Clinical And Laboratory Studies Of Patients Of Non-infant With Acquired Deficiency Of Vitamin K-dependent Coagulation Factors

The first section Clinical analysis of102non-infant patients withacquired deficiency of vitamin K-dependent coagulation factorsObjective To explore the clinical features and treatment of non-infant patients withacquired deficiency of vitamin K-dependent coagulation factors (ADVKDCF). MethodsAnalysis was performed on the data of the etiological factors, clinical manifestations,laboratory examinations, diagnoses and treatments of102non-infant patients with acquireddeficiency of vitamin K-dependent coagulation factors. Results There were85patientswith unknown cause (A subgroup),17patients with clear histories of anticoagulantrodenticide poisoning (B subgroup) and three with warfarin overdosage(C subgroup). Thepresentations of hemorrhage of the patients were various.The most common hemorrhagewas hematuria(52/102), followed by mucocutaneous bleeding(44/102).In28patients,hemoglobin (Hb) level was less than100g/L due to blood loss. And there were nodifference in Hb and the delayed time from hemorrhage manifestation to definite diagnosisamong the three subgroups. Eighty seven of102patients were misdiagnosed and themedian time from hemorrhage manifestation to definite diagnosis was8days (range,2daysto62months). Laboratory examinations showed normal platelet count,thrombin time andnormal fibrinogen concentration,but prolonged plasma prothrombin time(PT), activatedpartial prothrombin time (APTT) and international normalized ratio (INR)．Patients of Csubgroup only discontinued warfarin, while the rest patients had received intravenousvitamin K1with a dose of20to240mg/d.The bleeding symptoms disappeared in1to2days after treatment and the Hb level increased dramatically. There were significantdifferences in PT, APTT and INR in the patients before and after treatment (P <0.01).There was significant difference recurrence rate between the vitamin K sequential therapygroup and the non-sequential group (P=0.001). Conclusions The presentations of hemorrhage of the non-infant patients with ADVKDCF were various. The most commonhemorrhage symptom was hematuria, and the cause of major patients was unknown.Vitamin K sequential therapy is promptly effective and economic treatment to preventrecurrence. The anticoagulant rodenticide poisoning patients share same clinical featuresand favourable prognosis with those whose etiology is unknown.The second section Laboratory study on85patients of non-infant withacquired deficiency of vitamin K-dependent coagulation factorsObjective To investigate non-infant patients with acquired deficiency of the vitaminK-dependent coagulation factors (ADVKDCF) in etiology and laboratory examinations.Methods In85patients, anticoagulant rodenticides in blood and urine were tested by highperformance liquid chromatography tandem mass spectmmeny(LC-MS/MS).There were50patients whose PIVKA-Ⅱlevel assayed by ELISA, and PT and APTT measured withautomatic blood coagulation analyzer on day0,3,7after vitamin K treatment, and Ⅱ，Ⅶ，IX and X factor activities were measured before and after7days of medication. Twentyhealthy persons were used as a control group. Results Anticoagulant rodenticides werepositive in total85patients’ blood samples and in3urine samples, mostly werebromadiolone. The average level of PIVKA Ⅱof patients3.83ng/ml, and control group is1.30ng/ml. There was significant difference between two groups (P <0.05). ThePIVKA-Ⅱ level on0and3days of medication is no statistically significant (3.83ng/ml vs3.64ng/ml, P＞0.05). After7days treatment with vitamin K, PIVKA-Ⅱ level decreasedsignificantly compared to the control group(P <0.05).The PIVKA-Ⅱlevel in plasmatransfusion patients was3.78ng/ml, which was no statistically different compared to the notransfusion group(P＞0.05). Coagulation factor II, Ⅶ, IX, Ⅹ, PC and PS activitydecreased significantly before treatment, while APTT and PT was significantly prolonged(>100seconds). They were returned to normal after vitamin K treatment. All bleeding wascontrolled after vitamin K sequential thrapy. Only one patient relapsed due to ingestion ofrodenticides again, and the others were cured. Conclusions In ADVKDCF patients,coagulation factors II, VII, Ⅸ, Ⅹ,PC and PS activity decreased, but APTT, PT wasprolonged significantly. Anticoagulant rodenticides poisoning is the only causative inpatients with unknown ADVKDCF in China and related assays are needed as soon aspossible. The PIVKA-Ⅱ level in patients is significantly higher than normal within3days of vitamin K treatment. It has the value of early diagnosis to ADVKDCF, and theconcentration is not interfered by plasma transfusion. Patients with unknown ADVKDCFhas good prognosis, however, all patients must be aware of rodenticides poisoning again.The third section Study on diagnosis and treatment of non-infantpatients’ intracranial hemorrhage due to acquired deficiency of vitaminK-dependent coagulation factorsObjective Vitamin K is required for γ-carboxylation of glutamic acid residues of theprocoagulant factors II (prothrombin), VII, IX, and X and the anticoagulant factors proteinC and protein S. Acquired deficiency of vitamin K dependent coagulation factors (VKDCF)results from absolute vitamin K deficiency and/or abnormal cycling utilization. Thegreatest threat to life is the hemorrhage of central nervous system, which is rare but fatal.The clinical features and prognosis of4patients with intracranial hemorrhage (ICH) due toacquired deficiency of VKDCF were analyzed. Methods Initial prothrombin tim(PT),activated partial thromboplastin time (APTT) and coagulation factors analysis wasperformed on STA Compact analyazer. Factor’s activities were determined using standardtechniques of deficient plasma as substrate in PT or activated PPT testing. Anticoagulantrodenticide concentration was determined by high-performance liquidchromatography-tandem mass spectrometry (HPLC-MS/MS) with fluorescence detectionwith minimal detection capabilities of0.2ng/mL.The PIVKAⅡconcentration was assayedby ELISA. All patients received fresh frozen plasma (FFP) and venous high dose ofvitamin K1at the first3days and then were given oral vitamin K44mg.kg-1.d-1. Logisticregression was used to assess the high risk factors what was composed of APTT, PT, FC: II,FC: VII, FC:IX, FC:X activities, blood platelet counters and other bleeding sites.ResultsAll patients had various episodes of bleeding and manifestation with intracranialhypertension. Cranial CT and/or MRI demonstrated ICH.The coagulation tests showedthat the average activities of VKDCFs were decreased with markedly prolonged PT andAPTT that were corrected with normal plasma. Blood platelet count, fibrinogen, thrombintime (TT) and hepatic function were normal. Serum high bromadiolone levels were foundin total4patients. The plasma PIVKA-II concentration was significantly increased in ICHpatients than that of the no ICH patients (16.1ng/ml vs4.16ng/ml, P=0.001) All patientsimproved quickly and had no sequelae and adverse reaction after high dose and long time of vitamin K treatment. Multiple factors analysis showed that plasma PIVKA-IIconcentrations>10ng/ml and no effective treatment time for bleeding manifestation>6dayswere the independent factor in ICH.Conclusions Spontaneous and systemic hemorrhages are the main clinicalpresentation of acquired deficiency of VKDCF, whereas intracranial bleeding is rarely seen.The diagnosis depends on the history, laboratory examinations and response to high doseof vitamin K. Early diagnosis and rapid correcting dyscoagulatoin are the key measures ofmanagement of acquired deficiency of VKDCF complicated with ICHs. Invasiveexamination and/or treatment shoule be avoided in the patients. The prognosis of acquireddeficiency of VKDCF is favorable，even complicated with ICH, and the plasma PIVKA-IIconcentrations>10ng/ml and no effective time from bleeding manifestation>6days werethe independent factor in ICH.