytic activity determined on a synthetic chromogenic substrate, S-2366, and the total antigen measured by an ELISA utilizing a polyclonal antibody were both in the normal range, 74.1% and 83% of normal, respectively. Crossed immunoelectrophoresis showed more anodal migration than the normal control in the presence of calcium ions, and adsorption of protein C to barium citrate was insufficient. These data altogether indicated that a half population of protein C in the patient's plasma was dysfunctional in the Gla domain or its related structures. Four other members of his immediate family were found to have the same abnormality of protein C, although they had been all asymptomatic. We thus conclude that the dysfunctional protein C is hereditary, and that the abnormalities noted in several tests are most likely due to a structural defect residing in the Gla or its related regions. We hereby designate this abnormal protein C as protein C Yonago.     

Cerebral infarction associated with protein C deficiency.

BACKGROUND AND PURPOSE: A deficiency of plasma protein C, both the hereditary and acquired types, is one cause of thromboembolic disease. Several antineoplastic agents have been reported to decrease the production of protein C in the liver by impairing either the absorption or metabolism of vitamin K, leading to acquired protein C deficiency. CASE DESCRIPTION: We treated a young woman with protein C deficiency, who had developed a cerebral infarction of the right parietal cortex of sudden onset. On admission, the antigenic level of plasma protein C was 38%. Serial cerebral angiography revealed occlusion of the right middle cerebral artery, which subsequently recanalized completely. This patient had taken fluorouracil derivatives orally for as long as 3 years following a left mastectomy for stage II breast cancer. Tests revealed that the patient's mother had only one-half the normal activity of plasma protein C despite a normal antigenic level. CONCLUSIONS: We speculate that the etiology of the cerebral infarction in this patient might involve an embolic mechanism associated with protein C deficiency induced by an interaction between inherited and acquired factors.     

Homozygous protein C deficiency with moderately severe clinical symptoms

We report a large family with two members homozygotes for protein C deficiency, with activity levels of 5% and 9%. Thirteen additional members were heterozygotes, with protein C activity ranging from 36-66% and equally low levels of protein C antigen. The homozygotes presented with recurrent deep-vein thromboses and pulmonary emboli, but have reached the ages of 26 and 37 years. Hence, protein C levels of 5% appear sufficient to avoid life-threatening clinical symptoms in the neonatal period.     

Hereditary protein C deficiency associated with riboflavin-responsive lipid storage myopathy

We report a 14 year old patient who presented lung emboli and deep vein thrombosis in relationship to protein C deficiency. He had a carnitine-deficient lipid myopathy. Fresh muscle homogenate showed low activities in oxidizing [1-¹⁴C]-butyrate, [1-¹⁴C]-octonoate and [1-¹⁴C]-palmitate. A deficient short chain butyryl-CoA dehydrogenase (SCAD) was found in isolated muscle mitochondria. The patient improved dramatically with daily therapy of 200 mg riboflavin, 2 g carnitine and anticoagulation with Coumadin. The treatment was found to restore fatty acid oxidation in fresh muscle homogenate, deficient acylCoA-dehydrogenases in mitochondria and decrease lipid droplets. These results suggest that in this type of lipid myopathy riboflavin supplementation may be effective. The link with protein C deficiency is discussed.     

Protein C, an anticoagulant protein, is increased in healthy volunteers and surgical patients after treatment with stanozolol

On both oral and intramuscular administration, the anabolic steroid stanozolol was found to increase protein C antigen concentrations in circulating blood. In fourteen healthy young volunteers (who received stanozolol orally, dose 10 mg/day) the average increase was 1.5-1.6 times the normal concentrations after 3-6 weeks' treatment and was accompanied by more moderate increases in the other vitamin K-dependent factors II, IX and X to 1.4, 1.4 and 1.2 times their normal concentration respectively. However, there was no change in factor VII. In sixteen elderly surgical patients, intramuscular injection (50 mg) one day prior to surgery induced a moderate increase within 24 hours (to 1.11 times the pretreatment concentration) and seven days after operation (to 1.19 times), and reduced the postoperative fall in protein C. Stanozolol administration seems to be a promising pharmacological method for increasing anticoagulant protein C levels in congenital and acquired deficiencies.     

The fibrinolytic system in patients with congenital protein C deficiency

The endothelial cell is a rich source of plasminogen activator that is associated with fibrinolytic activity in blood vessel. Addition of sitosterol to the culture medium of endothelial cells from bovine carotid artery gave rise to a marked increment in the activity of plasminogen activator. Removal of sitosterol from the culture medium resulted in a decrease of plasminogen activator activity back to normal levels. Enhancement of plasminogen activator activity in cultured endothelial cells was not observed by cholesterol, 5-androsten-3β-ol and others.     

Long-term management of homozygous protein C deficiency: replacement therapy with subcutaneous purified protein C concentrate.

We present the case of a full-term newborn in whom purpura fulminans developed shortly after birth. A diagnosis of homozygous protein C deficiency was established based upon undetectable plasma protein C activity and antigenemia in the newborn infant, and was later confirmed by protein C gene analysis. Specific replacement therapy with intravenous protein C concentrate was started 9 days after birth. This rapidly led to the complete regression of cutaneous lesions and consumption coagulopathy. After stabilization, oral anticoagulation was initiated in association with prophylactic treatment with intravenous protein C concentrate. However, oral anticoagulation was finally abandoned as the patient presented several thrombotic and hemorrhagic episodes clearly related to difficulties with anticoagulation. Due to the hazards related to prolonged venous access, we are currently using subcutaneous infusion of protein C concentrate for the long-term management of this condition, with satisfactory results.     

Ischemic stroke due to protein C deficiency

Plasma protein C exerts anticoagulatory effects by inactivating factors V and VIII. Hereditary protein C deficiency is transmitted as an autosomal dominant disorder. Homozygous individuals usually develop purpura fulminans as newborns; heterozygous protein C-deficient individuals are at increased risk for venous thrombosis and pulmonary embolism. However, arterial thrombosis has been only rarely observed. We describe a young patient with heterozygous protein C deficiency who experienced a severe stroke due to thrombotic occlusion of the left middle cerebral artery.     

A case of hereditary ceruloplasmin deficiency with hemosiderosis]

We report a 49-year-old female with hereditary ceruloplasmin deficiency with hemosiderosis. There was a family history of the same symptoms; her brother showed hypoceruloplasminemia and decrease of the serum copper content. On physical examinations, dementia, dysarthria, downbeat nystagmus, sensorineural hearing disturbance, orthostatic hypotension, retinitis pigmentosa, diffuse goiter, and cerebellar ataxia were noted. Laboratory examinations disclosed leukopenia, diabetes mellitus, hypothyroidism, decrease of copper content in the serum and urine. Serum ferritin concentration was remarkably increased. Serum ceruloplasmin could not be detected. Biopsy of the liver showed that iron content in the liver was increased. On MRI study, dentate nucleus of the cerebellum, basal ganglia, and the liver showed low intensity in both T1 and T2 weighted images. A nonsense mutation in the ceruloplasmin gene was found in this patient. Systemic iron deposition and tissue damage were considered as caused by deficiency of function of ceruloplasmin as ferroxidase. To our knowledge, the characteristic combination of the clinical signs in this patient has not been reported.     

Defibrination during warfarin therapy in a man with protein C deficiency

A 57 year old man presented with apparently spontaneous lower extremity deep vein thrombosis and pulmonary embolism. He was treated in conventional fashion with intravenous heparin and oral warfarin. After 4 daily doses of warfarin the prothrombin and proconvertin (P+P) time was within therapeutic range, and heparin was stopped. Over the next six hours complete defibrination occurred, associated with severe bleeding complications. Functional protein C measured after normalization of routine coagulation tests averaged 40% of normal, and was only 3.5% of normal immediately prior to the episode of defibrination. We conclude that the very low functional protein C levels seen immediately prior to defibrination were caused by a combination of pre-existent protein C deficiency and warfarin therapy, and directly predisposed to defibrination once heparin was stopped, despite "therapeutic" warfarin anticoagulation. Exacerbation of intravascular coagulation should be considered a potential prothrombotic effect of warfarin therapy in protein C deficient individuals.     

Alexia without agraphia following cerebral venous thrombosis associated with protein C and protein S deficiency

A 26-year-old right handed female was admitted to hospital with right homonymous hemianopia associated with alexia without agraphia. Her cranial magnetic resonance imaging and magnetic resonance angiography revealed a left occipital venous infarction due to thrombosis of the left transverse, sigmoid sinuses and the left internal jugulary vein. The underlying conditions were protein C and protein S deficiency associated with the use of oral contraceptives. To our knowledge, alexia without agraphia has never been described due to a venous infarction associated with hereditary thrombophilia in the literature.