Bleeding Disorder

 Bleeding Disorder

A bleeding disorder is a condition that affects the way your blood normally clots. The clotting process, also known as coagulation, changes blood from a liquid to a solid. When you’re injured, your blood normally begins to clot to prevent a massive loss of blood. Sometimes, certain conditions prevent blood from clotting properly, which can result in heavy or prolonged bleeding. Bleeding disorders can cause abnormal bleeding both outside and inside the body. Some disorders can drastically increase the amount of blood leaving your body. Others cause bleeding to occur under the skin or in vital organs, such as the brain.

Causes a Bleeding Disorder?

Bleeding disorders often develop when the blood can’t clot properly. For blood to clot, your body needs blood proteins called clotting factors and blood cells called platelets. Normally, platelets clump together to form a plug at the site of a damaged or injured blood vessel. The clotting factors then come together to form a fibrin clot. This keeps the platelets in place and prevents blood from flowing out of the blood vessel.

In people with bleeding disorders, however, the clotting factors or platelets don’t work the way they should or are in short supply. When the blood doesn’t clot, excessive or prolonged bleeding can occur. It can also lead to spontaneous or sudden bleeding in your muscles, joints, or other parts of your body. The majority of bleeding disorders are inherited, which means they’re passed from a parent to their child. However, some disorders may develop as a result of other medical conditions, such as liver disease.

Bleeding disorders may also be caused by:

·        a low red blood cell count

·        a vitamin K deficiency

·        side effects from certain medications

Medications that can interfere with the clotting of the blood are called anticoagulants.

Types of Bleeding Disorders

Bleeding disorders can be inherited or acquired. Inherited disorders are passed down through genetics. Acquired disorders can develop or spontaneously occur later in life. Some bleeding disorders can result in severe bleeding following an accident or injury. In other disorders, heavy bleeding can happen suddenly and for no reason.

There are numerous different bleeding disorders, but the following are the most common ones:

·        Hemophilia A and B are conditions that occur when there are low levels of clotting factors in your blood. It causes heavy or unusual bleeding into the joints. Though hemophilia is rare, it can have life-threatening complications.

• Factor II, V, VII, X, or XII deficiencies are bleeding disorders related to blood clotting problems or abnormal bleeding problems.
• von Willebrand's disease is the most common inherited bleeding disorder. It develops when the blood lacks the von Willebrand factor, which helps the blood clot.

Symptoms?

The symptoms can vary depending on the specific type of bleeding disorder. However, the main signs include:

·        unexplained and easy bruising

·        heavy menstrual bleeding

·        frequent nosebleeds

·        excessive bleeding from small cuts or an injury

·        bleeding into joints

Schedule an appointment with your doctor right away if you have one or more of these symptoms. Your doctor can diagnose your condition and help to prevent complications associated with certain blood disorders.

Diagnosis

To diagnose a bleeding disorder, your doctor will ask you about your symptoms and medical history. They will also perform a physical examination. During your appointment, make sure to mention:

·        any medical conditions you currently have

·        any medications or supplements you may be taking

·        any recent falls or trauma

·        how often you experience the bleeding

·        how long the bleeding lasts

·        what you were doing before the bleeding began

After gathering this information, your doctor will run blood tests to make a proper diagnosis. These tests may include:

·        a complete blood count (CBC), which measures the amount of red and white blood cells in your body

·        a platelet aggregation test, which checks how well your platelets clump together

·        a bleeding time, which determines how quickly your blood clots to prevent bleeding

 

Hemostasis

 

Hemostasis or hemostasis is a process that causes bleeding to stop, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, blood changing from a liquid to a gel. Intact blood vessels are central to moderating blood's tendency to form clots. The endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin and prevent platelet aggregation with nitric oxide and prostacyclin. When an endothelial injury occurs, the endothelial cells stop the secretion of coagulation and aggregation inhibitors and instead secrete the von Willebrand factor which initiates the maintenance of hemostasis after injury. Hemostasis has three major steps:

1) Vasoconstriction,

2) Temporary blockage of a break by a platelet plug.

3) Blood coagulation, or formation of a fibrin clot. These processes seal the hole until tissues are repaired.

Mechanism

Hemostasis occurs when blood is present outside of the body or blood vessels. It is the instinctive response of the body to stop bleeding and the loss of blood. During hemostasis three steps occur in a rapid sequence. A vascular spasm is the first response as the blood vessels constrict to allow less blood to be lost. In the second step, platelet plug formation, platelets stick together to form a temporary seal to cover the break in the vessel wall. The third and last step is called coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin threads that act as a "molecular glue". Platelets are a large factor in the hemostatic process. They allow for the creation of the "platelet plug" that forms almost directly after a blood vessel has been ruptured. Within seconds of a blood vessel's epithelial wall being disrupted platelets begin to adhere to the sub-endothelium surface. It takes approximately sixty seconds until the first fibrin strands begin to intersperse among the wound. After several minutes the platelet plug is completely formed by fibrin. Hemostasis is maintained in the body via three mechanisms:

1.     Vascular spasm (Vasoconstriction) - Vasoconstriction is produced by vascular smooth muscle cells, and is the blood vessels first response to injury. The smooth muscle cells are controlled by vascular endothelium, which releases intravascular signals to control the contracting properties. When a blood vessel is damaged, there is an immediate reflex, initiated by local sympathetic pain receptors, which helps promote vasoconstriction. The damaged vessels will constrict (vasoconstrict) which reduces the amount of blood flow through the area and limits the amount of blood loss. Collagen is exposed at the site of injury; the collagen promotes platelets to adhere to the injury site. Platelets release cytoplasmic granules which contain serotonin, ADP, and thromboxane A2, all of which, increase the effect of vasoconstriction. The spasm response becomes more effective as the amount of damage is increased. Vascular spasm is much more effective in smaller blood vessels.

2.     Platelet plugs formation- Platelets adhere to damaged endothelium to form a platelet plug (primary hemostasis) and then DE granulate. This process is regulated through thrombo regulation. Plug formation is activated by a glycoprotein called Von Willebrand factor (vWF), which is found in plasma. Platelets play one of the biggest roles in the hemostatic process. When platelets come across the injured endothelium cells, they change shape, release granules and ultimately become ‘sticky’. Platelets express certain receptors, some of which are used for the adhesion of platelets to collagen. When platelets are activated, they express glycoprotein receptors that interact with other platelets, producing aggregation and adhesion. Platelets release cytoplasmic granules such as adenosine diphosphate (ADP), serotonin and thromboxane A2. Adenosine diphosphate (ADP) attracts more platelets to the affected area, serotonin is a vasoconstrictor and thromboxane A2 assists in platelet aggregation, vasoconstriction and degranulation. As more chemicals are released more platelets stick and release their chemicals; creating a platelet plug and continuing the process in a positive feedback loop. Platelets alone are responsible for stopping the bleeding of unnoticed wear and tear of our skin on a daily basis. This is referred to as primary hemostasis.^[5][7] There are a dozen proteins that travel along the blood plasma in an inactive state and are known as clotting factors. Once the platelet plug has been formed by the platelets, the clotting factors begin creating the clot. When this occurs the clotting factors begin to form a collagen fiber called fibrin. Fibrin mesh is then produced all around the platelet plug, which helps hold the plug-in place. Once this begins, red and white blood cells become caught up in the fibrin mesh which causes the clot to become even stronger. This step of coagulation is referred to as secondary hemostasis.

3.     Blood coagulation - Clots form upon the conversion of fibrinogen to fibrin, and its addition to the platelet plug (secondary hemostasis). Coagulation: The third and final step in this rapid response reinforces the platelet plug. Coagulation or blood clotting uses fibrin threads that act as a glue for the sticky platelets. As the fibrin mesh begins to form, the blood is also transformed from a liquid to a gel like substance through involvement of clotting factors and pro-coagulants. The coagulation process is useful in closing up and maintaining the platelet plug on larger wounds. The release of prothrombin also plays an essential part in the coagulation process because it allows for the formation of a thrombus, or clot, to form. This final step forces blood cells and platelets to stay trapped in the wounded area. Though this is often a good step for wound healing, it has the ability to cause severe health problems if the thrombus becomes detached from the vessel wall and travels through the circulatory system; If it reaches the brain, heart or lungs it could lead to stroke, heart attack, or pulmonary embolism respectively. However, without this process the healing of a wound would not be possible.^[3]

 

Types

Hemostasis can be achieved in various other ways if the body cannot do it naturally (or needs help) during surgery or medical treatment. When the body is under shock and stress, hemostasis is harder to achieve. Though natural hemostasis is most desired, having other means of achieving this is vital for survival in many emergency settings. Without the ability to stimulate hemostasis the risk of hemorrhaging is great. During surgical procedures the types of hemostasis listed below can be used to control bleeding while avoiding and reducing the risk of tissue destruction. Hemostasis can be achieved by chemical agent as well as mechanical or physical agents. Which hemostasis type used is determined based on the situation

Platelet Disorders

 

Platelets are little pieces of blood cells. Platelets help wounds heal and prevent bleeding by forming blood clots. Your bone marrow makes platelets. Problems can result from having too few or too many platelets, or from platelets that do not work properly.

If your blood has a low number of platelets, it is called thrombocytopenia. This can put you at risk for mild to serious bleeding. If your blood has too many platelets, you may have a higher risk of blood clots. With other platelet disorders, the platelets do not work as they should. For example, in von Willebrand Disease, the platelets cannot stick together or cannot attach to blood vessel walls. This can cause excessive bleeding.

The hemostatic system consists of platelets, coagulation factors, and the endothelial cells lining the blood vessels. The platelets arise from the fragmentation of the cytoplasm of megakaryocytes in the bone marrow and circulate in blood as disc-shaped a nucleate particle for 7-10 days.

Under normal circumstances, the resistance of the endothelial cell lining to interactions with platelets and coagulation factors prevents thrombosis. When endothelial continuity is disrupted and the underlying matrix is exposed, a coordinated series of events are set in motion to seal the defect (primary hemostasis).

Platelets play a primary role in this process, interacting with sub endothelium-bound von Willebrand factor (vWf) via the membrane glycoprotein (GP) Ib complex. This initial interaction (platelet adhesion) sets the stage for other adhesive reactions that allow the platelets to interact with each other to form an aggregate (see image below).

 

Normal hemostasis.

 

The platelet GP IIb/IIIa complex mediates platelet-to-platelet interactions (platelet aggregation). On resting platelets, GP IIb/IIIa is unable to bind fibrinogen or vWf. Platelet activation allows binding of these proteins, which bridges adjacent platelets. Morphologically, the platelets change dramatically from discs to spiny spheres in a process called shape change.

Platelets contain two unique types of granules: alpha granules and dense granules. The alpha granules contain hemostatic proteins such as fibrinogen, vWf, and growth factors (e.g., platelet-derived growth factor). The dense granules contain pro-aggregatory factors such as adenosine 5'-diphosphate (ADP), calcium, and 5-hydroxytryptamine (serotonin). During activation, the granules are centralized and their contents are discharged into the lumen of the open canalicular system, from which they are then released to the exterior (the release reaction).

Once activated, platelets have two major mechanisms to recruit additional platelets to the growing hemostatic plug. They release pro-aggregatory materials (eg, ADP) by the release reaction, and they synthesize thromboxane A₂ from arachidonic acid. Thus, the release reaction and prostaglandin synthesis act to consolidate the initial hemostatic plug by promoting the participation of other platelets in the growing hemostatic plug.

In addition, when platelets are activated, negatively charged phospholipids move from the inner to the outer leaflet of the membrane bilayer. This negative surface provides binding sites for enzymes and cofactors of the coagulation system, resulting in the formation of a clot (secondary hemostasis).

Thrombosis

Thrombosis is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets(thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot that breaks free and begins to travel around the body is known as anembolus.

When a thrombus is significantly large enough to reduce the blood flow to a tissue, hypoxia (oxygen deprivation) can occur and metabolic products such as lactic acid can accumulate. A larger thrombus causing a much greater obstruction to the blood flow may result in anoxia, the complete deprivation of oxygen and infarction, tissue death. There are also a number of other conditions that can arise according to the location of the thrombus and the organs affected.

Thromboembolism is the combination of thrombosis and its main complication, embolism.

Causes

The main causes of thrombosis are given in Virchow's triad which lists hypercoagulability, endothelial cell injury, and disturbed blood flow.

Hypercoagulability

Hypercoagulability or thrombophilia, is caused by, for example, genetic deficiencies or autoimmune disorders. Recent studies indicate that neutrophils play a pivotal role in deep vein thrombosis, mediating numerous pro-thrombotic actions.

Endothelial cell injury

Causes of injury to the vessel's wall include trauma, surgery, infection, or turbulent flow at bifurcations. The main mechanism is exposure of tissue factor to the blood coagulation system.

Disturbed blood flow

Causes of disturbed blood flow include stagnation of blood flow past the point of injury, or venous stasis which may occur in heart failure, in or after long periods of sedentary behavior, such as sitting on a long airplane flight. Also, atrial fibrillation, causes stagnant blood in the left atrium (LA) or left atrial appendage (LAA), and can lead to a thromboembolism.^[6] Cancers or malignancies such as leukemia may cause increased risk of thrombosis by possible activation of the coagulation system by cancer cells or secretion of procoagulant substances (paraneoplastic syndrome), by external compression on a blood vessel when a solid tumor is present, or (more rarely) extension into the vasculature (for example, renal cell cancers extending into the renal veins). Also, treatments for cancer (radiation, chemotherapy) often cause additional hypercoagulability. There are scores that correlate different aspects of patient data (comorbidities, vital signs, and others) to risk of thrombosis, such as the POMPE-C, which stratifies risk of mortality due to pulmonary embolism in patients with cancer, who typically have higher rates of thrombosis.

 

 

Classification

There are two distinct forms of thrombosis, venous thrombosis and arterial thrombosis, each of which can be presented by several subtypes.

Venous thrombosis

Venous thrombosis is the formation of a thrombus (blood clot) within a vein. There are several diseases which can be classified under this category:

Deep vein thrombosis

Deep vein thrombosis (DVT) is the formation of a blood clot within a deep vein. It most commonly affects leg veins, such as the femoral vein. Three factors are important in the formation of a blood clot within a deep vein—these are the rate of blood flow, the thickness of the blood and qualities of the vessel wall. Classical signs of DVT include swelling, pain and redness of the affected area.

Portal vein thrombosis

Portal vein thrombosis affects the hepatic portal vein, which can lead to portal hypertension and reduction of the blood supply to the liver. It usually has a pathological cause such as pancreatitis, cirrhosis, diverticulitis or cholangiocarcinoma.

Renal vein thrombosis

Renal vein thrombosis is the obstruction of the renal vein by a thrombus. This tends to lead to reduced drainage from the kidney. Anticoagulation therapy is the treatment of choice.

Jugular vein thrombosis

Jugular vein thrombosis is a condition that may occur due to infection, intravenous drug use or malignancy. Jugular vein thrombosis can have a varying list of complications, including: systemic sepsis, pulmonary embolism, and papilledema. Though characterized by a sharp pain at the site of the vein, it can prove difficult to diagnose, because it can occur at random.

Budd-Chiari syndrome

 

Budd-Chiari syndrome is the blockage of the hepatic vein or the inferior vena cava. This form of thrombosis presents with abdominal pain, ascites and hepatomegaly. Treatment varies between therapy and surgical intervention by the use of shunts.

Paget-Schroetter disease

Paget-Schroetter disease is the obstruction of an upper extremity vein (such as the axillary vein or subclavian vein) by a thrombus. The condition usually comes to light after vigorous exercise and usually presents in younger, otherwise healthy people. Men are affected more than women.

 

Cerebral venous sinus thrombosis

 

Cerebral venous sinus thrombosis (CVST) is a rare form of stroke which results from the blockage of the dural venous sinuses by a thrombus. Symptoms may include headache, abnormal vision, any of the symptoms of stroke such as weakness of the face and limbs on one side of the body and seizures. The diagnosis is usually made with a CT or MRI scan. The majority of persons affected make a full recovery. The mortality rate is 4.3%.

Cavernous sinus thrombosis

 

Cavernous sinus thrombosis is a specialized form of cerebral venous sinus thrombosis, where there is thrombosis of the cavernous sinus of the basal skull dura, due to the retrograde spread of infection and endothelial damage from the danger triangle of the face. The facial veins in this area anastomose with the superior and inferior ophthalmic veins of the orbit, which drain directly posteriorly into the cavernous sinus through the superior orbital fissure. Staphyloccoal or Streptococcal infections of the face, for example nasal or upper lip pustules may thus spread directly into the cavernous sinus, causing stroke-like symptoms of double vision, squint, as well as spread of infection to causemeningitis.

 

 

Arterial thrombosis

Arterial thrombosis is the formation of a thrombus within an artery. In most cases, arterial thrombosis follows rupture of atheroma, and is therefore referred to as atherothrombosis.

Another common cause of arterial occlusion is atrial fibrillation, which causes a blood stasis within the atria with easy thrombus formation. In addition, it is well known that the direct current cardioversion of atrial fibrillation carries a great risk of thromboembolism, especially if persisting more than 48 hours. Thromboembolism strikes approximately 5% of cases not receiving anticoagulant therapy. When cardiac rhythm is restored, clots are pushed out from atria to ventricles and from these to the aorta and its branches.

Arterial thrombosis can embolize and is a major cause of arterial embolism, potentially causing infarction of almost any organ in the body.

Stroke

A stroke is the rapid decline of brain function due to a disturbance in the supply of blood to the brain. This can be due to ischemia, thrombus, embolus (a lodged particle) or hemorrhage (a bleed). In thrombotic stroke, a thrombus (blood clot) usually forms around atherosclerotic plaques. Since blockage of the artery is gradual, onset of symptomatic thrombotic strokes is slower. Thrombotic stroke can be divided into two categories—large vessel disease and small vessel disease. The former affects vessels such as the carotids, vertebral and the circle of Willis. The latter can affect smaller vessels such as the branches of the circle of Willis.

Myocardial infarction

Myocardial infarction (MI) or heart attack, is caused by ischemia, (restriction in the blood supply), often due to the obstruction of a coronary artery by a thrombus. This restriction gives an insufficient supply of oxygen to the heart muscle which then results in tissue death,(infarction). A lesion is then formed which is the infarct. MI can quickly become fatal if emergency medical treatment is not received promptly. If diagnosed within 12 hours of the initial episode (attack) then thrombolytic therapy is initiated.

Other sites

Hepatic artery thrombosis usually occurs as a devastating complication after liver transplantation.

An arterial embolus can also form in the limbs.