Prevalence of cerebral venous thrombosis with the use of oral contraceptive pills during the Holy month of Ramadan.

OBJECTIVES: To identify the epidemiologic profile of cerebral vein thrombosis (CVT) among fasting women using oral contraceptive pills  (OCPs) during the holy month of Ramadan. Methods: This retrospective study was conducted on all patients diagnosed with CVT and using OCPs from records at a tertiary care hospital in Riyadh, Saudi Arabia during 2016-2017. The study participants were categorized into 2 groups (an intermittently fasting group during the holy month of Ramadan and a non-fasting group).  Results: Out of 108 female patients with CVT, 36.1% were secondary to OCP, of whom 41% participants were fasting. The most affected site was the transverse sinus. Holocephalic headache was more common amongst fasting group (68.8%) compared to non-fasting group (30.4%) (p=0.025). Dehydration (p=0.003) amongst the fasting group and protein S deficiency (p=0.027) in the non-fasting group were identified as the 2 prominent risk factors. Unfractionated heparin was the most common anticoagulant therapies used during the initiation phase for non-fasting (36.4%) and fasting groups (50%). Conclusion: All women who are using OCP should undergo formal written risk assessments for factors of CVT. Our study suggests that the negative effects of OCPs use might outweigh its benefits; thus, it should be prescribed with caution, more so in fasting patients.

Extensive Necrotic Skin Lesions Due to Post-varicella Protein S Deficiency.

Postvaricella protein S deficiency is a rare and severe disease. We report a case of extensive necrotic skin lesions of acute onset 7 days after varicella in a 4-year-old girl. Protein S antigen and activity were <10%, and antiprotein S antibodies were detected. She was treated with anticoagulation, plasmapheresis and fresh frozen plasma. She survived but required leg amputation.

HIV infection, hypercoagulability and ischaemic stroke in adults at the University Teaching Hospital in Zambia: a case control study.

BACKGROUND: In Zambia, 14.2% of adults have HIV/AIDS. There has been a substantial and significant increase in patients hospitalized for ischaemic stroke with co-existing HIV infection. However, little is known about the mechanism of stroke in these HIV + ve patients let alone studied in our region. The aim of this pilot study was to explore the association of hypercoagulability state in HIV + ve patients with ischaemic stroke. This was achieved by comparing hypercoagulability state markers between HIV + ve ischaemic stroke patients with HIV-ve and HIV + ve patients with and without ischaemic stroke respectively. METHODS: A matched case control study in which a total of 52 HIV + ve patients with ischaemic stroke were prospectively compared with control groups for the presence of protein S, protein C deficiencies and hyperhomocysteinaemia. The control groups comprised an equal number of consecutively matched for age and sex HIV-ve and HIV + ve patients with and without ischaemic stroke respectively. Data was analysed in contingency tables using Paired t- test, Chi square and conditional logistic regression. RESULTS: Ischaemic stroke of undetermined aetiology occurred more frequently in HIV + ve compared to HIV-ve patients (p < 0.001). In addition, protein S deficiency and Hyperhomocysteinaemia were more prominent in HIV + ve than HIV-ve ischaemic stroke patients (P = 0.011). There was no difference in the presence of hyperhomocysteinaemia or protein S deficiency in HIV + ve patients with or without ischaemic stroke. Protein C deficiency was not noted to be significantly different between the cases and the two control arms. CONCLUSION: Protein S deficiency and hyperhomocysteinaemia were associated with HIV infection, but not stroke in our study population. However, this is an area that requires extensive research and one that we cannot afford to ignore as it is an important bridge to all cardiovascular and cerebrovascular diseases.

Low levels of plasma protein S, protein C and coagulation factor XII during early pregnancy and adverse pregnancy outcome.

It was the study objective to evaluate whether low levels of plasma protein S (PS) activity, free PS, protein C (PC) activity and coagulation factor XII (FXII) during early pregnancy are related to adverse pregnancy outcomes. Peripheral blood samples were obtained at 8-14 gestational weeks (GW) from a consecutive series of 1,220 women. The levels of plasma PS activity, free PS, PC activity, and FXII were measured. Cut-off values were defined as < 1st, < 5th, and < 10th percentiles of values obtained from 933 women whose pregnancies ended in normal deliveries without complications. PS activity of < 10th percentile yielded risks of pregnancy-induced hypertension (PIH) and severe PIH, while free PS level of < 5th percentile yielded a risk of pre-eclampsia. FXII level of < 1st percentile yielded a risk of premature delivery (PD) at < 34 GW. None was associated with PD at < 37 GW, fetal growth restriction or fetal loss. A multivariate analysis demonstrated that PS activity of < 10th percentile (odds ratio 5.9, 95 % confidence interval 1.7-18.1) and body mass index (BMI) ≥ 25 kg/m² (4.3, 1.1-13.3) were independent risk factors for severe PIH. Similarly, free PS level of < 5th percentile (4.4, 1.0-14.3) and BMI ≥ 25 kg/m² (4.0, 1.3-10.9) were independent risk factors for pre-eclampsia. In conclusion, women with low levels of plasma PS activity and free PS during early pregnancy might have increased risks of PIH, severe PIH or pre-eclampsia. Women with low FXII level might have an increased risk of PD at < 34 GW.

Isolated midbrain ischemic infarct in association with hyperlipoproteinemia (a): a report of 2 adolescent patients.

Arterial ischemic strokes (AIS) localized solely to the midbrain are extremely uncommon in the pediatric population. Elevated lipoprotein (a), which promotes atherosclerosis and a prothrombotic state, has been associated with increased risk of AIS in children and adults. Here we describe a 17-year-old boy and a 15-year-old girl who presented with internuclear ophthalmoplegia secondary to an isolated midbrain AIS. Evaluation for risk factors for AIS in these otherwise healthy adolescents identified hyperlipoproteinemia (a) in combination with other potential prothrombotic conditions suggesting that hypercoagulable states such as hyperlipoproteinemia (a) may have contributed to development of small-vessel arteriopathy and localized AIS.

Sepsis Causing Acquired Protein C and Protein S Deficiency.

Warfarin Induced Skin Necrosis is a well-known and dreaded complication in patients who is being started on warfarin without adequate bridging with other anticoagulants. The mechanism is thought to be due to protein C deficiency acquired after initial exposure to warfarin. We present a rather unusual cause of protein C deficiency due to sepsis resulting in warfarin induced skin necrosis. 43 year old lady who has been on chronic warfarin therapy secondary to anti phospholipid syndrome was admitted to the hospital for acute ischemic cerebellar stroke. Warfarin was held due to acute thrombocytopenia. She was discharged after restarting the warfarin. She presented back with septic shock due to pneumonia. She was found to have multiple necrotic areas consistent with skin necrosis. Unfortunately, patient died due to multi organ failure despite goal directed therapy. This case demonstrates the importance of recognizing the sepsis as an acquired cause of protein C deficiency.

Thyroid storm presenting as congestive heart failure and protein-S deficiency-induced biventricular and internal jugular venous thrombii.

The thyroid storm is a medical emergency characterized by decompensation of one or more organ systems. Associated cardiac involvement carries poor prognosis. Early recognition and appropriate management of life-threatening thyrotoxicosis is vital to prevent the high morbidity and mortality that may accompany this disorder. We report a young lady presenting with thyroid storm presenting as acute heart failure with biventricular and bilateral internal jugular venous thrombi. In addition, she also had thyrotoxicosis-induced transient protein-S deficiency which recovered following remission.

[Acute illness following chicken pox: spleen infarction as a complication of varicella zoster infection]. / Acuut ziek na waterpokken: miltinfarcten als complicatie van varicella-zosterinfectie.

BACKGROUND: Varicella zoster virus (VZV) infection can cause temporary acquired protein S or C deficiency via cross reacting antibodies and consequently inducing a hypercoagulable state. CASE DESCRIPTION: A 6-year-old girl with a history of congenital cardiac disease was seen at an Emergency Department with acute chest pain, dyspnoea and fever, seven days after developing chicken pox. Diagnostic tests revealed massive infarction of the spleen, and a protein S and C deficiency. In addition, blood cultures revealed a Lancefield group A ß-haemolytic streptococcus (GABHS). The patient recovered fully after treatment with low molecular weight heparin and antibiotics. CONCLUSION: In this patient, septic emboli caused splenic infarction. Thromboembolic complications should be suspected in children with VZV who present with acute symptoms, in particular if bacterial superinfection is found.

Haemorrhagic transformation of cerebral infarction in an AIDS patient--thrombophilia screen essential!

Patients with advanced HIV disease with low CD4 count are more prone to thrombo-embolism and various predisposing factors have been identified. These include the presence of anticardiolipin antibodies and the lupus anticoagulant, deficiencies of proteins C and S, heparin co-factor II and antithrombin. Increased levels of Von Willebrand factor and d-dimers have also been linked with thrombo-embolism, as has the presence of concurrent infections and malignancies. We report a case of an AIDS patient who presented with acute hemiparesis. He was severely immunosuppressed. Computed tomography of the head confirmed cerebral infarction with haemorrhagic transformation. He had no known risk factors apart from being severely immunocompromised and had high anticardiolipin antibodies and low free protein S.

Nonbacterial purpura fulminans and severe autoimmune acquired protein S deficiency associated with human herpesvirus-6 active replication.

Nonbacterial purpura fulminans (PF) is rare, usually follows viral infection in young children, and is characterized by specific coagulation disorders, requiring specific therapy. Following a transient rash, a 2-year-old previously healthy girl developed PF without haemodynamic impairment. Laboratory data revealed disseminated intravascular coagulation and a severe transient protein S deficiency. Antiprotein S autoantibodies and active human herpesvirus-6 (HHV6) replication were demonstrated. Purpuric skin lesions spread very rapidly despite broad-spectrum antibiotics and right leg amputation. Plasmapheresis and intravenous immunoglobulins gave complete clinical recovery and normalization of protein S level within 10 days, with progressive clearance of antiprotein S autoantibodies. Transient severe protein S deficiencies have previously been reported in patients with nonbacterial PF, usually after varicella infection. This is the first documented case of PF after HHV6 infection.

[Purpura fulminans: a rare complication of chickenpox]. / Purpura fulminans, een zeldzame complicatie van waterpokken.

A 3.5-year-old boy presented with purpura on the buttocks extending towards both legs. Two weeks earlier, he had had chickenpox. Because of the rapidly progressing purpura with clinical signs of hypovolaemic shock, he was treated with fresh frozen plasma, packed red blood cells, intravenous immunoglobulins, prednisolone, acyclovir and ceftriaxone. The purpura stopped spreading. In the next few days, the skin at the site of the purpura became necrotic and was excised, as was the subcutis and part of the fascia on both legs and flanks. The right lower leg was amputated and a temporary colostomy was created to prevent faecal contamination of the wounds. The patient recovered and was discharged after three months. Purpura fulminans is a rare complication after a primary infection with varicella zoster virus. A varicella infection may lead to protein S deficiency resulting in diffuse intravascular coagulation and severe skin defects.

Intestinal lymphangiectasia with protein-losing enteropathy in Waldenstrom macroglobulinemia.

Gastrointestinal complications of Waldenstrom macroglobulinemia (WM) are unusual but often treatable. We report a case of WM associated with significant gastrointestinal involvement manifest as chronic diarrhea with protein-losing enteropathy and recurrent venous thromboses. Small bowel biopsy was negative for amyloidosis but revealed intestinal lymphangiectasia with deposition of monoclonal IgM. The patient was treated with cyclophosphamide, vincristine, and prednisone with rapid and complete resolution of the peripheral edema and diarrhea. We follow the case report with a retrospective analysis of patients with WM and gastrointestinal symptoms seen at our institution, and review the available literature on this unusual association. An increased awareness of the gastrointestinal manifestations of WM may help to explain and to treat the chronic, debilitating, and potentially life-threatening symptoms in patients with this lymphoproliferative disorder.

[Mesenteric vein thrombosis and protein C and S deficiency in a patient with chronic hepatitis C on treatment with interferon and ribavirin]. / Trombosis mesentérica y déficit de proteínas C y S en un paciente con hepatitis C crónica en tratamiento con interferón y ribavirina.

We describe the case of a 67 year old male with chronic hepatitis C on treatment with pegylated interferon and ribavirin who, after two and a half months of combined treatment, presented with a picture of acute mesenteric vein thrombosis that required urgent surgery. It re-occurred several days later and was his cause of death. In the thrombophilia study carried out immediately after surgery a decrease in protein C and S was considered as a cause of hypercoagulability. Protein C and S deficiency, natural anticoagulants synthesised in the liver, in patients without hepatic disease is a known cause of mesenteric thrombosis. Its decrease has also been described in the context of chronic hepatic diseases, including C virus chronic hepatitis, although it is not known for sure if this hypercoagulability state is a primary or secondary manifestation. Chronic hepatitis C and treatment with interferon has often been associated with a procoagulant state, and on many occasions due to different factors and mechanisms.

Catastrophic antiphospholipid syndrome associated with malignancies (case report and review of the literature).

We describe a 58-year old female patient with rapid development of arterial and venous thromboembolisms, including deep vein thrombosis (DVT) in the lower limbs, recurrent cerebral infarctions and bilateral pulmonary emboli. Her laboratory data on admission showed positive anticardiolipin antibody of IgG isotype (IgG aCL) and positive anti-beta2 glycoprotein-I antibody of IgG isotype (IgG abeta2-GPI), and decreased protein C activity and protein S antigen. Systemic examinations revealed the presence of an ovarian cancer. Surgical resection was attempted, but her cancer infiltrated the pelvic wall and could not be resected. Despite treatment with unfractionated heparin followed by warfarin, she died due to recurrent episodes of cerebral infarction. This case was considered as probable catastrophic antiphospholipid syndrome (CAPS), which might be associated with ovarian cancer. Known as Trousseau's syndrome, arterial and, more commonly, venous thrombosis is a frequent complication of cancer and sometimes a harbinger of occult cancer. Our case indicates that there is an overlap between antiphospholipid syndrome (APS) and Trousseau's syndrome. It is important to bear in mind that a thrombotic event associated with cancer can be the first manifestation of CAPS.

Molecular bases of type II protein S deficiency: the I203-D204 deletion in the EGF4 domain alters GLA domain function.

OBJECTIVE: To characterize the first type II protein S (PS) deficiency affecting the epidermal growth factor (EGF)4 domain, a calcium-binding module with a poorly defined functional role. PATIENTS: The proband suffered from recurrent deep vein thrombosis and showed reduced PS anticoagulant activity (31%), and total, free PS antigen and C4bBP levels in the normal range. RESULTS: Reverse transcription-polymerase chain reaction analysis showed the presence of the IVSg-2A/T splicing mutation that, by activating a cryptic splice site, causes the deletion of codons Ile203 and Asp204. Free PS, immunopurified from proband's plasma, showed an altered electrophoretic pattern in native condition or in the presence of Ca2+. The recombinant PS (rPS) mutant showed reduced anticoagulant (<10%) and activated protein C-independent activities (24-38%) when compared with wild-type rPS (rPSwt). Binding of the rPS variant to phospholipid vesicles (Kd 235.7 +/- 30.8 nM, rPSwt; Kd 15.2 +/- 0.9 nM) as well as to Ca2+-dependent conformation-specific monoclonal antibodies for GLA domain was significantly reduced. CONCLUSIONS: These data aid in the characterization of the functional role of the EGF4 domain in the anticoagulant activities of PS and in defining the thrombophilic nature of type II PS deficiency.

Anti-protein S antibodies following a varicella infection: detection, characterization and influence on thrombin generation.

Postinfectious purpura fulminans is a rare disease. Varicella is one of the precipitating conditions and we recently observed such a case. The 4-year-old child was found to have a severe transient protein S deficiency. By enzyme-linked immunosorbent assay and surface plasmon resonance we first demonstrated that anti-protein S antibodies were present and also transient. Next we characterized the epitopes against which these antibodies were directed and found that they predominantly recognized the N-terminal part of protein S. Finally we showed by thrombography a transient dramatic hypercoagulable state as a result of thrombin being unregulated by the dynamic protein C inhibitory system: in vitro thrombin generation, in response to a low concentration of tissue factor, was almost insensitive to activated protein C up to 25 nmol L(-1) on day 4 while it was normally sensitive on day 42. For the first time, we demonstrated a temporal relationship between protein S deficiency, antibodies to protein S and hypercoagulability, thus supporting the pathogenic role of these antibodies.