HEMOSTASIS AND THROMBOSIS
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, 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 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

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.
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

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.

Cardiopulmonary bypass: Platelet dysfunction due to platelet activation and fragmentation occurs in
the extracorporeal circuit during bypass surgery.

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.

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
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
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 is occlusion of the vascular or cardiac lumen by a thrombus, a fibrinous aggregate of
thrombocytes and/or clot occurring in vivo. This disorder is very common.
Having discussed the process of normal hemostasis, we can now turn our attention to the dysregulation
that underlies pathologic thrombus formation.
Three primary influences predispose to thrombus formation, the so-called Virchow triad: (1) endothelial
injury, (2) stasis or turbulence of blood flow, and (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:

Recurrence

Development at a young age

Family history of thrombotic episodes

Thrombosis in unusual anatomical locations

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
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.
 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 half-life) are used.
 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 age-matched 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 THROMBIThrombi 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. 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
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.
Fate of the Thrombus. 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:
 Propagation. The thrombus may accumulate more platelets and fibrin (propagate), eventually
obstructing some critical vessel.
 Embolization. Thrombi may dislodge and be transported to other sites in the vasculature.
 Dissolution. Thrombi may be removed by fibrinolytic activity.
 Organization and recanalization. Thrombi may induce inflammation and fibrosis (organization) and
may eventually become recanalized (re-establish vascular flow), or they may be incorporated into a
thickened vascular wall.
EMBOLISM
Embolism is process in which certain substances enter the bloodstream in larger vessels as coherent
bodies (emboli) and lodge in and occlude smaller vessels.
Several types of embolisms may be differentiated according to the material forming the embolus. In
descending order of incidence, these include:
— Thrombotic embolus;
— Fat embolus of plugs of fat or bone marrow;
— Air embolus of air bubbles or foam;
— Parasitic embolus of parasitic larvae;
— Bacterial embolus of fibrin-coated bacteria;
— Tumor embolus of fibrin-coated tumor cells
— Amniotic fluid embolus;
— Foreign body embolus, such as the tip of a venous catheter;
— Organ embolus, such as liver cells in ERCP.1
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.
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 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.