Paradoxical bleeding and thrombotic episodes of dysprothrombinaemia due to a homozygous Arg382His mutation

SummaryWe have characterised the pathogenic basis of dysprothrombinaemia in a patient exhibiting paradoxical bleeding and thrombotic defects during pregnancy and postpartum. Genetic analysis revealed that the proband is homozygous for the prothrombin Arg382His mutation, possessing only ~1 % clotting activity. The proband experienced severe bleeding episodes during her pregnancy, which required treatment with prothrombin complex concentrates, and then pulmonary embolism and deep-vein thrombosis at 28 days postpartum, which required treatment with LMWH and fresh frozen plasma. Analysis of haemostatic parameters revealed that the subject had elevated FDP and DD and decreased fibrinogen levels, indicating the presence of hyperfibrinolysis. Thrombin generation and clotting assays with the proband’s plasma in the presence of soluble thrombomodulin and tissue-type plasminogen activator indicated a defect in activation of both protein C and thrombin activatable fibrinolysis inhibitor (TAFI). Unlike normal plasma, no TAFI activation could be detected in the patient’s plasma. The expression and characterisation of recombinant prothrombin Arg382His indicated that zymogen activation by prothrombinase was markedly impaired and the activation of protein C and TAFI by thrombin-Arg382His was impaired 600-fold and 2500-fold, respectively. The recombinant thrombin mutant exhibited impaired catalytic activity toward both fibrinogen and PAR1 as determined by clotting and signalling assays. However, the mutant activated factor XI normally in both the absence and presence of polyphosphates. Arg382 is a key residue on (pro)exosite-1 of prothrombin and kinetic analysis of substrate activation suggested that the poor zymogenic activity of the mutant is due to its inability to bind factor Va in the prothrombinase complex.Supplementary Material to this article is available online at www.thrombosis-online.com.

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CONGENITAL SEVERE PROTEIN C DEFICIENCY IN ADULTS

10.1055/s-0038-1644304 ◽

1987 ◽

Author(s):

S Kakkar ◽

E Melissari ◽

V V Kakkar

Keyword(s):

Protein C ◽

Purpura Fulminans ◽

Renal Vein Thrombosis ◽

Fresh Frozen Plasma ◽

High Titre ◽

Protein C Deficiency ◽

Vein Thrombosis ◽

Fresh Frozen ◽

The One ◽

D Dimer

We (Melissari et al, 1985, T.R. 29 [1985] 641) were the first to identify the occurrence of severe protein C deficiency in an adult with thrombophilia and undetectable protein C levels. This report documents our clinical and laboratory resuts of this patient and his family, as well as another 8 patients, in two more, unrelated families. In these unique families with members suffering from severe protein C deficiency (≤6%), no one had experienced neonatal purpura fulminans. Symptoms started mainly in their early twenties, except in 2 patients who first had symptoms at the ages of 11 and 13. The expression of the protein C deficiency was mainly recurrent superficial and deep iliofemoral vein thrombosis and pulmonary embolism. The protein C deficiency was also expressed as generalised peritonitis due to massive messenteric vein thrombosis, cavernus sinus, renal vein thrombosis and priapism. In one of these families, five members died of intra-abdominal thrombosis before the age of 40. A compensated diffuse intra- vascular coagulation syndrome was observed during massive thromboembolic attacks as evidenced by high levels of D-Dimer (≥5000ng/ml). The treatment of choice was heparin or urokinase (with the exception of one patient), followed by heparin and fresh frozen plasma. Long term prophylaxis was LMW heparin or low dose warfarin plus stromba. The one patient who did not respond to the thrombolytic treatment with urokinase was found to have in his plasma a high titre of inhibitor against urokinase and prourokinase. This patient responded to streptokinase treatment. D-Dimer levels in these patients in non-crisis state were raised and proportional to the degree of the protein C deficiency.

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Severe Inherited “Homozygous” Protein C Deficiency in a Newborn Infant

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661136 ◽

1984 ◽

Vol 52 (01) ◽

pp. 053-056 ◽

Cited By ~ 77

Author(s):

A Estellés ◽

I Garcia-Plaza ◽

A Dasí ◽

J Aznar ◽

M Duart ◽

...

Keyword(s):

Newborn Infant ◽

Protein C ◽

Skin Lesions ◽

Fresh Frozen Plasma ◽

Clinical Syndrome ◽

Assay Method ◽

Enzyme Linked Immunosorbent Assay ◽

Protein C Deficiency ◽

Fresh Frozen ◽

Frozen Plasma

SummaryA relapsing clinical syndrome of skin lesions and disseminated intravascular coagulation (DIC) that showed remission with the infusion of fresh frozen plasma is described in a newborn infant with homozygous deficiency of protein C antigen.This patient presented since birth a recurrent clinical picture of DIC and ecchymotic skin lesions that resembled typical ecchymosis except for the fact that they showed immediate improvement with the administration of fresh frozen plasma. Using an enzyme linked immunosorbent assay method, the determination of protein C antigen levels in the patient, without ingestion of coumarin drugs, showed very low values (<1%).No other deficiencies in the vitamin-K-dependent factors or in anti thrombin III, antiplasmin, and plasminogen were found. Seven relatives of the infant had heterozygous deficiency in protein C antigen (values between 40-55%), without clinical history of venous thrombosis. The pedigree analysis of this family suggests an autosomal recessive pattern of inheritance for the clinical phenotype, although an autosomal dominant pattern has been postulated until now in other reported families.We conclude that our patient has a homozygous deficiency in protein C and this homozygous state may be compatible with survival beyond the neonatal period.

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Direct (new) oral anticoagulants (DOACs): Drawbacks, bleeding and reversal

Cardiovascular & Hematological Agents in Medicinal Chemistry ◽

10.2174/1871525719666210914110750 ◽

2021 ◽

Vol 19 ◽

Author(s):

Ozgur Karcioglu ◽

Sehmus Zengin ◽

Bilgen Ozkaya ◽

Eylem Ersan ◽

Sarper Yilmaz ◽

...

Keyword(s):

Oral Anticoagulants ◽

Fresh Frozen Plasma ◽

New Oral Anticoagulants ◽

Coagulation Cascade ◽

Thrombin Inhibitor ◽

Severe Bleeding ◽

Prothrombin Complex Concentrates ◽

Clinical Scenarios ◽

Fresh Frozen ◽

Frozen Plasma

Background and Objective: Direct (new) Oral Anticoagulants (DOACs) have emerged as a contemporary and promising option in the treatment of thromboses and VTE, while protecting the coagulation cascade against untoward bleeding events. They are used in the management and prophylaxis of Venous Thromboembolism (VTE) and other thrombotic diseases. The most prominent complication of these agents is bleeding. These agents have similar or lower rates of major intracranial hemorrhages, while they had a higher risk of major gastrointestinal bleeding when compared to warfarin. This manuscript is aimed to revise and update the literature findings to outline the side effects of DOACs in various clinical scenarios. Methods: A narrative review of currently published studies was performed. Online database searches were performed for clinical trials published before July 2021, on the efficacy and adverse effects attributed to the anticoagulant treatment, especially DOACs. A literature search via electronic databases was carried out, beginning with the usage of the agents in the Western Languages papers. The search terms initially included direct (new) oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, idarucizumab, andexanet, prothrombin complex concentrates, and fresh frozen plasma. Papers were examined for methodological soundness before being included. Results: Severe bleeding episodes require aggressive interventions for successful management. Therefore, bleeding should be evaluated in special regard to the location and rate of hemorrhage, and total volume of blood loss. Patient's age, weight and organ dysfunctions (e.g., kidney/liver failure or chronic respiratory diseases) directly affect the clinical course of overdose. Conclusion: Management recommendations for hemorrhage associated with DOAC use vary, depending on the class of the culprit agent (direct thrombin inhibitor vs. FXa inhibitor), the clinical status of the patient (mild/ moderate vs. severe/life-threatening), and capabilities of the institution. Specific reversal agents (i.e., idarucizumab and andexanet alfa) can be used if available, while prothrombin complex concentrates, fresh frozen plasma and/ or tranexamic acid can also be employed as nonspecific replacement agents in the management of DOAC-related bleeding diathesis.

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Purpura Fulminans in a Chinese Boy With Congenital Protein C Deficiency

PEDIATRICS ◽

10.1542/peds.77.5.670 ◽

1986 ◽

Vol 77 (5) ◽

pp. 670-676

Author(s):

Patrick Yuen ◽

Alfred Cheung ◽

Hsiang Ju Lin ◽

Faith Ho ◽

Jun Mimuro ◽

...

Keyword(s):

Disseminated Intravascular Coagulation ◽

Protein C ◽

Purpura Fulminans ◽

Fresh Frozen Plasma ◽

Protein C Deficiency ◽

Intravascular Coagulation ◽

The Family ◽

Fresh Frozen ◽

Frozen Plasma ◽

Congenital Protein C Deficiency

Severe and recurrent purpura fulminans developed in a Chinese boy at one day of age. Results of coagulation studies performed on the patient during attacks were compatible with the diagnosis of disseminated intravascular coagulation. Subsequent investigations have revealed that the patient is homozygous and that his parents are heterozygous for protein C deficiency. Cryoprecipitate and fresh frozen plasma induced a remission, and administration of warfarin has been successful in preventing recurrence of attacks for as long as 8 months without infusion of any plasma components. None of the family members who are heterozygous for protein C deficiency have had thrombotic episodes.

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Variations and obstacles in the use of coagulation factor concentrates for major trauma bleeding across Europe: outcomes from a European expert meeting

European Journal of Trauma and Emergency Surgery ◽

10.1007/s00068-020-01563-2 ◽

2021 ◽

Author(s):

Vladimir Černý ◽

Marc Maegele ◽

Vanessa Agostini ◽

Dietmar Fries ◽

Santiago R. Leal-Noval ◽

...

Keyword(s):

Coagulation Factor ◽

Fresh Frozen Plasma ◽

Severe Bleeding ◽

Fibrinogen Concentrate ◽

European Guidelines ◽

First Line Therapy ◽

Fresh Frozen ◽

Coagulation Factor Concentrates ◽

Barriers To Use ◽

Definition Of

Abstract Purpose Trauma is a leading cause of mortality, with major bleeding and trauma-induced coagulopathy (TIC) contributing to negative patient outcomes. Treatments for TIC include tranexamic acid (TXA), fresh frozen plasma (FFP), and coagulation factor concentrates (CFCs, e.g. prothrombin complex concentrates [PCCs] and fibrinogen concentrate [FCH]). Guidelines for TIC management vary across Europe and a clear definition of TIC is still lacking. Methods An advisory board involving European trauma experts was held on 02 February 2019, to discuss clinical experience in the management of trauma-related bleeding and recommendations from European guidelines, focusing on CFC use (mainly FCH). This review summarises the discussions, including TIC definitions, gaps in the guidelines that affect their implementation, and barriers to use of CFCs, with suggested solutions. Results A definition of TIC, which incorporates clinical (e.g. severe bleeding) and laboratory parameters (e.g. low fibrinogen) is suggested. TIC should be treated immediately with TXA and FCH/red blood cells; subsequently, if fibrinogen ≤ 1.5 g/L (or equivalent by viscoelastic testing), treatment with FCH, then PCC (if bleeding continues) is suggested. Fibrinogen concentrate, and not FFP, should be administered as first-line therapy for TIC. Several initiatives may improve TIC management, with improved medical education of major importance; generation of new and stronger data, simplified clinical practice guidance, and improved access to viscoelastic testing are also critical factors. Conclusions Management of TIC is challenging. A standard definition of TIC, together with initiatives to facilitate effective CFC administration, may contribute to improved patient care and outcomes.

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Evaluation of Thromboelastometry in Sepsis in Correlation With Bleeding During Invasive Procedures

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029617731624 ◽

2017 ◽

Vol 24 (6) ◽

pp. 993-997 ◽

Cited By ~ 1

Author(s):

Pavel Lukas ◽

Miroslav Durila ◽

Jakub Jonas ◽

Tomas Vymazal

Keyword(s):

Venous Catheter ◽

International Normalized Ratio ◽

Fresh Frozen Plasma ◽

University Hospital ◽

Severe Bleeding ◽

Invasive Procedures ◽

Extrinsic Pathway ◽

Fresh Frozen ◽

Assigned Number ◽

Frozen Plasma

Prolongation of prothrombin time (PT) is often encountered in patients with sepsis. On the other hand, thromboelastometry as a global coagulation test might yield normal results. The aim of our study was to evaluate whether prolonged PT in the presence of normal thromboelastometry parameters is associated with severe bleeding in patients with sepsis undergoing invasive procedures. In patients with sepsis undergoing low-risk bleeding invasive procedures (central venous catheter placement, dialysis catheter insertion, drain insertion, and so on) or high-risk bleeding invasive procedures (surgical tracheostomy, surgical laparotomy, thoracotomy, and so on), coagulation was assessed by thromboelastometry using EXTEM test (test for evaluation of the extrinsic pathway of coagulation, contains activator of extrinsic pathway) and with PT. For period of years 2013 to 2016, we assessed occurrence of severe bleeding during those procedures and 24 hours later in patients with prolonged PT and normal thromboelastometry results. This retrospective study was performed at Department of Anaesthesiology and Intensive Care Medicine of Motol University Hospital in Prague. Data from 76 patients with sepsis were analyzed. Median value of international normalized ratio (INR) was 1.59 (min—1.3 and max—2.56), and median value of prothrombin ratio (PR) was 1.5 (min—1.23 and max—2.55) with normal thromboelastometry finding. Despite prolonged INR/PR, no severe bleeding was observed during invasive procedures. Our data show that sepsis may be accompanied by normal thromboelastometry results, despite prolonged values of PT, and invasive procedures were performed without severe bleeding. This approach to coagulation assessment in sepsis may reduce administration of fresh frozen plasma to the patients. The study was registered at Clinical Trials.gov with assigned number NCT02971111.

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Coagulation Profile in neonates with perinatal asphyxia

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20193627 ◽

2019 ◽

Vol 6 (5) ◽

pp. 1922

Author(s):

Ruchi Jha ◽

Neelam Verma

Keyword(s):

Perinatal Asphyxia ◽

Mode Of Delivery ◽

Birth Asphyxia ◽

Fresh Frozen Plasma ◽

Control Group ◽

Severe Bleeding ◽

Care Seeking ◽

Second Stage Of Labour ◽

Care Seeking Behavior ◽

Fresh Frozen

Background: Perinatal Asphyxia refers to a condition during the first and second stage of labour in which impaired gas exchange leads to fetal acidosis, hypoxemia and hypercarbia. It accounts for about 23 per cent of the four million newborn deaths worldwide.Methods: To estimate the magnitude of coagulation derangement in babies who suffered birth asphyxia and compare it with non-asphyxiated controls.Results: There were 61.9% and 64 % males in both the groups outnumbering females suggesting that the health care seeking behavior for male children is more than for their female counterparts. Birth weight and mode of delivery are comparable in both the groups. PT and APTT were significantly higher in the asphyxiated babies than in their respective control group. It may be noted , however, that PT and APTT values were higher in the control group also, when compared with the reference values. This may indicate that the hemostatic mechanisms are already compromised in the newborns and perinatal asphyxia further augment the situation tilting it in favour of bleeding. Thrombocytopenia is observed in the asphyxiated group which may be due to placental insufficiency. Severe bleeding is significant in asphyxiated group as compared to the control.Conclusion: Dyscoagulation should be considered in all asphyxiated babies, and they may present with clinically significant bleeding, which may require fresh frozen plasma to restore and maintain their coagulation status.

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A case of thrombomodulin mutation causing defective thrombin binding with absence of protein C and TAFI activation

Blood Advances ◽

10.1182/bloodadvances.2019001155 ◽

2020 ◽

Vol 4 (12) ◽

pp. 2631-2639

Author(s):

Masahiko Okada ◽

Norio Tominaga ◽

Goichi Honda ◽

Junji Nishioka ◽

Nobuyuki Akita ◽

...

Keyword(s):

Protein C ◽

In Vitro Assays ◽

Thrombin Activatable Fibrinolysis Inhibitor ◽

Soluble Thrombomodulin ◽

First Case ◽

Fibrinolysis Inhibitor ◽

Total Lack ◽

Recombinant Thrombomodulin ◽

Recombinant Human Soluble Thrombomodulin

Abstract Thrombomodulin functions as an anticoagulant through thrombin binding and protein C activation. We herein report the first case of hereditary functional thrombomodulin deficiency presenting with recurrent subcutaneous hemorrhage and old cerebral infarction. The patient had a homozygous substitution of glycine by aspartate at amino acid residue 412 (Gly412Asp) in the thrombin-binding domain of the thrombomodulin gene (designated thrombomodulin-Nagasaki). In vitro assays using a recombinant thrombomodulin with the same mutation as the patient showed a total lack of thrombin binding and activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI). Marked clinical and laboratory improvement was obtained with recombinant human soluble thrombomodulin therapy.

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Acquired factor VII deficiency causing severe bleeding disorder secondary to AL amyloidosis of the liver

Hematology Reports ◽

10.4081/hr.2018.7235 ◽

2018 ◽

Vol 10 (3) ◽

Cited By ~ 2

Author(s):

Anthony L. Nguyen ◽

Muhammad Kamal ◽

Ravi Raghavan ◽

Gayathri Nagaraj

Keyword(s):

Factor Viia ◽

Aminocaproic Acid ◽

Fresh Frozen Plasma ◽

Factor Vii ◽

Al Amyloidosis ◽

Severe Bleeding ◽

Factor Vii Deficiency ◽

Fresh Frozen ◽

Hepatic Amyloidosis ◽

Mucosal Bleeding

A 52 year-old male presented with neck pain after undergoing thyroidectomy for a goiter three weeks prior which was complicated by a neck hematoma requiring evacuation. Computed tomography (CT) scan showed a neck hematoma requiring evacuation and he received desmopressin with cessation of bleeding. Coagulation studies were normal. He returned eighteen months later with severe oral mucosal bleeding after a dental procedure and required transfusions with red blood cells, platelets, and fresh frozen plasma (FFP) in addition to desmopressin, Humate-P, aminocaproic acid, and surgical packing. A comprehensive bleeding diathesis workup was normal. He was readmitted six months later due to abdominal pain and distention and found to have massive hepatosplenomegaly on CT. A new coagulopathy workup revealed prolonged INR to 1.5, corrected prothrombin time mixing study, and a low factor VII level (29%), suggesting acquired factor VII deficiency. A transjugular liver biopsy revealed extensive involvement by ALamyloidosis- Kappa type. He then developed a large right retroperitoneal hematoma which required multiple transfusions with FFP, cryoprecipitate, aminocaproic acid, and vitamin K with slight success. Hemorrhage was subsequently stabilized with recombinant factor VIIa administered every four hours which corresponded with correction of factor VII levels and PT and eventual cessation hemorrhage. Acquired factor VII deficiency causing severe coagulopathy was attributed to hepatic amyloidosis ALkappa subtype. We started treatment with bortezomib, dexamethasone, and cyclophosphamide, however, the patient succumbed to uncontrolled hemorrhage. Acquired factor VII deficiency is extremely rare and to our knowledge, this is the only known case of factor VII deficiency secondary to amyloidosis involving the liver.

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