Multiple Factor Deficiency Research Articles

A Case of Haemorrhages caused by Multiple Myeloma Induced Factor Deficiencies: A Bleeding Enigma

A 74-year-old male patient presented with anaemia, thrombocytopenia, and extensive haemorrhages over both thighs and back. A coagulation work-up revealed markedly elevated Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT). Reduced functional values of fibrinogen as determined by clot-based assay (126.4 mg/dL), as well as factor V (17.5%) and factor X (27.8%), were noted. These abnormalities were corrected by mixing studies with normal plasma. Neoplastic plasma cells were seen in the bone marrow biopsy, while abdominal fat biopsies showed no amyloid deposition. Serum electrophoresis and immunofixation were positive for monoclonal gammopathy. The patient was diagnosed with multiple myeloma complicated by multiple acquired factor deficiencies. The patient showed a complete response within six months of treatment, which included bortezomib and cyclophosphamide. Multiple myeloma is a monoclonal proliferation of plasma cells that results in increased production of free immunoglobulin light chains, resulting in increased paraproteins. These paraproteins bind with and inhibit various clotting factors, resulting in their inactivation and depletion. Factor X deficiency in these cases is usually attributed to concomitant amyloidosis, whose fibrils bind to Factor X. However, these deficiencies can occur in the absence of amyloidosis as well. While various reports of this entity have highlighted isolated factor deficiencies including factors V, VII, IX, and X, multiple factor deficiency is a rare occurrence, with no other cases being reported from southern India.

Analysis of seven cases of multiple myeloma with initial manifestation of bleeding

A retrospective analysis of 7 patients of multiple myeloma (MM) with initial manifestation of bleeding and coagulation abnormalities were performed. Clinical manifestations, laboratory and imaging examinations were collected. The activity of coagulation factors was measured before the treatment. Single factor X deficiency was seen in one patient. Two cases had factor Ⅶ deficiency, while four other patients had multiple factor deficiency. The time from onset of symptoms to diagnosis ranged from 2 to 10 months. After anti-MM treatment started and plasma or coagulation factors were transfused, the prolonged coagulation time returned to normal from 28-84 days. Most of these patients presented large, deep and multiple sites of hematoma, which caused concerns of bone marrow puncture and may direct to other differential diagnoses. This is helpful to improve physicians' understanding of the special clinical characteristics in MM patients.

Paired APTTs of low and high lupus anticoagulant sensitivity permit distinction from other abnormalities and achieve good lupus anticoagulant detection rates in conjunction with dRVVT

A prolonged activated partial thromboplastin time (APTT) may be indicative of a specific or multiple factor deficiency, therapeutic anticoagulation, presence of a nonspecific factor inhibitor, or lupus anticoagulant (LA). Recently, pairing of the LA-sensitive APTT and standard APTT reagents, Cephen LS and Cephen, respectively, has been shown to be effective in LA detection. The present study aimed to evaluate the usefulness of this reagent pair for discriminating between causes of APTT elevation and the detection of LA in conjunction with dilute Russell's viper venom time (dRVVT). Plasma samples from 50 normal and 105 non-anticoagulated LA-positive patients in routine dRVVT and/or dilute APTT (dAPTT) via the percent correction formula were employed. Cephen LS/Cephen and dRVVT reagents LA1/LA2 were used to screen/confirm, respectively. Thirty-four symptomatic LA-negative, 25 warfarinised non-antiphospholipid syndrome, 6 coagulation inhibitors, 17 samples with hereditary elevated APTT, and 24 FVIII/IX/XI/XII and 17 FII/V/X artificial single deficiency plasmas were used. Thirty-three samples out of 105 (31%) were LA-positive in Cephen LS/Cephen. The total percent positivity in Cephen LS/Cephen and LA1/LA2 pairs was 89.1% against samples with the routine dRVVT/dAPTT double positive. The percent corrections of Cephen LS/Cephen in the routine dAPTT/dRVVT positive group were significantly higher than those in all other groups. The percent correction of the APTT reagent pair showed higher values in LA-positive samples. The combination will be useful with respect to differentiating LA from other abnormal samples and is effective in LA detection when paired with dRVVT.

Evaluation of prothrombin time and activated partial thromboplastin time mixing studies using an estimated factor correction method.

Mixing studies for prolonged prothrombin time (PT)/activated partial thromboplastin time (aPTT) are used to estimate whether the prolongation is due to an inhibitor or factor deficiency. We propose a new method of mixing study interpretation based on estimation of average factor level changes. Factor level vs. PT/aPTT curves were prepared for single factor, vitamin K-dependent factor, and all factor deficiencies. These curves were used to predict the factor level in the sample and the correction needed to differentiate deficiencies from inhibitors. We compared this estimated factor correction (EFC) method to normal range, percentage correction, and Rosner index. For a given factor level, multiple factor deficiencies prolonged the PT/aPTT more than single factor deficiency, necessitating different thresholds for defining correction on mixing studies. The EFC method was superior to other the correction methods, correctly identifying 38 of 39 known inhibitors, single and multiple factor deficiencies, and correctly identifying inhibitor vs. deficiency in 50 of 59 patient samples. In 99 adult patient mixing studies over 18 months, 30% showed deficiency only, 30% inhibitor only, whereas 40% showed evidence of both. The EFC method for PT/aPTT mixing study interpretation was more accurate than the comparison methods at determining deficiency versus inhibitor.

Red Cell Microparticles (RMP) Correct Factor Deficiencies and Hemodilution: Evaluation by Thromboelastography (TEG)

Abstract 2254 Introduction:We have recently reported that RMP are active in correcting a wide range of clotting defects, and suggested that RMP could be useful as a hemostatic agent for treating bleeding conditions. In this report, we investigate the effect of RMP on factor-deficient plasmas, and hemodilution in whole blood, by TEG. We tested varying levels of factor-deficient plasmas, and several degrees of hemodilution. Factor deficiency can range from mild (∼50%) to severe (∼99%), abrogating fibrin formation. Similarly, infusions of IV fluids in management of patients with trauma after massive hemorrhage resulting in hemodilution, leading to complex coagulopathy. This includes dilution of coagulation factors and release of inhibitors that can lead to a prothrombotic state, which can then result in factor exhaustion, exacerbating hemorrhagic diathesis. The effects of RMP on this complex coagulopathy is investigated. Methods:(i) RMP were prepared by high-pressure extrusion of washed packed RBCs. (ii) Factor deficient plasmas (FII, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII) were mixed with pooled normal plasma to achieve deficiencies ranging from 75%-95% depletion, in 5% increments, incubated with kaolin for 2 min, then assayed by TEG +/− RMP. (iii) For hemodilution experiments, whole citrated blood from healthy controls was mixed with increasing volume percentages of saline, then subjected to TEG +/− RMP. Results:(1) Factor Deficiency: RMP effectively shortened R (lag to reaction) and k (clotting rate) in all deficient plasmas, most prominently in FII, FVIII, FIX, and FX. While in other factors the RMP effect disappeared at >85% deficiency, these factors (II, VIII, IX, X) were significantly corrected even at 90% and 95% deficiency. The CI (coagulation index) was also consistently higher in presence of RMP, suggesting a global correction of coagulation profile, but MA (maximum amplitude) and G (shear elastic modulus) were unaffected by RMP at all levels of deficiency. (2) Hemodilution: Addition of RMP improved R time by 50% and k time by 40% on average, both at p<0.01. Angle ‘a' was increased by 30–50% (p=0.01), although this effect was pronounced only at milder levels of dilution. Again, MA and G were not significantly affected, except for modest improvement (10–15%) in the least diluted samples. However, CI consistently reflected an improved coagulation profile in presence of RMP (p<0.03). Counter-intuitively, R time initially decreased as dilution increased, but at >50% dilution this trend reversed and R times became longer with more dilution. Conclusions:(1) With regard to the use of RMP in therapy for bleeding, these results suggest efficacy of RMP in the treatment or prevention of coagulopathies due to hemodilution, and for factor deficiencies, especially of FII, FVIII, FIX, and FX. (2) With regard to mechanism, the absence of an effect of RMP on MA or G, which depend strongly on platelets, indicates that RMP cannot substitute for all aspects of platelet function. (Platelets were essentially absent from the deficient plasmas.) We surmise that the main activity of RMP in these experiments is to provide procoagulant phospholipids, especially for the tenase complex, but they may contribute other activities as well. In summary, these data further support the potential for RMP to correct a wide variety of coagulopathies resulting from single or multiple factor deficiencies, and may be an effective treatment for conditions including hemophilia, thrombocytopenia, and coagulopathy from hemodilution. Disclosures:No relevant conflicts of interest to declare.

Comparing the prothrombin time INR versus the APTT to evaluate the coagulopathy of acute trauma

Introduction In trauma patients, PT/INR or aPTT cutoffs of ≥ 1.5× normal are often used as triggers for the transfusion of plasma. Material and methods To evaluate the ability of the PT/INR or aPTT to predict low coagulation factor levels, these tests were compared to coagulation factor levels in samples with artificially prepared single and multiple factor deficiencies, 9 heparin-contaminated samples, 10 lupus inhibitor-containing samples, 21 samples with elevated factor VIII levels, and 35 samples from acute trauma patients. Results and conclusions The PT/INR and aPTT showed comparable sensitivity for single or multiple factor deficiencies in artificially deficient plasmas, but the PT/INR was more sensitive than the aPTT to low coagulation factor levels in actual trauma patients (sensitivity 84% versus 50%). The aPTT can show false positives with lupus anticoagulants and heparin contamination and false negatives in samples with elevated factor VIII. Thus, in the acute trauma setting, the PT/INR cutoff is a more reliable indicator of reduced coagulation factor levels.

Cryoprecipitate. Patterns of use.

The type of coagulation factors and proteins in cryoprecipitate determine the appropriate indications for its use. To determine the pattern of use at a tertiary care medical center, we performed a retrospective audit of cryoprecipitate utilization. A total of 51 patients received 88 pools of cryoprecipitate. In 39 patients, cryoprecipitate was transfused for appropriate indications: hypofibrinogenemia (n = 19), tissue plasminogen activator reversal (n = 1), management of massive transfusion (n = 7), correction of uremic bleeding (n = 2), and for making fibrin sealant (n = 10). Overall, these patients used approximately 80% of the cryoprecipitate transfused. In 12 other patients, cryoprecipitate was transfused inappropriately to attempt reversal of the anticoagulant effects of warfarin therapy (n = 6), to treat impaired surgical hemostasis in the absence of hypofibrinogenemia (n = 4), and to treat hepatic coagulopathy with multiple factor deficiencies (n = 2). The patterns of misuse, involving 24% of all cryoprecipitate orders, suggest a widespread misunderstanding and need for focused education about the coagulation factors and proteins present in cryoprecipitate and appropriate indications for its use.

Familial multiple coagulation factor deficiencies. I. Review of the literature: Differentiation of single hereditary disorders associated with multiple factor deficiencies from coincidental concurrence of single factor deficiency states.

Familial multiple coagulation factor deficiencies. I. Review of the literature: Differentiation of single hereditary disorders associated with multiple factor deficiencies from coincidental concurrence of single factor deficiency states.

Comparison of tissue and plasma thromboplastic activities.

Summary1. A lengthening of saline-re-calcification time beyond normal occurred in plasma deficient in any one of the following: platelets, AHF, PTC, PTA, Hageman factor, proaccelerin, or proconvertin. It also occurred in certain acquired multiple factor deficiencies, and in heparinized plasma. 2. Brain thromboplastin recalcification times were normal in platelet, AHF, PTC, PTA and Hageman factor deficiencies, but prolonged in proconvertin or proaccelerin deficiency or heparinized plasma. 3. Plasma thromboplastin recalcification times were normal in these same deficiencies and, in addition, in proconvertin or proaccelerin deficiency. This latter activity seemed due to incorporation of (pro) convertin and (pro) accelerin into the plasma thromboplastin complex, rather than to any free proconvertin and proaccelerin in solution. 4. Formed plasma thromboplastin is inactive in absence of optimal calcium concentration.