OVERVIEW OF COAGULATION

• Hemostasis depends on a system of checks and

balances between thrombosis and hemorrhage that
includes both procoagulants and anticoagulants
(vascular system, platelets, coagulation system, fibrinolytic
system, and inhibitors)
• fluidity is maintained by the anticoagulant,
profibrinolytic, and antiplatelet properties of the
normal endothelium.
• Coagulation is divided into two major systems:
• primary
• comprises platelet function and vasoconstriction.
• secondary
• involves coagulation proteins and a series of enzymatic reactions
Events Following Vascular Injury
1. Thromboresistant properties of a blood vessel
maintain blood in a fluid state.
2. After vascular injury, subendothelial components of
collagen induce platelet aggregation, which is
mediated by vWF and platelet receptor glycoprotein Ib.
3. Further platelet recruitment occurs as a result from
fibrinogen binding to its platelet receptor, glycoprotein
IIb/IIIa.
4. Tissue factor generates thrombin, which results in cross-
linked fibrin strands that reinforce the platelet plug.
5. Platelet actomyosin mediates clot retraction to compact
the platelet mass.
 SECONDARY HEMOSTASIS
• involves a series of blood protein reactions through a
cascade-like process that concludes with the formation
of an insoluble fibrin clot
• involves multiple enzymes and several cofactors as
well as inhibitors to keep the system in balance
• The initiation of clotting begins with the activation
of two enzymatic pathways that will ultimately lead to
fibrin formation:
• Intrinsic activation occurs by trauma within the vascular
system, such as exposed endothelium. This system is
slower and yet more important
• Extrinsic pathway is initiated by an external trauma, such as
a clot and occurs quickly.
Coagulation factors
1. The fibrinogen group: factors I, V, VIII, and XIII.
• They are consumed during coagulation. Factors V and VIII
are labile and will increase during pregnancy and
inflammation.
2. The prothrombin group: Factors II, VII, IX, and X
• all are dependent on vitamin K during their synthesis.
This group is stable and remains preserved in stored
plasma.
3. The contact group: Factor XI, factor XII, prekallikrein,
and high-molecular-weight kininogen (HMWK)
• are involved in the intrinsic pathway, moderately
stable, and not consumed during coagulation.
Factor I, Fibrinogen Component
Factor II, Prothrombin Factor X, Stuart-Prower
Factor III, Thromboplastin Factor XI, Plasma
Factor IV, Ionized Calcium Thromboplastin
Factor V, Proaccelerin or Antecedent
Labile Factor Factor XII, Hageman factor
Factor VI, Nonexistent Factor XIII, Fibrin
Factor VII, Proconvertin or Stabilizing Factor
High-Molecular-Weight Kininogen
Stable Factor
Prekallikrein, Fletcher Factor
Factor VIII, Antihemophilic
Factor IX, Plasma
Thromboplastin
Activated Partial Thromboplastin Time
• measures the intrinsic pathway
• It will detect abnormalities to factors VIII, IX, XI, and XII
QUANTITATIVE DISORDERS OF PLATELETS
• A normal platelet count is 150 to 450 109/L
• A decrease in platelet count will cause bleeding from the
mucous membranes such as gum bleeding (gingival
bleeding), nose bleeding (epistaxis), extensive bruising
(ecchymoses), or petechiae (pinpoint hemorrhages)
• platelet count 60,000: bleed in surgery
• platelet count 30,000: petechial bleeding
• At < 5,000 platelets: risk of bleeding into the CNS
• Decreased production of platelets or increased
destruction of platelets usually accounts for the
pathophysiology of most quantitative defects in
platelets.
Thrombocytopenia Related to Sample Integrity/Preanalytic
Variables
• Sample tubes must be at least 90% full and the
phlebotomy must be nontraumatic
• Platelet satellitism
• in vitro phenomenon in which the patient’s
platelets rosette around segmented neutrophils,
monocytes, and bands; occurs only in EDTA
Thrombocytopenia Related to Decreased Production
• Any condition that leads to bone marrow aplasia or
a lack of megakaryocytes
• leukemia
• blasts of any cellular origin
• megaloblastic anemias
• Cytotoxic agents or chemotherapy
• Infections
• viral agent (CMV, EBV, varicella, and rubella)
megakaryocytic suppression
• bacterial (direct toxicity of circulating platelets)
Thrombocytopenia Related to Altered Distribution of Platelets
• The normal spleen holds one third of the platelet
Volume
• myeloproliferative disorders, extramedullary
hematopoiesis, and hemolytic anemias
• massive transfusion
Thrombocytopenia Related to the Immune Effect of Specific
Drugs or Antibody Formation
• Drug-induced immune thrombocytopenia
• quinines, NSAIDs sulfonamides, and diuretics
• an antidrug antibody formation that binds to a
glycoprotein on the platelet surface and be removed by
the RES
• The drug combining with a larger carrier protein to
form an antigen that triggers an antibody response
and subsequent platelet destruction, potentially in
the spleen
• posttransfusion purpura (PTP),
• neonatal isoimmune thrombocytopenia,
Thrombocytopenia Related to Consumption of Platelets
• excessive clots are formed throughout the body,
which consume platelets
Idiopathic (Immune) Thrombocytopenic Purpura(ITP)
• Isolated thrombocytopenia
• normal bone marrow
• the absence of other causes
of thrombocytopenia

• a decreased platelet count

is thought to be a result of
immune destruction of platelets.
• In 66% of cases, the antibody is an autoantibody directed
against specific sites on glycoprotein(GP) IIb-IIIa or GP Ib-IX.
 Chronic and Acute Idiopathic Thrombocytopenic Purpura

Acute ITP Adults

Young children
History of No prior history
Age rubella,rubeola, or
Prior chickenpox
infection 30,000 - 80,000
Platelet < 20,000 Months to years
count 2 to 6 weeks
Steroids, splenectomy
Duration None
Therapy

Chronic ITP
 Thrombotic Thrombocytopenic Purpura (TTP)
• devastating platelet disorder which is acute and
nonpredictable
• More prevalent in women than in men
• can occur in women postpartum or near delivery in
those who have suffered from other immune disorders
like SLE, and in those with previous viral infections or gastric
carcinomas
• Platelet counts are < 20 x109/L but other coagulation testing
such as PT and PTT are within reference range
• Platelet thrombi are dispersed throughout the arterioles and
capillaries subsequent to the accumulation of large vWF
multimers made by the endothelial cells and platelets
• deficiency of ADAMTS-13 (a large metalloprotease responsible for
cleaving large vWF multimers into smaller proteins).
• Schistocytes are seen in the peripheral smear
• severe anemia with a high level of hemolysis, with
increased LDH
• Microangiopathic hemolytic anemia
• neurological complications (mild presentations of visual
impairment and intense headache ranging to more severe
presentations such as coma and paresthesias)
• Renal dysfunction (increased protein and possibly some blood
in the urine)
• a diagnosis of exclusion
• Corticosteroids are often used in conjunction with
plasma exchange (has dramatically improved the survival
rate from a low of 3% before 1960 to 82% presently)
von Willebrand’s Disease (vWD)
• The most important disease of platelet adhesion
• is the most prevalent inherited bleeding disorder
worldwide(affecting 1% to 3%)
• is an autosomal dominant disorder marked by easy
bruising, nosebleeds, heavy menses, and excessive
bleeding after tooth extraction or dental procedures
• The basic pathophysiology in vWD is a qualitative or
quantitative defect in vWF
• Type 1 disorders characterized by an abnormal bleeding
time and an increased PTT in most patients (70%)
• Type 2 vWD is the result of a qualitative defect of wVF
• Type 3, the rarest type, is characterized by a total
absence of vWF multimers and
is autosomal recessive
Treatment :
• DDAVP
• factor VIII
 THE CLASSIC HEMOPHILIAS
• Hemophilias represent any of a group of disorders in
which a particular clotting factor is decreased
• hemophilia A: factor VIII deficiency and
• hemophilia B: factor IX deficiency.
• are sex-linked recessive disorders
• Most clotting factors need to be available in the
body at a minimum of 30% to achieve hemostasis.
• There are three levels of clotting factor activity in
hemophilia:
• Severe, <1%
• Moderate, 1% to 5%
• Mild, 6% to 24%
• Patients with severe hemophilia A will manifest
early bleeding such as circumcisional bleeds or
umbilical cord bleeding
As they become more mobile, ordinary activities such as
crawling, walking, or running may present challenges
• bleeding continues for a longer period of time
• the most debilitating bleeds are muscle bleeds or joint
bleeds, which have the potential for causing long-term
disability, reduced range of motion, and intense pain
• Hemarthrosis
• Internal hemorrhages into the muscles and deep soft
tissues may compress and damage nerves
• Intracranial bleeding is a leading cause of death in
hemophilia A individuals
Laboratory Diagnosis
• bleeding time test is normal
• PT is normal
• aPTT is elevated, and
• factor assays: the % activity of a clotting factor
Treatment
• Cryoprecipitate (contains fibrinogen, factor VIII, and vWF)
• clotting factor products
• Approximately 80% to 90% of hemophilia A patients
treated with factor concentrates became infected with
the HIV virus.
• Gene therapy:
• to insert a copy of the factor VIII or factor IX gene into a
virus vector that will then lodge in the body and start
producing normal amounts of circulating factor
Hemophilia B or Christmas Disease
• lack factor IX
• clinical symptoms, laboratory diagnosis, and
complications are the same for severe hemophilia B
• have a prolonged aPTT and will have decreased factor
assay activity
• Treatment of hemophilia B consists of factor IX
concentrates or prothrombin complex that is a mixture
of factors II, VII, IX, and X.
 Hypercoagulable States
• Normal clot formation and clot dissolution is
accomplished by interaction among five major components:
• vascular system,
• platelets,
• coagulation system,
• fibrinolytic system, and
• inhibitors.
• Imbalance in any of the above components will tilt the
hemostatic scale in favor of bleeding or thrombosis.
• Pathological thrombosis includes
• deep venous thrombosis,
• arterial thrombosis, and
• pulmonary embolism
•
  Causes of hypercoagulability.
Acquired    
• Cancer   
• Inflammatory disorders: ulcerative colitis   
• Myeloproliferative disorders   
• Postoperative   
• Estrogens, pregnancy   
• Lupus anticoagulant   
• Heparin-induced thrombocytopenia  
•  Anticardiolipin antibodies   
• Paroxysmal nocturnal hemoglobinuria
Congenital    
• Antithrombin III deficiency   
• Factor V Leiden   
• Protein C deficiency   
• Protein S deficiency   
• Dysfibrinogenemia   
• Abnormal plasminogen   
• Activated protein C resistance
• Arterial thrombosis is primarily composed of platelets
with small amounts of fibrin and red and white cells
(“white clot.”)
• Factors causing arterial thrombosis are
• hypertension,
• hyper viscosity,
• qualitative platelet abnormalities, and
• atherosclerosis.
• Venous thrombosis is composed of large amounts of
fibrin and red cells.
• is associated with
• slow blood flow,
• activation of coagulation,
• impairment of the fibrinolytic system, and
• deficiency of physiological inhibitors.
• Hemostatic changes that are important in the
pathogenesis of thrombosis are
• vascular injury due to the toxic effect of chemotherapy;
• platelet abnormalities
• coagulation abnormalities,
• fibrinolytic defects, and
• deficiencies of the antithrombotic factors
• Antithrombin
• Heparin Cofactor II
• Protein C and Protein S
 Deep-Vein Thrombosis (DVT)
• is the result of occlusive clot formation in the veins
• has an estimated annual incidence of 67/100 000
among the general populations.
• mainly in the deep veins of the leg
• symptoms of venous thrombosis are nonspecific
• risk factors: related either to immobilization or to
hypercoagulability
• tends to recur
• incidence of a first venous thrombosis is 1–3/1000
persons/year.
• ~2/3rd manifest as DVT of the leg, and 1/3rd as PE.
Diagnosis
• Imaging tests
• Compression ultrasonography is the imaging test of choice
• Lack of compressibility of a venous segment
• Doppler (including color flow)
• sensitivity
• Proximal veins (97%)
• Calf veins (73%)
• Clinical prediction rules
• D-dimer testing
• Venography
• invasive nature
• technical demands
• costs
• potential risks
• allergic reactions and
• renal dysfunction
 Clinical model for predicting pretest probability of DVT*
Clinical characteristic† Score
• Active cancer (treatment ongoing, administered within
previous 6 mo or palliative) 1
• Paralysis, paresis or recent plaster immobilization of the
lower extremities 1
• Recently bedridden > 3 d or major surgery within
previous 12 wk requiring general or regional anesthesia 1
• Localized tenderness along the distribution of the deep
venous system 1
• Swelling of entire leg 1
• Calf swelling > 3 cm larger than asymptomatic side
(measured 10 cm below tibial tuberosity) 1
• Pitting edema confined to the symptomatic leg 1
• Collateral superficial veins (nonvaricose) 1
• Previously documented DVT 1
• Alternative diagnosis at least as likely as DVT —2
*A score of 2 or higher indicates that the probability of DVT is “likely”; a score of less than 2 indicates that the probability is “unlikely.”
†In patients who have symptoms in both legs, the more symptomatic leg is used.
Treatment
• goal of the therapy
• lower-extremity DVT is to prevent the extension of
thrombus and pulmonary embolism
• the short-term and to prevent recurrent events in the
long-term.
• Initial anticoagulation
• LMW heparin once 1-2x/d for 5–7 days followed by
warfarin
• Unfractionated heparin given IV is an alternative
• warfarin can be safely started at the same day
(INR target: 2.5 range 2–3)
• duration of treatment: 3-12m
 Hematological manifestation of HIV
• Persistent Generalized Lymphadenopathy (PGL)
• enlarged lymph nodes (>1 cm) in two or more
extrainguinal sites for >3 months without an obvious cause
• due to marked follicular hyperplasia in the node in response
to HIV infection
• at any point in the spectrum of immune dysfunction
• Anemia
• is the most common hematologic abnormality in HIV-
infected patients
• in the absence of a specific treatable cause is independently
associated with a poor prognosis
• causes: drug toxicity, systemic fungal and mycobacterial
infections, nutritional deficiencies, and parvovirus B19
infections
• neutropenia
• in approximately half of patients
• most frequent in patients with severely advanced HIV disease
and in myelosuppressive therapies
• Thrombocytopenia
• ~ 3% of untreated HIV infection + CD4+ T cell counts ≥400/μL
have platelet counts <150,000/L.
• untreated + CD4+ T cell counts <400/μL, incidence increases
to 10%.
• venous thrombotic events (5%)
• deep vein thrombosis
• pulmonary embolism
• factors associated with clinical thrombosis
• are age over 45,
• history of an opportunistic infection
• estrogen use.
• Abnormalities of the coagulation cascade
• decreased protein S activity,
• increases in factor VIII, and
• the presence of anticardiolipin antibodies
• malignancies
• Kaposi's sarcoma
• HHV-8 or KSHV has been strongly implicated
• Lymphomas
• at least 6% of all patients with AIDS (120-fold increase in
incidence )
• is a late manifestation of HIV infection, generally occurring in
patients with CD4+ T cell counts <200/L
• grade III or IV immunoblastic lymphoma
• Burkitt's lymphoma
• primary CNS lymphoma