Patients With Bleeding Tendency

PATIENTS WITH BLEEDING TENDENCY

Dr. Zeki Ali MohamedMRCP UK ( Edinburgh & London ) / FIBMS - Haematology Consultant Physician & Haematologist Azadi Teaching Hospital Lecturer / Departmeent of MedicineDuhok University – Faculty of Medical SciencesSchool of Medicine *

Normal Haemostasis OVERVIEW 

The normal haemostatic response to vascular damage depends on a closely linked interaction between the blood vessel wall, circulating platelets and blood coagulation factors An efficient and rapid mechanism for stopping bleeding from sites of blood vessel injury is clearly essential for survival. Nevertheless, such a response needs to be tightly controlled to prevent extensive clots developing and to break down such clots once damage is repaired. The haemostatic system thus represents a delicate balance between procoagulant and anticoagulant mechanisms allied to a process for fibrinolysis. When there is injury to a blood vessel, a series of events is initiated which results in controlled haemostasis. This involves: 1 Local vasoconstriction 2 Adhesion and aggregation of platelets 3 Activation of the clotting cascade to form a fi brin clot 4 Activation of coagulation inhibitors to ensure coagulation is restricted to the site of injury 5 Late fibrinolysis to restore patency of the vessel. These complex interacting systems can be disturbed by inherited or acquired factors, resulting in bleeding or thrombotic disorders
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The involvement of blood vessels, platelets and blood coagulation in haemostasis. ADP

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Bleeding disorders 

The approach to a patient with a suspected bleeding disorder involves medical history, examination, coagulation screening tests and specialist coagulation tests. History in a suspected bleeding disorder • Type of bleeding: mucocutaneous, haemarthroses/muscle haematomas • Severity of bleeding: blood transfusions, anaemia • Previous tests of the haemostatic system • Operations • Dental extractions • Trauma • Childbirth • Age of onset • Family history • Other medical problems • Drugs: aspirin, non-steroidal anti-inflammatory drugs *

Investigations in suspected abnormal bleeding Screening tests • Full blood count • Prothrombin time • Activated partial thromboplastin time • Thrombin time or fi brinogen • PFA100 closure or bleeding time Other first line investigations • Factor VIII, von Willebrand factor (VWF) activity, VWF antigen • Platelet aggregation • Platelet nucleotides Second line investigations • Factor XIII • α2-antiplasmin History suggestive of mucocutaneous bleeding • Prolonged epistaxis • Cutaneous haemorrhage and bruising with minimal or no apparent trauma • Prolonged bleeding from trivial wounds • Oral cavity bleeding • Spontaneous gastrointestinal bleeding • Menorrhagia not associated with structural lesions of the uterus *

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Laboratory investigation

Most important bleeding disorders can be excluded if the full blood count (FBC), prothrombin time (PT), activated partial thrombo-plastin time (APTT), thrombin time (TT) or fibrinogen, and closure time on the PFA100 platelet function analyser or bleeding time are normal. However, it is important to realize that mild VWD and some mild platelet defects, such as storage pool disease, can be missed by these screening tests. If a bleeding disorder is strongly suspected, factor VIII, von Willebrand factor (VWF) activity and VWF antigen should be measured, and platelet aggregation and platelet nucleotide measurements performed. If all these tests are normal in a case with a convincing history, deficiencies of factor XIII and α2-antiplasmin should be considered (Box 10.4). Figure shows a simplified version of the coagulation cascade. This representation, although non-physiological, enables us to interpret the coagulation screening tests. *


Abnormal bleeding
This may result from: 1 Vascular disorders 2 Thrombocytopenia 3 Defective platelet function or Defective coagulation. The pattern of bleeding is relatively predictable depending on the aetiology. Vascular and platelet disorders tend to be associated with bleeding from mucous membranes and into the skin whereas in coagulation disorders the bleeding is often into joints or soft tissue
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Vascular bleeding disorders

The vascular disorders are a heterogeneous group of inherited or acquired conditions characterized by easy bruising and spontaneous bleeding from the small vessels. The underlying abnormality is either in the vessels themselves or in the perivascular connective tissues. Most cases of bleeding caused by vascular defects alone are not severe. Frequently, the bleeding is mainly in the skin causing petechiae, ecchymoses or both. There may also bleeding from mucous membranes. All the standard screening tests are normal.
(a) Hereditary haemorrhagic telangiectasia. (b) Senile purpura. (c) Perifollicular petechiae in vitamin C deficiency (scurvy).
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Inherited vascular disorders

Hereditary haemorrhagic telangiectasiaThis uncommon disease is transmitted as an autosomal dominant trait. There are dilated microvascular swellings which appear during childhood and become more numerous in adult life. These telangiectasia develop in the skin, mucous membranes and internal organs. Pulmonary, hepatic, splenic and cerebral arteriovenous shunts are seen in a minority of cases. Recurrent epistaxes are frequent and recurrent gastrointestinal tract haemorrhage may cause chronic iron deficiency anaemia. Treatment is with embolization, laser treatment, oestrogens, tran-examic acid and iron supplementation.Connective tissue disordersIn the Ehlers–Danlos syndromes there are hereditary collagen abnormalities with purpura resulting from defective platelet aggregation, hyper-extensibility of joints and hyperelastic friable skin. Pseudoxanthoma elasticum is associated with arterial haemorrhage and thrombosis. Patients may present with superficial bruising and purpura following minor trauma or after the application of a tourniquet. Bleeding and poor wound healing after surgery may be a problem.Giant cavernous haemangiomaThese congenital malformations occasionally cause chronic activation of coagulation leading to laboratory features of disseminated intravascular coagulation (DIC) and in some cases thrombocytopenia. *

Acquired vascular defects

1- Simple easy bruising is a common benign disorder which occurs in otherwise healthy women, especially those of child- bearing age.2 - Senile purpura caused by atrophy of the supporting tissues of cutaneous blood vessels is seen mainly on dorsal aspects of the forearms and hands3 - Purpura associated with infections, 4 - The Henoch–Schцnlein syndrome usually in children after URTI. It is (IgA)-mediated vasculitis. The characteristic purpuric rash with localized oedema and itching most prominent on the buttocks and extensor surfaces of the lower legs and elbows. Painful joint swelling, haematuria and abdominal pain may also occur. It is usually a self-limiting condition but occasional patients develop renal failure.5 - Scurvy. In vitamin C deficiency, defective collagen may cause perifollicular petechiae, bruising and mucosal haemorrhage.6 - Steroid purpura. The purpura, which is associated with long-term steroid therapy or Cushing’s syndrome, is caused by defective vascular supportive tissue.Tranexamic acid and aminocaproic acid are useful antifibrinolytic drugs that may reduce bleeding resulting from vascular disorders or thrombocytopenia but contraindicated in the presence of haematuria as they might lead to clots obstructing the renal tract. *

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Platelet Disorders 

Platelets are small anucleate cells produced predominantly by the bone marrow megakaryocytes as a result of budding of the cytoplasmic membrane. Megakaryocytes are derived from the haemopoietic stem cell, which is stimulated to differentiate to mature megakaryocytes under the influence of various cytokines (thrombopoietin). Platelets play a key role in securing primary haemostasis.
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Once released from the bone marrow, young platelets are trapped in the spleen for up to 36 hours before entering the circulation, where they have a primary haemostatic role. Their normal lifespan is 7–10 days and the normal platelet count for all age groups is 150– 450 Ч 109/L. The mean platelet diameter is 1–2 μm, and the normal range for cell volume (mean platelet volume; MPV) is 8–11fL. Al-though platelets are non-nucleated cells, those that have recently been released from the bone marrow contain RNA and are known as reticulated platelets. They normally represent 8–16% of the total count and they indirectly indicate the state of marrow production. The platelet membrane containss integral glycoproteins essential in the initial events of adhesion and aggregation, leading to the forma- tion of the platelet plug during haemostasis
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Congenital abnormalities of platelets can be divided into disorders of - platelet production - platelet function. - Are very rare. - cause moderate to severe bleeding problems. Fanconi’s anaemia Thrombocytopenia with absent radii Wiskott–Aldrich syndrome MYH9-related thrombocytopenias Disorders of the surface membrane Bernard–Soulier syndrome Glanzmann’s thrombasthenia *

Thrombocytopenia / Thrombocytopathy

Abnormal bleeding associated with thrombocytopenia or abnormal platelet function is characterized by spontaneous skin purpura and mucosal haemorrhage and prolonged bleeding after trauma
(a) Typical purpura (b) massive subcutaneous haemorrhage in drug-induced thrombocytopenia
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Increased destruction of platelets

Autoimmune (idiopathic) thrombocytopenic purpura (ITP) may be divided into chronic and acute forms.Chronic idiopathic thrombocytopenic purpuraThis is a relatively common disorder. The highest incidence has been considered to be in women aged 15–50 years although some reports suggest an increasing incidence with age. It is the most common cause of thrombocytopenia without anaemia or neutropenia. It is usually idiopathic but may be seen in association with other diseases such as systemic lupus erythematosus (SLE), human immunodeficiency virus (HIV) infection or Helicobacter pylori, chronic lymphocytic leukaemia (CLL), Hodgkin lymphoma or autoimmune haemolytic anaemia *


Clinical features
The onset is often insidious with petechial haemorrhage, easy bruising and, in women, menorrhagia. Mucosal bleeding (e.g. epistaxes or gum bleeding) occurs in severe cases but fortunately intracranial haemorrhage is rare. The severity of bleeding in ITP is usually less than that seen in patients with comparable degrees of thrombocytopenia from bone marrow failure; this is attributed to the circulation of predominantly young, functionally superior platelets in ITP. Chronic ITP tends to relapse and remit spontaneously so the course may be difficult to predict. Many asymptomatic cases are discovered by a routine blood count. The spleen is not palpable unless there is an associated disease causing splenomegaly.
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Diagnosis

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Treatment

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Hereditary coagulation disorders

Hereditary deficiencies of each of the coagulation factors have been described: - Haemophilia A (factor VIII deficiency). - Haemophilia B (Christmas disease, factor IX deficiency) - von Willebrand disease (VWD) are the most frequent; the others are rarer.
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Haemophilia A & B is the most common of the hereditary clotting factor deficiencies. The prevalence is of the order of 30–100 per million population. The inheritance is sex-linked but up to one-third of patients have no family history and result from recent mutation.The defect is an absence or low level of plasma factor VIII. Approximately half of the patients have missense or frameshift mutations or deletions in the factor VIII gene. In others a characteristic ‘flip-tip’ inversion is seen in which the factor VIII gene is broken by an inversion at the end of the X chromosome This mutation leads to a severe clinical form of haemophilia A. Factor VIII deficiency (Haemophilia A) Factor IX deficiency (Haemophilia B, Christmas disease)
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Clinical features - Infants may develop profuse post-circumcision haemorrhage or joint and soft tissue bleeds and excessive bruising when they start to be active. Recurrent painful haemarthroses and muscle haematomas lead to progressive joint deformity and disability Local pressure can cause entrapment neuropathy or ischaemic necrosis. Prolonged bleeding occurs after dental extractions. Spontaneous haematuria and gastrointestinal haemorrhage,. Spontaneous intracerebral haemorrhage is an important cause of death in patients with severe disease. Haemophilic pseudotumours are large encapsulated haematomas with progressive cystic swelling from repeated haemorrhage. As a result of human immunodeficiency virus (HIV) present in concentrates made from human plasma during the early 1980s, over 50% of haemophiliacs treated in the USA or Western Europe became infected with HIV. Acquired immune deficiency syndrome (AIDS) has been a common cause of death in severe haemophilia. Thrombocytopenia from HIV infection may exacerbate bleeding episodes.
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Laboratory findings The following tests are abnormal: 1- Activated partial thromboplastin time (APTT). 2 - Factor VIII & IX clotting assay. The platelet function analysis-100 (PFA-100) (and bleeding time) and prothrombin time (PT) are normal.
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Von Willebrand disease

In this disorder there is either a reduced level or abnormal function of von Willebrand factor (VWF). VWF is produced in endothelial cells and megakaryocytes. It has two roles. It promotes platelet adhesion to subendothelium at high shear rates and it is the carrier molecule for factor VIII, protecting it from premature destruction. The latter property explains the reduced factor VIII levels found in VWD. VWD is the most common inherited bleeding disorder. Usually, the inheritance is autosomal dominant. The severity of the bleeding is highly variable depending on mutation type and epistatic genetic effects such as ABO blood group. Women are worse affected than men at a given VWF level. Typically, there is mucous membrane bleeding (e.g. epistaxes, menorrhagia), excessive blood loss from superficial cuts and abrasions, and operative and post-traumatic haemorrhage. The severity is variable in the different types. Haemarthroses and muscle haematomas are rare, except in type 3 disease.
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Laboratory findings 1- The PFA-100 test is abnormal. This has largely replaced the bleeding time test. 2 - Factor VIII levels are often low. If low, a factor VIII/VWF binding assay is performed. 3 - The APTT may be prolonged. 4 - VWF levels are usually low. 5 - There is defective platelet aggregation by patient plasma in the presence of ristocetin (VWF: Rco). Aggregation to other agents (adenosine diphosphate (ADP), thrombin or adrenaline) is usually normal. 6 - Collagen-binding function (VWF: CB) is usually reduced. 7 - Multimer analysis is useful for diagnosing different subtypes (Table 26.3). 8 - The platelet count is normal except for type 2B disease (where it is low).
Treatment1- Local measures and antifibrinolytic agent (e.g. tranexamic acid for mild bleeding).2- DDAVP infusion for those with type 1 VWD. This releases VWF from endothelial cells 30 min after intravenous infusion.3 - High – purity VWF concentrates for patients with very low VWF levels. Plasma-derived factor VIII/ VWF concentrates are used. Recombinant VWF is now in phase II clinical trials. *

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