17. HEMOSTASIS DISORDERS.pptx

Editor's Notes

• #4: Hemostasis, the cessation of bleeding, is a process which requires the combined activity of 3 categories of factors: vascular, platelet, and plasma factors. Regulatory mechanisms counterbalance the tendency of clots to form.
• #5: Blood vessels contribute to hemostasis via several processes: vasoconstriction: an immediate and transient response (less than 1 minute duration), which reduces the blood loss from the damaged zone through: - Reflex (neurogenic) mechanisms - Humoral mechanisms: endothelin released by endothelial cells and thromboxane A2 (TxA2) released by platelets Vascular endothelium: 1) synthesizes the von Willebrand factor (vWF), with an essential role in platelet adhesion (vWF is also the carrier for the clotting factor VIII) 2) synthesizes prostacyclines (PGI2) with antiagregant and vasodilator effects 3) releases the tissue factor (TF), a process induced by cytokines (TNF, IL-1); TF activates further the extrinsic pathway of coagulation Subendothelial structures (collagen, fibronectine) initiates the adhesion, aggregation, and secretion (release of granule content) → Platelet plug formation activates factor XII (Hageman) → initiates the intrinsic pathway of coagulation.
• #6: Thrombocytes: - potentiate the vascular spasm via vasoconstrictor factors (TxA2, serotonin) - contribute to the primary haemostasis via the platelet plug formation - participate in the secondary haemostasis via the release of platelet membrane phospholipids
• #7: Secondary hemostasis (coagulation) involves a series of enzymatic reactions occurring through the activation of 2 pathways: intrinsic pathway and extrinsic pathway. Coagulation requires the activity of plasma coagulation factors which interact to produce thrombin, which converts soluble fibrinogen to the fibrin
• #8: In the intrinsic pathway (contact phase), factor XII (Hageman), in the presence of high molecular weight kininogen (HMW-kininogen) and prekallikrein, will activate factor XI (to XIa) that in turn will trigger the generation of factor IXa from factor IX. Factor IXa then combines with factor VIIIa and procoagulant phospholipid (present on the surface of activated platelets and tissue cells) to form a complex that activates factor X. In the extrinsic pathway (tissue factor dependent phase), factor VIIa and tissue factor directly activate factor X.
• #9: Control of haemostasis include: - Inactivation of the soluble activated clotting factors Fibrinolysis (lysis of the fibrin clot) Plasma protease inhibitors inactivate the clotting factors in order to prevent the further generation of the fibrin clot. Antithrombin III (AT III) inhibits thrombin (f. IIa), factor Xa, factor XIIa, factor XIa, and factor IXa. Protein C and free protein S (cofactor of protein C) inactivates factors VIIIa and Va by proteolysis. The fibrinolytic system is responsible for the dissolution of the already existent fibrin clot by plasmin that will split fibrin into soluble fibrin degradation products (FDP) that are swept away in the circulation. Plasmin result from the activation of plasminogen under the action of: tissue plasminogen activator (tPA), released from endothelial cells, kallikrein urokinase (released by epithelial cells that line excretory passages, eg, renal tubes) drugs: streptokinase, recombinant tPA Fibrinolysis is regulated by: plasminogen activator inhibitors (PAIs), released by endothelial cells (inactivate tPA and urokinase) plasmin inhibitors (α2-antiplasmin, thrombin-activatable fibrinolysis inhibitor = TAFI).
• #10: Excessive bleeding can result from (1) increased fragility of vessels, (2) platelet deficiency or dysfunction, and (3) derangement of coagulation, alone or in combination. Let’s review the common laboratory tests used in the evaluation of a bleeding diathesis. The normal hemostatic response involves the blood vessel wall, the platelets, and the clotting cascade.
• #11: Tests used to evaluate different aspects of hemostasis are the following: • Prothrombin time (PT). This test assesses the extrinsic and common coagulation pathways. A prolonged PT can result from deficiency or dysfunction of factor V, factor VII, factor X, prothrombin, or fibrinogen. • Partial thromboplastin time (PTT). This test assesses the intrinsic and common clotting pathways. Prolongation of the PTT can be due to deficiency or dysfunction of factors V, VIII, IX, X, XI, or XII, prothrombin, or fibrinogen, or to interfering antibodies to phospholipids. • Platelet counts. The reference range is 150 × 103 to 300 × 103 platelets/μL. • International normalized ratio (INR) (the reference range is less than 1.3)
• #12: VASCULAR disorders (vascular purpuras) do not usually cause serious bleeding problems small blood vessels are affected (capillaries and arterioles) small visible hemorrhages (petechiae and purpura) but internal hemorrhages can take the form of menorrhagia, gastrointestinal bleeding, or hematuria. the platelet count and the coagulation tests (PT, aPTT) are usually normal bleeding time (BT) is prolonged.
• #13: Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome) is hereditary disorder of vascular malformation transmitted as autosomal dominant disorder, with an equal incidence in both men and women. Clinical features: dilated small blood vessels with thin walls that are very fragile; bleeding from capillaries and arterioles, most common at the mucous membranes of the nose (epistaxis – the most frequent sign), tongue, mouth, eyes, and the gastrointestinal tract (which eventually lead to iron deficiency anemia). Pathogenesis: gene mutations, which lead to abnormal functioning of endothelial proteins involved in transduction of the transforming growth factor β superfamily (TGFβ), which are decreased. We don’t know the exact mechanism, probabilly is due to an imbalance between pro- and antiangiogenic signals in blood vessels. Diagnosis is based on the finding of typical arterio-venous malformations on the face, mouth, nose, and digits.
• #14: Acquired vascular purpuras is a group of secondary pupruras, which are not inborn diseases.
• #15: Purpura from vitamin C deficiency (scurvy) microvascular bleeding resulting from impaired formation of collagens (defect in synthesis of hydroxyproline & hydroxylisine required for collagen synthesis) fragile vessel walls. Clinical signs are: Swelling and bleeding of the gums Disseminated petechiae Poor wound healing Hair and tooth loss Small bleeding around the hair follicles (Corkscrew hair) Small bleeding under nails Dry, pale skin
• #17: Purpura due to chronic steroid therapy, including local therapy, or due to Cushing syndrome/disease, is characterized by a predisposition to skin hemorrhages, due to: loss of perivascular supporting tissue because of protein-wasting effects of high corticosteroid level impaired collagen synthesis.
• #19: Allergic vascular purpuras is the group of syndromes characterized by cutaneous petechiae and purpura induced by deposition of immune complexes (IC) in the vessel walls (type III hypersensitivity). This class of purpuras can be caused by viruses, drugs (phenacetin, penicillin, quinidine), serum sickness, collagen disorders. One of the most common allergic vascular purpuras is anaphylactoid purpura (Schonlein-Henoch syndrome), induced 2-3 weeks after an infection with streptococcus ß-hemolytic in children/young adults. Circulating immune complexes damage the blood vessels and glomerular mesangial regions. 􀀐 extrarenal manifestations – triade: cutaneous rash, colicky abdominal pain (due to focal hemorrhages in GI tract) polyarthralgia (transient arthralgia of large joints) 􀀐 renal: acute glomerulonephritis & renal failure
• #20: Platelet disorders (thrombocytic purpuras) are classified in 2 major categories: 􀂾 Thrombocytopenia: decreased platelet number. 􀂾 Thrombocytopathia: decreased platelet function.
• #21: Thrombocytopenia General features: 􀀐 Reduction in platelet number < 100.000/mm3 􀀐 However, spontaneous bleeding does not become evident until the count falls below 20.000/mm3 􀀐 Spontaneous bleeding associated with thrombocytopenia most often involves small vessels. 􀀐 The common sites: skin and the mucous membranes of the gastrointestinal and genitourinary tracts. !Intracranial bleeding is a threat to any patient with a markedly depressed platelet count.
• #22: The main causes of thrombocytopenia are presented in Table 1
• #23: Idiopathic/Immune Thrombocytopenic Purpura is the most common cause of immune thrombocytopenia ITP is caused by the formation of autoantibodies (IgG type, in 80% of the cases) against platelet membrane glycoproteins (IIb-IIIa or Ib). Opsonized platelets are rendered susceptible to phagocytosis by the cells of the mononuclear phagocyte system. About 75% to 80% of patients are remarkably improved after splenectomy, indicating that the spleen is the major site of removal of sensitized platelets. Removal of the source of autoantibodies has also benefits to the patients. There is some evidence that megakaryocytes may be also damaged by autoantibodies, leading to impairment of platelet production.
• #24: Acute form is typical for children. The thrombocytopenia is abrupt, following a viral infection. It is a self limited disorder usually resolving spontaneously within 6 months Chronic form is more dangerous and has a bad prognosis because of progressive onset. The bleeding time is prolonged, but PT and APTT are normal.
• #25: Heparin-Induced Thrombocytopenia (HIT) is caused by an immune reaction directed against a complex of heparin and platelet factor 4 (PF4), a normal component of platelet granules that binds tightly to heparin. It appears that heparin binding modifies the conformation of PF4, making it susceptible to immune recognition. Binding of antibody to PF4 produces immune complexes that activate platelets, promoting thrombosis even in the setting of marked thrombocytopenia. The mechanism of platelet activation is not understood. 􀂃 Types: 􀂾 Type I HIT – rapid onset (1-4 days) & good prognosis (typically resolves upon heparin interruption) 􀂾 Type II HIT – onset at 5-14 days from tm initiation & severe prognosis due to autoAb (IgG) against heparin – PF4 with multiple thrombosis of the internal organs
• #26: Thrombotic Thrombocytopenic Purpura (TTP) – severe disorder, with fulminant evolution; lethal, characterized by the generalized occlusion of arterioles/capillaries by thrombi. In familial form: deficit of a plasmatic metalloprotease, ADAMTS 13, which is responsible for cleaving the multimer von Willebrand factor in monomers (ADAMTS = A Disintegrin And Metalloproteinase with Thrombospondin Motifs). In the absence of this enzyme, very high molecular weight of vWF accumulate in plasma. Platelet microaggregates form throughout the microcirculation. 􀂾 Non-familial form: Ab IgG against the enzyme ADAMTS 13 􀂃 Treatment: Plasma exchange ± infusion of fresh frozen plasma can be life saving by providing the missing enzyme (curative in 80% of the cases)
• #27: Hemolytic-Uremic Syndrome (HUS) – disorder, similar to PTT, characterized by the occlusion of small blood vessels localized ONLY at the renal level. Widespread formation of hyaline thrombi, comprised primarily of platelet aggregates, in the afferent arterioles and glomerular capillaries. It ussually occurs due to infectious gastroenteritis with E.Coli → endotoxin release → damage of endothelilal cells → initiation of PLT activation & aggregation (ADAMTS13 is normal !). 􀂃 Manifestations: HUS is also associated with thrombocytopenia, fever, and microangiopathic hemolytic anemia, but is distinguished from TTP by the absence of neurologic symptoms, the prominence of acute renal failure, and frequent incidence in children. 􀂃 Treatment: dialysis.
• #30: Adhesion requires: von Willebrand factor synthesized by the endothelium GpIb receptor on the platelets Aggregation involves: the GpIIb-IIIa receptors that link platelets via fibrinogen bridges.
• #31: Disorders of adhesion Bernard–Soulier syndrome is a rare autosomal recessive disorder. It impairs platelet adhesion via a defect in the glycoprotein Ib. Bleeding may be severe. Unusually large platelets can be identified on peripheral blood smear. Bleeding time is prolonged. Disorders of aggregation Glanzmann thrombasthenia is a rare autosomal recessive disorder causing a defect in the platelet glycoprotein IIb/IIIa complex (role of receptor for fibrinogen): platelets cannot aggregate. Patients may have severe mucosal bleeding. TREATMENT: Platelet transfusion
• #32: Disorders of platelet activation are the most common hereditary intrinsic platelet disorders and produce mild bleeding. They may result from decreased ADP in the platelet granules (storage pool deficiency), from an inability to generate TxA2 from arachidonic acid, or from an inability of platelets to aggregate in response to TxA2. The same pattern can result from use of NSAIDs or aspirin because of irreversible or reversible inhibition of COX-1
• #34: von Willebrand disease (vWD) is a hereditary deficiency of von Willebrand factor (vWF), which causes platelet dysfunction. vWF promotes the platelet adhesion of platelets to the vessel wall. vWF is also required to maintain normal plasma factor VIII activity. Thus, deficiency in vWF will be responsible for: 􀂾 Reduced platelet adhesion = abnormal primary hemostasis. 􀂾 Reduced levels of factor VIIIa = abnormal secondary hemostasis. Manifestations: mixed hemorrhagic syndrome (mild to moderate): 􀀐 Screening coagulation tests are normal exclude prolonged BT, platelet count is normal
• #35: HEMOPHILIA A - factor VIII deficiency, represents 80% of cases. Severity of the disease is given by the percent of normal factor VIII activity in the blood circulation: 􀂃 Clinical manifestations: - Bruises and hematoma - Bleeding into joints with pain and swelling (hemarthrosis): most common manifestation responsible for the chronic hemophilic arthropathy: Gastrointestinal and urinary tract hemorrhage blood in stool and urine ! Never purpura and petechiae (since primary hemostasis is not affected) - Positive diagnosis: prolonged APTT normal BT, PT, and platelet count Factor VIII assay determine the severity of the hemophilia. Treatment: recombinant factor VIII, sometimes antifibrinolytics
• #36: Diagram showing how in hemophilia patients, blood cannot clot properly because of poor platelet plug
• #38: Vitamin K is required for the carboxylation (activation) of the clotting factors II (prothrombin), VII, IX, X. In vitamin K deficiency, gamma-carboxyglutamic acid is replaced by glutamic acid, as a result there is no activation of prothrombin to thrombin. Causes of vitamin K deficiency: 􀀐 decreased synthesis by intestinal bacteria (only in newborns after broad-spectrum antibiotherapy) 􀀐 impaired intestinal absorption (in liver & gall bladder diseases due to the lack of bile salts) 􀀐 inhibition of activity in vitamin K antagonists over dosage (oral anticoagulant drugs of coumar type) 􀂃 Diagnosis: Koller test is positive (administration of vitamin K normalizes PT).
• #40: DIC is not a disease entity but an event that can accompany various disease processes.
• #41: There are three stages in DIC syndrome : 1. Stage of hypercoagulation and thrombosis2. The stage of consumption coagulopathy3. Stage hypocoagulation
• #42: The hematologic derangements seen in DIC result from the following 4 simultaneously occurring mechanisms [14] : TF-mediated thrombin generation Dysfunctional physiologic anticoagulant mechanisms (eg, depression of antithrombin and protein C system), which cannot adequately balance this thrombin generation Impaired fibrin removal due to depression of the fibrinolytic system – This is mainly caused by high circulating levels of plasminogen activator inhibitor type 1 (PAI-1); however, in exceptional forms of DIC, fibrinolytic activity may be increased and contribute to bleeding Inflammatory activation Generally DIC is a complex alteration in the blood clotting mechanism characterized by the: – Primary activation of coagulation resulting in thrombosis – Secondary activation of fibrinolysis resulting in thrombolysis As a result of the depletion of clotting factors, hemorrhage occurs simultaneously, a paradoxical clinical association of “clotting and hemorrhage”. DIC is diagnosed by thrombocytopenia, an elevated PTT and PT, increased levels of plasma D-dimers (or serum fibrin degradation products), and a low plasma fibrinogen level. DIC is a secondary event from activation of one of the coagulation pathways, either: 1. Extrinsic via tissue injury: shock or trauma, infections – sepsis, obstetric complications, malignancies. 2. Intrinsic via blood vessel injury: infectious vasculitis, hemolysis, snakebite, pancreatitis, severe liver disease. Systemic activation of the coagulation system will lead to 1) thrombi formation; 2) compromising blood supply to various organs; 3) consumption of platelets and coagulation factors → hemorrhage. Treatment: correction of the cause and replacement of platelets, coagulation factors (in fresh frozen plasma), and fibrinogen (in cryoprecipitate) to control severe bleeding. Heparin is used as therapy (or prophylaxis) in patients with slowly evolving DIC who have (or are at risk of) venous thromboembolism.
• #44: A. Primary Hypercoagulability: - Mutations of factor V (factor V Leiden) that make it resistant to its normal inactivation by activated protein C.. - Protein C deficiency: because activated protein C degrades clotting factors Va and VIIIa, deficiency of protein C predisposes to venous thrombosis. - Protein S deficiency: because protein S helps activated protein C degrade clotting factors Va and VIIIa, deficiency of protein S predisposes to venous thrombosis. - Antithrombin III deficiency: because antithrombin inhibits thrombin and factors Xa, IXa, and XIa, deficiency of antithrombin predisposes to venous thrombosis. - Hyperhomocysteinemia may predispose to arterial and venous thrombosis through unclear mechanisms, possibly because of injury to vascular endothelial cells. By far the most common causes of hyperhomocysteinemia are acquired deficiencies of folate, and vitamin B12. B. Secondary Hypercoagulability: - Increased PLATELET function - Increased CLOTTING activity - Both
• #45: Increased PLATELET function Etiology: 1) atherosclerosis; 2) Smoking; 3) Diabetes mellitus; 4) Hyperlipidemia/Obesity; 5) Increased platelet count (thrombocytosis > 1.000.000/mm3); 6) Malignancies (myeloproliferative disorders, eg CML) Mechanisms: - Flow disturbances and endothelial damage - Increased sensitivity of platelets to factors that induce adhesiveness/aggregation. Type of thrombosis: ARTERIAL, white thrombi (platelets and little fibrin). Complications: 1. Transient/permanent ischemia; 2) Infarction.
• #46: Etiology: - Postsurgical states - Prolonged immobility - Pregnancy and puerperium (postpartum period) - Congestive heart failure - Malignant disease - Sepsis Mechanisms: - Blood stasis, responsible for: - Accumulation of activated clotting factors - Prevention of their interaction with the inhibitors - Increased release of tissue factor by tumor cells. Type of thrombosis: VENOUS, red thrombi (few platelets, fibrin, and trapped RBCs). Complications: embolism