Understanding Hemostasis

Hemostasis

• The biological system responsible for preventing and stopping bleeding
• Involves restoration of the vascular wall
• Preserves liquid blood content with localized and reversible thrombosis
• Ensures sufficient blood supply to organs

Three Basic Components of Hemostasis

• Vascular components use the vascular wall to spasm injured vessels, triggering coagulation and thrombus formation
• Cellular components create a white thrombus involving thrombocytes and leukocytes
• Plasmatic components include the coagulation system (fibrin for red/mixed thrombi) and the anticoagulation/fibrinolytic systems

Hemostasis Triggering

• All three components are triggered simultaneously when a vessel is injured
• The primary mechanism for cellular and plasmatic components is contact between blood and an injured vascular wall, or negatively charged molecules/surfaces

Types of Hemostasis

• Primary hemostasis is vascular-thrombocyte, involving thrombocytes and microvessels to stop bleeding in small vessels (under 100 μm diameter)
• Secondary hemostasis occurs with plasmatic factors, where fibrin clots form and thrombi are fixed in vessels.
• Secondary hemostasis occurs in larger vessels (over 100 μm) and involves all components, mainly fibrin

Hemostasis Imbalance

• Can arise from pathologies of thrombocytes, plasmatic systems, or the vascular wall
• Manifests as hemorrhagic syndrome (hemorrhagic hemostasiopathy) with bleeding (hemorrhagic diathesis)
• Can also result in thrombotic syndrome (thrombotic hemostasiopathy) with thrombus formation, or a combination as thrombohemorrhagic hemostasiopathy (DBC-syndrome)

Vscular-Thrombocyte Hemostasis Impairments

• When a microvessel wall is damaged, thrombocytes adhere, change structurally, release granules, and aggregate
• Results in a thrombocyte plug formation and cessation of bleeding in microvessels
• The damaged vessel spasms

Immune Thrombocytopenia (ITP)

• A group of diseases where thrombocyte lifespan decreases due to antibodies
• There are autoimmune and haptenous forms of ITP

Autoimmune ITP Forms

• Symptomatic forms occur with systemic connective tissue diseases, chronic lympholeukemia, lymphogranulomatosis, or lymphomas
• Idiopathic forms have no association with previous diseases, e.g., Werlhof’s disease has a chronic course with megakaryocytosis, giant thrombocytes, and antithrombocyte bodies

Haptenous ITP Forms

• Related to certain medicinal preparations(quinine, quinidine, gold preparations)

ITP Clinical Picture

• Characterized by petechial eruptions, bruises, and cerebral hemorrhages

Coagulatory Hemostasis Impairments

• Secondary hemostasis involves coagulating, anti-coagulating, and fibrinolytic blood systems

Coagulating Blood System

• A series of linked reactions involving proteolytic enzymes and plasmatic proteins (coagulation factors)
• Results in the formation of a permanent thrombus

Coagulopathies

• Pathologies of the coagulation system that can be hereditary or acquired

Hereditary Coagulopathies

• Diseases mainly caused by deficiency of factors VIII and IX (over 95% of cases)
• Deficiencies in factors VII, X, V, and XI make up to 1.5%
• Deficiencies of factors XII, II, I, and XIII are rare

Hemophilia A

• Deficiency of factor VIII that is inherited recessively and linked to the X chromosome
• Males are primarily affected (10 in 100,000)
• FVIII deficiency increases prothrombin complex formation time leading to continuous bleeding with slight injury and characterized by hematomas

Hemophilia A Disease Severity

• Slight form: bleedings possible only in severe injuries/interventions with subclinical course
• Severe/very severe forms (2% or less, 1%) has recurrent hemorrhages into large joints causing ankylosis; large hematomas; frequent bleedings with persistent gastro-intestinal and renal bleedings

Hemophilia B

• Christmas disease with FIX deficiency
• Inherited recessively, linked to the X chromosome
• Defect inhibits prothrombinase complex formation, resulting in hematoma development
• Clinical picture is identical to Hemophilia A

Hemophilia C

• Deficiency of factor XI that is inherited autosomally-recessively
• Heterozygotes have slight bleeding; homozygotes with FXI deficiency have few bleeding complications except in lesions/surgeries when severe bleeding can occur with hemarthrosis and hematomas

Parahemophilia

• FV deficiency that is inherited autosomally-dominantly
• Causes hemorrhagic syndrome whose expressivity depends on FV deficiency in plasma
• Most severe bleeding occurs with FV levels < 2%
• Marked by petechiae, ecchymoses, nose bleeds, gum bleeding, gastro-intestinal bleeding, and menorrhagia
• Patients often have prolonged bleeding after tooth removal, traumas, and lacerations

Disseminated Intravascular Coagulation (DIC)

• A nonspecific pathologic process characterized by generalized activation of the hemostasis system
• Occurs when regulatory systems of the blood aggregate condition is in disagreement

DIC Etiological Factors

• Generalized/septic infections
• Shock
• Surgical interventions
• Tumors
• Tissue lesions/embolism
• Burns
• Immune/allergic/immune-complex diseases
• Massive blood losses
• Transfusions
• Poisonings
• Hemolysis
• Hypoxia
• Hypothermia
• Hyperthermia
• Dehydration

DIC Accompaniments

• Impairment of vascular-thrombocyte and coagulation hemostasis

DIC Pathogenesis

• Systemic damage and abnormality of vascular endothelium
• Activation of the coagulation system and thrombocytes
• Primary/secondary depression of the anti-coagulatory system

DIC Clinical Picture: Stages

• Stage 1: Symptoms of the basic disease and signs of thrombohemorrhagic syndrome; hypovolemia, impaired microcirculation, organ dysfunction
• Stage 2: Polyorgan damage and blockade of microcirculation in parenchymatous organs, hemorrhagic syndrome
• Stage 3: Polyorgan insufficiency (respiratory, cardio-vascular, hepatic, renal, intestinal) and metabolic impairments, anemic syndrome, and mixed-type hemorrhagic syndrome
• Stage 4: Gradual normalization of vital functions and hemostasis factors
• DIC may be swift (minutes to hours), acute (1-10 days), subacute (up to 1 month), chronic (over 1 month), or recurrent

Pathology of the Anti-Coagulatory System

• Factors include inhibitors of proteinases
• Main factors are antithrombin III (heparin factor I) and heparin cofactor II
• Deficiency causes functional impairments of the anti-coagulatory system which may be hereditary or acquired

Hereditary Factor Deficiency in Anti-Coagulatory System

• Clinically shown by venous thrombosis resistant to anti-coagulation therapy
• Venous thrombosis of lower extremities can cause thromboembolism of the pulmonary artery in patients with this deficiency

Acquired Impairments

• Antiphospholipid syndrome (APS)
• Antiphospholipid antibodies (anti-PL) appear in the blood

Antiphospholipid Syndrome (APS)

• Can be primary without other diseases, although this is rare
• More often secondary, associated with autoimmune systemic diseases/connective tissue diseases (systemic erythema centrifugum, rheumatoid arthritis), malignant growths, AIDS, and other viral/bacterial infections
• Clinical picture manifests as venous thrombosis and arterial thrombosis with damage to coronary, cerebral, or peripheral arteries
• Includes transient ischemic attacks, cerebral infarctions, worsening vision, temporary blindness, vasculitis, rash, arthralgias, migraine, retina exfoliation, endocarditis
• In pregnancy, there is a high risk of miscarriage

Hemostasis Impairments of the Vascular and Mixed Genesis

• There are hereditary and acquired vasopathies

Osler’s Disease

• (Hereditary hemorrhagic teleangioectasia)
• Common hereditary vasopathy inherited on an autosomal-dominant pattern with varying penetrance
• Decreased collagen in the subendothelial layer of the vascular wall leads to thinning/dilation of the microvessel lumen and abnormal vascular thrombocyte hemostasis

Osler’s Disease Bleeding Causes

• Low resistance
• Vascular wall vulnerability
• Endothelium dysfunction at angioectasia sites
• Impaired thrombocyte aggregation

Osler’s Disease Skin Manifestations

• Teleangioectasias as irregular spots, vascular bundles, or bright-red round/oval nodes
• Form from 6th-10th year of life, initially appear at the wings of the nose and on mucous membranes/skin of face
• Bleeding becomes more frequent and severe with age as these spots increase
• Internal mucous membranes display recurrent nasal, pulmonary-bronchial, and gastro-intestinal bleeding
• Arteriovenous aneurysms appear on the lungs, liver, kidneys, and spleen
• Characterized by posthemorrhagic anemia from persistent bleeding
• Abnormal mesenchymal tissues, skin elasticity, ligament apparatus weakness
• Posthemorrhagic anemia, hypercoagulation, thrombocytosis and thrombocytopenia

Schönlein’s Disease

• (Acquired hemorrhagic immune microthrombovasculitis)
• Common hemorrhagic disease
• Multiple microthrombovasculitis affects skin vessels and internal organs
• Common during childhood and may be triggered by infectious (viral, bacterial, streptococcal) and noninfectious factors (vaccinations, medicinal drugs, food allergens, parasitic invasions, cold)

Schönlein’s Disease Pathogenesis

• Immune-complex inflammation of the vascular wall
• Immune complexes are fixed in vessel walls, activating the complement system
• Process destroys the vascular wall, leading to hemorrhagic rash (hemorrhagic syndrome) and intravascular blood coagulation (thrombotic syndrome)
• There is also inhibited fibrinolysis

Schönlein’s Disease Clinical Picture

• Skin manifestations: Symmetric affection of extremities, superficial extensors of the arms and buttocks with pappular-hemorrhagic rash
• Arthral syndrome: Pains in large joints (knee, ankle)
• Abdominal syndrome: Severe, colicky pains due to hemorrhages in intestinal wall or mesentery
• Renal syndrome: Acute or chronic glomerulonephritis
• Neurotic manifestations: Headaches, meningeal symptoms, epileptiform seizures
• Pulmonary manifestations: Pulmonary vessel affection with severe bleeding

Schönlein’s Disease Blood Findings

• Moderate neutrophilic leukocytosis with shift of leukocytes to the left
• Acute posthemorrhagic anemia during profuse bleeding
• Thrombocyte count may be increased or normal
• ESR is accelerated, with shift towards hypercoagulation
• Immunologic examination shows high levels of circulating immune complexes and IgA