Download Regional Blood Flow Disturbances Thrombosis. Embolism. Normal

REGIONAL BLOOD FLOW DISTURBANCES
Thrombosis. Embolism.
Normal hemostasis results from well-regulated processes that maintain blood in a fluid, clot-free state
in normal vessels while inducing the rapid formation of a localized hemostatic plug at the site of vascular
injury. The normal vascular system maintains a delicate balance between clotting mechanisms and clot
lysis, with the result that internal or external bleeding is controlled and pathologic thrombosis prevented.
We begin our discussion with the process of normal hemostasis and a description of how it is regulated.
NORMAL HEMOSTASIS.
Proper blood clotting and prevention of blood loss requires the interaction of blood vessels, platelets,
coagulation factors, and fibrinolytic agents.
A. Anticoagulants normally found in small blood vessels (capillaries, venules, arterioles)
1. Heparin: enhances antithrombin III activity, thus neutralizing serine protease coagulation factors,
such as XII, XI, IX, X, II (prothrombin), and thrombin
2. Prostaglandin 12 (prostacyclin): vasodilator that inhibits platelet aggregation; synthesized by
endothelial cells
3. Proteins C and S: vitamin K-dependent factors that inactivate factors V and VIII and enhance
fibrinolysis
4. Tissue plasminogen activator (tPA): activates plasminogen to release plasmin, which degrades
coagulation factors and lyses fibrin clots.
B. Procoagulants released in small-vessel injury
1. Thromboxane A2 (TXA2), converted from prostaglandin H2 by thromboxane synthase in platelets.
Functions: vasoconstriction, enhanced platelet aggregation
2. Von Willebrand's factor (vWF) is synthesised by endothelial cells and megakaryocytes. It binds
platelets to collagen, thus contributing to platelet adhesion and complexes with factor VIII coagulant
(VIII:C) in the circulation, thereby stabilizing it. Factor VIII:C is synthesized in the liver. When VIII:C is
activated by thrombin, it dissociates from the VIII:vWF complex and functions as a coagulant.
3. Tissue thromboplastin (factor III): exposed on damaged tissue and activates factor VII in the
extrinsic coagulation system
4. Extrinsic and intrinsic coagulation factors include factors extrinsic and intrinsic pathways,
thrombinogen, thrombin, fibrinogen, fibrin, (more detailed see below).
Vitamin K-dependent factors are synthesized in the liver as nonfunctional precursor proteins. Epoxide
reductase activates vitamin K in the liver to become vitamin K1. The factors are functional because of γcarboxylation by vitamin K1 , which binds them to Ca2+ and PF3 in the clotting cascade.
C. Platelets. Platelet membrane with platelet factor 3 (PF3): phospholipid substrate required for the
clotting sequence. Contractile elements (e.g., thrombosthenin) aid in clot retraction. Dense bodies contain
adenosine diphosphate (ADP), an aggregating agent, and calcium (Ca2+), a binding agent for vitamin Kdependent factors. a-Granules contain vWF and PF4 (heparinneutralizing factor).
THROMBOGENESIS
Thrombogenesis is the process common to both hemostasis (i.e., normal blood clot formation) and
thrombosis. Hemostasis is physiologic blood clotting. Injury to the endothelium-lined vessel wall initiates
a four-phase process:
1. Vascular phase. Vasoconstriction.
Arteriolar smooth muscle cells react to neurogenic stimuli and endothelin, a potent vasoconstrictor
secreted by endothelial cells. Factor VII is activated by tissue thromboplastin; Exposed collagen activates
factor XII.
2. Platelet phase. Hemostatic plug formation (primary hemostasis).
When vascular endothelium is disrupted, platelets respond by creating a platelet plug to minimize
bleeding. Platelets are particularly important in sealing damaged blood vessels that are subjected to high
shear rate, such as arteries and arterioles. Platelets are attracted to the subendothelial extracellular matrix,
which was exposed by the injury. The platelets adhere to the extracellular matrix (a process mediated by
von Willebrand factor), change shape, and release secretory granules (e.g., thromboxane A2). These
secretory granules recruit more platelets (a process called aggregation). Thus the surface of activated
platelets is an optimal environment for propagating assembly of the coagulation-factor complex,
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including the prothrombinase complex. The resulting thrombin has many consequences, particularly
further platelet activation.
3. Coagulation phase. Fibrin clot formation (secondary hemostasis).
Extrinsic system: Tissue thromboplastin released from injured tissue activates factor VII, resulting in
the formation of factor VIIa. In the final pathway, factor VIIa activates factor X.
Intrinsic system: Exposed subendothelial collagen and highmolecularweight kininogen activate factor
XII (Hageman factor) to form factor XIIa. Factor XIIa activates three substances.
Factor XI to form XIa
Plasminogen to form plasmin
Kininogen system to produce kallikrein and bradykinin
XIa activates factor IX to form a four-component complex (factor IXa, factor VIII, PF3, Ca2+). This
complex activates factor X.
In the final common pathway (extrinsic and intrinsic) prothrombin complex including four-component
system (factor Xa, factor V, PF3, Ca2+) is formated.
The prothrombin complex cleaves prothrombin to the enzyme thrombin.
The activation of thrombin during the coagulation sequence leads to further aggregation of platelets.
Thrombin, which binds to the platelet surface, causes platelet contraction (viscous metamorphosis),
thereby sealing the clot and making it permanent.
Thrombin acts on fibrinogen to produce soluble fibrin monomers and fibrinopeptides A and B and
activates fibrin-stabilizing factor XIII. Activated fibrin-stabilizing factor XIIIa converts soluble fibrin
monomers to insoluble fibrin by enhancing cross-linking between proteins to strengthen the fibrin clot.
4 . Fibrinolytic
phase: plasmin cleaves
the insoluble fibrin
monomers that hold the
platelet plug together
and reestablishes blood
flow.
Activation of
fibrinolytic system:
tPA and factor XIIa
activates plasminogen,
forming the enzyme
plasmin. Functions of
plasmin is cleaves
insoluble fibrin
monomers and
fibrinogen into fibrin
and fibrinogen degradation products (FDPs)
ANTICOAGULANT PARTHWAY.
An anticoagulant complex activates protein C. The protein Case complex is composed of thrombin and
thrombomodulin in the endothelial cell plasma membrane. Endothelial protein C receptor also participates
in forming this cell surface complex. Activated Protein C, with its cofactor Protein S, inactivates the key
cofactors VIIIa and Va, thus limiting further generation of Xa and IIa.
Antithrombin inhibits thrombin activity. Antithrombin also cleaves activated factors IXa, Xa, XIa, and
XIIa. In vivo this effect is accentuated by heparan sulfate proteoglycans and, most dramatically, by
therapeutic administration of heparin.
HEMOSTATIC DISORDERS
Defects of the system for maintaining fluid blood passage through intact vessels fall into two
categories: hemostatic disorders and thrombotic disorders.
Failure of the hemostatic system to restore the integrity of an injured vessel causes bleeding. The
clinical manifestations of hemorrhage associated with disorders of each component of the hemostatic
system (vessels, platelets, coagulation factors, and coagulation fibrinolytic agents) tend to be distinctive.
Platelet abnormalities result in both petechiae and purpuric hemorrhages in the skin and mucous
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membranes. Deficiencies of coagulation factors lead to hemorrhage into muscles, viscera, and joint
spaces. Disorders of the blood vessels usually cause purpura.
Inability to maintain the fluidity of blood results in thrombosis. It can be thought of as the formation of
a blood clot (thrombus) in uninjured vessels, or thrombotic occlusion of a vessel after relatively minor
injury.
Principal Causes of Hemorrhagic Disorders:
1 Vascular defects
a. Simple and senile purpura (increased capillary fragility especially in the elderly)
b. Hypersensitivity vasculitis; many autoimmune disorders (inflammation)
c. Vitamin C deficiency (scurvy, defective collagen)
d. Amyloidosis (affected vessels fail to constrict)
e. Excess adrenocorticosteroids (therapeutic or Cushing's disease)
f. Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)
g. Ehlers-Danlos disease (defective collagen)
h. Henoch-Schönlein purpura
i. Marfan's syndrome (defective elastin)
2. Disorders of platelets
a. Decrease (thrombocytopenia)
b. Abnormal platelet function
3. Disorders of coagulation
a. Deficiency of coagulation factors
b. Presence of anticoagulant factors
4. Excessive fibrinolysis
a. Disseminated intravascular coagulation
b. Primary fibrinolysis
Dysfunction of Vascular or Extravascular Tissues
Dysfunction of the extravascular or vascular tissues may cause hemorrhages ranging from cosmetic
blemishes to life-threatening blood loss.
Extravascular Dysfunction
Senile purpura: The most common disorder in extravascular dysfunction, senile purpura, is age-related
atrophy of supporting connective tissues. Senile purpura is associated with superficial, sharply
demarcated, persistent purpuric spots on the forearms and other sun-exposed areas.
Purpura simplex: A similar type of purpura occurs principally in women during menses. Purpura
simplex occurs in the deep dermis and resolves quickly.
Scurvy: Collagen synthesis is disturbed in vitamin C deficiency, and purpura is a common
manifestation. Perifollicular hemorrhages are characteristic.
Vascular Dysfunction
Along with thrombocytopenia, vascular defects represent the most common cause of bleeding
diathesis. In certain vascular disorders, the underlying defect relates to production of abnormal collagen
or elastin; in vasculitis, inflammation is the cause.
Henoch-Schönlein purpura (anaphylactoid purpura) deserves special mention as a poststreptococcal
disease of childhood. It occurs 1–3 weeks after streptococcal infection and is thought to be mediated by
deposition of cross-reactive IgA or immune complexes plus complement on the endothelium. Occasional
cases have been reported with apparent hypersensitivity to other bacteria, insect bites, or food (milk, eggs,
crab, strawberries). Clinically, there is purpura, abdominal pain (due to mucosal involvement in the gut,
often with frank bleeding), arthralgia or arthritis, and glomerulonephritis. Fever is often present. The
prognosis is determined by the severity of the renal lesion (focal glomerulonephritis with deposition of
IgA and complement.
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) is inherited as an autosomal
dominant trait and manifested by multiple capillary microaneurysms in the skin and mucous membranes.
The lesions tend to become more conspicuous with age and are exceedingly fragile, predisposing both to
episodes of acute severe bleeding and to chronic blood loss from the intestinal tract with resulting iron
deficiency anemia.
The Most Common Platelet Disorders Impair Hemostasis
Platelet disorders which may result in impair hemostasis include:
Thrombocytopenia as result from
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Decreased production or ineffective production
Increased destruction
Increased sequestration
Dilutional
Impaired function
Thrombocytopenia
Thrombocytopenia is defined as platelet counts under 150,000/ВµL. The lower the platelet count, the
greater the risk of traumatic and perioperative bleeding. Patients with fewer than 10,000 platelets/ВµL are
at increased risk of spontaneous hemorrhage.
Decreased production and Ineffective production
Principal Causes: aplastic anemia, bone marrow infiltration (neoplastic, fibrosis), bone marrow
suppression by drugs or radiation, megaloblastic anemia, myelodysplasias
Bone marrow infiltration with leukemic cells or metastatic cancer impair megakaryopoiesis.
Ineffective megakaryopoiesis in myelodysplasia also results in thrombocytopenia. Bone marrow failure in
patients with aplastic anemia or who received radiotherapy or chemotherapy produces pancytopenia,
including thrombocytopenia. Certain viral infections such as cytomegalovirus or any megaloblastic
anemia may cause severe thrombocytopenia.
May-Hegglin anomaly is a hereditary defect in megakaryocyte maturation in which thrombocytopenia
is associated with circulating giant platelets and blue cytoplasmic inclusions within neutrophils. These are
giant platelet syndromes caused by mutations in the myosin heavy chain 9 gene.
Increased destruction
The causes: immunologic (idiopathic, HIV, drugs, alloimmune, posttransfusion purpura, neonatal),
nonimmunologic (DIC, vascular malformations, drugs);
Increased platelet destruction may reflect immune-mediated damage and removal of circulating
platelets, as in idiopathic thrombocytopenic purpura and drug-induced thrombocytopenia. Alternatively,
intravascular platelet aggregation may produce thrombocytopenia.
Idiopathic thrombocytopenic purpura (ITP) is a decrease in blood platelets caused by antibodies
against platelet or megakaryocytic antigens. It is, thus, more appropriatedly called immune
thrombocytopenic purpura. ITP occurs in two forms: an acute, self-limited, hemorrhagic syndrome in
children; and a chronic bleeding disorder in adolescents and adults.
Pathogenesis
ITP reflects antibody-mediated destruction of platelets or their precursors. In most patients, these
autoantibodies are of the IgG class, but IgM antiplatelet antibodies also occur.
Acute ITP typically appears in children of either sex after a viral illness and is likely caused by virusinduced changes in platelet antigens that elicit autoantibodies. Complement bound at the surface causes
platelets to be lysed in the blood or phagocytosed and destroyed by splenic and hepatic macrophages.
Chronic ITP occurs mainly in adults (male to female ratio of 1:2.6) and may be associated with
collagen vascular diseases (e.g., systemic lupus erythematosus) or a malignant lymphoproliferative
disease, especially chronic lymphocytic leukemia. It is also common in people infected with human
immunodeficiency virus (HIV).
Drug-Induced Thrombocytopenia. Many drugs are known to cause immune-mediated platelet
destruction: quinine, quinidine, heparin, sulfonamides, gold salts, antibiotics, sedatives, tranquilizers, and
anticonvulsants. The drug often forms a complex with a platelet-related protein to make a neoepitope that
elicits antibody production. By contrast, chemotherapeutic agents, ethanol, and thiazides cause
thrombocytopenia by suppression of platelet production.
Dilutional Thrombocytopenia. Blood and plasma transfusions.Platelet loss occurs in patients who
have massive hemorrhage, such as in bleeding from a peptic ulcer or during surgery with heavy blood
loss. Transfused blood does not contain viable platelets because it is stored at 4 °C before administration.
Thus, thrombocytopenia in transfused patients is due to platelet loss and dilution. Platelet transfusion may
be used to prevent development of thrombocytopenia.
Increased sequestration - Splenic Sequestration of Platelets
Many patients with splenomegaly, irrespective of the cause, show hypersplenism, a syndrome that
includes sequestration of platelets in the spleen. One third of platelets are normally stored temporarily in
the spleen, but in massive splenomegaly, up to 90% of the total platelet pool may be captured in that
organ. Interestingly, the platelet life span is normal or only slightly reduced. Thrombocytopenia
associated with hypersplenism is rarely severe and by itself does not produce a hemorrhagic diathesis.
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At thrombocytopenia patients may have a history of easy bruising or life-threatening bleeding.
Bleeding can occur in any damaged vascular bed, but a particular pattern of mucocutaneous bleeding,
including gingival bleeding, epistaxis, and menorrhagia, is common. More severe manifestations are
bleeding into the gastrointestinal tract, genitourinary tract, and brain. Petechiae, which are characteristic
of platelet disorders, are nonblanching red lesions less than 2 mm in size. They usually occur in lower
extremities, in dependent regions of the body, on the buccal mucosal and soft palate and at pressure points
(waistband, wristwatch band). Petechiae may also occur in vascular disorders.
Abnormalities of Platelet Function
Qualitative platelet disorders (abnormal function) result from:
Inherited diseases
Defects of adhesion: Bernard-Soulier disease is autosomal recessive disease with absent platelet
receptors for vWF.
Defects of aggregation: thrombasthenia (Glanzmann's disease) is autosomal recessive disease
with absent fibrinogen receptors and absent thrombosthenin
Abnormal granule release: storage pool disease
Acquired
Uremia
Dysproteinemias
Chronic liver disease, especially alcoholic
Drug-induced: aspirin, phenylbutazone
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Renal failure: End-stage kidney disease is often accompanied by a qualitative platelet defect that
results in a prolonged bleeding time and a tendency towards hemorrhage. The platelet abnormality is
heterogeneous and is aggravated by uremic anemia. Restoring a normal hematocrit by administering EPO
may restore bleeding time to normal without affecting the azotemia.
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Cardiopulmonary bypass: Platelet dysfunction due to platelet activation and fragmentation occurs
in the extracorporeal circuit during bypass surgery.
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Hematologic malignancies: In chronic myeloproliferative disorders and myelodysplastic
syndromes, platelet dysfunction is due to intrinsic platelet defects. In dysproteinemias, platelets are
impaired because they are coated with plasma paraprotein.
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Drugs: Various drugs can impair platelet function. Aspirin irreversibly acetylates
cyclooxygenase, primarily COX-1 and thus blocks production of platelet thromboxane A2, which is
important in platelet aggregation. Platelets cannot synthesize cyclooxygenase, so the aspirin effect lasts
for the life span of platelets (7 to 10 days). Nonsteroidal analgesics, such as indomethacin or ibuprofen,
impair platelet function, but as their inhibition of cyclooxygenase is reversible, their effect on platelets is
short. Antibiotics (penicillin and cephalosporins), can cause platelet dysfunction. Ticlopidine, which is
used to suppress platelet function in patients with thromboembolic disease, causes marked impairment of
platelet function.
Platelet function abnormalities are characterized by symptoms and signs of platelet deficiency (ie,
abnormal bleeding) but with a normal platelet count. Tests of platelet function such as clot retraction,
platelet adhesion, and aggregation in response to different agents are abnormal and are valuable in
separating the different disease processes
Disorders of Blood Coagulation
There are three principal groups of coagulation disorders.
Deficiency of Coagulation Factors
Presence of Circulating Anticoagulants
Fibrinolytic Activity
Deficiency of Coagulation Factors
Deficiencies of individual coagulation factors may occur as inherited diseases. Of these, factor VIII
deficiency (hemophilia A and von Willebrand's disease) and factor IX deficiency (Christmas disease) are
the most common. Acquired deficiencies of coagulation factors occur in severe liver disease (affects all
factors produced by the liver) and in vitamin K deficiency (prothrombin and factors VII, IX, and X).
Factor VIII Deficiency
Factor VIII coagulant (VIII:c) is a critical component of the intrinsic coagulation pathway and is also
known as antihemophilic globulin (deficiency produces hemophilia A). Factor VIII von Willebrand factor
(VIII:vWF) is by much the larger part of the factor VIII complex. Factor VIII:vWF serves two functions.
First, it plays a critical role in platelet aggregation. Second, it enhances factor VIII:C activity at the site of
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injury and serves as a carrier of circulating VIII:c. Deficiency of factor VIII:vWF produces von
Willebrand's disease.
Hemophilia A
Hemophilia A (classic hemophilia) is inherited as an X-linked recessive trait, occurring mainly in
males. Females develop hemophilia only when they have the abnormal gene on both X chromosomes
(homozygous)—a rare event that occurs when a hemophiliac male mates with a carrier female or when a
single functional X chromosome carries the abnormal gene.
The presence of the abnormal gene results in deficient synthesis of the coagulant subunit of the factor
VIII molecule (VIII:C). Factor VIII-related antigen (factor VIII-von Willebrand factor) continues to be
present in normal amounts.
Von Willebrand's Disease
Von Willebrand's disease is inherited as an autosomal dominant trait characterized by deficiency of the
entire circulating factor VIII complex. Factor VIII coagulant activity and the von Willebrand factor
(factor VIII-related antigen) are decreased to the same extent, so that the ratio of these two components is
normal. Variants exist in which factor VIII:C is near normal.
Factor IX Deficiency (Christmas Disease; Hemophilia B)
Christmas disease is uncommon and results from a deficiency of factor IX.
Christmas disease is characterized by X-linked recessive inheritance, greater prevalence in males, and
a clinical picture identical to that of hemophilia A. The diagnosis is made when factor VIII coagulant
activity is normal in a patient with symptoms of hemophilia. Plasma factor IX assay shows greatly
decreased levels and is diagnostic. Treatment is with fresh plasma or factor IX concentrate; factor IX is
not present in cryoprecipitate.
Other Coagulation Factor Deficiencies
Deficiencies of all coagulation factor proteins, including factors VII, X, V, XI, II (prothrombin), and
fibrinogen, have been noted in humans. As expected, the severity of bleeding usually correlates with the
level of functional protein activity.
Prolonged PT or PTT in patients with bleeding manifestations helps to identify a problem with
coagulation factors. Factor-specific assays confirm the diagnosis. The thrombin time helps to screen for
deficiency or dysfunction of fibrinogen. Deficiency of fibrinogen causes bleeding. By contrast,
dysfibrinogenemia may cause bleeding but more often leads to thrombosis.
Liver Disease
Many coagulation factors are produced in the liver (e.g., II, V, VII, IX, X). Severe liver disease may
cause impaired secretion of these proteins as a manifestation of the general protein synthetic defect. In
this case, levels of all liver-synthesized coagulation factors are low, and both PT and PTT are prolonged.
Vitamin K Deficiency
Liver-derived coagulation factors depend on vitamin K as an essential cofactor in γ-carboxylation of
glutamic acid. By contrast, factor V is made in the liver but does not require vitamin K. Thus, in vitamin
K deficiency activities of factors II, VII, IX, and X are low but factor V activity is normal. However, in
severe liver disease, all of these factors have low activity.
Presence of Circulating Anticoagulants
Factor deficiencies may also be induced by anticoagulant therapy with coumarin derivatives (which
interfere with vitamin K, thereby inhibiting synthesis of prothrombin and of factors VII, IX, and X).
Directly acting anticoagulants that antagonize some of the coagulation cascade include (a) drugs such as
heparin (an antithrombin), (b) antibodies (factor VIII inhibitor and lupus anticoagulant, an antibody in
systemic lupus erythematosus), and (c) natural anticoagulants (antithrombin and fibrin degradation
products).
Acquired inhibitors of coagulation factors, circulating anticoagulants, are usually IgG autoantibodies.
Most are directed against factor VIII and vWF, although rarely antibodies against most of the other
coagulation factors are seen. In hereditary coagulation disorders, especially hemophilia, circulating
anticoagulants arise in response to administration of plasma concentrates containing the deficient factor.
Anticoagulants also develop in some patients with autoimmune disorders (e.g., systemic lupus
erythematosus, rheumatoid arthritis), presumably as a result of abnormal immune regulation. Finally,
acquired anticoagulants often appear in apparently normal persons.
Fibrinolytic Activity
Increased fibrinolytic activity in the blood results from increased activation of the plasmin system.
Clinical Features
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Patients with disorders of coagulation tend to bleed excessively following minor trauma such as
dentistry. In severe cases, spontaneous bleeding occurs (ie, bleeding without evident trauma)—commonly
into joints (hemarthrosis) and muscles. Bleeding is usually slow but persistent and can be halted by
replacement of the deficient factor.
All coagulation disorders have similar clinical manifestations. Determination of the cause of the
abnormality requires bleeding and coagulation testing
DISSEMINATED INTRAVASCULAR COAGULATION
DIC refers to widespread ischemic changes secondary to microvascular fibrin thrombi, which are
accompanied by consumption of platelets and coagulation factors and a hemorrhagic diathesis. DIC is a
serious, often fatal, disorder that typically occurs as a complication of many disease and conditions.
Causes of DIC include: infection, including gram-negative or gram-positive septicemia and viral,
fungal, rickettsial, or protozoal infection, obstetric complications, including abruption placentae, amniotic
fluid embolism, retained dead fetus, septic abortion, eclampsia, neoplastic disease, including acute
leukemia, metastatic carcinoma, aplastic anemia, disorders that produce necrosis, including extensive
burns and trauma, brain tissue destruction, transplant rejection, hepatic necrosis, other conditions,
including heatstroke, shock, poisonous snakebite, cirrhosis, fat embolism, incompatible blood transfusion,
cardiac arrest, surgery requiring cardiopulmonary bypass, giant hemangioma, severe venous thrombosis,
and purpura fulminans.
The phases
1. Activation of coagulation.
2. Thrombotic phase
3. Consumption phase
4. Secondary fibrinolysis
Pathogenesis
The triggering listed above initiate widespread activation of coagulation pathway. Hypoxemia and
acidemia develop, damaging the endothelial cells of the vasculature. Multiple endothelial cell injuries
initiate extensive activation of the platelets and the intrinsic coagulation pathway, leading to
microthrombi throughout the vascular system. Tissue damage, occurring as the precipitating event or after
hypoxia and acidemia, causes the production of thromboplastin, which activates the extrinsic coagulation
pathway. Clotting is extensive, with fibrin strands firming and holding the emboli.
As the coagulation cascades proceed, fibrinolytic processes (breaking down of fibrin strands) are
accelerated. These processes result in the release of anticoagulation enzymes into the circulation.
Eventually, clotting factors and platelets are used up and hemorrhage and oozing of blood into mucous
membranes occur. The loop is completed with bleeding and clotting occurring simultaneously.
Clinical Features
The symptoms of DIC reflect both microvascular thrombosis and a bleeding tendency. Ischemic
changes in the brain lead to seizures and coma. Depending on the severity of DIC, renal symptoms range
from mild azotemia to fulminant acute renal failure. Acute respiratory distress syndrome may supervene,
and acute gastrointestinal ulcers may bleed. The bleeding diathesis is evidenced by cerebral hemorrhage,
ecchymoses and hematuria. Patients with DIC are treated with (1) heparin anticoagulation to interrupt the
cycle of intravascular coagulation and (2) replacement of platelets and clotting factors to control the
bleeding.
THROMBOSIS.
Thrombosis (Greek thrombōsis - clotting) - intravital formation of blood clots in the
lumen of the blood vessels or heart cavities. This disorder is very common.
Causes of thrombosis:
- Physical
- Chemical
- Mechanical
- Biological
- Social
Conditions of occurrence of the thrombosis:
1. The strength of the stimulus.
2. Place of action.
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3. Duration of action.
4. The initial state of the organism at the time of action of the stimulus.
Three primary influences predispose to thrombus formation, the so-called Virchow triad:
1) endothelial injury;
2) stasis or turbulence of blood flow;
3) blood hypercoagulability.
Endothelial Lesion (“wall factor”)
The most common causes of endothelial injury.
Atherosclerotic lesion, hemodynamic stress associated with hypertension, bacterial endotoxins, virus
and immune complexes, some drugs may damage blood vessels by causing allergic reactions of type I or
type II. Even relatively subtle influences such as homocystinuria, hypercholesterolemia, radiation, or
products absorbed from cigarette smoke may be sources of endothelial injury and dysregulation.
Regardless of the cause, physical loss of endothelium leads to exposure of subendothelial collagen
(and other platelet activators), adherence of platelets, release of tissue factor, and local depletion of PGI2
and PA. Dysfunctional endothelium may elaborate greater amounts of procoagulant factors (e.g.,
adhesion molecules to bind platelets, tissue factor, PAI, etc.) and smaller amounts of anticoagulant
effectors (e.g., thrombomodulin, PGI2, t-PA).
Alterations in normal blood flow.
Normal blood flow is laminar such that the platelet elements flow centrally in the vessel lumen,
separated from the endothelium by a slower-moving clear zone of plasma.
Both high and lowrates of flow promote thrombosis.
Decelerated blood flow causes venous thrombosis.
Etiologic factors include:
— Widening of the vessels (varicose veins; );
— Increased hematocrit levels (as in desiccation);
— Increased viscosity (as in paraproteinemia);
— Vascular impingement (as in bedridden patients).
This leads to agglutination of erythrocytes and aggregation of thrombocytes. Stagnating blood
flowalso causes an oxygen deficit leading to endothelial injury.
Accelerated blood flow in combination with turbulence causes arterial thrombosis.
Etiologic factors include local vascular stenosis. This presses thrombocytes against the surface of the
endothelium, creating a platelet thrombus
Maelstrom in the blood flow. Etiologic factors include:
— Local widening of the vessel (such as an aneurysm);
— Impaired passage (such as calcified venous valves);
— Vascular bifurcations.
The resulting turbulence in the blood flow develops shear forces that can cause the endothelium to
separate from underlying tissue.
Hypercoagulability
Hypercoagulability generally contributes less frequently to thrombotic states but is nevertheless an
important (and interesting) component in the equation. It is loosely defined as any alteration of the
coagulation pathways that predisposes to thrombosis.
Laboratory evaluation of an underlying hypercoagulable state is warranted in persons who have
unexplained thrombotic episodes that show one or more of the following:
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Recurrence
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Development at a young age
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Family history of thrombotic episodes
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Thrombosis in unusual anatomical locations
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Difficulty in controlling with anticoagulants
Hypercoagulability can be divided into primary (genetic) and secondary (acquired) disorders.
The main mechanisms of hypercoagulatin
- Excessive activation of procoagulant and proaggregant factors
- Increased concentration of procoagulant and proaggregant factors in blood
- Decreased concentration or activity of anticoagulant and antiaggregant factors
- Decreased level or impaired activity of fibrinolytic factors.
Inherited Hypercoagulability
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Of the inherited causes of hypercoagulability, mutations in the factor V gene and prothrombin gene are
the most common. The characteristic alteration is a mutant factor Va that cannot be inactivated by protein
C; as a result, an important antithrombotic counter-regulatory pathway is lost.
Less common primary hypercoagulable states include inherited deficiencies of anticoagulants such as
antithrombin III, protein C, or protein S; affected patients typically present with venous thrombosis and
recurrent thromboembolism in adolescence or early adult life. The acquired disorders.
Although these hereditary disorders are uncommon, the basis of the thrombotic tendencies is
reasonably well understood. However, the pathogenesis of acquired thrombotic diatheses in a number of
common clinical settings is more complicated and multifactorial. In some of the acquired conditions (e.g.,
cardiac failure or trauma), factors such as stasis or vascular injury may be most important.
Among acquired causes (oral contraceptive use and the hyperestrogenic state of pregnancy),
hypercoagulability may be related to increased hepatic synthesis of coagulation factors and reduced
synthesis of antithrombin III. In disseminated cancers, release of procoagulant tumor products
predisposes to thrombosis. The hypercoagulability seen with advancing age may be due to increasing
platelet aggregation and reduced PGI2 release by endothelium. Smoking and obesity promote
hypercoagulability by unknown mechanisms.The so-called heparin-induced thrombocytopenia (HIT)
syndrome and antiphospholipid antibody syndrome (APS; previously called the lupus anticoagulant
syndrome) deserve special mention.
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HIT syndrome. This syndrome is estimated to affect 3% to 5% of the population; it occurs when
administration of unfractionated heparin (for purposes of therapeutic anticoagulation) induces circulating
antibodies that can bind to molecular complexes of heparin and a platelet membrane protein (platelet
factor 4). This antibody can then attach to similar complexes present on platelet and endothelial surfaces;
the result is platelet activation and endothelial cell injury, and a prothrombotic state. To circumvent this
problem, specially manufactured low-molecular-weight heparin preparations that retain anticoagulant
activity but do not interact with platelets (and have the additional advantage of a prolonged serum halflife) are used.
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APS. This syndrome refers to a number of heterogeneous clinical manifestations-including
recurrent thrombosis-associated with high titers of antibodies directed against anionic phospholipids (e.g.,
cardiolipin) or, more accurately, plasma protein antigens that are unveiled by binding to such
phospholipids. In vitro, these antibodies interfere with the assembly of phospholipid complexes and
inhibit coagulation (hence the designation lupus anticoagulant). In contrast, the antibodies in vivo induce
a hypercoagulable state. The exact incidence of the syndrome is unknown, although it is being
increasingly recognized as a possible culprit in a number of thrombotic states; for example, approximately
20% of patients with a recent stroke were found to have anticardiolipin antibodies, versus none in agematched controls without stroke.
Thrombocythemia
Thrombocythemia is an increase in the number of circulating platelets. Thrombocythemia is associated
with increased risk of thrombosis (clotting) in the vasculature.
Primary thrombocythemia may occur with malignancy, polycythemia vera, and other diseases of the
bone marrow. Secondary causes of thrombocythemia include acute infection, exercise, stress, and
ovulation. Secondary thrombocythemia caused by these conditions is usually short-lived. However,
prolonged secondary thrombocythemia may occur after removal of the spleen because this organ
normally stores some platelets until they are needed in the circulation. Inflammatory diseases such as
rheumatoid arthritis may also be associated with prolonged thrombocythemia
THE THROMBI
Thrombi may develop anywhere in the cardiovascular system: within the cardiac chambers, on valve
cusps, or in arteries, veins, or capillaries. They are of variable size and shape, depending on the site of
origin and the circumstances leading to their development.
Types of thrombi depending on the structure and appearance:
-white thrombi;
-red thrombi;
-mixed (layered) thrombi;
-hyaline thrombi.
White thrombi are composed of:
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-platelet;
-fibrin;
-leukocytes.
Are formed slowly during rapid blood stream (usually in the arteries).
Red thrombi are composed of:
- platelet;
- fibrin;
- contain a a large number of erythrocytes.
Are formed quickly during slow stream of blood (usually in the veins).
Mixed thrombi (occur more often):
Have a layered structure (layered thrombus) and mottled appearance, contain elements of both
white and red thrombus.
In the mixed thrombus distinguished:
- head (a structure of white thrombus);
- the body (actually the mixed thrombus);
- tail (a structure of red thrombus).
Hyaline thrombi are composed of:
- from the destroyed red blood cells;
- platelets;
- precipitating the plasma proteins;
- rarely contain fibrin.
Thrombotic mass similar to hyaline.
These thrombi are occur in the blood vessels of the microcirculatory bed.
Depending on the size of thrombus in the vessel lumen, distinguished:
-parietal thrombi;
-occlusive thrombi.
Рarietal thrombi often found:
-in the heart on the valve or parietal endocardium when inflammation (nonbacterial
thrombotic endocarditis);
-in the ears and between the trabeculae in chronic heart failure (heart disease, chronic
ischemic heart disease);
-in large arteries in atherosclerosis;
-the veins in their inflammation (thrombophlebitis), heart and vascular aneurysms.
Occlusive thrombi often formed:
-in veins and small arteries in the growth of parietal thrombus;
-less often - in the major arteries and the aorta.
Arterial or cardiac thrombi usually begin at a site of endothelial injury (e.g., atherosclerotic plaque) or
turbulence (vessel bifurcation); venous thrombi characteristically occur in sites of stasis.
Arterial thrombi are usually occlusive; the most common sites, in descending order, are coronary,
cerebral, and femoral arteries. The thrombus is usually superimposed on an atherosclerotic plaque,
although other forms of vascular injury (vasculitis, trauma) may be involved. The thrombi typically are
firmly adherent to the injured arterial wall and are gray-white and friable, composed of a tangled mesh of
platelets, fibrin, erythrocytes, and degenerating leukocytes.Arterial thrombosis due to atherosclerosis is
the most common cause of death in Western industrialized countries. Since most arterial thrombi occlude
the vessel, they often lead to ischemic necrosis of tissue supplied by that artery (i.e., an infarct). Thus,
thrombosis of a coronary or cerebral artery results in myocardial infarct (heart attack) or cerebral infarct
(stroke), respectively. Other end-arteries that are affected by atherosclerosis and often suffer thrombosis
include mesenteric arteries (intestinal infarction), renal arteries (kidney infarcts), and arteries of the leg
(gangrene).
Thrombosis in the Heart
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As in the arterial system, endocardial injury and changes in blood flow in the heart may lead to mural
thrombosis, i.e., a thrombus adhering to the underlying wall of the heart. The disorders in which mural
thrombosis occurs include: myocardial infarction, atrial fibrillation, cardiomyopathy, endocarditis.
The major complication of thrombi in any location in the heart is detachment of fragments and their
lodging in blood vessels at distant sites (embolization).
Venous thrombosis, or phlebothrombosis, is almost invariably occlusive; the thrombus often creates
a long cast of the vein lumen. Because these thrombi form in the slowly moving venous blood, they tend
to contain more enmeshed erythrocytes and are therefore known as red, or stasis thrombi.
Phlebothrombosis most commonly (90% of cases) affects the veins of the lower extremities. Less
commonly, venous thrombi may develop in the upper extremities, periprostatic plexus, or ovarian and
periuterine veins; under special circumstances they may be found in the dural sinuses, portal vein, or
hepatic vein.
Small thrombi in the calf veins are ordinarily asymptomatic, and even larger thrombi in the iliofemoral
system may cause no symptoms. Some patients have calf tenderness, often associated with forced
dorsiflexion of the foot. Occlusive thrombosis of femoral or iliac veins leads to severe congestion, edema,
and cyanosis of the lower extremity. In some cases, a filter is inserted into the vena cava to prevent
pulmonary embolization.
The function of venous valves is always impaired in a vein subjected to thrombosis and organization.
As a result, chronic deep venous insufficiency (i.e., impaired venous drainage) is virtually inevitable.
The outcome of thrombosis
If a patient survives the immediate effects of a thrombotic vascular obstruction, thrombi undergo some
combination of the following events in the ensuing days or weeks.
Favorable outcomes include:
-aseptic fibrinolysis of thrombus that occurs under the influence of proteolytic enzymes of
leukocytes;
-small thrombi are can completely subjected to aseptic autolysis;
-thrombi, especially large, are organized. Possible calcification of thrombus, its petrification in
the veins, in this case sometimes occur stones - flebolitys.
Adverse outcomes of thrombosis:
-formation of thromboembolus, which is the source of thromboembolism;
-septic meltdown of thrombus that occurs when pyogenic bacteria enter in the thrombotic mass
that lead to trombobacterial embolism of vessels of various organs and tissues (in sepsis).
Manifestations of occlusive thrombus depending on the location:
-thrombosis of the venous sinuses of the dura mater can lead to the disorder of cerebral
circulation;
-portal vein thrombosis - a portal hypertension and ascites;
-splenic vein thrombosis - a splenomegaly;
-thrombosis of renal vein - nephrotic syndrome or renal venous infarcts;
-mesenteric vein thrombosis - gangrene of the intestine;
-thrombophlebitis (phlebitis complicated by thrombosis) of the lower extremities,
phlebothrombosis (venous thrombosis) becomes a source of pulmonary embolism.
EMBOLISM
Embolism - typical pathological process caused by the presence and circulation in the
blood or lymph of particles, not meeting there in normal conditions, often causing the
occlusion (blockage) of the vessel to a subsequent breach of the local blood supply. Often
accompanied by a sudden vascular occlusion.
Types of embolisms in origin and nature of the embolus:
1) Exogenous:
-air embolism;
-gas embolism;
-drug embolism;
-embolism of by foreign bodies.
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2) Еndogenous:
-thromboembolism;
-embolism by fluids (amniotic fluid);
-fat embolism;
-tissue embolism;
-bacterial embolism;
-embolism by solid particles (tissue, microbes, parasites, foreign bodies).
Embolisms are also differentiated according to the underlying hemodynamic mechanism:
— Orthograde embolism (direct embolisms) is an embolism occurring in the direction of blood flow.
This is common. As the veins become wider in the direction of blood (except for the branches of the
portal vein), this type of embolism usually occurs in the arteries.
— Retrograde embolism is very rare. One example of such an embolism is an embolus of tumor cells
carried opposite to the direction of blood flow from the prevertebral venous plexus toward the spinal
column due to increased abdominal pressure.
— Crossed embolism (paradoxical embolism) is rare. Such embolism may occur in the presence of an
open foramen ovale or defect in the septum of the left atrium. Where the pressure in the right atrium also
greatly exceeds that of the left atrium (as in right heart insufficiency), an embolus from the pulmonary
vessels can pass into the extrapulmonary vessels.
Types of embolisms depending on the final stopping point emboli in the bloodstream:
1. Embolism of the systemic circulation.
2. Embolism of pulmonary circulation
3. Embolism of the portal vein system.
Thromboembolism
Thromboembolism is passage of thrombus material into the arterial or venous system. Venous
Thromboembolism (very common) This type of embolism usually occurs as a pulmonary embolism, less
often as a portal vein embolism.
Pulmonary Embolism is passage of thrombus material into the pulmonary veins, resulting in vascular
occlusion and life-threatening venous thrombosis.
Thrombogenetic factors:
— Weight: Obese patients are more often affected than slender patients.
— Gender: Men are twice as like to develop pulmonary embolisms as women.
— Age: Older patients are more often affected than younger patients.
— Meteorology: Passage of atmospheric fronts affects thromboembolism.
Location of source thrombus: The thrombus originates in veins of the thigh or pelvis in 90% of all
cases; in 10%, it originates in the deep veins of the calf or in the periprostatic or periuterine venous
plexus.
Dislodging factors of the source thrombus:
— Abrupt alternating dorsiflexion and plantar flexion of the foot acts as a pump and accelerates blood
flow in the calf.
— The inguinal ligament can cut off a red thrombus as the patient sits up in bed.
— Venous pressure is increased when the patient defecates and coughs.
— Fibrinolysis leads to thrombus loosening and fragmentation.
A small (peripheral) embolism,“Shrapnel” embolism, is brittles red thrombi that fragment upon
breaking free of the vessel wall or as they hits a vascular bifurcation. These fragments then occlude
central and peripheral pulmonary arteries.
A central and peripheral embolism, straddling embolism, is pliable laminated thrombi that straddle a
vascular bifurcation, occluding the trunk of the pulmonary artery of the entire outflow tract.
Complications of pulmonary embolism:
Acute cor pulmonale results where an embolism occludes more than 85% of the cross-section of the
pulmonary flow tract. Death occurs due to right heart failure.
Chronic cor pulmonale may occur secondary to massive pulmonary embolism with subtotal occlusion
of the central branches of the pulmonary artery or as a result of recurrent peripheral embolisms.
Pulmonary infarction: The lungs have a double vascular supply via the right heart and pulmonary
arteries and via the left heart and bronchial arteries. As a result, pulmonary infarction occurs only where
embolic occlusion of a branch of the pulmonary artery occurs in the presence of left heart insufficiency
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such as mitral stenosis. The slight residual flow through the bronchopulmonary anastomoses causes
extravasation of capillary blood in the walls of the dying alveoli. As a result, a pulmonary infarction is
almost always hemorrhagic (with few exceptions) and exhibits a characteristic wedge shape.
Fat Embolism.
Microscopic fat globules may be found in the circulation after fractures of long bones (which have
fatty marrows) or, rarely, in the setting of soft tissue trauma and burns. Presumably, the fat is released by
marrow or adipose tissue injury and enters the circulation by rupture of the marrow vascular sinusoids or
rupture of venules. Although traumatic fat embolism occurs in some 90% of individuals with severe
skeletal injuries, fewer than 10% of such patients show any clinical findings. Fat embolism syndrome is
characterized by pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia and is
fatal in about 10% of cases. Typically, the symptoms appear 1 to 3 days after injury, with sudden onset of
tachypnea, dyspnea, and tachycardia. Neurologic symptoms include irritability and restlessness, with
progression to delirium or coma.
The pathogenesis of this syndrome probably involves both mechanical obstruction and chemical
injury. While microemboli of neutral fat cause occlusion of pulmonary or cerebral microvasculature, free
fatty acids released from fat globules also cause local toxic injury to endothelium. A characteristic
petechial skin rash is related to rapid onset of thrombocytopenia, presumably caused by platelets adhering
to the myriad fat globules and being removed from the circulation.
Air Embolism.
Gas bubbles within the circulation can obstruct vascular flow (and cause distal ischemic injury) almost
as readily as thrombotic masses. Air may enter the circulation during obstetric procedures or as a
consequence of chest wall injury. Generally, in excess of 100 mL of air is required to produce a clinical
effect; the bubbles act like physical obstructions and may coalesce to form frothy masses sufficiently
large to occlude major vessels.
A particular form of gas embolism called decompression sickness occurs when individuals are
exposed to sudden changes in atmospheric pressure.
Amniotic Fluid Embolism.
Amniotic fluid embolism is a grave but fortunately uncommon complication of labor and the
immediate postpartum period. It has a mortality rate in excess of 80%, and as other obstetric
complications (e.g., eclampsia, pulmonary embolism) have been better controlled, amniotic fluid
embolism has become an important cause of maternal mortality. The onset is characterized by sudden
severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. If the patient survives
the initial crisis, pulmonary edema typically develops, along with (in half the patients) DIC, due to release
of thrombogenic substances from amniotic fluid.
The underlying cause is the infusion of amniotic fluid (and its contents) into the maternal circulation
via a tear in the placental membranes and rupture of uterine veins.
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