Hypercoagulability as a Cause of Sudden Neurosensory Hearing Loss

1979 ◽  
Vol 87 (2) ◽  
pp. 268-273 ◽  
Author(s):  
Joan T. Zajtchuk ◽  
Maj William H. Falor ◽  
Mai Miller F. Rhodes
Keyword(s):  
Hearing Loss ◽  
Platelet Count ◽  
Generation Time ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Coagulation Abnormalities ◽  
Show Evidence ◽  
Phase Platelet ◽  
Antithrombin Iii Activity

Fourteen patients with a documented sudden neurosensory hearing loss and four patients with other diseases causing neurosensory hearing loss were studied. The standardized coagulation workup included hematocrit, activated partial thromboplastin generation time, thrombin generation, prothrombin time, phase platelet count, platelet adhesivity, protamine sulfate, serum antithrombin III activity, fibrinogen, and Factor VIII values. Only those patients having documented evidence of a neurosensory hearing loss occurring within hours or days were included in this study. Eight of the 14 patients with a documented sudden neurosensory hearing loss satisfied our laboratory criteria for a diagnosis of in vitro hypercoagulability. Three of these patients had abnormal thrombin generation values, 4 had abnormal serum antithrombin III values, and 1 had an elevated platelet count. Four other patients with other diseases causing neurosensory hearing loss did not show evidence of in vitro hypercoagulability. It would appear from this data that coagulation abnormalities play a role in the pathogenesis of sudden neurosensory hearing loss.

Hypercoagulability as a Cause of Sudden Neurosensory Hearing Loss

1979 ◽  
Vol 87 (2) ◽  
pp. 268-273 ◽  
Author(s):  
Joan T. Zajtchuk ◽  
William H. Falor ◽  
Miller F. Rhodes
Keyword(s):  
Hearing Loss ◽  
Platelet Count ◽  
Generation Time ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Coagulation Abnormalities ◽  
Show Evidence ◽  
Phase Platelet ◽  
Antithrombin Iii Activity

Fourteen patients with a documented sudden neurosensory hearing loss and four patients with other diseases causing neurosensory hearing loss were studied. The standardized coagulation workup included hematocrit, activated partial thromboplastin generation time, thrombin generation, prothrombin time, phase platelet count, platelet adhesivity, protamine sulfate, serum antithrombin III activity, fibrinogen, and Factor VIII values. Only those patients having documented evidence of a neurosensory hearing loss occurring within hours or days were included in this study. Eight of the 14 patients with a documented sudden neurosensory hearing loss satisfied our laboratory criteria for a diagnosis of in vitro hypercoagulability. Three of these patients had abnormal thrombin generation values, 4 had abnormal serum antithrombin III values, and 1 had an elevated platelet count Four other patients with other diseases causing neurosensory hearing loss did not show evidence of in vitro hypercoagulability. It would appear from this data that coagulation abnormalities play a role in the pathogenesis of sudden neurosensory hearing loss.

scholarly journals Thrombin Generation in Two Families with Myh-9-Related Platelet Disorder

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2783-2783
Author(s):  
Eva Zetterberg ◽  
Margareta S Carlsson Alle ◽  
Juliane Najm ◽  
Andreas Greinacher
Keyword(s):  
Myocardial Infarction ◽  
Hearing Loss ◽  
Platelet Count ◽  
Arterial Thrombosis ◽  
Inclusion Bodies ◽  
Thrombin Generation ◽  
Bleeding Tendency ◽  
Endogenous Thrombin Potential ◽  
Related Disease ◽  
Low Platelet Count

Abstract MYH-9 related platelet disorders are inherited macrothrombocytopenias. Before the genetic cause was identified, four overlapping syndromes (May-Hegglin, Epstein, Fechtnerand Sebastian syndrome) described the additional clinical manifestations in MYH-9 disorders including renal failure, hearing loss, pre senile cataract and inclusion bodies in leucocytes that are present in different combinations. The MYH-9-gene codes for the cytoplasmic contractile protein non muscular myosin heavy chain IIA, present in several tissues, which explains the additional symptoms. The bleeding tendency is usually mild to moderate but rarely, thrombotic complications are also seen (1). We report on the thrombin generation potential (ETP) in MYH9 patients with and without arterial thrombosis. In the first family (family A) 4 members were evaluated: a 51 year old woman (platelet count 36), her 24 year old daughter (platelet count 46), and the brother of the woman (57 years; platelet count 39) and his 30 year old son (platelet count 44). All four were affected by MYH-9 disorder with macrothrombocytopenia and inclusion bodies in the leucocytes and a 5521G>A mutation, causing Glu1841Lys. 3 of them had a moderate bleeding tendency [ISTH /SSC bleeding scores 9, 13, 4 where <4 is normal) (3)] and in the 51 year old women and her brother, renal insufficiency and hearing loss were already present. Both patients had an arterial thrombosis (myocardial infarction and pons infarction respectively) before 50 year of age. Both showed hyperlipidemia and hyperhomocysteinemia. In the second family (Family B) macrothrombocytopenia and small to medium size inclusion bodies in the leucocytes were found in the mother (38 years; platelet count 36) and the daughter (age15 years, platelet count 46) caused by a c. 4679 T>G mutation resulting in p.Val1560Gly. Their bleeding tendency was mild (bleeding scores 4 and 3 respectively). Thrombelastography (ROTEM) was normal in all five individuals. ETP was seen to be below the normal range in family B. However, in family A, the two members affected by thrombosis had a normal ETP (Fig 1), indicating that other factors compensated for the low platelet count and clinically even led to a breakthrough of arterial thrombosis despite the low platelet count. We suggest that other centers also assess the ETP in their MYH-9 patients according tour protocol to gather data on the potential association of the ETP with the phenotype. References Althaus K, Greinacher A: MYH-9 Related Platelet Disorders: Strategies for Management and Diagnosis. Transfus Med Hemother. 2010 October; 37(5): 260–267. Girolami A , Vettore S, Bonamigo E, Fabris F: Thrombotic events in MYH9 gene-related autosomal macrothrombocytopenias (old May–Hegglin, Sebastian, Fechtner and Epstein syndromes) J Thromb Thrombolysis. 2011 Nov;32(4):474-73. Rodeghiero F, Tosetto A, Abshire T et al.; ISTH/SSC Joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessmenttool: a standardizedquestionnaire and a proposal for a newbleedingscore for inherited bleeding disorders. J Thromb Haemost 2010; 8: 2063–5. Figure 1. Endogenous thrombin potential in two families with MYH-9 related disease Figure 1. Endogenous thrombin potential in two families with MYH-9 related disease Thrombin generation was performed on frozen platelet rich plasma on 5 members from two different families (family A and B) with MYH-9 related disease. Two members in the first family (A:1 and A:2) had a previous arterial thrombosis (pons infarction and myocardial infarction, respectively, marked with a star). Disclosures No relevant conflicts of interest to declare.

Bleeding in Uremic Patients after Carbenicillin

1976 ◽  
Vol 36 (01) ◽  
pp. 115-126 ◽  
Author(s):  
K Andrassy ◽  
E Weischedel ◽  
E Ritz ◽  
T Andrassy
Keyword(s):  
Platelet Function ◽  
Antithrombin Iii ◽  
Serum Levels ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Hemorrhagic Diathesis ◽  
Thrombin Time ◽  
Antithrombin Iii Activity

SummaryHemorrhagic diathesis was observed in patients with renal insufficiency after carbenicillin at serum levels > 300 μg/ml. Normal coagulation factors (F. I, II, V, VII, VIII, X), normal PTT, normal platelet counts, negative ethanol gelation test (fibrin monomers) were found as well as a prolongation of thromboplastin time (Quick), thrombin time, reptilase time and thrombin coagulase time. Platelet function was disturbed. In addition, the plasmatic system was involved: inhibition of fibrinogen-fibrin conversion (Belitser assay) and enhanced antithrombin III activity; in vivo the latter was ascribed to a heparin-like activity. In vitro, abnormal fibrinogen-fibrin conversion and a modified electrophoretic mobility of antithrombin III was seen: however an enhanced antithrombin III activity in vitro was not found with carbenicillin and various penicillin derivatives.This study demonstrates that carbenicillin, in addition to its known effect on platelet function, also disturbs the plasmatic coagulation system. This additional effect of carbenicillin is clinically important since protamin chloride effectively blocks bleeding without interfering with antibacterial activity.Both penicillin and penicillin derivatives have been shown to interfere with hemostasis and to cause clinically manifest hemorrhagic diathesis (Fleming and Fish 1947, Lurie et al. 1970a, b, McClure et al. 1970, Yudis et al. 1972, Demos 1971, Waisbren et al. 1971). Carbenicillin interferes with ADP-, collagen- or thrombin-induced platelet aggregation and with the release reaction both in vivo (McClure et al. 1970, Cazenave et al. 1973) and in vitro (McClure et al. 1970, Cazenave et al. 1973). In addition Lurie and colleagues (1970b) concluded that an inhibition of the conversion of fibrinogen to fibrin is involved although no experimental details were given. Later Brown and colleagues (1974) concluded that carbenicillin at usual dose levels “only affects the platelet component of hemostasis and has little effect on fibrin formation or other phases of coagulation in patients with normal renal function”.

Effect of Heparin on Antithrombin III Activity During Delivery and Early Puerperium

1975 ◽  
Author(s):  
I. Rákóczi ◽  
B. Garadnay ◽  
L. Arnold ◽  
I. Gáti
Keyword(s):  
Pregnant Women ◽  
Blood Coagulation ◽  
Antithrombin Iii ◽  
Modified Method ◽  
Heparin Treatment ◽  
At Iii ◽  
Antithrombin Iii Activity

It is known that antithrombin III (AT III) is the main inhibitor of blood coagulation. It inactivates thrombin and activated × factor. Heparin increases the AT III activity in vitro as well as in vivo. The authors have studied the AT III activity in sera of 30 pregnant women, at term, before labour started (2–24 hrs) and 30 as well as 60 min after the birth of placenta and daily for five days after delivery. The AT III activity was determined using the modified method of Gerendas. Out of the 30 women 15 were given 5000 IU heparin subcutaneously 1½—2 hours before delivery. In the 15 women with no heparin treatment AT III activity of serum significantly decreased after birth of placenta compared with the predelivery value and became normal on the fifth postpartum day. Heparin given subcutaneously prevented development of this decrease.

scholarly journals In Vitro Assessment of Altered Thrombin-Fibrinogen Interaction As a Mechanism for Acute Traumatic Coagulopathy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1075-1075
Author(s):  
Michael Adam Meledeo ◽  
Armando C Rodriguez ◽  
Chet R Voelker ◽  
James A Bynum ◽  
Andrew P Cap
Keyword(s):  
Dose Response ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Conflicts Of Interest ◽  
Platelet Rich Plasma ◽  
Clot Formation ◽  
Acute Traumatic Coagulopathy ◽  
Clot Strength ◽  
Traumatic Coagulopathy

Abstract Introduction The acute traumatic coagulopathy (ATC) which develops within 30 min following severe trauma with tissue damage and shock is defined by an increased prothrombin time (PT) and international normalized ratio (INR). While reduced thrombin might be expected in conjunction with elevated PT, recent clinical studies reveal paradoxically elevated thrombin generation potential in patients with ATC. We therefore hypothesized that the quantity of thrombin and the timing of thrombin-fibrinogen interactions both have an impact on clot quality; the exuberant production of thrombin found in trauma results in improper clot formation. Methods In vitro studies were conducted in human blood products and simplified synthetic plasma (consisting of purified human coagulation factors in HEPES buffered saline). Turbidimetry was used to observe fibrin crosslinking, while thromboelastography (TEG) was used to quantify clot formation parameters. Quantitation of fibrin(ogen) degradation products (FDPs) was conducted with the STA-R Evolution coagulation analyzer and by ELISA. A fluorogenic substrate was used to observe thrombin generation. Results Increasing the amount of prothrombin or thrombin (0-1400nM) in prothrombin-immunodepleted citrated plasma resulted in reduced clot times. The same dose response was examined in a buffered mixture of fibrinogen (300 mg/dl), FXIII (31.25nM), Ca2+ (2mM), and FXa (170nM-only used with prothrombin samples). However, while increasing prothrombin increased clot strength in both FII-deficient plasma and in the synthetic plasma, direct addition of thrombin decreased clot strength and by 3-fold at 1000nM versus 100nM (Figure 1; *p<0.05; **p<0.01; ***p<0.001 between groups at given concentration); fibrin density was similarly reduced in turbidimetric assays. In TEG, the thrombin dose response did not affect whole blood or platelet-rich plasma, but in platelet-poor plasma the same clot strength inhibition trend was observed. Thrombin generation from the combination of prothrombin (0-1000 nM), FXa (170 nM), and Ca2+ (2 mm) was found to be saturated above an initial prothrombin concentration of 500nM. An examination of FDPs from plasmin-degraded fibrinogen ± thrombin ± FXIII showed that FDPs from both crosslinked and uncrosslinked fibrin had 4-fold higher amounts of fibrin monomer and D-dimer than those produced from plasmin digestion of pure fibrinogen. When FDPs from thrombin +fibrinogen ± FXIII were supplemented back into fresh fibrinogen (0-50% of the final mixture) and allowed to clot again, there was a concentration-dependent decrease in fibrin formation rate (control: 0.15 OD/min; 50% FDP: 0.07 OD/min; p<0.001) which was not observed in samples treated with non-thrombin exposed FDPs. The use of these FDPs allowed for simulations of trauma patient plasma to be constructed using concentrations of plasma proteins associated with both "normal" trauma and the hypocoagulable state which manifests in ATC. When combining relevant levels of thrombin, fibrinogen, FDPs, and antithrombin III as are found in trauma patients that trend toward either good or bad outcomes, differences in TEG tracings can be observed illustrating the validity of these in vitro systems (Figure 2). Conclusions The dose responses of prothrombin versus thrombin reveal the significance of the timing of these reactions on proper clot formation. The conversion of prothrombin to thrombin mediated through FXa and FVa results in strong clots under normal circumstances. These results were reflected in both turbidimetry and TEG, indicating that fibrin crosslinking is being hindered by the presence of excess thrombin even in the presence of the antithrombin III. Additionally, FDPs from crosslinked substrates reduce new clot-making efficiency. Excess thrombin and significant increases in FDPs (which can result from fibrinolytic feedback loops) both contribute to an in vitro phenotype that may represent an underlying factor in the development of ATC. Disclosures No relevant conflicts of interest to declare.

scholarly journals Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L'Asparaginase-induced antithrombin III deficiency

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 386-391 ◽  
Author(s):  
L Mitchell ◽  
H Hoogendoorn ◽  
AR Giles ◽  
P Vegh ◽  
M Andrew
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Combination Chemotherapy ◽  
Protein C ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Thrombotic Complications

Abstract Pediatric patients with acute lymphoblastic leukemia (ALL) are at an increased risk of thromboembolic events. Potential responsible mechanisms include the disease process itself, treatment with chemotherapeutic agents (particularly L-Asparaginase [ASP]), or a combination of the disease and treatment. We studied thrombin regulation in 26 consecutive children with ALL and 14 healthy age- matched controls by: (1) plasma concentrations of prothrombin; (2) plasma inhibition of 125I-alpha-thrombin; and (3) four biochemical markers of in vivo thrombin activation (thrombin complexed to its inhibitor antithrombin III [ATIII; TAT], prothrombin fragment 1.2 (F1.2), activated protein C complexed to the inhibitors alpha 1 antitrypsin [APCAT]), and protein C inhibitor (APC-PCI). Measurements were made at presentation before treatment, after treatment with ASP alone, and during combination chemotherapy with and without ASP. At presentation, the capacity to generate thrombin (reflected by plasma prothrombin concentrations) and the capacity to inhibit thrombin (125I- alpha-thrombin--inhibitor complex formation) were similar in children with ALL compared with that for healthy children. After ASP alone or as part of combination chemotherapy, prothrombin levels were preserved, whereas plasma inhibition of 125I-alpha-thrombin decreased significantly because of a decrease in plasma concentrations of inhibitors, most importantly ATIII. After combination chemotherapy without ASP, plasma concentrations of ATIII and the capacity to inhibit 125I-alpha-thrombin returned to normal values, whereas prothrombin levels increased above control values. Thrombin generation in vivo also differed from healthy controls. At presentation, plasma concentrations of three of four markers of in vivo thrombin activity (TAT, F1.2, APCAT, but not APC-PCI) were increased in children with ALL. Neither ASP alone nor combination chemotherapy with or without ASP significantly altered values of these three markers. In summary, although the in vitro capacity to generate thrombin was preserved, the in vitro capacity to inhibit 125I-alpha-thrombin decreased after ASP therapy. Evidence for increased endogenous thrombin generation was documented in children with ALL at presentation and throughout treatment. We speculate that poor regulation of this thrombin may contribute to thrombotic complications in children with ALL.

Alterations in Antithrombin III Activity and other Blood Coagulation Parameters after Retinal Detachment Surgery

2000 ◽  
Vol 10 (4) ◽  
pp. 318-323 ◽  
Author(s):  
G. Malukiewicz-Wiśniewska ◽  
M. Kotschy
Keyword(s):  
Platelet Count ◽  
Retinal Detachment ◽  
Blood Coagulation ◽  
Antithrombin Iii ◽  
Arterial Disease ◽  
Fibrinogen Concentration ◽  
Coagulation Activity ◽  
Retinal Detachment Surgery ◽  
At Iii ◽  
Antithrombin Iii Activity

Purpose To evaluate perioperative changes in blood coagulation in patients undergoing retinal detachment surgery. Materials Prospective study of 56 patients, aged from 19 to 82 (mean ± S.D. 53 ± 16.8) years, undergoing retinal detachment surgery (encirclement with scleral buckling) under general anesthesia. Excluded were patients with venous or arterial disease and any other factors that could affect the parameters under consideration. Methods Blood was sampled from the cubital vein one day before surgery, immediately after induction of anesthesia but before surgery, immediately after completion of the operation but before the termination of anesthesia and on days 1 and 4 after the operation. We measured antithrombin III activity (AT III), platelet count, fibrinogen concentration, activated partial thromboplastin time (aPTT) and prothrombin time (PT). Results Intraoperative AT III activity and platelet count were significantly lower, aPTT was shortened and PT prolonged, although all values remained within the normal range. These results indicate moderate activation of coagulation during retinal detachment surgery. On the first postoperative day coagulation activity was reduced, with increases in AT III activity, fibrinogen concentration and platelet count and prolongation of aPTT. Conclusions During retinal detachment surgery there is moderate activation of coagulation in the systemic circulation.

Thrombogenicity of Human Factor IX Concentrates. In vitro Studies

1975 ◽  
Author(s):  
G. Sas ◽  
R. Owen ◽  
J. K. Smith ◽  
S. Middleton ◽  
J. D. Cash
Keyword(s):  
Thrombin Generation ◽  
Human Factor ◽  
Antithrombin Iii ◽  
Factor Ix ◽  
In Vitro Studies ◽  
Biologically Active ◽  
Clotting Time ◽  
Human Factor Ix ◽  
Recalcification Time

A series of in vitro studies, designed to ascertain the potential in vivo thrombogenicity of human factor IX containing concentrates, is described. Using concentrates obtained from several different centres the fibrinogen clotting time with some preparations was less than 6 hours and/or the recalcification time of normal plasma was shortened. In some preparations however, the plasma recalcification time was lengthened.Further studies revealed that all diluted factor IX concentrates generated thrombin after recalcification, and that the rate of thrombin generation appeared to be characteristic of a particular preparation. This characteristic we have expressed as the TGt50 which is the incubation period in minutes required, after recalcification, to obtain a 50 second clotting time of a fibrinogen substrate. The TGt50 was found to correlate most strongly with recalcification time of celite exhausted plasma (p < 0.001), but no correlation was observed between it and the immunological factor VIII or antithrombin III levels. However some factor IX concentrates contained antithrombin III in a free (biologically active) and in a complexed (inactive) form.Evidence is presented which suggests that the thrombin generation test and recalcification time of celite exhausted plasma may represent suitable in vitro quality control assays for the potential thrombogenicity of factor IX concentrates.

Adverse Effect of Heparin in Thrombin-Antithrombin III Interaction

1975 ◽  
Vol 34 (03) ◽  
pp. 748-762 ◽  
Author(s):  
Ewa Marciniak
Keyword(s):  
Adverse Effect ◽  
Antithrombin Iii ◽  
Enzyme Inhibitor ◽  
Active Form ◽  
Factor Xa ◽  
Heparin Therapy ◽  
Inhibitory Capacity ◽  
Antithrombin Iii Activity

SummaryThrombin, while reacting in the presence of heparin, impairs the inhibitory capacity of antithrombin III so that subsequent inhibition of thrombin or factor Xa is decreased or abolished. This adverse effect of heparin has been observed directly with at least 1.5 Iowa units of thrombin per each unit of purified human antithrombin III participating in the reaction. The inhibitory capacity was then totally destroyed and some residual thrombin remained in the active form. With a lower enzyme/inhibitor ratio inactivation of thrombin in the presence of heparin was fast and complete, however, a significant decrease of inhibitory capacity below that found in reaction without heparin, has been established by measuring the residual antithrombin III activity. In defibrinated human plasma at least 2 units of thrombin per each antithrombin III unit were required to demonstrate directly the adverse effect of heparin, but a fast depletion of inhibitory capacity has been also observed after repeated additions of small thrombin portions into plasma heparinized in vitro or in vivo. Portions of enzyme initially added disappeared with great velocity; subsequent portions, however, accumulated building up a high thrombin level not seen in the absence of heparin. The accumulation of residual enzyme was more extensive in plasma containing about 1 heparin unit per ml than anticoagulant at lower concentrations and was particularly noticeable in antithrombin III deficient plasma. These results may have some bearings on the approach to heparin therapy in the event when thrombin continuously generates or when a marked deficiency of antithrombin III exists.

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