User:Synonymous-solecism/Coagulopathy

Coagulopathy (also known as a bleeding disorder) is a condition where the blood's ability to coagulate (form clots) is impaired, a critical factor in preventing severe blood loss. This can cause prolonged or excessive bleeding (bleeding diathesis), which may occur following an injury, during menstruation, due to medical (including dental) procedures or without obvious cause. Coagulopathies can be hereditary or acquired.

Coagulopathies are sometimes erroneously referred to as "clotting disorders"; a clotting disorder is a predisposition to clot formation (thrombus), also known as a hypercoagulable state or thrombophilia.

Overview
Normally, blood clotting begins within seconds after any vascular injury, but this process depends on the interplay of various proteins in the blood. Coagulopathies can result from deficiencies of any of the key components in hemostasis (the process to prevent and stop bleeding) such as platelets (small disk-shaped bodies in the bloodstream that aid in the clotting process) or blood-clotting proteins, known as coagulation or clotting factors. The body produces thirteen clotting factors; if any of these are reduced or absent, a bleeding disorder can result.

Acquired
Causes of acquired coagulopathies are broad and can include chronic kidney disease (involving delayed formation of clots, but decreased clot breakdown), acquired coagulation factor antibodies (autoantibodies or alloantibodies), traumatic injury, liver disease (cirrhosis also causes reduced levels of prothrombin and factor II, VII, IX and X), autoimmune disease, chronic inflammation, surgical procedures, infections, and Vitamin K deficiency. Medications which impede clotting such as warfarin, heparin or oral factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) can lead to coagulopathy. More rarely, medications which impede platelet clumping like aspirin and clopidogrel can cause coagulopathy.

Traumatic
Coagulopathies after traumatic injuries are a potentially preventable (with early recognition and treatment) cause of fatality. Up to 40% of trauma deaths are due to uncontrolled bleeding or its consequences. In 2003, Karim Brohi, Professor of Trauma Sciences at Queen Mary University of London, introduced the term Acute Traumatic Coagulopathy (ATC), establishing that coagulopathy induced by trauma results in more severe bleeding, multiple organ dysfunction syndrome and high mortality. Traumatic coagulopathies are also associated with hypothermia, acidosis (increased acidity in the blood), blood protein and clotting factor dilution, and tissue destruction.

Hereditary
Hereditary coagulopathies are genetic disorders that include Von Willebrand disease, which involves the deficiency or dysfunction of von Willebrand factor (a protein that mediates adherence of platelets into clots); hemophilia and other factor deficiencies, which involves the fixed reduction or absence of certain clotting factors and proteins (depending on which type); and congenital Vitamin K-dependant clotting factors deficiency which involves variably decreased levels of clotting factors and the natural anticoagulants protein C, protein S and protein Z.

Von Willebrand disease is the most common type of hereditary coagulopathy.

Hemophilia
Hemophilia is the overarching term for mostly hereditary coagulopathies as a result of deficiencies of clotting factor VIII, factor IX or factor XI. Factor VIII deficiency is known as hemophilia A (classic hemophilia), factor IX deficiency is known as hemophilia B (Christmas disease), and factor XI is known as hemophilia C (plasma thromboplastin antecedent (PTA) deficiency or Rosenthal syndrome). The severity of hemophilia is measured by how much of the clotting factor affected is present; mild disease is considered more than 5%, moderate is 1-5% and severe is less than 1%.

Acquired hemophilia is a rare autoimmune disorder found in people with no history of bleeding disorders who develop autoantibodies (inhibitors) to clotting factors. The most common type is autoantibodies to factor VIII, mimicking congenital hemophilia A. In 50% of cases, an underlying cause can be identified (including, but not limited to, childbirth, cancer, other autoimmune conditions, inflammatory bowel disease or diabetes), but in the others it is idiopathic. Acquired hemophilia C is found in individuals with systemic lupus erythematosus and other immunological disorders, because of developing autoantibodies to factor XI.

Severe disorders
Autosomal recessive platelet function abnormalities such as Glanzmann thrombasthenia and Bernard–Soulier syndrome are rare disorders that present with severe symptoms. Glanzmann thrombasthenia is when the platelets contain defective or low levels of glycoprotein IIb/IIIa (GpIIb/IIIa), a receptor for fibrinogen (the base protein that creates fibrin-based blood clots), thus blood clotting is severely affected and bleeding time is significantly prolonged. Bernard–Soulier syndrome is a giant platelet disorder where there's a deficiency of the glycoprotein Ib-IX-V complex (GPIb-IX-V), resulting in poor platelet adhesion to von Willebrand factor.

Mild bleeding disorders
Mild bleeding disorders (MBD) is a term used to signify a laboratory marker of disease such as deficiencies in clotting factors or parts of the hemostatic system without significant clinical signs or a clear phenotype. These disorders may be characterised by the presence of more frequent bleeding symptoms than in the normal population, but without serious complications.

Signs and symptoms
Symptoms of coagulopathies can range from mild to severe. Some of the most common ones are:


 * Minor wounds which bleed for more than ten minutes
 * Frequent nosebleeds (more than five in a year) which last longer than ten minutes
 * Heavy periods (menorrhagia)
 * Low iron and anemia (often found correspondingly in people with heavy periods)
 * Frequent unexplained or excessive bruising
 * Heavy bleeding from dental surgery, other surgery or medical procedures, or childbirth
 * Spontaneous miscarriages
 * In infants, umbilical cord bleeding after birth
 * Family history of bleeding disorders or frequent bleeding and bruising in the absence of other explanations (such as connective tissue disorders)

Not all coagulopathies show obvious outward signs. For instance, Von Willebrand disease type 1 often involves non-specific mild bleeding symptoms and reduced von Willebrand factor levels show low heritability, with weak risk factors for bleeding, making it difficult to classify for diagnosis. However, although Von Willebrand disease is theorised to affect an equal number of men and women, more women are diagnosed than men because the bleeding associated is more easily detected in menstruation and childbirth.

Another coagulopathy that is often asymptomatic and found incidentally on routine bloodwork (such as pre-surgery assessments) is Factor XII deficiency; it's frequently called benign as other clotting factors compensate for the reduction so it doesn't cause excessive bleeding. However, paradoxically, it's been linked in rare cases to thromboembolic (formation of clots which block blood vessels) complications.

Furthermore, over 25% of healthy controls have been found to have at least one bleeding symptom and it's estimated that 26% to 45% people have a history of nose bleeds, easy bruising, or gum bleeding, making it difficult to determine if this is incidental or the result of an underlying disorder.

Diagnosis
The investigation of a patient with a bleeding symptoms begins with a full history and physical examination. It is important to look for any indications of hemostatic abnormalities such as bruising or petechiae. In cases of acute symptoms, it is important to assess for neurologic impairment, evidence of hematomas or internal bleeding, gastrointestinal bleeding and a history of recent trauma.

History
A positive history of abnormal bleeding is a prerequisite for inherited coagulopathy diagnosis and should guide further investigations. When inherited coagulopathies are suspected, standardised assessments such as Bleeding Assessment Tools (BAT) can be used to quickly assess presence and severity of bleeding symptoms. The ISTH-SSC Bleeding Assessment Tool consists of fourteen categories which allows diagnosticians to assess the presence and severity of bleeding symptoms retrospectively; a high score has high sensitivity for the presence of an inherited bleeding disorder. However, it is insensitive in children with a possible inherited bleeding disorder as they may not yet have experienced the events (eg, prior surgery) asked about.

Physical examination
Scars on the elbows and knees are a feature of hemophilia A. Grey Turner's sign is discolouration (bruising) of the skin on the flanks due to bleeding, which have been found in people with coagulopathies or who have taken much anticoagulative medication.

Laboratory tests
Certain laboratory blood tests can be used to assess both acquired and inherited coagulopathies. These include bleeding time, a complete blood count, prothrombin time (PT) along with a calculation of the international normalized ratio (INR) to standardize for different reagents, activated partial thromboplastin time (aPTT) and a fibrinogen level. It's important not to place too much emphasis on only laboratory tests as these may show reduced clotting factors without a clear etiology, and there isn't a reliable relationship between partial deficiency and residual activity or bleeding severity.

Complications
Coagulopathies can cause uncontrolled internal bleeding, such as gastrointestinal bleeding, or external bleeding. Left untreated, uncontrolled bleeding (hemorrhage) may cause damage to joints, muscles, or internal organs and may be life-threatening. People should seek urgent medical care for serious symptoms like heavy external bleeding, blood in the urine or stool. They should seek prompt medical care if they experience mild but unstoppable external bleeding or joint swelling and stiffness.

Double vision, severe headache of rapid onset, neck stiffness and meningism, fever, repeated vomiting, difficulty walking, difficulty speaking, loss of co-ordination and balance, altered level of consciousness, convulsions, seizures, stroke symptoms (such as weakness, numbness, facial paralysis) or other neurologic deficits could be a sign of a subarachnoid haemorrhage or intracerebral hemorrhage which can be fatal and require immediate medical care.

Chronic
Hemophilic arthropathy (joint disease) is a known complication from chronic or repeated bleeding into joints (hemarthrosis), which is found in hemophilia A and B.

Acute
Coagulopathies heighten the risk of acute compartment syndrome (a build-up of blood increasing pressure within a fascial compartment), even without clear cause or trauma. This can cause irreversible tissue damage and cell death and is a medical emergency.

Treatment
Treatment of coagulopathies varies depending on their cause, severity or whether there is any active bleeding. The primary goal is to prevent excessive or dangerous bleeding in the least invasive way, which may be with medications or replacement therapy.

Pharmacological
Medication options for the treatment of coagulopathies remain limited. Desmopressin can be used in mild forms of hemophilia A (factor VIII coagulant activity of more than 5%) or mild to moderate type 1 von Willebrand disease (factor VIII coagulant activity of more than 5%), but is not suitable for hemophilia B, severe hemophilia A or patients with factor VIII antibodies. Antifibrinolytics, which prevent the breakdown of blood clots (fibrinolysis), can be used although this is frequently off-label. These include aprotinin, tranexamic acid and aminocaproic acid/epsilon-aminocaproic acid. Major side effects of antifibrinolytics include hypotension, cardiac arrhythmias, rhabdomyolysis, and obstructive or dangerous blood clots. Other medications used are aprotinin and concentrated oestrogens.

Topical agents
In cases of external bleeding or intraoperative bleeding, some local hemostatic agents and tissue adhesives can be applied to support the defective clotting process; for example, topical thrombin or fibrin glue provide exogenous thrombin or fibrinogen, making them effective in congenital or acquired coagulopathies. In surgery, these can be used in addition to other surgical hemostasis techniques like compression, sutures or electrocoagulation. Other mechanical hemostatic agents like Bovine microfibrillar collagen are not considered effective as they rely on the body's plasma constituents and fibrin to achieve hemostasis, which requires a normal coagulation system. However, there has been some success with the use of mechanical hemostatic agents in hemophilic patients recently treated with supplementary clotting factor concentrates.

Replacement therapy
In replacement therapy, the affected clotting factors are replaced clotting factor concentrates (CFCs) derived from either human blood (plasma-derived factor concentrates) or created in the laboratory (recombinant factor concentrates). Plasma-derived concentrates are collected from many different donors who have been screened for viruses, then they're separated into components, freeze-dried, and finally tested and treated once again to kill viruses before use.

Recombinant factor concentrates are genetically engineered using DNA. This therapy may be given either to treat bleeding that has already begun (on-demand (OD) therapy) or to prevent bleeding from occurring (prophylactic therapy). Prophylactic administration is utilised frequently in more severe coagulopathies.

Risks
Because between 10,000-50,000 different donations have to be pooled into a single lot before precipitating out fractions with cold ethanol, the major risk of human-derived plasma in replacement therapy is blood-borne infections. Prior to the development of widely available tests to screen donors such as nucleic acid amplification testing and antigen testing, there was a high incidence of post-transfusion virus infections such as hepatitis and HIV. By 1984, around 80% of all hemophilia A and 50% of all hemophilia B patients were infected with HIV via blood and 100% of those who received more than 500,000 units of Factor VIII were infected; by 1990, antibodies to hepatitis C virus were detected in up to 80% of hemophiliacs tested. However, modern safety techniques, donor testing and viral inactivation steps have made this exceedingly rare; in the United States, for example, the chance of HIV infection around 1:5 to 1:8 million products transfused.

In some cases, replacement therapy can have a serious complication of developing neutralizing antibodies (inhibitors), known as alloantibodies, due to exposure to foreign proteins (rather than an individual's own proteins). These alloantibodies may be directed against clotting factors, such as hemophilia-related factor VIII or IX inhibitors, or alloantibodies against von Willebrand factor, and make it harder to treat the patient in question as the original treatment is no longer effective.

There are several other possible risks, such as transfusion-related acute lung injury, acute respiratory distress syndrome, multiple organ dysfunction syndrome, major hemorrhage, and venous thromboembolism.

Critical care
An important area in the treatment of coagulopathies is managing people with major bleeding in a critical setting, such as an emergency department. This is a time-sensitive medical emergency in which all facets of care should be performed simultaneously; initial treatment focuses on stabilising a bleeding patient with intravenous (IV) access, airway management, fluid resuscitation, and control of active bleeding sites.

Further treatment can be transfusing a combination of red cells with one of the following options:
 * Blood plasma
 * Prothrombin complex concentrate, factor XIII, and fibrinogen
 * Fibrinogen with tranexamic acid

Tranexamic acid reduces bleeding by inhibiting lysine binding sites on the zymogen plasminogen, preventing its conversion to the enzyme plasmin, a serine protease that degrades blood plasma proteins like fibrin clots. Thus, tranexamic acid inhibits clot breakdown, and can help control blood loss. Administration of tranexamic acid within one hour of bleeding onset in trauma significantly reduces risk of death (and between one and three hours moderately reduces risk of death) without increased thromboembolic events. When given after three hours has elapsed, there are no recorded benefits, and it may in fact be detrimental.

The use of tranexamic acid is the only option supported by reliable evidence of effectiveness from a randomized controlled trial for major traumatic bleeding, with the greatest benefit to patients with severe injuries and those who receive massive transfusions. However, a trial of 12,000 patients showed it's ineffective and can increase side effects in severe gastrointestinal bleeding. Furthermore, there isn't any evidence for the use of tranexamic acid in children and it's not indicated for isolated head injuries.

The most common acquired coagulopathy disorder seen in emergency care is thrombocytopenia, which can be the result of dilution from massive blood transfusions, and in these cases it is important not to dilute the clotting factors with further transfusions without replacement therapy.