Neglected vitamin K deficiency causing coagulation dysfunction in an older patient with pneumonia: a case report.

BACKGROUND: The development of coagulation disorders can be dangerous and fatal in the older people, especially those with multiple medical conditions. Vitamin K-dependent coagulation disorders are easily overlooked when anticoagulant drugs are not used and the patient shows no signs of bleeding. CASE PRESENTATION: We report a case of a 71-year-old male suffering from pulmonary infection with severe coagulation disorder without bleeding symptoms. He also had a history of Parkinson's disease, Alzheimer's disease and cardiac insufficiency. Coagulation tests were normal at the time of admission, prothrombin time (PT) is 13.9 (normal, 9.5-13.1) seconds and the activated partial thromboplastin time (APTT) is 30.2 (normal, 25.1-36.5) seconds. But it turned severely abnormal after 20 days (PT: 136.1 s, APTT: 54.8 s). However, no anticoagulants such as warfarin was used and no bleeding symptoms were observed. Subsequent mixing studies with normal plasma showed a decrease in prothrombin times. Vitamin K deficiency was thought to be the cause of coagulation disorders considering long-term antibiotic therapy, especially cephalosporins, inadequate diet and abnormal liver function. After supplementation with 20 mg of vitamin K, coagulation dysfunction was rescued the next day and serious consequences were effectively prevented. CONCLUSIONS: Overall, timely vitamin K supplementation with antimicrobials that affect vitamin K metabolism requires clinician attention, especially in older patients who are multimorbid, frail or nutritionally compromised, and are admitted to hospital because of an infection that needs antimicrobial therapy are at risk of clotting disorders due to abnormal vitamin K metabolism secondary to altered gut flora, which can exacerbate existing nutritional deficiencies.

An Unusual Presentation of Hemorrhagic Disease in an Infant: A Probable Case of Abetalipoproteinemia.

We report a probable case of abetalipoproteinemia in an infant who presented with unusual symptoms of late-onset vitamin K deficiency. Abetalipoproteinemia is a rare autosomal recessive disease caused by mutation of the microsomal triglyceride transfer protein gene, resulting in the absence of microsomal triglyceride transfer protein function in the small bowel. It is characterized by the absence of plasma apolipoprotein B-containing lipoproteins, fat malabsorption, hypocholesterolemia, retinitis pigmentosa, progressive neuropathy, myopathy, and acanthocytosis. A biopsy of the small intestine characteristically shows marked lipid accumulation in the villi of enterocytes. Large supplements of fat-soluble vitamins A, D, E, and K have been shown to limit neurologic and ocular manifestations. Dietary fat intake is limited to medium-chain triglycerides.

Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysis patients.

The cardinal biological role of vitamin K is to act as cofactor for the carboxylation of a number of vitamin K-dependent proteins, some of which are essential for coagulation, bone formation and prevention of vascular calcification. Functional vitamin K deficiency is common and severe among dialysis patients and has garnered attention as a modifiable risk factor in this population. However, no single biochemical parameter can adequately assess vitamin K status. For each biological function of vitamin K, the degree of carboxylation of the relevant vitamin K-dependent protein most accurately reflects vitamin K status. Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) is the best biomarker for vascular vitamin K status when cardiovascular endpoints are studied. Dp-ucMGP levels are severely elevated in haemodialysis patients and correlate with markers of vascular calcification and mortality in some but not all studies. The aetiology of vitamin K deficiency in haemodialysis is multifactorial, including deficient intake, uraemic inhibition of the vitamin K cycle and possibly interference of vitamin K absorption by phosphate binders. The optimal vitamin K species, dose and duration of supplementation to correct vitamin K status in dialysis patients are unknown. Dp-ucMGP levels dose-proportionally decrease with supraphysiological vitamin K2 supplementation, but do not normalize even with the highest doses. In the general population, long-term vitamin K1 or K2 supplementation has beneficial effects on cardiovascular disease, bone density and fracture risk, and insulin resistance, although some studies reported negative results. In haemodialysis patients, several trials on the effects of vitamin K on surrogate markers of vascular calcification are currently ongoing.

Late-Onset Vitamin K Deficiency Presenting as Scrotal Bruising and Mediastinal Mass.

Although there are several reports of intracranial hemorrhage associated with vitamin K deficient bleeding, there are few reported cases of extracranial manifestations, specifically involving the thymus. Here, we discuss the unique case of a 4-week-old infant presenting with scrotal discoloration, respiratory distress, and widened mediastinum, found to have thymic hemorrhage related to confirmed coagulopathy secondary to late-onset vitamin K deficiency bleeding of the newborn.

Coagulopathy in Zellweger spectrum disorders: a role for vitamin K.

INTRODUCTION: Zellweger spectrum disorders (ZSDs) are caused by an impairment of peroxisome biogenesis, resulting in multiple metabolic abnormalities. This leads to a range of symptoms, including hepatic dysfunction and coagulopathy. This study evaluated the incidence and severity of coagulopathy and the effect of vitamin K supplementation orally and IV in ZSD. METHODS: Data were retrospectively retrieved from the medical records of 30 ZSD patients to study coagulopathy and the effect of vitamin K orally on proteins induced by vitamin K absence (PIVKA-II) levels. Five patients from the cohort with a prolonged prothrombin time, low factor VII, and elevated PIVKA-II levels received 10 mg of vitamin K IV. Laboratory results, including thrombin generation, at baseline and 72 h after vitamin K administration were examined. RESULTS: In the retrospective cohort, four patients (13.3%) experienced intracranial bleedings and 14 (46.7%) reported minor bleeding. No thrombotic events occurred. PIVKA-II levels decreased 38% after start of vitamin K therapy orally. In the five patients with a coagulopathy, despite treatment with oral administration of vitamin K, vitamin K IV caused an additional decrease (23%) of PIVKA-II levels and increased thrombin generation. CONCLUSION: Bleeding complications frequently occur in ZSD patients due to liver disease and vitamin K deficiency. Vitamin K deficiency is partly corrected by vitamin K supplementation orally, and vitamin K administered IV additionally improves vitamin K status, as shown by further decrease of PIVKA-II and improved thrombin generation.

Review on Vitamin K Deficiency and its Biomarkers: Focus on the Novel Application of PIVKA-II in Clinical Practice.

BACKGROUND: Vitamin K (VK) is a co-factor of the γ-glutamyl carboxylase that catalyzes the conversion of glutamate residues to γ-carboxyglutamate in VK-dependent proteins. The carboxylation reaction imparts the essential calcium-binding residues for the biological function of several proteins involved in the process of coagulation and bone metabolism. VK deficiency is frequently encountered in newborns and can lead to fatal hemorrhagic complications. This review describes and discusses the clinical application of VK deficiency testing. METHODS: References and data were researched in PubMed and reviewed. RESULTS: In adults, VK deficiency is associated with uncontrolled bleeding, liver dysfunction, osteoporosis, and coronary diseases. An improved understanding of the role of VK deficiency in health and illness can be achieved by setting a gold-standard in the inter-laboratory estimations of VK. However, conventional methods used to measure the VK deficiency based upon the coagulation time lack sensitivity and specificity. Recently, the alterations in proteins induced by VK absence or antagonism (PIVKA) have proven to be suitable biomarkers for detecting VK deficiency. The measurement of PIVKA-II exhibits an enhanced sensitivity and specificity in comparison to other methods conventionally used for the assessment of VK deficiency in newborns and adults. CONCLUSIONS: PIVKA-II could potentially be employed as an effective biomarker in the diagnosis of VK deficiency.

Diagnostic Error of a Patient with Combined Inherited Factor VII and Factor X Deficiency due to Accidental Ingestion of a Diphacinone Rodenticide.

BACKGROUND: To explore the characteristics of laboratory examination and confirm the diagnosis of a patient with combined inherited FVII and FX deficiency after he ingested diphacinone rodenticide accidentally. METHODS: The coagulant parameter screening tests and coagulation factor activities were tested many times in the patient due to accidental ingestion of a diphacinone rodenticide. After the patient was treated for more than one year, gene analysis of correlated coagulation factors was analyzed in the patient and other family members by DNA direct sequencing. 106 persons were selected as controls from routine health examinations. RESULTS: After the patient was admitted to hospital, routine coagulation screening tests revealed the prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) and low levels of vitamin K-dependent coagulation factors (FII, FVII, FIX, FX) activity, which was 102.4 seconds, 88.5 seconds, 7%, 3%, 8%, and 2%, respectively. During more than one year of treatment, the value of PT and APTT still showed significantly prolonged activity and FVII and FX activity levels were about 5%. While FII and FIX activity levels were in the normal range after 12 weeks of treatment. Two homozygous mutations, g.11267C>T of F7 gene resulting in the substitution Arg277Cys and g.28139G>T of F10 gene leading to the substitution Val384Phe, were identified in the patient. The patient's parents and sister was heterozygous for Arg277Cys and Val384Phe mutations. FVII and FX antigen levels in the patient were 7% and 30%, respectively. CONCLUSIONS: There were many similarities in the characteristics of laboratory examination between combined inherited FVII and FX deficiency and acquired vitamin K deficiency. The best way to identify them was gene analysis.

A Blown Pupil and Intracranial Hemorrhage in a 4-Week-Old: A Case of Delayed Onset Vitamin K Deficiency Bleeding, a Rare "Can't Miss" Diagnosis.

BACKGROUND: Infants are at risk for vitamin K deficiency bleeding (VKDB) because of limited stores of vitamin K (VK) at birth and a low concentration of VK in human breast milk. Therefore, the administration of intramuscular (IM) VK at birth has been recommended since 1961 in the United States. Infants who do not receive IM VK and who are exclusively breast-fed are at increased risk for VKDB. While VKDB is rare, a common presentation of late onset VKDB is intracranial hemorrhage. CASE REPORT: We report the case of a 4-week-old infant who presented to the emergency department with lethargy and a grossly dilated right pupil. The parents denied trauma. A computed tomography scan revealed a right-sided subdural hematoma with midline shift. The infant's international normalized ratio was >10.9 and his prothrombin time PT was >120 seconds. VK was administered and the child was transferred to a tertiary care center for emergent neurosurgery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The difficult part of making this critical diagnosis is considering it. Any bleeding in a newborn without trauma should prompt inquiry regarding neonatal VK administration and a serum prothrombin time level. Fortunately, once the diagnosis is made, therapy in the emergency department can be lifesaving and is familiar to emergency physicians. Treatment parallels usual care for the adult with excess anticoagulation caused by warfarin. Prompt intravenous VK is universally accepted. Studies to support fresh frozen plasma or prothrombin complex concentrate are lacking but make good clinical sense for life-threatening bleeding.

Vitamin K status and mortality after kidney transplantation: a cohort study.

BACKGROUND: Vitamin K modulates calcification by activating calcification inhibitors such as matrix Gla protein (MGP). In kidney transplant recipients, vitamin K insufficiency is common, but implications for long-term outcomes are unclear. STUDY DESIGN: Single-center observational study with a longitudinal design. SETTING & PARTICIPANTS: 518 stable kidney transplant recipients; 56% men; mean age, 51±12 (SD) years; and a median of 6 (IQR, 3-12) years after kidney transplantation. FACTOR: Plasma desphosphorylated-uncarboxylated MGP (dp-ucMGP) levels, reflecting vitamin K status. OUTCOMES: All-cause mortality and transplant failure. RESULTS: At inclusion, median dp-ucMGP level was 1,038 (IQR, 733-1,536) pmol/L, with 473 (91%) patients having vitamin K insufficiency (defined as dp-ucMGP>500pmol/L). During a median follow-up of 9.8 (IQR, 8.5-10.2) years, 152 (29%) patients died and 54 (10%) developed transplant failure. Patients in the highest quartile of dp-ucMGP were at considerably higher mortality risk compared with patients in the lowest quartile (HR, 3.10; 95% CI, 1.87-5.12; P for trend<0.001; P for quartile 1 [Q1] vs Q4<0.001). After adjustment for potential confounders, including kidney function and exclusion of patients treated with a vitamin K antagonist, this association remained significant. Patients in the highest quartile also were at higher risk of developing transplant failure (HR, 2.61; 95% CI, 1.22-5.57; P for trend=0.004; P for Q1 vs Q4=0.01), but this association was lost after adjustment for baseline kidney function (HR, 1.20; 95% CI, 0.52-2.75; P for trend=0.6; P for Q1 vs Q4=0.7). LIMITATIONS: Although MGP exists as various species, only dp-ucMGP was measured. No data were available for vascular calcification as an intermediate end point. CONCLUSIONS: Vitamin K insufficiency, that is, a high circulating level of dp-ucMGP, is highly prevalent in stable kidney transplant recipients and is associated independently with increased risk of mortality. Future studies should address whether vitamin K supplementation may lead to improved outcomes after kidney transplantation.

Suboptimal vitamin K status and its risk factors in a population of Chinese chronic haemodialysis patients.

AIMS: Vitamin K deficiency is known to be common in haemodialysis patients and associates with adverse outcomes in this population, particularly vascular calcification. We aimed to investigate the vitamin K status in a population of Chinese haemodialysis (HD) patients. METHODS: We collected demographic and biochemical data from a population of maintenance HD (MHD) patients in our unit and a control group composed of healthy subjects from our outpatient clinic. Fasting serum samples from all subjects were collected for the measurement of known vitamin K-dependent proteins i.e. matrix Gla protein (MGP), osteocalcin (OC) and uncarboxylated osteocalcin (ucOC). We also quantified the fraction of ucOC to total OC (%ucOC). Differences of these parameters between groups were analyzed and risk factors of vitamin K deficiency based on the definition as per %ucOC were investigated. RESULTS: We enrolled 93 MHD patients as a test group and 93 healthy subjects as a control group. There was no significant difference in MGP between groups (4.0 ± 2.8 pg/mL in MHD vs 4.2 ± 1.2 pg/mL in control; P = 0.676). Mean %ucOC was significantly greater in the MHD patients as compared to control subjects (76.4 ± 20.0% in MHD vs 48.56 ± 15.5%; P < 0.001). Time on dialysis and low-density lipoprotein cholesterol level appeared to be indicators of vitamin K deficiency, with the former being an independent risk factor. CONCLUSIONS: Defining Vitamin K deficiency by %ucOC, suboptimal vitamin K levels appear common in Chinese MHD patients. Time on dialysis and LDL cholesterol level predict vitamin K deficiency.

Toddler with unexplained multiple bruises.

It is often very challenging for clinicians to distinguish between accidental, intentional, and other causes of bruising such as underlying bleeding disorder in a child with extensive bruising. We present a case of a 17-month-old healthy male who presented to our emergency department with multiple unexplained bruises after an unwitnessed fall and was subsequently diagnosed with congenital vitamin K-dependent clotting factor deficiency. This case illustrates the importance of thorough assessment in evaluating a child with multiple bruises to differentiate accidental from intentional injuries as well as to recognize bleeding disorders, which warrant specific diagnostic workup.

[The diagnostic value of protein induced by vitamin K absence or antagonist-II in non-infant patients with acquired deficiency of vitamin K-dependent coagulation factors].

OBJECTIVE: To explore the diagnostic value of protein induced by vitamin K absence or antagonist -II(PIVKA-II) in non-infant with acquired deficiency of vitamin K-dependent coagulation factors(ADVKCF). METHODS: PIVKA-II levels were measured by ELISA in 50 patients with ADVKCF on day 0, 3, 7 after vitamin K treatment. Prothrombin time(PT), APTT, FII: C, FVII: C, FIX: C, and FX: C were analyzed simultaneously. Twenty healthy subjects were enrolled as controls. RESULTS: The average level of PIVKA-II in ADVKCF group was (3.83 ± 1.40)µg/L, while (1.30 ± 0.54) µg/L in the control group (P < 0.05). The PIVKA-II levels on day 0 and 3 did not show significant difference [(3.83 ± 1.40) µg/L vs (3.79 ± 0.66) µg/L, P > 0.05], but decreasing significantly on day 7 compared to the control group(P < 0.05). The PIVKA-II level was (3.78 ± 1.30) µg/L in patients receiving plasma transfusion, while (3.91 ± 1.49)µg/L in no-plasma-transfusion group (P > 0.05). Coagulation factors II, VII, IX and X activity which decreased significantly before treatment returned to normal range after one week use of vitamin K, leading to complete correction of prolonged APTT and PT (>100 seconds). CONCLUSIONS: The PIVKA-II level in ADVKCF patients is significantly higher than that of healthy subjects within one week treatment of vitamin K, which is not influenced by plasma transfusion. This study suggests that PIVKA-II is a more sensitive parameter than APTT, PT and the activity of coagulation factor, which could be a valuable factor in the early diagnosis of ADVKCF.

Take the Shot: A Review of Vitamin K Deficiency.

Vitamin K is essential for the process of coagulation. In its absence, severe and sometimes fatal bleeding events can occur, especially in newborns. Vitamin K prophylaxis at birth has been shown to prevent morbidity and mortality associated with vitamin K deficiency bleeding (VKDB) and is recommended by multiple organizations including the American Academy of Pediatrics and the World Health Organization. Pediatricians should feel comfortable explaining the risks and benefits of vitamin K prophylaxis to families and should be equipped to recognize signs of VKDB, especially given increasing rates of parental refusal. This article aims to improve understanding of VKDB, including prevention, early recognition, and treatment. [Pediatr Ann. 2023;52(2):e42-e45.].

Late-type vitamin K deficiency bleeding: experience from 120 patients.

BACKGROUND: Deficiency of vitamin K predisposes to early, classic, or late vitamin K deficiency bleeding (VKDB), of which late VKDB may be associated with serious and life-threatening intracranial bleeding. Late VKDB is characterized with intracranial bleeding in infants aged 2-24 weeks due to severe vitamin K deficiency, occurring primarily in exclusively breast-fed infants. Late VKDB is still an important cause of mortality and morbidity in developing countries. MATERIALS AND METHODS: We presented 120 cases of late VKDB, which were evaluated at Erciyes University Medical Faculty Hospital between June 1990 and June 2006. RESULTS: Signs and symptoms of the patients were bulging fontanels (70%); irritabilities (50%); convulsions (49%); bleeding and ecchymosis (47%); feeding intolerance, poor sucking, and vomiting (46%); diarrhea (34%); jaundice (11%); and pallor (9%), and among these infants, 21% received medication before the diagnosis (10%, antibiotics; 3%, simethicone; 4%, paracetamol; and 4%, phenobarbital). Intracranial hemorrhage in 88 (73%) patients has been observed. The hemorrhage was subdural in 34 (28%) cases, intracerebral in 28 (23%), subarachnoid in 17 (14%), intraventricular in 9 (8%), intracerebral and subdural in 12 (10%), subdural and subarachnoid in 6 (5%), and combination of intracerebral, subdural, and intraventricular in 14 (12%), and the mortality rate was 31%. CONCLUSION: Although late VKDB leads to significant morbidity and mortality, it can be avoided by providing vitamin K prophylaxis to all newborns. Administration of vitamin K (1 mg) at birth can prevent intracranial bleeding and other hemorrhagic manifestations.

Warfarin hypersensitivity due to gluten-sensitive enteropathy: a case study.

A 53 year old female who was maintained on long-term warfarin therapy due to history of pulmonary embolism, repeatedly presents with an abnormally prolonged Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT). After many asymptomatic episodes were corrected with Vitamin K therapy to temporarily reverse the effects of the warfarin, the cause of the apparent coagulopathy was further investigated. Factor Activity Assays of the common pathway factors II, IX, and X all revealed critically low values; below the threshold even a loading dose of warfarin is typically capable of eliciting. The patient tested strongly positive for Tissue Transglutaminase IgA, which is highly suggestive of a gluten-sensitive enteropathy. One effect of this condition is malabsorption due to flattened intestinal villi. The patient was determined to have an acquired vitamin K deficiency secondary to gluten-sensitive enteropathy. Her condition was exacerbated by the long-term warfarin therapy, resulting in the prolonged PT and PTT. The patient was treated with vitamin K therapy, which reversed the deficiency and corrected her abnormal coagulation results.

Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth.

BACKGROUND: There is near-global consensus that all newborns be given parenteral vitamin K1 (VK1 ) at birth as prophylaxis against VK deficiency bleeding (VKDB). Breastmilk has a low VK content and cases of late VKDB are reported in exclusively breastmilk-fed preterm infants despite VK prophylaxis at birth. OBJECTIVES: To assess the prevalence of functional VK insufficiency in preterm infants based on elevated under-γ-carboxylated (Glu) species of Gla proteins, factor II (PIVKA-II), and osteocalcin (GluOC), synthesized by liver and bone, respectively. PATIENTS/METHODS: Prospective, multicenter, observational study in preterm infants born <33 weeks' gestation. Blood samples and dietary history were collected before hospital discharge, and after discharge at 2-3 months' corrected age. Outcome measures were serum VK1 , PIVKA-II, and %GluOC (GluOC as a percentage of the sum of GluOC plus GlaOC) compared between exclusively breastmilk-fed and formula/mixed-fed infants after discharge. RESULTS: After discharge, breastmilk-fed babies had significantly lower serum VK1 (0.15 vs. 1.81 µg/L), higher PIVKA-II (0.10 vs. 0.02 AU/ml) and higher %GluOC (63.6% vs. 8.1%) than those receiving a formula/mixed-feed diet. Pre-discharge (based on elevated PIVKA-II), only one (2%) of 45 breastmilk-fed infants was VK insufficient. After discharge, eight (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only one (4%) of 25 formula/mixed-fed babies. CONCLUSIONS: Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK1 supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.

Vitamin K Supplementation in Chronic Kidney Disease Patients: Where is the Evidence?

Vascular calcification (VC) is highly prevalent in Chronic Kidney Disease (CKD) patients, progresses gradually with deterioration of kidney function and is a strong, independent predictor of cardiovascular (CV) mortality. Matrix Gla Protein (MGP), the most potent inhibitor of VC, requires vitamin K as a co-factor to become biologically active. Accumulating epidemiological data have associated vitamin K depletion with VC progression and CV outcomes. CKD patients are characterized by poor vitamin K status and at the same time, pronounced CV calcification. In early and advanced CKD, including end-stage kidney disease, exogenous supplementation of vitamin K (especially with menaquinone 7, its most bioavailable form) might decrease the inactive form of MGP (dephosphorylated, uncarboxylated MGP) and probably retard the progression or even reverse VC. Here, we focus and discuss the interventional human studies of vitamin K supplementation in CKD patients and suggest future directions in this area of interest.

Atypical presentation of pseudoxanthoma elasticum with abdominal cutis laxa: evidence for a spectrum of ectopic calcification disorders?

A patient is presented with severe cutis laxa of the abdomen. Molecular investigations, including sequencing of the fibulin-5 and elastin gene, failed to endorse the diagnosis of inherited cutis laxa. Ultrasonographical discovery of renal calcifications during his general work-up suggested a possible diagnosis of pseudo-xanthoma elasticum (PXE). A discrete yellowish reticular pattern in the anterior neck region was detected upon careful clinical examination. Clinically, the patient presented characteristics of both classic PXE (retinopathy, renal calcifications) and the PXE-like syndrome (cutis laxa beyond the flexural areas). Skin biopsy and ophthalmological examination confirmed the diagnosis of PXE. In addition, ultrastructural evaluation revealed calcium deposits in the periphery of elastic fibers, a typical observation in the PXE-like syndrome. Immunohistochemical experiments and ELISA tests for various inhibitors of calcification displayed results which were partly reminiscent of both PXE and the PXE-like syndrome. Molecular analysis revealed not only two ABCC6 mutations (related to PXE), but also a gain of function SNP in the GGCX gene, in which loss-of-function mutations cause the PXE-like syndrome. We conclude that the patients phenotype and--to a further extent--the PXE-like syndrome, are part of a spectrum of ectopic calcification disorders which are clinically and/or pathogenetically related to PXE. The molecular findings in this patient are however insufficient to explain the entire phenotype and suggest a role for multiple genetic factors in soft tissue mineralization.