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Hemostasis and bleeding disorders
Bleeding disorders are a group of heterogeneous conditions characterized by defects in hemostasis that lead to an increased susceptibility to bleeding (also known as hemorrhagic diathesis). They are classified into disorders of primary hemostasis (when caused by a platelet abnormality), disorders of secondary hemostasis (when caused by defects in the extrinsic and/or intrinsic pathway of the coagulation cascade), and hyperfibrinolysis (when there is increased clot degradation). Although clinical features may overlap, mucocutaneous bleeding (e.g., epistaxis, petechiae, gastrointestinal bleeding) is associated with disorders of primary hemostasis, and bleeding into potential spaces (e.g., hemarthrosis, muscular bleeding) is characteristic of disorders of secondary hemostasis. The diagnostic workup of a bleeding disorder begins with a detailed clinical assessment, the CBC, and a coagulation panel. This typically allows the disorder to be classified as one of primary or secondary hemostasis. Specialized studies are then required to determine the specific etiology so that treatment can be initiated. Treatment may include transfusion of blood products, replacement of specific coagulation factors, or administration of adjuvant medications (e.g., tranexamic acid or desmopressin).
Hemostasis
Hemostasis is the physiological process by which a bleeding stops. Its final result is a thrombus (blood clot), which consists of blood cells and fibrin strands. Hemostasis involves the following mechanisms:
Primary hemostasis
Vascular hemostasis: transient vasoconstriction and vWF activation following endothelial injury
Platelet hemostasis: adhesion, activation, and aggregation of platelets, which results in the formation of a platelet plug (white thrombus)
Secondary hemostasis: activation of the coagulation cascade, which results in the formation of a fibrin clot (red thrombus)
Definition: : processes involved in the formation of a platelet plug (white thrombus) following endothelial injury
Vascular hemostasis
Endothelial injury results in:
Neural stimulation reflexes and endothelin release → transient vasoconstriction, leading to:
Reduced blood flow
Platelet accumulation at the vessel walls
Exposure of subendothelial collagen → circulating von Willebrand factor binds to the exposed collagen
Von Willebrand factor (vWF): plasma protein that is synthesized by and stored in endothelial cells (in Weibel-Palade bodies) and platelets (in α-granules)
Mediates platelet adhesion and aggregation
Binds factor VIII (and thereby prevents its degradation)
Platelet hemostasis
Platelet adhesion: platelets bind to vWF via platelet GpIb receptor at the endothelial injury site
Ristocetin normally activates vWF to bind to glycoprotein Ib
Platelet activation: After binding to vWF, platelets change their shape and release mediators that lead to activation of more platelets (positive feedback). ; These mediators include:
Adenosine diphosphate (ADP): promotes adhesion of platelets to endothelium
Thromboxane A2 (TXA2): activates additional platelets and promotes vasoconstriction
Calcium: required for secondary hemostasis
Platelet-activating factor (PAF): a phospholipid mediator that is produced by platelets and inflammatory cells (e.g., neutrophils, monocytes, macrophages), involved in platelet aggregation and activation and local inflammatory response
Platelet aggregation
Mediated by GpIIb/IIIa-receptor and fibrinogen → formation of a white thrombus composed of platelets and fibrinogen
A white thrombus is transient, unstable, and easily dislodged. It stabilizes through the process of secondary hemostasis.
Secondary hemostasis
Definition: : processes that lead to stabilization of the platelet plug; (white thrombus; ) by creating a fibrin network
Coagulation cascade: a sequence of events triggered by the activation of the intrinsic or extrinsic pathway of coagulation that results in the formation of a stable thrombus
Coagulation factors
Substances that interact with each other to promote blood coagulation
Activated factors are designated with an "a" (e.g., activated factor VII = factor VIIa).
Extrinsic pathway of coagulation: triggered by endothelial injury
Tissue factor (factor III) activates factor VII.
Tissue factor is expressed on the surface of subendothelial muscle cells and fibroblasts.
Factor VII: vitamin K-dependent coagulation factor produced by the liver
Factor VIIa and tissue factor form a complex (TF-FVIIa). This step requires calcium (factor IV) found on the surface of fibrocytes and activated platelets.
TF-FVIIa activates factor X and factor IX.
Intrinsic pathway of coagulation
Exposed collagen, kallikrein, and kininogen (HMWK) activate factor XII.
Factor XII (Hageman factor): coagulation factor that also plays a role in inflammatory response by activating the kallikrein system, which leads to the production of bradykinin
Factor XIIa activates factor XI.
Thrombin activates factor XI and factor VIII.
Factor XIa activates factor IX.
Factors VIIIa and IXa form a complex (mediated by calcium) that activates factor X.
This causes a positive feedback loop of factor X and thrombin activation via the intrinsic pathway.
Common pathway of coagulation: The extrinsic end intrinsic pathway both end in the common pathway.
Factor Xa and factor Va form a complex (mediated by calcium) that cleaves prothrombin (factor II) to thrombin (factor IIa).
Thrombin cleaves fibrinogen (factor I) into insoluble fibrin (factor Ia) monomers.
Crosslinks of the fibrin network are stabilized by factor XIIIa; → formation of a fibrin network → fibrin closely binds to the platelet plug, forming a stable thrombus (secondary thrombus or red thrombus)
Overview of coagulation factors
Factor number
Descriptive name
Activated by
Involvement in pathways
Extrinsic
I†
Fibrinogen*
Active form (Ia): fibrin
Stabilization of the platelet plug
Prothrombin*
Active form (IIa): thrombin
Factor Xa/Va complex
Cleaves fibrinogen to fibrin
Activates numerous other coagulation factors
III†
Tissue factor* (TF)
Endothelial injury
Activates factor VII
Tissue factor and factor VIIa form a complex that activates factor X.
IV†
Calcium* (Ca2+)
Released by platelets and fibrocytes
Required for complex formation and other reactions in the coagulation cascade
Proaccelerin†
Factors Va and Xa form a complex that cleaves prothrombin to thrombin.
VII*
Proconvertin†
Tissue factor
Factor VIIa and tissue factor form a complex that activates factor X.
VIII*
Antihemophilic factor (AHF)
Factors VIIIa and IXa form a complex that activates factor X.
IX*
Plasma thromboplastin component (PTC)
Christmas factor
Factor XIa
X*
Stuart factor
Complexes TF-VIIa and VIIIa-IXa
Factors Xa and Va form a complex that cleaves prothrombin to thrombin.
XI*
Plasma thromboplastin antecedent (PTA)
Factor XII
Activates factor IX
XII*
Hageman factor
Exposed collagen
Kininogen (HMWK)
Activation of:
Factor XI
Kallikrein system: leads to the production of bradykinin
XIII*
Fibrin-stabilizing factor
Stabilizes the fibrin network by introducing crosslinks
* = preferred term [3]
† = rarely used term
The coagulation cascade requires the presence of calcium ions (factor IV).
A helpful way of remembering the coagulation factors of the extrinsic pathway is 3 + 7 = 10: Tissue factor (factor III) and factor VII form a complex that activates factor X of the common pathway.
A helpful way of remembering the coagulation factors of the common pathway is 10/5 = 2 × 1: Factors Xa and Va form a complex that cleaves prothrombin (factor II) to thrombin (IIa). Factor IIa then cleaves fibrinogen (I) into insoluble fibrin monomers (Ia).
Inhibition of hemostasis
In order to prevent hypercoagulability as well as excessive bleeding, activation of the coagulation cascade and the processes that inhibit it occur simultaneously in the circulatory system (procoagulant-anticoagulant balance).
Tissue factor pathway inhibitor: inhibits tissue factor
Protein C and protein S: Activated protein C and its cofactor protein S form the activated protein-C complex (APC complex), which inhibits factors Va and VIIIa.
Vitamin K-dependent synthesis in the liver
Shorter half-life than vitamin K-dependent coagulation factors (relevant for treatment with vitamin K antagonists, e.g., warfarin)
Clinical relevance
APC resistance
Factor V Leiden
Protein C deficiency, protein S deficiency
Antithrombin
Degrades thrombin and factors IXa and Xa
Activates tissue plasminogen activator (tPA)
Clinical relevance: antithrombin III deficiency (e.g., due to liver failure or kidney failure)
Nonspecific inhibitors: protease inhibitors in plasma (e.g., alpha-1-antitrypsin, alpha-2-macroglobulin)
Drug-induced: anticoagulant treatment (see "Oral anticoagulants" and "Parenteral anticoagulants")
Protein Z (factor X inhibitor)
Heparin-like glycosaminoglycans (boosts antithrombin)
Heparin cofactor II (requires heparin for activation)
Diseases that affect the inhibitors of the coagulation cascade may lead to hypercoagulability.
Fibrinolysis
Overview [2]
Definition: degradation of the fibrin network of thrombi by the enzyme plasmin
Tissue injury leads to the release and activation of plasminogen activators, which convert plasminogen to its active form plasmin.
Tissue plasminogen activator (tPA)
Urokinase (see fibrinolytics)
Plasmin breaks down and deactivates fibrin and fibrinogen → release of fibrin degradation products (e.g, D-dimers)
Plasminogen activator inhibitors (e.g., PAI-1) inhibit tPA
Plasmin inhibitors (e.g., PPIC)
Fibrinolytic therapy [4]
Agents: Fibrinolytics promote the degradation of thrombi by activating plasminogen to plasmin.
Fibrin-specific agents
Recombinant plasminogen activators (rtPA): tPAs that are produced by recombinant biotechnology techniques
Alteplase
Reteplase (rPA)
Tenecteplase (TNK-tPA)
Non-fibrin-specific agents
Streptokinase: enzyme produced by group A streptococci; catalyzes the conversion of plasminogen to plasmin
Urokinase: serine protease found in plasma, urine, and various types of tissue that is also used in fibrinolytic therapy
Mechanism of action: : directly or indirectly increase the concentration of plasmin; → cleavage of thrombin and fibrin [5]
↑ PT
↑ PTT
Normal platelet count
Bleeding (e.g., intracranial hemorrhage)
Hypersensitivity reactions (esp. to streptokinase) [6]
Early STEMI (< 12 hours)
Early ischemic stroke (< 3 hours)
Massive pulmonary embolism
Contraindications to fibrinolytic therapy
Active bleeding
Prior intracranial hemorrhage
Recent surgery
Known bleeding diathesis
Reversal of adverse effects
Antifibrinolytics: group of drugs that impair fibrinolysis, typically by interfering with plasmin formation
Tranexamic acid: a synthetic lysine analog and inhibitor of plasminogen with antifibrinolytic action
Aminocaproic acid: a lysine derivative and inhibitor of plasminogen activators and plasmin with antifibrinolytic action
Fresh frozen plasma (FFP), PCC, or cryoprecipitate (Cryoprecipitate is obtained from frozen blood plasma via centrifuge and contains more factor VIII and fibrinogen than FFP.)
Platelet transfusions (if necessary)
Alteplase is a synthetic tissue plasminogen activator that converts plasminogen to plasmin. It is used in the treatment of STEMI, massive pulmonary embolism, and ischemic stroke.
Disorders of fibrinolysis
Hypoplasminogenemia [7]
Definition: inherited genetic condition characterized by abnormally low levels of plasminogen, which results in a build-up of fibrin
Epidemiology: rare disease; prevalence is estimated to be approx. 1:625,000
Etiology: autosomal recessive inherited mutations in the PLG gene
Pathophysiology: : mutations of the PLG gene → ↓ concentrations and/or functional impairment of plasminogen → ↓ plasmin → ↓ fibrinolysis → accumulation of fibrin
Clinical features: usually manifest in early infancy
Formation of inflamed, thick, wood-like growths (ligneous pseudomembranes) on mucous membranes (especially the conjunctiva) that appear white, yellow, or red
Other areas that can be affected: skin, CNS, gingiva, gastrointestinal tract, lungs, female genital tract (e.g., fallopian tubes)
Not associated with thrombophilia
Initially: clinical presentation, laboratory tests for plasminogen activity
Genetic testing confirms the diagnosis.
Differential diagnosis: infections (most common), but also conditions such as allergies, GERD, IBD, endometriosis, depending on the area affected
Intravenous injection of ryplazim [8]
Plasma-derived human plasminogen used in the treatment of hypoplasminogenemia
Adverse effects include gastrointestinal upset, extremity pain, and hemorrhage.
Surgical removal of growths is usually not recommended due to rapid regrowth.
Corneal scarring, loss of vision
Duodenal ulcers
Occlusive hydrocephalus
Can reduce fertility
Hemorrhagic diathesis is the abnormally increased susceptibility to bleeding.
Disorders of primary hemostasis
Platelet disorders [9]
Platelet deficiency (see "Etiology" in "Thrombocytopenia")
Platelet dysfunction (thrombocytopathy): disorders that lead to dysfunctional adhesion or aggregation of platelets
Von Willebrand disease
Bernard-Soulier syndrome
Glanzmann thrombasthenia
Drug-induced: e.g., aspirin, NSAID, clopidogrel
Immune thrombocytopenic purpura
Cardiopulmonary bypass [10]
See also "Differential diagnosis of platelet disorders."
Disorders affecting the vessel wall
Vascular hemorrhagic diathesis (e.g., IgA vasculitis, hereditary hemorrhagic telangiectasia)
Thrombotic microangiopathy (e.g., HUS and TTP)
Conditions with impaired collagen synthesis (e.g., scurvy, Ehlers-Danlos syndrome)
Disorders of secondary hemostasis (disorders of the coagulation cascade)
Intrinsic pathway
Factor VIII deficiency (hemophilia A)
Factor IX deficiency (hemophilia B)
Factor XI deficiency (hemophilia C)
Extrinsic pathway: : factor VII deficiency (autosomal recessive bleeding disorder caused by mutation of the F7 gene)
Both pathways
Deficiency or inhibition of vitamin K-dependent coagulation factors II, VII, IX, and X
Vitamin K deficiency: e.g., malabsorption syndrome, depletion of gut flora (e.g., following antibiotic administration), vitamin K deficiency bleeding of the newborn
Vitamin K antagonist therapy (e.g., warfarin)
Inhibition of coagulation factors by autoantibodies (most commonly anti-factor VIII) [11]
Disseminated intravascular coagulation (DIC)
Impaired hepatic production of coagulation factors (e.g., cirrhosis)
Fibrinogen deficiency
Anticoagulant treatment
In disorders of primary hemostasis, platelet aggregation is impaired, whereas in disorders of secondary hemostasis it is the coagulation cascade that is impaired.
Hyperfibrinolysis [12]
Definition: pathological fibrinolysis, which leads to bleeding
Disseminated intravascular coagulation (secondary to liver dysfunction, sepsis, etc.)
Peripartum complications
Treatment with fibrinolytics
Surgery in tPA-rich organs such as the prostate and uterus
Prostate carcinoma (paraneoplastic)
Pathophysiology: excessive plasmin activity → increased fibrin degradation → thrombus instability and dissolution shortly after formation
Hypofibrinogenemia [13]
Definition: : a disorder characterized by low plasma fibrinogen levels
Congenital: mutation of fibrinogen genes (FGA, FGB, FGG) on chromosome 4
Acquired: associated with liver failure, disseminated intravascular coagulation, liver transplantation, massive blood transfusion, hemodilution, consumption of clotting factors [14]
Congenital: mutation → lack of functional fibrinogen glycoprotein → ↓ production of fibrinogen → hemorrhagic diathesis
Acquired: ↓ fibrinogen concentration (various causes) → hemorrhagic diathesis
Symptoms and findings: epistaxis, gastrointestinal hemorrhage, gingival bleeding
Clinical features of bleeding disorders [15][16]
Onset of bleeding
Primary hemostasis disorders [9]
Immediately after trauma
Bleeding of mucous membranes, e.g.:
Epistaxis
Cutaneous and subcutaneous bleeding, e.g.:
Petechiae
Superficial ecchymoses
Prolonged and excessive bleeding after surgery
Secondary hemostasis disorders
Delayed (minutes to hours after trauma)
Deep tissue bleeding, e.g.:
Hemarthrosis (esp. in hemophilia)
Large, palpable ecchymoses
Disseminated intravascular coagulation
Variable (depends on underlying cause)
Bleeding symptoms may include:
Petechial bleeding
Ecchymosis
Oozing of blood from surgical wounds and intravenous lines
Symptoms of hypercoagulation (see "Clinical features" in "DIC")
A thorough physical examination is essential for diagnosing bleeding disorders and should include the inspection of the entire skin, mucosa (esp. oral cavity), and joints.
Watch out for signs of physical abuse, which may produce patterns of bruising that resemble those of bleeding disorders. Signs of physical abuse include:
Inconsistency of clinical findings and history
Atypical bruising patterns (e.g., on back, forehead, ears, neck) and/or retinal hemorrhages in children ≤ 4 years (see "Battered child syndrome")
Superficial, petechial bleeding indicates defects of primary hemostasis, whereas large, palpable ecchymoses and deep tissue bleeding suggest defects of secondary hemostasis!
Clinical assessment and basic laboratory testing are used to differentiate between primary and secondary disorders of hemostasis. Advanced testing is used to identify the specific disorder.
Clinical assessment [17][18][19]
Ask about features of mucosal, skin, and deep-tissue bleeding (see "Clinical features").
Quantify bleeding severity with a bleeding assessment tool.
Features associated with bleeding disorders
Known bleeding disorder in a family member
Chronic illness: e.g., chronic kidney disease, liver disease, malignancy, autoimmune diseases, malabsorption
Acute illness: e.g., recent infections , sepsis , use of mechanical circulatory support
Poor nutritional status
Use of medications
Antithrombotic agents: anticoagulants, antiplatelet agents
Other drugs that can affect platelet function and/or count, including:
Chemotherapeutic agents
Phosphodiesterase inhibitors (e.g., cilostazol, sildenafil, theophylline)
Antimycotis and antibiotics (e.g., miconazole, nitrofurantoin)
Most bleeding disorders are acquired; i.e., secondary to medications or associated with acute or chronic illness. [17]
Women presenting with menorrhagia should also be evaluated by a gynecologist.
Bleeding assessment tools (BATs) [20][21][22]
BATs are questionnaires that standardize the assessment of bleeding symptoms and identify patients who may benefit from advanced testing. Multiple tools are available.
The International Society of Thrombosis and Hemostasis BAT includes the following symptoms: [21][22][23]
Mucocutaneous symptoms: cutaneous signs of bleeding, bleeding from minor wounds, epistaxis, bleeding in the oral cavity
Bleeding after procedures: after a surgery or dental extraction
Musculoskeletal bleeding: hemarthroses, or muscular hematomas
CNS bleeding
Gynecological bleeding: menorrhagia or postpartum hemorrhage
Each symptom receives a score based on its severity.
An elevated total score should prompt evaluation for bleeding disorders. [22][24] [25][26]
A low score does not exclude bleeding disorder.
Initial laboratory studies [18][19][20][27]
History or physical examination suggestive of a bleeding disorder
Elevated BAT score
CBC, BMP, liver chemistries
Peripheral blood smear
Platelet clumping: suggests pseudothrombocytopenia
Schistocytes or other fragmented cells: consistent with microangiopathic hemolytic anemia (e.g., thrombotic thrombocytopenic purpura)
Identification of blasts: suggests hematologic malignancies
Coagulation panel; including fibrinogen level: Elevated PT/INR and/or aPTT are suggestive of disorders of secondary hemostasis.
Platelet function analysis (PFA): Abnormal platelet function (or, if not available, a prolonged bleeding time; ) suggests a disorder of primary hemostasis. [19]
vWF antigen and vWF activity (vWF ristocetin activity): for diagnosis of vWD
Von Willebrand disease is the most common inherited bleeding disorder, affecting up to 1% of the population. Von Willebrand factor concentration and vWF activity are now commonly part of initial diagnostic studies. [20][27]
Interpretation of laboratory findings in bleeding disorders [18][20][28]
Defective pathway
PFA or bleeding time
PT/INR
aPTT
Platelet dysfunction (e.g., aspirin therapy)
Disorders of secondary hemostasis
Extrinsic pathway (e.g., factor VII deficiency)
Intrinsic pathway (e.g., hemophilia, heparin therapy)
Intrinsic and extrinsic pathways (e.g., deficiency of vitamin K-dependent coagulation factors)
Disorders of primary AND secondary hemostasis
Normal/↑ [27]
DIC is characterized by thrombosis, hemorrhage, and organ dysfunction and can be a medical emergency that requires immediate treatment.
A detailed clinical assessment and initial laboratory studies are sufficient to diagnose the most common disorders of hemostasis (e.g., platelet dysfunction secondary to medications or bleeding disorders associated with acute or chronic disease).
Advanced laboratory studies [18][19]
Advanced laboratory studies help identify specific disorders. The choice of studies depends on the suspected underlying pathology and usually requires specialist consult.
Disorders of primary hemostasis: low platelet count or abnormal platelet function test with normal INR and PTT
Disorders of secondary hemostasis: abnormal INR or PTT with normal platelet counts and platelet function
Unclear after initial studies: normal platelet count and function and normal coagulation panel but high clinical suspicion for a bleeding disorder
Suspected disorders of primary hemostasis
Low platelet count
Base further testing on clinical suspicion. For example:
Thrombocytopenia in a pregnant patient: Start investigations for HELLP syndrome.
Anemia and thrombocytopenia in a patient with suggestive symptoms: Start investigations for TTP.
Presence of B symptoms or other abnormalities on CBC and/or blood smear: Start investigations for a hematologic malignancy.
See "Diagnostics" in "Thrombocytopenia" for details.
Abnormal platelet function [29]
Acquired (most common): etiology (e.g., medications or chronic illness) usually clear after initial evaluation
Inherited (rare): advanced testing to further assess platelet function and identify the etiology
See also "Differential diagnoses of platelet disorders."
Suspected disorders of secondary hemostasis [19][30]
Congenital factor deficiencies: confirmed with factor assays (low factor concentrations)
Presence of factor inhibitors: can be diagnosed using mixing studies
Possible mechanisms and coagulation factors affected in disorders of secondary hemostasis [19][30]
Elevated PT/INR
Normal PT/INR
Elevated aPTT
Factors II, V, VIII, or X (common pathway)
Factors VIII, IX, or XI (intrinsic pathway)
Normal aPTT
Factor VII (extrinsic pathway)
See "Disorder unclear after initial testing" below
Disorder unclear after initial testing [19]
Additional testing is required if suspicion of a bleeding disorder is high but coagulation testing is normal. Possible etiologies include:
Hyperfibrinolysis: Testing includes alpha 2-antiplasmin level and plasminogen activation inhibitor-1 level. [31]
Vascular disorders (e.g., Ehler Danlos syndrome, hereditary hemorrhagic telangiectasia): Genetic testing is required.
Factor XIII deficiency
Combined coagulation factor deficiency
If the diagnosis remains unclear, repeat testing for vWD is recommended. [19]
Treatment should be guided by a specialist and target the specific cause of the bleeding. Occasionally, the transfusion of blood products may be indicated. For patients with acute or major bleeding, see "Management of acute bleeding" below.
General principles [30][32]
Avoid medications that may impair hemostasis.
Ensure optimal preventive medical and dental health care.
Consult a specialist to determine any preventive measures that are necessary before invasive procedures.
Provide patient education on lifestyle modification in the setting of bleeding disorders.
Consider screening for HIV and hepatitis if the patient has a history of multiple transfusions.
Disorders of primary hemostasis [33][34]
Platelet transfusion
Used in the treatment of both thrombocytopenia and platelet dysfunction
Prevention of bleeding during invasive procedures
Prophylactically in patients with extremely low platelet count [30]
Disease-specific treatment
Uremic platelet dysfunction [35]
Preventative measures include dialysis, erythropoietin, and conjugated estrogens. [36]
Desmopressin: may be used prior to invasive procedures or to treat active bleeding
Drug-related platelet dysfunction [33]
Discontinue medications causing dysfunction.
Consider desmopressin
Immune thrombocytopenia: Treatment may include corticosteroids and IVIG. Platelet transfusion is typically ineffectual.
Heparin-induced thrombocytopenia: Stop all heparin and initiate an alternative form of anticoagulation.
HELLP syndrome: Consult obstetrician immediately for specific management.
One random donor platelet unit typically increases platelet count by 5,000–10,000/mm3 in a 70-kg patient. One apheresis unit (the equivalent of 6–8 single units) increases platelet count by 30,000–40,000/mm3. [37]
Inherited coagulation factor deficiency [27]
Depending on the etiology, treatment can include one or more of the following:
Blood product transfusions
Replacement of specific coagulation factors, e.g.:
Factors VIII, IX, or XI (e.g., for hemophilia)
Concentrates containing vWF and factor VIII (for vWD)
Pharmacological therapy (e.g., desmopressin, antifibrinolytics)
Intravenous immunoglobulin therapy
See "Treatment" in "Hemophilia" and in "Von Willebrand Disease" for specific recommendations.
Acquired coagulation factor deficiency
Vitamin K deficiency [38]
Vitamin K replacement: phytonadione
Optimize enteral or parenteral nutrition.
Associated with anticoagulant use: See "Anticoagulant reversal" for specific recommendations.
Liver disease: complex management [39][40][41]
Consult gastroenterology and hematology early.
Consider vitamin K replacement for patients with abnormal coagulation studies. [40][42]
Screen for and manage comorbid conditions that affect hemostasis (e.g., uremia, bacterial overgrowth, portal hypertension, thrombocytopenia).
The effect of liver disease on hemostasis is complex: The clinical effects of thrombocytopenia and reduced coagulation factor synthesis are often negated by a simultaneous decrease in the production of profibrinolytic factors. Bleeding often does not occur, even if the laboratory values of hemostasis are markedly abnormal. [39]
Impaired coagulation factor function
Therapeutic or accidental anticoagulant use: See "Anticoagulant reversal."
Coagulation factor inhibitors: Treatment includes immunosuppression (e.g., glucocorticoids) and occasional use of bypassing agents. [43]
Patients with an inhibitor to a coagulation factor are at high risk of severe or fatal bleeding. [43]
Management of acute bleeding
Management [17]
Start ABCDE approach and stabilize the patient as needed.
Establish appropriate IV access.
Consult hematology service.
Assess the need for anticoagulant reversal, discontinue ongoing anticoagulants and platelet inhibitors, unless contraindicated.
Consider consultation for a procedural intervention to control bleeding (e.g., upper endoscopy, colonoscopy, surgery).
Start transfusion of blood products if needed (see also "Massive transfusion").
pRBCs: Target Hb using a liberal or restrictive transfusion strategy.
Platelet transfusion: for thrombocytopenia or as part of a massive transfusion protocol
Fresh frozen plasma (FFP), cryoprecipitate : as part of massive transfusion protocol or to replace coagulation factors and/or fibrinogen
Prothrombin complex concentrate: Use only with expert guidance; potentially fatal thrombotic complications may occur. [44][45]
Consider replacement of specific coagulation factors
Known hemophilia: factors VIII, IX, or XI
Known von Willebrand disease (vWD): concentrates containing vWF and factor VIII
Consider adjuvant drug therapy depending on suspected etiology
Anticoagulant reversal, e.g., Vitamin K (phytonadione ) [38]
Desmopressin [46]
Antifibrinolytics (e.g., for hyperfibrinolysis)
Diagnostics should not delay factor replacement therapy in patients with known bleeding disorders presenting with major bleeding. [47][48][49]
Patients with a suspected disorder of secondary hemostasis presenting with major bleeding can benefit from the transfusion of fresh frozen plasma while diagnostic studies are performed. [17]
Diagnostics [17]
CBC with blood smear, BMP, liver chemistries, and type and cross
Coagulation studies: Obtain a coagulation panel and measure vWF and vWF activity.
Viscoelastic hemostatic assays (VHAs): a point-of-care test with rapid results that provides a comprehensive assessment of hemostatic function [50][51][52]
Common modalities: thromboelastogram (TEG®), rotational thromboelastometry (ROTEM®), and Sonoclot®
Uses [52][53][54][55][56]
Rapid bleeding (e.g., cardiac and liver transplant surgery, trauma, DIC, peripartum hemorrhage)
Complex hemostasis disorders (e.g., liver disease)
Girolami A, Luzzatto G, Varvarikis C, Pellati D, Sartori R, Girolami B. Main clinical manifestations of a bleeding diathesis: an often disregarded aspect of medical and surgical history taking. Haemophilia. 2005; 11 (3): p.193-202. doi: 10.1111/j.1365-2516.2005.01100.x . | Open in Read by QxMD
Drews RE. Approach to the adult patient with a bleeding diathesis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/approach-to-the-adult-patient-with-a-bleeding-diathesis?source=machineLearning&search=hemostasis%20disorders&selectedTitle=1~150&sectionRank=2&anchor=H10#H6.Last updated: January 11, 2017. Accessed: February 8, 2017.
Overview of Platelet Disorders. http://www.merckmanuals.com/professional/hematology-and-oncology/thrombocytopenia-and-platelet-dysfunction/overview-of-platelet-disorders. Updated: September 1, 2014. Accessed: February 8, 2017.
Walls R, Hockberger R, Gausche-Hill M. Rosen's Emergency Medicine. Elsevier Health Sciences ; 2018
Neutze D, Roque J. Clinical Evaluation of Bleeding and Bruising in Primary Care. Am Fam Physician. 2016; 93 (4): p.279-86.
Boender J, Kruip MJHA, Leebeek FWG. A diagnostic approach to mild bleeding disorders. J of Thromb and Haemost. 2016; 14 (8): p.1507-1516. doi: 10.1111/jth.13368 . | Open in Read by QxMD
Rodeghiero F, Pabinger I, Ragni M, et al. Fundamentals for a Systematic Approach to Mild and Moderate Inherited Bleeding Disorders: An EHA Consensus Report. Hemasphere. 2019; 3 (5). doi: 10.1097/hs9.0000000000000286 . | Open in Read by QxMD
RODEGHIERO F, TOSETTO A, ABSHIRE T, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J of Thromb and Haemost. 2010; 8 (9): p.2063-2065. doi: 10.1111/j.1538-7836.2010.03975.x . | Open in Read by QxMD
Adler M, Kaufmann J, Alberio L, Nagler M. Diagnostic utility of the ISTH bleeding assessment tool in patients with suspected platelet function disorders. J Thromb Haemost. 2019; 17 (7): p.1104-1112. doi: 10.1111/jth.14454 . | Open in Read by QxMD
Elbatarny M, Mollah S, Grabell J, et al. Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project. Haemophilia. 2014; 20 (6): p.831-835. doi: 10.1111/hae.12503 . | Open in Read by QxMD
Moenen FCJI, Nelemans PJ, Schols SEM, Schouten HC, Henskens YMC, Beckers EAM. The diagnostic accuracy of bleeding assessment tools for the identification of patients with mild bleeding disorders: A systematic review. Haemophilia. 2018; 24 (4): p.525-535. doi: 10.1111/hae.13486 . | Open in Read by QxMD
Fasulo MR, Biguzzi E, Abbattista M, et al. The ISTH Bleeding Assessment Tool and the risk of future bleeding. Journal of Thrombosis and Haemostasis. 2017; 16 (1): p.125-130. doi: 10.1111/jth.13883 . | Open in Read by QxMD
Lowe GC, Lordkipanidzé M, Watson SP. Utility of the ISTH bleeding assessment tool in predicting platelet defects in participants with suspected inherited platelet function disorders. Journal of Thrombosis and Haemostasis. 2013; 11 (9): p.1663-1668. doi: 10.1111/jth.12332 . | Open in Read by QxMD
James PD, Goodeve AC. von Willebrand disease. Genetics in Medicine. 2011; 13 (5): p.365-376. doi: 10.1097/gim.0b013e3182035931 . | Open in Read by QxMD
Bashawri LA, Ahmed MA. The approach to a patient with a bleeding disorder: for the primary care physician.. Journal of family & community medicine. 2007; 14 (2): p.53-8.
Paniccia R, Priora R, Alessandrello Liotta A, Abbate R. Platelet function tests: a comparative review. Vasc Health Risk Manag. 2015 : p.133. doi: 10.2147/vhrm.s44469 . | Open in Read by QxMD
Kruse-Jarres R, Singleton TC, Leissinger CA. Identification and basic management of bleeding disorders in adults.. J Am Board Fam Med. 2014; 27 (4): p.549-64. doi: 10.3122/jabfm.2014.04.130227 . | Open in Read by QxMD
Longstaff C. Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haem. 2018; 16 (4): p.652-662. doi: 10.1111/jth.13957 . | Open in Read by QxMD
Drebes A, de Vos M, Gill S, et al. Prothrombin Complex Concentrates for Coagulopathy in Liver Disease: Single‐Center, Clinical Experience in 105 Patients. Hepatology Communications. 2019 . doi: 10.1002/hep4.1293 . | Open in Read by QxMD
Sorensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity. Critical Care. 2011; 15 (1): p.201. doi: 10.1186/cc9311 . | Open in Read by QxMD
Iau P, Ong V, Tan WT, Koh PL, Hartman M. Use of Activated Recombinant Factor VII in Severe Bleeding – Evidence for Efficacy and Safety in Trauma, Postpartum Hemorrhage, Cardiac Surgery, and Gastrointestinal Bleeding. Transfus Med and Hemother. 2012; 39 (2): p.139-150. doi: 10.1159/000338034 . | Open in Read by QxMD
Schulman S, Furie B. How I treat poisoning with vitamin K antagonists. Blood. 2015; 125 (3): p.438-442. doi: 10.1182/blood-2014-08-597781 . | Open in Read by QxMD
Obaji S, Alikhan R, Rayment R, Carter P, Macartney N, Collins P. Unclassified bleeding disorders: outcome of haemostatic challenges following tranexamic acid and/or desmopressin. Haemophilia. 2015; 22 (2): p.285-291. doi: 10.1111/hae.12811 . | Open in Read by QxMD
Savage SA, Sumislawski JJ, Zarzaur BL, Dutton WP, Croce MA, Fabian TC. The new metric to define large-volume hemorrhage. Journal of Trauma and Acute Care Surgery. 2015; 78 (2): p.224-230. doi: 10.1097/ta.0000000000000502 . | Open in Read by QxMD
The National Blood Authority's Patient Blood Management Guideline: Module 1 – Critical Bleeding/Massive Transfusion. https://www.blood.gov.au/pbm-module-1. Updated: January 1, 2011. Accessed: February 17, 2021.
Guidelines for Emergency Department Management of individuals with hemophilia and other bleeding disorders. https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-257-guidelines-for-emergency-department-management-of-individuals-with-hemophilia-and-other-bleeding-disorders. Updated: December 5, 2019. Accessed: April 22, 2021.
Müller MC, Meijers JC, Vroom MB, et al. Utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systematic review. Crit Care. 2014; 18 (1): p.R30. doi: 10.1186/cc13721 . | Open in Read by QxMD
Müller MCA, Meijers JC, van Meenen DM, Thachil J, et al. Thromboelastometry in critically ill patients with disseminated intravascular coagulation.. Blood Coagul Fibrinolysis. 2019; 30 (5): p.181-187. doi: 10.1097/MBC.0000000000000808 . | Open in Read by QxMD
Curry NS, Davenport R, Pavord S, et al. The use of viscoelastic haemostatic assays in the management of major bleeding. Br J Haematol. 2018; 182 (6): p.789-806. doi: 10.1111/bjh.15524 . | Open in Read by QxMD
Whiting P, Al M, Westwood M, et al. Viscoelastic point-of-care testing to assist with the diagnosis, management and monitoring of haemostasis: a systematic review and cost-effectiveness analysis. Health Technol Assess (Rockv). 2015; 19 (58): p.1-228. doi: 10.3310/hta19580 . | Open in Read by QxMD
Wikkelsø A, Wetterslev J, Møller AM, Afshari A. Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment in bleeding patients: a systematic review with meta-analysis and trial sequential analysis. Anaesthesia. 2017; 72 (4): p.519-531. doi: 10.1111/anae.13765 . | Open in Read by QxMD
Fahrendorff M, Oliveri RS, Johansson PI. The use of viscoelastic haemostatic assays in goal-directing treatment with allogeneic blood products – A systematic review and meta-analysis. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 2017; 25 (1). doi: 10.1186/s13049-017-0378-9 . | Open in Read by QxMD
Whiting D, DiNardo JA. TEG and ROTEM: Technology and clinical applications. Am J Hematol. 2014; 89 (2): p.228-232. doi: 10.1002/ajh.23599 . | Open in Read by QxMD
Leung LLK, Mannucci PM, Tirnauer JS. Overview of Hemostasis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/overview-of-hemostasis.Last updated: December 15, 2016. Accessed: August 29, 2017.
Hall JE. Guyton and Hall Textbook of Medical Physiology. Elsevier ; 2016
Giangrande PLF. Six Characters in Search of An Author: The History of the Nomenclature of Coagulation Factors. Br J Haematol. 2003; 121 (5): p.703-712. doi: 10.1046/j.1365-2141.2003.04333.x . | Open in Read by QxMD
Rydz N, James P. Approach to the Diagnosis and Management of Common Bleeding Disorders. Semin Thromb Hemost. 2012; 38 (07): p.711-719. doi: 10.1055/s-0032-1326783 . | Open in Read by QxMD
Konkle BA. Acquired Disorders of Platelet Function. Hematology Am Soc Hematol Educ Program. 2011; 2011 (1): p.391-396. doi: 10.1182/asheducation-2011.1.391 . | Open in Read by QxMD
DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction.. Am J Hematol. 1990; 33 (1): p.39-45. doi: 10.1002/ajh.2830330108 . | Open in Read by QxMD
Hedges SJ, Dehoney SB, Hooper JS, Amanzadeh J, Busti AJ. Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol. 2007; 3 (3): p.138-153. doi: 10.1038/ncpneph0421 . | Open in Read by QxMD
Fraser IS, Porte RJ, Kouides PA, Lukes AS. A benefit-risk review of systemic haemostatic agents: part 1: in major surgery.. Drug Saf. 2008; 31 (3): p.217-30. doi: 10.2165/00002018-200831030-00003 . | Open in Read by QxMD
Mohanty D. Current concepts in platelet transfusion. Asian Journal of Transfusion Science. 2009; 3 (1): p.18. doi: 10.4103/0973-6247.45257 . | Open in Read by QxMD
Caldwell SH, Hoffman M, Lisman T, et al. Coagulation disorders and hemostasis in liver disease: Pathophysiology and critical assessment of current management. Hepatology. 2006; 44 (4): p.1039-1046. doi: 10.1002/hep.21303 . | Open in Read by QxMD
Hunt BJ. Bleeding and Coagulopathies in Critical Care. N Engl J Med. 2014; 370 (9): p.847-859. doi: 10.1056/nejmra1208626 . | Open in Read by QxMD
Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Research and Practice in Thrombosis and Haemostasis. 2017; 1 (2): p.150-161. doi: 10.1002/rth2.12028 . | Open in Read by QxMD
Kujovich JL. Coagulopathy in liver disease: a balancing act. Hematology. 2015; 2015 (1): p.243-249. doi: 10.1182/asheducation-2015.1.243 . | Open in Read by QxMD
W Collins P, Chalmers E, et al. Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO. Br J Haematol. 2013; 162 (6): p.758-773. doi: 10.1111/bjh.12463 . | Open in Read by QxMD
Marder VJ, Novokhatny V.. Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential.. Journal of Thrombosis and Haemostasis. 2010 .
Nazari J, Davison R, Kaplan K, Fintel D. Adverse Reactions to Thrombolytic Agents. Med Toxicol. 1987; 2 (4): p.274-286. doi: 10.1007/bf03259869 . | Open in Read by QxMD
Hypoplasminogenemia. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=722. Updated: September 1, 2021. Accessed: October 22, 2021.
RYPLAZIM® (plasminogen, human-tvmh). https://www.fda.gov/media/149806/download. . Accessed: October 22, 2021.
Weerasinghe A, Taylor KM. The platelet in cardiopulmonary bypass. Ann Thorac Surg. 1998; 66 (6): p.2145-2152. doi: 10.1016/s0003-4975(98)00749-8 . | Open in Read by QxMD
Franchini M, Castaman G, Coppola A, et al. Acquired inhibitors of clotting factors: AICE recommendations for diagnosis and management. Blood Transfus. 2015; 13 (3): p.498-513. doi: 10.2450/2015.0141-15 . | Open in Read by QxMD
Fay WP, Leung LLK, Tirnauer JS. Thrombotic and Hemorrhagic Disorders due to Abnormal Fibrinolysis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/thrombotic-and-hemorrhagic-disorders-due-to-abnormal-fibrinolysis.Last updated: May 26, 2017. Accessed: August 28, 2017.
Thompson RJ, Portmann BC, Roberts EA. Genetic and metabolic liver disease. Elsevier ; 2011 : p. 157-259
Shaz BH, MD BH, Hillyer CD, MD CD, Gil MR. Transfusion Medicine and Hemostasis. Elsevier Science ; 2019 : p. 1050


text:
Manchester reaches deal with feds to improve river quality
U. S. Environmental Protection Agency
By MICHAEL CASEY - Associated Press - Monday, July 13, 2020
Two federal agencies have reached a deal with New Hampshire's largest city to enact measures aimed at helping reduce river pollution.
The agreement announced Monday between the U.S. Environmental Protection Agency, the U.S. Department of Justice and Manchester calls for implementing a 20-year plan to control and significantly reduce overflows of its sewer system into the Merrimack River. The state joined the U.S. government as a co-plaintiff on the agreement, which also settles alleged Clean Water Act violations by city. The proposed consent decree was filed in federal court in Concord.
Officials said the measures, which will cost over $231 million, should cut down on the amount of sewage from the city's wastewater treatment systems that reaches the river.
The Merrimack River, the main source of drinking water for more than 500,000 people, is stocked with bass and trout and is popular with boaters.
"This agreement means a healthier Merrimack River and cleaner water for the communities along the river in both New Hampshire and Massachusetts," EPA New England Regional Administrator Dennis Deziel said in a statement. "EPA has long been committed to working with our state and federal partners and cities like Manchester to improve water quality along the Merrimack, which is an important source of drinking water and recreation destination."
Mayor Joyce Craig welcomed the agreement, which she described as part of the city's continued effort to improve its combined sewer overflow system and improve the river's water quality.
The agreement targets the city's combined sewer system, which during heavy rains often discharges raw sewage, industrial waste and other pollutants into the Merrimack River and its tributaries. Under the deal, the city is expected to reduce those discharges by 74%.
The settlement also requires upgrades at Manchester's wastewater treatment plant to reduce discharges of phosphorous.

redpajama_set_name: RedPajamaCommonCrawl


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Why Choose Novatia for your NMR Needs?
Novatia's NMR spectroscopists have combined industrial and academic experience of over 50 years ranging from polymers, pharmaceuticals, natural products and biomolecules. If NMR can solve your problem, Novatia can help.
There are two equipment factors to consider when selecting a NMR vendor: magnet field strength and probe technology. These factors directly affect the resolution and sensitivity – and therefore the quality – of the collected data. A higher field strength instrument will provide better resolution and sensitivity. Better resolution means less peak overlap in your spectra, and easier interpretation. Better sensitivity means more signal and less noise. In practice, the most useful benefit of collecting data at higher field strength is increased sensitivity.
Probe technology also affects sensitivity. Cryo- or cold probes are about 2 (nitrogen-cooled Prodigy cryoprobe) to 5 (helium-cooled cryoprobes) times more sensitive than room temperature probes.
Novatia's NMR instrumentation is a 500 MHz Bruker Avance HD III with a Prodigy BBO Cryoprobe. Novatia's NMR will collect comparable signal intensity to a room-temperature 800 MHz NMR on the same timescale, and to a 300 MHz NMR in 1/16th the amount of time.
Many labs offer Mass Spectrometry, fewer offer NMR Spectroscopy and only a handful integrate MS and NMR with isolation and identification expertise. Novatia fits into the third category, offering rapid and reliable isolation and elucidation of impurities in active pharmaceutical ingredients (APIs), Drug Product stability samples, and metabolite mixtures.
Novatia has been providing NMR services to researchers for over 15 years. Our purpose is to help customers solve their research problems. Our experienced staff offers "full ownership" of research problems by designing an experimental approach, then collecting, analyzing and reporting the interpreted results in a research report. We also offer "data only" service where we collect the NMR data using state-of-the-art instrumentation and deliver the results via our secure website. We Either way, Novatia is focused on answering questions and supporting our customers' research efforts.


In mid-2017, the Dutch government announced a number of envisaged amendments to existing Dutch employment and dismissal law (as discussed previously here). These amendments will affect employers, employees and independent contractors. The proposals are now becoming more concrete, following the publication of a first draft legislative proposal on 9 April 2018. Internet consultation will be open until 7 May 2018; this means that the content of the proposed legislation may be subject of change. You can find a link to the legislative proposal here (Dutch only).
The most important proposed amendments are listed below.
in a temporary contract for longer than two years, parties can agree to a maximum trial period of three months instead of two months.
The possibility of agreeing on a longer trial period is a once-only right, and does not apply to successive agreements, unless the successive agreement significantly requires different skills and responsibilities on the part of the employee.
Under current legislation, an employer can only terminate an employment agreement if one of the statutory, reasonable grounds for dismissal is fulfilled. As a result, the threshold for termination is rather high – too high, according to many employers and the government. Therefore, an additional reasonable ground for dismissal (known as the "i-ground") is proposed. The i-ground allows employers to terminate an employment agreement if, although none of the statutory reasonable grounds is completely fulfilled, a combination of factors and circumstances referred to in the statutory grounds for dismissal occurs and gives rise to the conclusion that an employer cannot reasonably be expected to continue the employment agreement. If the court terminates the employment agreement based on the i-ground, the court can grant the employee an additional remuneration of up to 50% of the transition payment.
Under the current system, an employee is not entitled to the transition payment if the employment agreement is terminated during the first two years of employment. As a result, employers have an incentive to enter into temporary agreements for less than two years. The government would like to encourage employers to offer longer-term or permanent agreements, and therefore proposes removing the condition of two years of employment in determining entitlement to the transition payment.
The government also proposes a new method for calculating the transition payment. Each year of employment will have the same value for the accrual of the transition payment; for each year of service, the employee will accrue one third of the gross monthly salary as a transition payment. The differentiation that is currently made between the first ten years of employment (one third of monthly salary) and the period afterwards (half of monthly salary) will disappear.
for the business cessation of a small employer due to the retirement or illness of the employer.
To make temporary contracts less attractive to employers, the government also proposes some amendments concerning the law on successive employment agreements. Under current legislation, a chain of successive temporary agreements convert into a permanent agreement upon entering into a fourth successive temporary agreement, or after two years have passed since first entering into an employment agreement. Employment agreements are successive if six months or less have passed between two employment agreements. First, the government proposes changing the two-year period back to a three-year period, as it was previously. Second, the possibilities to deviate from the six-month period between different employment agreements will be expanded.
Payrolling is a specific form of hiring staff, where a payroll company hires an employee and then proceeds to second these employees to a specific client who, in turn, is responsible for recruiting the candidate and will be the material employer throughout the employment period.
the payroll company may end the employment agreement if the hirer terminates the contract with the payroll company.
the provisions on successive temporary employment agreements only applies after 26 weeks. This period can be extended to a maximum of 78 weeks by collective agreement.
the exception to the obligation to continue to pay wages if an employee is unable to work due to a reason caused by the employer, applies. This means that this obligation will only arise after 78 weeks of employment.
employees who are employed by a payroll company are not entitled to the same terms of employment as the employees of the hirer because they are generally not covered by the same collective agreements.
the proposal includes a legal definition of payrolling, which previously had yet to be defined.
payroll companies must offer their employees the same primary and secondary terms of employment as the employees of the hirer (with the exception of the employment conditions on pensions).
statutory provisions on successive temporary employment agreements will apply. The proposal includes a possibility to divert from the provision by collective agreement.
the exception to the obligation to continue to pay wages if the employee is unable to work due to a reason caused by the employer only applies if this exception is also regularly used with the employees of the hirer, or if the possibility arises from a collective agreement that applies to the employees of the hirer.
payroll employees have a right to participate in an adequate pension scheme. What constitutes an adequate pension scheme will be addressed in a specific general administrative measure (algemene maatregel van bestuur).
Current legislation does not provide rules on the notice period required between the moment the employer calls the employee and the moment the employee must report to work. This leads to the employee having to be permanently available, which the government finds undesirable. Thus, the government proposal includes a provision that requires a four-day notice period. If an employer alerts an employee within a shorter period, the employee is not required to report to work.
The notice period also applies in situations where the employer wants to cancel a work request. If the employer fails to adhere to the notice period, the employee is entitled to a wage payment for the hours that would have been worked if the employer had not cancelled. Finally, the government has applied the same notice period of four days for situations where an employee wishes to terminate the contract with the employer.
The government proposes making the legal presumption related to working hours applicable to min-max contracts. In the case of min-max contracts, the government proposes that the presumed working time should not be the agreed-upon minimum number of working hours (as is currently the case), but the average of the hours worked by the employee in the previous three months.
In addition to this, the government proposes that in the case of employment agreements without "guaranteed working hours", the employer should offer the employee a contract with guaranteed working hours in the 13th month of employment. The offered guaranteed working hours in the new employment agreement should be the calculated on the basis of the average hours the employee has worked over the previous 12 months. If the employer fails to make such a proposal, the employee is entitled to compensation for the working hours not worked.
Generally, the first draft legislative proposal does not include any surprises, as most of the policy changes had already been announced in the coalition agreement. The proposed changes regarding payrolling are, however, more far-reaching than predicted. Also, the changes regarding the law on dismissals have caused quite a stir. If the changes regarding the law of dismissal are implemented, we will abandon our rather new, closed system of grounds for dismissal. Instead, we will return to the previous system, but without the luxury of the sub-district court formula (de kantonrechtersformule).
The new proposal has not been universally popular; the FNV and CNF trade unions believe that the new legislative measures will encourage the further flexibilisation of the labour market, which will lead to less certainty for employees. On the other hand, the employer's association, MKB Nederland, is critical about the increased costs that will arise through stricter regulation of payrolling and temporary agency work.
Internet consultation will be open until 7 May 2018. After this date, the government will review all responses to the draft legislative proposal. This means that the content of the proposed legislation is subject to change. Minister Koolmees plans to send a new draft legislative proposal to the Council of State before the summer, and afterwards to the House of Representatives. We will keep you updated.


Summer is my favorite time of year. I love sticky, hot days with salt in the air. Very ripe peaches, long hours of sunlight, ice cold beer, and sitting around with friends are some of the highlights.
But tomatoes are pure summer gold. In fact my favorite and easiest vegan meal is sliced tomatoes with basil on bread. If you're feeling adventurous, you could add some vegan cheese.
This is another fast meal. It's perfect if you're on the go. It's delicious both as a soup or gazpacho.
Quarter the onion. Peel the cloves and leave whole. Cut the stems off the peppers and in half. Halve the tomatoes. Toss all of the vegetables in oil.
Combine all of the ingredients in a blender with 2 cups of vegetable stock.
It also makes a great dinner. I like to fry up some peppers, andouille sausage, and I'll make a big batch of herbed rice.
It's perfect if you're in an inter-dietary relationship. (That's where you can't eat the same thing whether by choice or allergies.) I'll eat some peppers, and Justin gets the sausage.
Dinner is on the table in 30 minutes and everyone is happy! Is anyone else in an inter-dietary relationship? What are some of your favorite meals?


text:
The HBCU Advocate
Serving the alumni, students, faculty, staff and friends of HBCUs
Jubilation! An Enduring Musical Union" Concert
8 months ago K. Alston
By: Fisk University
On the heels of celebrating their 150th anniversary, the Fisk Jubilee Singers® will hit another milestone on June 28th, as they usher in Ryman Auditorium's 130th anniversary on the sacred stage of the Mother Church.
The two Nashville institutions have enjoyed a thriving relationship since 1892 when the Fisk Jubilee Singers first performed at the Ryman during its inaugural year, and will again join forces for a celebratory night of music: "Jubilation! An Enduring Musical Union."
The multi-award-winning ensemble, who took home the GRAMMY for Best Roots Gospel Album in 2021, will perform during the first half of the program, then support three-time GRAMMY nominee Allison Russell for the second half of the show. Newcomers O.N.E The Duo will open for Allison.
"This is an extraordinary year for the Ryman as we celebrate 130 years, and we couldn't imagine commemorating the historic milestone without the Fisk Jubilee Singers," says Gary Levy, General Manager of Ryman Auditorium. "It's always a special night in Nashville when the Fisk Jubilee Singers perform at the Ryman, much like their inaugural performance in 1892 when they became one of the first musical acts to perform in the building, and we are honored to be a part of their continued legacy."
"I had the pleasure of meeting Dr. Kwami when we participated in last year's Americana Honors and Awards show," says Allison Russell. "We were on our way upstairs to have our portraits taken. As we walked up the steps of that historic stairwell, we came up with this idea together. I'm thrilled it's come to fruition and I'm honored to be a part of this landmark evening celebrating two iconic Nashville entities."
Adds Fisk Jubilee Singers' Musical Director Dr. Paul Kwami, "Two important institutions are celebrating their 130th reunion anniversary. As Ryman Auditorium celebrates this milestone, it also marks 130 years since the Fisk Jubilee Singers first performed in this sacred space in 1892. Both institutions continue to support and enhance the wonderful music culture of Nashville through collaborations with various guest artists. It is, therefore, only fitting that on June 28th, The Fisk Jubilee Singers will present another concert in the Ryman Auditorium with the amazing Allison Russell. This event is important to the music culture of Nashville, and I hope many people will join us in this celebration."
"Jubilation! An Enduring Musical Union" tickets are on sale now, HERE.
Proceeds from the event will benefit Fisk Jubilee Singers Endowed Scholarship Fund. Donations to the fund may be made HERE.
Tags: Fisk Jubilee Singers, GRAMMY for Best Roots Gospel Album, hbcu, Jubilation!, Musical Union, O.N.E The Duo
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text:
Q: How to copy a specific range between two mmap? How is it possible to only copy a specific part of one mmap into another via slices?
#!/usr/bin/python3

import mmap

a = mmap.mmap(-1, 5)
b = mmap.mmap(-1, 5)

a[0:] = b'12345'
b[0:] = b'67890'

a[2:6] = b[0:4]

print(a[:])

Is there a way to copy such a range via slices? If this is not possible, what other solutions exist?

A: I think you mush be getting below error:

IndexError: mmap slice assignment is wrong size

change a[2:6] = b[0:4] to
a[1:5] = b[0:4]

output:
b'16789' # print(a[:])

A: Although it isn't really clear what you are expecting, the above code will not work because you are using an invalid range. Calling a[2:6] will return a slice of size three, (i.e. it will return a[2:5] since a[6] doesn't actually exist) resulting in an error IndexError: mmap slice assignment is wrong size
Try running this with a[1:5] = b[0:4]. This yields:
print(a[:])
b'16789'

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Watch Unlucky Stars (2015) On Viooz : When Peru\'s Biggest Action Film Star and Jordan\'s newest rising talent find themselves pursued by a notorious Bookie, a couple of private investigators are forced to choose between their job and their conscience.
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text:
Peer 1 maps the 'Net on iOS and Android
Mark Gibbs (Network World) 07 March, 2013 14:14
When you're talking to a n00b -- say, your CEO or VP of sales and marketing (or maybe even your CIO) -- it can be hard to get them to understand just how big and complex the Internet is. Sure, they hear about the billions of people on the 'Net and all of the companies making money through e-commerce of one kind or another (which hopefully includes yours), but what they will often have a problem grasping is the sheer scale of the Internet and how it's grown. What they need is a visual aid.
So what can you show the n00bs to clue them in? Try a new free app for iOS (iPad and iPhone) and Android called "Map of the Internet," published just this week by Peer 1 Hosting.
[ IN PICTURES: The evolution of the Internet ]
A couple of years ago Peer 1 published a great infographic depicting a map of the Internet which was greeted with considerable enthusiasm and is still available online as a zoomable image, desktop wallpaper and a PDF. This map, dated Jan. 2, 2011, shows "19,869 autonomous system nodes, joined by 44,344 connections" (autonomous systems are networks under a single administrative control).
The data for the map came from the Cooperative Association for Internet Data Analysis (CAIDA), "a collaborative undertaking among organizations in the commercial, government, and research sectors aimed at promoting greater cooperation in the engineering and maintenance of a robust, scalable global Internet infrastructure."
CAIDA makes the various datasets it collects about Internet connections and topology available for free. The actual dataset used by Peer 1was the IPv4 Routed /24 AS Links Dataset.
The map was visually impressive and Peer 1 explained how it was created: "The sizing and layout of the autonomous systems [the nodes of the map] are based on their eigenvector centrality, which is a measure of how central to the network each autonomous system is: an autonomous system is central if it is connected to other autonomous systems that are central. This is the same graph-theoretical concept that forms the basis of Google's PageRank algorithm." Good to know.
Well, neither time nor the Internet stand still, and as groovy as the original static Peer 1 map was, the Internet carried on evolving even more rapidly. So to really bring the evolution and status of the 'Net to life, software was needed, and thus the Peer 1 iOS and Android "Map of the Internet" apps were created.
Now, while the new Peer 1 apps don't give a realtime view of the Internet, they are accurate to within the last few months and will be updated. Using the timeline view you can examine any single year from 1994 through to 2020.
The current version uses simulated data from 1994 through to 2000 (the data collected prior to 2000 wasn't as detailed or accurate as it became in later years) along with comprehensive data from 2000 through late 2012 and extrapolated data for 2013 through to 2020.
The new apps display the CAIDA data in either a globe view that geolocates the ASes or as a network view that organizes the ASes according to how they are connected hierarchically. You can also use the timeline option to show the ASes that existed at a particular time in either view, zoom and rotate the display with multi-touch gestures, click on an AS to find its name and number of connections, search for a named node, find the AS you are connected to, and run a traceroute to a selected AS from your current location.
This is an amazing tool for showing n00bs or, for that matter, anyone how the 'Net has evolved and just how massive and complex it really is and thus the Peer 1 "Map of the Internet" apps gets a Gearhead rating of 5 out of 5! Outstanding!
Gibbs knows where he is in Ventura, Calif. Locate your node to gearhead@gibbs.com and follow him on Twitter and App.net (@quistuipater) and on Facebook (quistuipater), and check out the Predictions blog.
Tags wirelessNetworkingsoftwaremobile appsLAN & WANPeer 1 Map of the InternetCAIDAPeer 1 HostingCooperative Association for Internet Data AnalysisMap of the Internet
Connecting businesses, governments, and communities in uncertain times
Life's complicated at the best of times.


text:
Q: How do I amend the RoamingPreferredBandType property of my users' wireless network adapters? We've been seeing intermittent issues with users connecting to wifi.
It seems that this may be due to interference, with the recommended solution being to change the RoamingPreferredBandType to 5GHz.
Per this thread, this can be done by amending the registry setting RoamingPreferredBandType's value to 2.  Some code (for both bat and powershell have been included on that thread; but these seem to scan through a large chunk of the registry finding and updating all properties with this value.  Whilst it's pretty unlikely that other entries will have a property with this name, I don't like code that works on assumptions; and this approach isn't overly efficient.  Is there a better way to do this, targeting only those entries that matter?

A: This is a modified version of the script on the Intel forum thread (linked in the question), which takes advantage of a couple of things to improve on their script:

*

*The GUID {4D36E972-E325-11CE-BFC1-08002BE10318} is always the one which will have network adapters under it, helping us narrow down the registry path: https://technet.microsoft.com/en-us/library/jj130901.aspx

*We can get the device id/index of a network adapter from the WMI class Win32_NetworkAdapter, which combined with the above gives us the full path to our adapter's registry key.

.
Get-WmiObject -Class Win32_NetworkAdapter | ?{$_.Name -like '*Wireless*'} | %{("HKLM:\SYSTEM\CurrentControlSet\Control\Class\{{4D36E972-E325-11CE-BFC1-08002BE10318}}\{0:0000}" -f ([int]$_.Index))} | %{
    if(get-itemproperty -Path $_ -Name 'RoamingPreferredBandType' -ErrorAction SilentlyContinue) {
        Set-ItemProperty -Path $_ -Name 'RoamingPreferredBandType' -Value 2
    } else {
        New-ItemProperty -Path $_ -Name 'RoamingPreferredBandType' -PropertyType String -Value 2
    }
}

i.e.

*

*get a list of all network adapters

*filter for the wireless ones

*use the device id / index of each wireless adapter to get the full registry path for this device/these devices

*for each device found, check if the RoamingPreferenceBandType property exists:

*

*If so, set it to 2 (if it doesn't exist this will create it).

*If not, create a new one with value 2 (this scenario's unlikely; but best to cater for)


text:
Stored platelets contain residual amounts of tissue factor: Evidence from studies on platelet concentrates stored for prolonged periods
Silvia Pérez-Pujol, Omer Aras, Miguel Lozano, Debra Cooking-Johnson, Nigel S. Key, James G. White, Jeffrey McCullough, Ginés Escolar
Laboratory Medicine and Pathology
BACKGROUND: The advent of new strategies for pathogen reduction has raised the question of whether platelet (PLT) concentrates (PCs) exposed to longer periods of storage retain adequate hemostatic function. STUDY DESIGN AND METHODS: The effects of prolonged storage on adhesive and procoagulant functions of PLTs in PCs have been analyzed. The ability of PLTs to interact with surfaces was assessed by en face electron microscopy. Exposure of anionic phospholipids or tissue factor (TF) antigen on PLTs was assessed by flow cytometry and by immunocytochemical methods at the ultrastructural level. Studies were performed in six different PCs followed 0, 3, 5, 7, and 11 days of storage RESULTS: A progressive impairment of PLT-adhesive functions was observed after 5 days of storage. A progressive increase in expression of anionic phospholipids and development of procoagulant activity (PCA) measured by a modified prothrombin time (mPT) was observed along the storage. Incubation of PLTs with a specific anti-TF resulted in prolongation of the mPT by approximately 10 to 15 percent. Flow cytometry revealed minimal TF expression at later storage times. Immunocytochemical studies showed minimal TF labeling when studies were performed on PLT whole mounts. Labeling was markedly improved when PLTs were previously exposed to sonication. CONCLUSION: Prolonged storage of PCs was associated with decreased PLT-adhesive capacities and enhanced PCA. Current preparation procedures and storage media have important limitations for preserving PCs for longer than 1 week. PLTs in PCs retain residual amounts of TF as assessed by immunocytochemical and functional assays. The origin and hemostatic significance of this TF should be investigated further.
Dive into the research topics of 'Stored platelets contain residual amounts of tissue factor: Evidence from studies on platelet concentrates stored for prolonged periods'. Together they form a unique fingerprint.
Thromboplastin Medicine & Life Sciences 100%
Blood Platelets Medicine & Life Sciences 70%
Adhesives Medicine & Life Sciences 42%
Prothrombin Time Medicine & Life Sciences 33%
Hemostatics Medicine & Life Sciences 31%
Phospholipids Medicine & Life Sciences 26%
Electron Microscopy Medicine & Life Sciences 12%
Pérez-Pujol, S., Aras, O., Lozano, M., Cooking-Johnson, D., Key, N. S., White, J. G., McCullough, J., & Escolar, G. (2005). Stored platelets contain residual amounts of tissue factor: Evidence from studies on platelet concentrates stored for prolonged periods. Transfusion, 45(4), 572-579. https://doi.org/10.1111/j.0041-1132.2005.04224.x
Stored platelets contain residual amounts of tissue factor : Evidence from studies on platelet concentrates stored for prolonged periods. / Pérez-Pujol, Silvia; Aras, Omer; Lozano, Miguel et al.
In: Transfusion, Vol. 45, No. 4, 01.04.2005, p. 572-579.
Pérez-Pujol, S, Aras, O, Lozano, M, Cooking-Johnson, D, Key, NS, White, JG, McCullough, J & Escolar, G 2005, 'Stored platelets contain residual amounts of tissue factor: Evidence from studies on platelet concentrates stored for prolonged periods', Transfusion, vol. 45, no. 4, pp. 572-579. https://doi.org/10.1111/j.0041-1132.2005.04224.x
Pérez-Pujol S, Aras O, Lozano M, Cooking-Johnson D, Key NS, White JG et al. Stored platelets contain residual amounts of tissue factor: Evidence from studies on platelet concentrates stored for prolonged periods. Transfusion. 2005 Apr 1;45(4):572-579. doi: 10.1111/j.0041-1132.2005.04224.x
Pérez-Pujol, Silvia ; Aras, Omer ; Lozano, Miguel et al. / Stored platelets contain residual amounts of tissue factor : Evidence from studies on platelet concentrates stored for prolonged periods. In: Transfusion. 2005 ; Vol. 45, No. 4. pp. 572-579.
@article{27ba07e9d8764b5eac3ad0409e8a2f05,
title = "Stored platelets contain residual amounts of tissue factor: Evidence from studies on platelet concentrates stored for prolonged periods",
abstract = "BACKGROUND: The advent of new strategies for pathogen reduction has raised the question of whether platelet (PLT) concentrates (PCs) exposed to longer periods of storage retain adequate hemostatic function. STUDY DESIGN AND METHODS: The effects of prolonged storage on adhesive and procoagulant functions of PLTs in PCs have been analyzed. The ability of PLTs to interact with surfaces was assessed by en face electron microscopy. Exposure of anionic phospholipids or tissue factor (TF) antigen on PLTs was assessed by flow cytometry and by immunocytochemical methods at the ultrastructural level. Studies were performed in six different PCs followed 0, 3, 5, 7, and 11 days of storage RESULTS: A progressive impairment of PLT-adhesive functions was observed after 5 days of storage. A progressive increase in expression of anionic phospholipids and development of procoagulant activity (PCA) measured by a modified prothrombin time (mPT) was observed along the storage. Incubation of PLTs with a specific anti-TF resulted in prolongation of the mPT by approximately 10 to 15 percent. Flow cytometry revealed minimal TF expression at later storage times. Immunocytochemical studies showed minimal TF labeling when studies were performed on PLT whole mounts. Labeling was markedly improved when PLTs were previously exposed to sonication. CONCLUSION: Prolonged storage of PCs was associated with decreased PLT-adhesive capacities and enhanced PCA. Current preparation procedures and storage media have important limitations for preserving PCs for longer than 1 week. PLTs in PCs retain residual amounts of TF as assessed by immunocytochemical and functional assays. The origin and hemostatic significance of this TF should be investigated further.",
author = "Silvia P{\'e}rez-Pujol and Omer Aras and Miguel Lozano and Debra Cooking-Johnson and Key, {Nigel S.} and White, {James G.} and Jeffrey McCullough and Gin{\'e}s Escolar",
T1 - Stored platelets contain residual amounts of tissue factor
T2 - Evidence from studies on platelet concentrates stored for prolonged periods
AU - Pérez-Pujol, Silvia
AU - Aras, Omer
AU - Lozano, Miguel
AU - Cooking-Johnson, Debra
AU - Key, Nigel S.
AU - White, James G.
AU - McCullough, Jeffrey
AU - Escolar, Ginés
N2 - BACKGROUND: The advent of new strategies for pathogen reduction has raised the question of whether platelet (PLT) concentrates (PCs) exposed to longer periods of storage retain adequate hemostatic function. STUDY DESIGN AND METHODS: The effects of prolonged storage on adhesive and procoagulant functions of PLTs in PCs have been analyzed. The ability of PLTs to interact with surfaces was assessed by en face electron microscopy. Exposure of anionic phospholipids or tissue factor (TF) antigen on PLTs was assessed by flow cytometry and by immunocytochemical methods at the ultrastructural level. Studies were performed in six different PCs followed 0, 3, 5, 7, and 11 days of storage RESULTS: A progressive impairment of PLT-adhesive functions was observed after 5 days of storage. A progressive increase in expression of anionic phospholipids and development of procoagulant activity (PCA) measured by a modified prothrombin time (mPT) was observed along the storage. Incubation of PLTs with a specific anti-TF resulted in prolongation of the mPT by approximately 10 to 15 percent. Flow cytometry revealed minimal TF expression at later storage times. Immunocytochemical studies showed minimal TF labeling when studies were performed on PLT whole mounts. Labeling was markedly improved when PLTs were previously exposed to sonication. CONCLUSION: Prolonged storage of PCs was associated with decreased PLT-adhesive capacities and enhanced PCA. Current preparation procedures and storage media have important limitations for preserving PCs for longer than 1 week. PLTs in PCs retain residual amounts of TF as assessed by immunocytochemical and functional assays. The origin and hemostatic significance of this TF should be investigated further.
AB - BACKGROUND: The advent of new strategies for pathogen reduction has raised the question of whether platelet (PLT) concentrates (PCs) exposed to longer periods of storage retain adequate hemostatic function. STUDY DESIGN AND METHODS: The effects of prolonged storage on adhesive and procoagulant functions of PLTs in PCs have been analyzed. The ability of PLTs to interact with surfaces was assessed by en face electron microscopy. Exposure of anionic phospholipids or tissue factor (TF) antigen on PLTs was assessed by flow cytometry and by immunocytochemical methods at the ultrastructural level. Studies were performed in six different PCs followed 0, 3, 5, 7, and 11 days of storage RESULTS: A progressive impairment of PLT-adhesive functions was observed after 5 days of storage. A progressive increase in expression of anionic phospholipids and development of procoagulant activity (PCA) measured by a modified prothrombin time (mPT) was observed along the storage. Incubation of PLTs with a specific anti-TF resulted in prolongation of the mPT by approximately 10 to 15 percent. Flow cytometry revealed minimal TF expression at later storage times. Immunocytochemical studies showed minimal TF labeling when studies were performed on PLT whole mounts. Labeling was markedly improved when PLTs were previously exposed to sonication. CONCLUSION: Prolonged storage of PCs was associated with decreased PLT-adhesive capacities and enhanced PCA. Current preparation procedures and storage media have important limitations for preserving PCs for longer than 1 week. PLTs in PCs retain residual amounts of TF as assessed by immunocytochemical and functional assays. The origin and hemostatic significance of this TF should be investigated further.


It's easy to get angry at others. It's much harder to look at ourselves for solutions.
Every time I look at myself for an explanation for the problems in my life, I find something I can improve.
I keep a notepad on my desk for random thoughts. Sometimes, I find myself doodling on it. Weirdly, there are times when that doodling will cause me to put together some idea in my head.
Something that seems like a time waster isn't really a time waster.
We are who we are. We can't change that.
We succeed when we accept who we are and think about how we can use that in the world.
The evenings are getting very cool here and the leaves are just starting to turn.
Thanks to Yves Cosentino for the picture.
Impulsiveness is our biggest opponent in life. It's exciting, but it's also quite capable of sinking our ship.
Patience, on the other hand, keeps our ship headed the right way.
The reason I love baseball so deeply was rekindled this past week with perhaps the single best evening of sports I've ever seen in my life.
I would have given anything to watch all of those games with my father and my grandfather there.
Thanks to Sean Winters for the picture.
Whenever I struggle with time management, I come back to this quote.
The entire reason for thinking about time management is to have more time for the stuff you want to do. Nothing more, nothing less.
Something about this puts a big smile on my face every time.
This is just an amazing performace.
This is just an amazing site. If you've ever wanted to understand the perspectives that others have on an issue, particularly those that disagree with you, this is the place for you.
I've met people on both sides of the political spectrum who seem to not fundamentally understand what the other side thinks or wants (or else abstracts it to the point of nonsense). I wish I could send this to every one of them and that they'd actually take a moment to use it.
Money isn't what you want.
Money is a tool to achieve what you want.