Coagulation disorders 28 th March 2016
Fibriniolysis: The excessive deposition of fibrin within The circulation is prevented by fibrinolytic system. This pathway is principally initiated by Tpa which is released from endothelial cells, These convert the circulating inactive zymogene, Plasminogen to the active enzyme, plasmin which Hydrolyses fibrin. The digested fibrin fragments,D-dimers, can be detected within the circulation and their concentration Is raised in the presence of venous thrombosis.Coagulation factor deficiency may be congenital or acquired and may affect one or several of the coagulation factors . Inherited disorders are almost uniformly related to decreased synthesis, as a result of mutation in the gene encoding a key protein in coagulation. Von Willebrand disease is the most common inherited bleeding disorder. Haemophilia A and B are the most common single coagulation factor deficiencies, but deficiencies of all the other coagulation factors are seen
. Acquired disorders may be due to: 1-under-production (e.g. in liver failure). 2-increased consumption (e.g. in disseminated intravascular coagulation) or 3-inhibition of function (such as heparin therapy or immune inhibitors of coagulation, e.g. acquired haemophilia A).
Haemophilia A
Factor VIII deficiency resulting in haemophilia A affects 1/10 000 individuals. It is the most common congenital coagulation factor deficiency. Factor VIII is primarily synthesised by the liver and endothelial cells, and has a half-life of about 12 hours. It is protected from proteolysis in the circulation by binding to von Willebrand factor (vWF).Genetics
haemophilia A is a sex-linked disorder . Thus all daughters of haemophiliacs are obligate carriers and they, in turn, have a 1 in 4 chance of each pregnancy resulting in the birth of an affected male baby, a normal male baby, a carrier female or a normal female. Antenatal diagnosis by chorionic villous sampling is possible in families with a known mutation.Clinical features 1-Bleeding
The extent and patterns of bleeding are closely related to residual factor VIII levels. Patients with severe haemophilia (< 1% of normal factor VIII levels) present with spontaneous bleeding into skin, muscle and joints. Retroperitoneal and intracranial bleeding is also a feature.Babies with severe haemophilia have an increased risk of intracranial haemorrhage and, although there is insufficient evidence to recommend routine caesarean section for these births, it is appropriate to avoid head trauma and to perform imaging of the newborn within the first 24 hours of life.
Individuals with moderate and mild haemophilia (factor VIII levels 1-40%) present with the same pattern of bleeding, but usually after trauma or surgery when bleeding is greater than would be expected from the severity of the insult.
The major morbidity of recurrent bleeding in severe haemophilia is musculoskeletal. Bleeding is typically into large joints, especially knees, elbows, ankles and hips.
2-Muscle haematomas are also characteristic, most commonly in the calf and psoas muscles. If early treatment is not given to arrest bleeding, a hot, swollen and very painful joint or muscle haematoma develops.
Complications of muscle haematomas depend on their location. -A large psoas bleed may extend to compress the femoral nerve. - calf haematomas may increase pressure within the inflexible fascial sheath causing a compartment syndrome with ischaemia, necrosis, fibrosis, and subsequent contraction and shortening of the Achilles tendon.
3-sever haemophilia: recurrent haemarthroses in large Joints, usually begin spontaneously without apparent Trauma and most commonly affect the knees, elbows, Ankles and hips. Atypical sever haemophiliac may have one or two bleeds Each week. patients are aware that bleeding has started Because they experience an abnormal sensation in the Joint. If treatment is not giving at this stage ,bleeding continues Resulting in a hot, swollen and very painful joint, which May persist for days before gradually subsiding.
Recurrent bleeds into joints lead to synovial Hypertrophy, destruction of the cartilage and Secondary osteoarthroses. The resultant limitation of movement may Greatly reduce the function of joint, making Walking difficult.
Bleeding can occur at almost any site. It is serious if it takes place in a confined anatomical Space associated with vital structures, such as Intracranial area where haemorrhage, unless Treated very promptly, is fatal. Moderate haemophilia only haemorrhage after minor Trauma. Mild haemophilia haemorrhage following more major Trauma or surgery. Whereas sever haemophilia is usually diagnosed Within the first 2 years of life, individuals with mild And moderate forms may escape diagnosis until Adulthood.
Management
Factor VIII concentrate prepared from blood donor plasma is now screened for HBV, HCV and HIV, and undergoes two separate viral inactivation processes during manufacture; these preparations have a good safety record. However, factor VIII concentrates prepared by recombinant technology are now widely available and, although more expensive, are perceived as being safer than those derived from human plasma
Should achieve plasma level of factor VIII activity of25-30% For minor or traumatic bleeding (haemarthroses, persistent Haematurea). At lest 50% of factor activity for treatment or prevention Sever bleeding (major dental surgery ,maintenance Replacement therapy after major surgery or trauma) 80-100%activity for life threatening hemorrhagic event as in Major surgery and trauma.
2- resting of the bleeding site by either bed rest or a splint reduces continuing haemorrhage. Once bleeding has settled, the patient should be mobilised and physiotherapy used to restore strength to the surrounding muscles.
3-The vasopressin receptor agonist DDAVP raises the vWF and factor VIII levels by 3-4-fold, which is useful in arresting bleeding in patients with mild or moderate haemophilia A. The dose required for this purpose is high, typically 0.3 μg/kg given intravenously or subcutaneously. Alternatively, the same effect can be achieved by intranasal administration of 300 μg. Following repeated administration of DDAVP, patients need to be monitored for evidence of water retention which can result in significant hyponatraemia
DDAVP is contraindicated in patients with a history of severe arterial disease because of a propensity to provoke a thrombotic event.
In addition to treatment 'on demand' for bleeding, factor VIII can be administered 2 or 3 times per week as 'prophylaxis' to prevent bleeding in severe haemophilia. This is most appropriate in children, but its widespread use is limited by the high cost of factor VIII preparations.
However, for practical purposes, the dose of factor VIII is based on the knowledge that 1 U of factor VIII per kilogram of body weight raises the circulating factor VIII level approximately 0.02 U/mL. Thus, to raise the factor VIII level to 100 percent, that is, 1 U/mL, the dose of factor VIII required is approximately 50 U per kilogram of body weight, assuming the patient's baseline factor VIII level is less than 1 percent of normal. The site and severity of hemorrhage determine the frequency and dose of factor VIII to be infused.
Surgery n haemophiliacs can be safely performed Provided the patient dose not have an inhibitor to Factor VIII and receives appropriate dose of concentrate A single infusion of factor VIII is adequate for simple Dental extraction in an individual with sever haemophilia Along with a 10 days course of Tranexamic acid and An antibiotic. Major surgery, such as orthopaedic, requires twice-daily Therapy for 14 days or longer.
Complications of coagulation factor therapy 1-infections: Before 1986, coagulation factor concentrates from human plasma were not virally inactivated with heat or chemicals, and many patients became infected with HIV and hepatitis viruses HBV and HCV.
In exposed patients with severe haemophilia, infection with HCV is almost universal, 80–90% have evidence of HBV exposure, and60% became HIV-positive. Since 1989, viral inactivation of these blood products has eradicated the risk of viralinfection.
Concern that the infectious agent that causes vCJD might be transmissible by blood and blood products has been confirmed in recipients of red cell transfusion, and in one recipient of factor VIII.Pooled plasma products, including factor VIII concentrate, are now manufactured from plasma collected in countries with a low incidence of bovine spongiform encephalopathy.
2-Another serious complication of factor VIII infusion is the development of anti-factor VIII antibodies, which arise in about 20% of severe haemophiliacs. Such antibodies rapidly neutralise therapeutic infusions, making treatment relatively ineffective. Treatment Infusions of activated clotting factors, e.g. VIIa or factor VIII inhibitor bypass activity (FEIBA), may stop bleeding.
Haemophilia B (Christmas disease)
Aberrations of the factor IX gene, which is also present on the X chromosome, result in a reduction of the plasma factor IX level, giving rise to haemophilia B. This disorder is clinically indistinguishable from haemophilia A but is less common. The frequency of bleeding episodes is related to the severity of the deficiency of the plasma factor IX level. Treatment is with a factor IX concentrate, used in much the same way as factor VIII for haemophilia A. Although factor IX concentrates shared the problems of virus transmission seen with factor VIII, they do not commonly induce inhibitor antibodies (< 1% patients); when this does occur, however, it may be heralded by the development of a severe allergic-type reaction.Von Willebrand disease Von Willebrand disease is a common but usually mild bleeding disorder caused by a quantitative (types 1 and 3) or qualitative (type 2) deficiency of von Willebrand factor (vWF), a protein synthesised by endothelial cells and megakaryocytes, which is involved in both platelet function and coagulation.
It normally forms a multimeric structure which is essential for its interaction with subendothelial collagen and platelets . vWF acts as a carrier protein for factor VIII, to which it is non-covalently bound; deficiency of vWF lowers the plasma factor VIII level.
vWF also forms bridges between platelets and subendothelial components (e.g. collagen, allowing platelets to adhere to damaged vessel walls; deficiency of vWF therefore leads to impaired platelet plug formation.
Blood group antigens (A and B) are expressed on vWF, reducing its susceptibility to proteolysis; as a result, people with blood group O have lower circulating vWF levels than individuals with non-O groups. This needs to be borne in mind when making a diagnosis of von Willebrand disease.
Most patients with von Willebrand disease have a type 1 disorder, characterised by a quantitative decrease in a normal functional protein. Patients with type 2 disorders inherit vWF molecules that are functionally abnormal.
The type of abnormality depends on the site of the mutation in the vWD gene. 1-Patients with mutations in platelet binding have type 2A disease, 2- those with mutations in the platelet glycoprotein Ib binding site have type 2B, 3- those with mutations in the factor VIII binding site have type 2N disease, 4- and thosewith other abnormalities in platelet binding have type2M
The gene for vWF is located on chromosome 12 and the disease is usually inherited as an autosomal dominant, except in cases of type 2N and type 3, when it is recessive.
Clinical features Patients present with haemorrhagic manifestation Similar to those in individuals with reduced Platelet function. Superficial bruising , epistaxis, menorrhagia and GI haemorrhage are common . Bleeding episodes much less common than in sever Haemophilia and excessive haemorrhage may only Be observed after trauma or surgery.
Within a single family the disease can be of very Variable expression so that some members may Have quite sever and frequent bleeds, whereas Others are relatively little troubled.
Investigations The disorder is characterised by reduced activity of vWF and factor VIII. The disease can be classified using a combination of assays which include 1-functional and antigenic measures of vWF, 2-multimeric analysis of the protein, 3-and specific tests of function to determine binding to platelet glycoprotein Ib (RIPA) and factor VIII 4- In addition, analysis for mutations in the vWF gene is informative in most cases
Management Many episodes of mild haemorrhage can be Successfully treated with desmopressin, which Raises the vWF level , resulting in a secondary Increase in factor VIII. For more serious or persistent bleeds haemostasis Can be achieved with selected factor VIII Concentrates which contain considerable Quantities of vWF in addition to factor VIII.
Young children and patients with severe arterial disease should not receive DDAVP, and patients with type 2B disease develop thrombocytopenia which may be troublesome following DDAVP. Bleeding in type 3 patients responds to nothing apart from concentrates.
Rare inherited bleeding disorders
Deficiencies of factor VII, X and XIII occur as autosomal recessive disorders. They are rare but are associated with severe bleeding. Typical features include haemorrhage from the umbilical stump and intracranial haemorrhage. Factor XIII deficiency is typically associated with female infertility.Factor XI deficiency may occur in heterozygous or homozygous individuals. Bleeding is very variable and is not accurately predicted by coagulation factor levels. In general, severe bleeding is confined to patients with levels below 15% of normal.
Disseminated intravascular coagulation (DIC)
DIC may complicate a range of illnesses . It is characterised by systemic activation of the pathways involved in coagulation and its regulation. This may result in the generation of intravascular fibrin clots causing organ failure, with simultaneous coagulation factor and platelet consumption causing bleeding.ACQUIRED BLEEDING DISORDERS
The systemic coagulation activation is induced either through cytokine pathways which are activated as part of a systemic inflammatory response, or by the release of procoagulant substances such as tissue factor. In addition, suboptimal function of the natural anticoagulant pathways and dysregulated fibrinolysis contribute to DIC.
There is consumption of platelets, coagulation factors (notably factors V and VIII) and fibrinogen. The lysis of fibrin clot results in production of fibrin degradation products (FDP), including D-dimers.
Disseminated intravascular coagulation
Underlying conditionsInfection/sepsis Trauma Obstetric, e.g. amniotic fluid embolism, placental abruption, pre-eclampsia Severe liver failure Malignancy, e.g. solid tumours and leukaemias
Tissue destruction, e.g. pancreatitis, burns Vascular abnormalities, e.g. vascular aneurysms, liver haemangiomas Toxic/immunological, e.g. ABO incompatibility, snake bites, recreational drugs
Clinical features the clinical manifestations are determined by The nature, intensity and duration of the stimulus. Low grade DIC is often asymptomatic and Diagnosed by laboratory abnormalities. Bleeding is the most common clinical finding in Acute un compensated DIC, which tend to be Generalized in more sever cases. Gangrene of the digits or extremities,haemorrhagic Necrosis of the skin or purpura fulminans also Might be a manifestation of DIC.
Investigations: Definitive diagnosis depends on the finding Of 1-thrombocytopenia, 2-prolongation of Prothrombin time due to factor V and Fibrinogen deficiency. 3-Prolongation of activated partial thromboplastinTime due to factor V,VIII and fibrinogen Deficiency.
4-A low fibrinogen concentration. 5-Increased level of D-dimer(cleaved from fibrin By plasmin,establishing evidence of fibrin lysis
Management
Therapy is primarily aimed at the underlying cause. These patients will often require intensive care to deal with concomitant issues, such as acidosis, dehydration, renal failure and hypoxia. Blood component therapy, such as fresh frozen plasma, cryoprecipitate and platelets, should be given if the patient is bleeding or to cover interventions with high bleeding risk, but should not be given routinely based on coagulation tests and platelet counts alone.Prophylactic doses of heparin should be given, unless there is a clear contraindication. Established thrombosis should be treated cautiously with therapeutic doses of unfractionated heparin, unless clearly contraindicated. Some patients with sepsis-associated DIC benefit from treatment with activated protein C concentrate. Patients with DIC should not in general be treated with antifibrinolytic therapy, e.g. tranexamic acid.
Liver disease: In sever parenchymal liver disease , bleeding may Arise from many different causes. 1-Bleeding from oesophageal varices or peptic ulcer may Be difficult to arrest because of deficiencies in Components of the haemostatic system. This may arise because of reduced hepatic synthesis, e.g.factor II,VII,IX,X and fibrinigen, DIC, reduced Clearance of plasminogen activator , or Thrombocytopenia secondary to hypersplenism.
In cholestatic jaundice, there is reduced vitamin K absorption, leading to deficiency of factors II, VII, IX and X.
Treatment with plasma products or platelet transfusion should be reserved for acute bleeds or to cover interventional procedures such as liver biopsy. Vitamin K deficiency can be readily corrected with parenteral administration of vitamin K.
Renal failure The severity of the haemorrhagic state in renal failure Is proportional to the plasma urea concentration. Bleeding manifestations are of platelet type, with GI Bleeding ,being common. Causes: 1-anaemia and mild thrombocytopenia. 2-accumulation of low molecular waste products, normally Excreted by the kidney, that inhibit platelet function.
Treatment 1-dialysis,to reduce urea concentration. 2-platelet concentrate infusion. 3-red cell transfusion to rise the haemoglobin and decrease The propensity to bleed. 4-increasing the concentration of vWF, either by Cryoprecipitate or by desopressin(DDAVP) may promote Haemostasis.
FFP(150-300ml): Dose15ml/kg. indications: replacement of coagulation factor deficiency.
Cryoprecipitate:( 10-12 ml pck): Contain fibrinogen(150-300 mg) And coagulation factors (80-120u FvIII and VWF) Indications: Hypofibrinogaemia, VW disease and haemophilia.