https://www.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1538-7836.2006.01753.x

International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).

https://journal.chestnet.org/article/S0012-3692(12)60137-8/pdf

Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other haemostatic challenges. VWD may be disproportionately symptomatic in women of child-bearing age. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD. These evidence-based guidelines for diagnosis and management of VWD from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of VWD pathophysiology and classification, and present consensus diagnostic and management recommendations based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective information about bleeding symptoms, advancements in diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more detailed document, a synopsis of these recommendations, and patient education information.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2516.2007.01643.x

von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA).

http://icnapedia.org/guidelines/open/Chest-2008-Monagle-887S-968S.pdf

Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

Platelet activation and blood coagulation are complementary, mutually dependent processes in haemostasis and thrombosis. Platelets interact with several coagulation factors, while the coagulation product thrombin is a potent platelet-activating agonist. Activated platelets come in a procoagulant state after a prolonged elevation in cytosolic [Ca2+]i. Such platelets, e. g. when adhering to collagen via glycoprotein VI, expose phosphatidylserine (PS) at their outer surface and produce (PS-exposing) membrane blebs and microvesicles. Inhibition of aminophospholipid translocase and activation of phospholipid scramblase mediate the exposure of PS, whereas calpain-mediated protein cleavage leads to membrane blebbing and vesiculation. Surface-exposed PS strongly propagates the coagulation process by facilitating the assembly and activation of tenase and prothrombinase complexes. Factor IXa and platelet-bound factor Va support these activities. In addition, platelets can support the initiation phase of coagulation by providing binding sites for prothrombin and factor XI. They thereby take over the initiating role of tissue factor and factor VIIa in coagulation activation.

Platelet activation and blood coagulation.

Studies were performed on a French-Canadian family afflicted with a bleeding disorder exhibiting an autosomal dominant inheritance pattern and a severe bleeding diathesis after trauma. Clinical laboratory coagulation tests were unimpressive; the only persistent abnormalities include mild thrombocytopenia and moderately reduced Factor V clotting activities. Some individuals had prolonged Stypven times when platelet-rich plasma was used, suggesting that their platelets could not support functional prothrombinase complex assembly. Detailed studies were performed by use of plasma and isolated, washed platelets from a sister and brother. Bioassay data indicate that both individuals had Factor V activities of approximately 40 and 36% of normal, respectively. A comparison of the Factor V radioimmunoassay and bioassay data on the brother's plasma indicated that the circulating amount of Factor V functional activity was low relative to Factor V antigen concentration (approximately 65-75%). In both individuals, the platelet Factor V functional activities were extremely low (2-4%) relative to antigen levels present as determined by radioimmunoassay. These discrepancies between Factor V activities and antigen concentration do not appear to be due to an unstable Factor V molecule or to the presence of a Factor V or Factor Va inhibitor or inactivator. Kinetics of prothrombin activation by use of purified clotting factors indicated that thrombin-activated platelets from both individuals supported prothrombinase complex assembly identical to controls in the presence of added purified Factor Va. Consequently, their bleeding diathesis appears to reflect their platelet, rather than their plasma, Factor V activity. These results suggest that platelet Factor V is an essential component in maintaining stable and prolonged hemostasis after trauma.

/pdf/factor-v-quebec-a-bleeding-diathesis-associated-with-a-161wfqrbon.pdf

Factor v (quebec): a bleeding diathesis associated with a qualitative platelet factor v deficiency

Predictive value of persistent versus transient antiphospholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus

Parameters of the fibrinolytic system were studied in a primate model where the generation of thrombin was promoted in vivo. The procoagulant stimulus used was a combination of human factor Xa in combination with phosphatidylcholine/phosphatidylserine lipid vesicles (PCPS) as the source of coagulant active phospholipid. The dosage of each component was formulated to provide a gradation of thrombin generating potential assessed prior to in vivo study in an in vitro clotting assay. These ranged from 25.25-36.60 pMole/kg (factor Xa) and 18.85-56.30 nMole/kg (PCPS). In each case, the ratio of the dose of factor Xa/PCPS was maintained at 0.65 (pMole factor Xa/nMole PCPS). Individual dosage combinations producing recalcification clotting times in vitro of 15, 20, 25 and 30 s were used in detailed in vivo studies. Previous studies in dogs had confirmed the thrombin generating potential of factor Xa/PCPS infusions and demonstrated an associated activation of protein C and increased fibrinolytic activity. This has now been extensively characterized in the chimpanzee as follows: 10 min after the infusion of the highest dose (36.6 pMole factor Xa/56.3 nMole PCPS kg bodyweight), the level of circulating t-PA had risen to 900 ng/ml (antigen), 885 IU/ml (functional). Dosage was observed with the lowest dose of 12.25 pMole factor Xa and 18.85 nMole PCPS being associated with relatively minor increases in circulating t-PA activity. There were no changes in u-PA at any dosage during the full time course of the experimental period (90 min). Plasminogen activation was also apparent with alpha-2 antiplasmin levels falling to 30-40% of pre-infusion levels at the highest dosages.(ABSTRACT TRUNCATED AT 250 WORDS)

The fibrinolytic potential of the normal primate following the generation of thrombin in vivo.

Activation and inactivation of protein C during the clinical course of disseminated intravascular coagulation (DIC) was studied in three patients by qualitative (Western blotting) and quantitative (ELISA) analysis and the intensity of procoagulant activity monitored by the measurement of thrombin and factor Xa antithrombin III complexes. In one patient, inhibitor complexes of APC with protein C inhibitor (PCI) and alpha 1-antitrypsin (alpha 1-AT) were observed and the latter predominated at presentation. Both disappeared during the development of remission but the loss of alpha 1-AT complexes preceded PCI complexes which on Western blotting appeared to increase in intensity prior to disappearance. The two other patients bled to death from uncontrollable haemorrhage. In both cases, APC/inhibitor complexes with alpha 2-macroglobulin (alpha 2-M) in addition to PCI and alpha 1-AT were detected and persisted until death. Although PCI appeared to be the primary inhibitor in all three cases, alpha 1-antitrypsin and particularly alpha 2-macroglobulin appeared to assume greater roles in the two fatal cases. These data are similar to previous findings in an experimental animal model of DIC that suggested that alpha 2-macroglobulin and alpha 1-antitrypsin become more important inhibitors of APC as the primary inhibitor PCI is consumed in the face of a sustained procoagulant challenge.

Activation of protein C and its distribution between its inhibitors, protein C inhibitor, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with disseminated intravascular coagulation.

Type IIb von Willebrand's disease has been found to be associated with the development of thrombocytopenia following the infusion of DDAVP (desmopressin). It has also been associated with sporadic thrombocytopenia and evidence of spontaneous platelet aggregation. A family with documented Type IIb von Willebrand's disease is described, where two of the affected females presented with moderate to severe thrombocytopenia developing during pregnancy with reversal to normal or minimally reduced platelet counts in the early post gestational period. In each case, the levels of factor VIII:C, von Willebrand factor antigen and von Willebrand factor ristocetin co-factor activity rose during pregnancy but there were notable discrepancies between the levels of each in any one individual. It is suggested that pregnancy resulted in increased synthesis of the variant form of von Willebrand factor resulting in progressively increasing platelet/variant form von Willebrand factor interaction and subsequent thrombocytopenia. Whether this reflects consumption or sequestration remains uncertain. Although spontaneous platelet aggregation was observed in some family members, the majority did not exhibit this phenomenon. Circulating platelet aggregates could not be detected. Both pregnancies were relatively uneventful and there is no history of unusual bleeding associated with pregnancy in the family. These observations suggest that Type IIb von Willebrand's disease should be considered in the differential diagnosis of thrombocytopenia developing during pregnancy, particularly in those individuals where evidence supporting the diagnosis of immune mediated thrombocytopenia is not forthcoming. Where the diagnosis of Type IIb von Willebrand's disease is established, active intervention other than confinement in a hospital with experience in haemostatic disorders is probably not required as the development of thrombocytopenia does not appear to exert an additive effect on the underlying defect relating to the variant form of von Willebrand's disease.

Hugh Hoogendoorn

Papers

Factor v (quebec): a bleeding diathesis associated with a qualitative platelet factor v deficiency

Predictive value of persistent versus transient antiphospholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus

The fibrinolytic potential of the normal primate following the generation of thrombin in vivo.

Activation of protein C and its distribution between its inhibitors, protein C inhibitor, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with disseminated intravascular coagulation.

Type IIB von Willebrand's disease presenting as thrombocytopenia during pregnancy.