This document discusses hemostasis and disorders of hemostasis. It begins by describing the normal hemostatic system, including primary hemostasis involving platelet plug formation and secondary hemostasis involving the coagulation cascade. It then discusses disorders that can cause a tendency for thrombosis or bleeding. Specific platelet, coagulation, and fibrinolytic disorders are outlined, along with evaluation and treatment approaches. Laboratory tests for evaluation of hemostasis and specific coagulation defects are also summarized.

1. BLEEDING AND THROMBOSIS
! Vessel wall , blood platelets and plasma proteins
! Normal hemostatic system = balance between thrombosis and bleeding
! Tendency for thrombosis :
1. immobilized after surgery
2. chronic heart failure
3. atherosclerotic vascular disease
4. malignancy
5. pregnancy
! Patient’s history : mode of onset, sites of bleeding, family bleeding
tendency, drug ingestion
! Physical examination : bleeding in the skin or joint deformities ( due to
previous hemarthroses )
! General screening test " more specific test ( immunologic, functional or
genetic tests )
! Hypercoagulable or prothrombotic pt :
a. repeated episodes of thromboembolism without an obvious
predisposing condition
b. family history of thrombosis
c. thromboembolism in the adolescent and young adults
NORMAL HEMOSTASIS
! trauma, disease or surgery " disrupts the vascular subendothelium
connective tissue
! Primary hemostasis : platelet plug formation ; within seconds , capillaries,
small arterioles and venules
! Secondary hemostasis
# plasma coagulation system
# result in fibrin formation
# several minutes ; strengthens the primary hemostatic plug
# larger vessels
# lasts for hours or days
! Primary and secondary hemostasis are closely linked
! Activated platelets accelerate plasma coagulation reaction and thrombin
induce platelet activation

2. Figure 53-2
PRIMARY HEMOSTASIS
! A) Platelet activation and adhesion, B) aggregation, and C) granule release
! Platelets adhere to collagen fibrils in vascular subendothelium via
(Gp) /Ia/IIa and GpVI ( see figure 53-2 )
! GpVI binding " binds collagen " activates platelet via the Fc receptor
gamma ( FcRγ) .
! Von Willebrand factor ( vWF) – an adhesive glycoprotein allow the platelets
to remained attached to the vessel wall by forming a link between the
platelet receptor Gp Ib/IX and collagen fibrils
! Activated platelets " release preformed granules with mediators ( Fig 53-1)
( Fig 53-1)
! Platelet activation and secretion regulated by : changes in cyclic
nucleotides, influx of calcium, hydrolysis of membrane phospholipids and
phosphorylation of critical intracellular proteins
Prothombotic mechanism :
! Binding of agonists ( epinephrine, collagen or thrombin ) to the platelet
surface receptors " activates membrane enzymes ( phospholipase C
and phospholipase A2 ) " (+) release Arachidonic Acid (AA) from the
membrane phospholipids (phospatidylinositol and phospahatidylcholine)
! AA" Thromboxane A2 via the cyclooxygenase " ( +) phospholipase C

3. ! Generation of thromboxane A2 in platelets and prostacyclin ( PGI2) in
endothelial cells
! Four receptors for platelet adhesion:
o Gp Ib/IX " binds to vWF
o Gp IIb/IIIb " binds to fibrinogen
o Gp Ia/ IIa and Gp VI " binds to collagen
Platelet Granule release ( See Fig 53- 1 ) :
! Platelets secrete their granules in the plasma
! Endoglycosidase and Heparin cleaving enzymes
! vWF, fibronectin, thrombospondin, platelet derived growth factor ( PDGF)
and heparin neutralizing factor ( platelet factor 4) : released form α
granules
! released ADP binds to purigenic receptors and changes the conformation
of Gp IIb/IIIa " binds to fibrinogen " linking other platelets" hemostatic
plug
! P2Y12 – principal activating receptor on the platelet
! PDGF " (+) growth and migration of fibroblast and smooth muscle cells
within the vessel wall ( repair process )
Antithrombotic mechanism :
! Prostacylin - from the endothelium , inhibits platelet activation via
increase in the intraplatelet cAMP
! Endothelium " ecto-ADPase " hydrolyse the agonist platelet ADP

4. COAGULATION REACTIONS / CASCADE
Intrinsic ( vascular ) pathway : factors 12 (Hageman )! 11! 9 + 8 ! 10
Extrinsic (tissue ) pathway : factors 7! 10
Common pathway : factors 10 !5 ! 2 ! 1 ( thrombin ) ! 13 !fibrin
NOTE :” Factors “ should be in “ Roman numerals “ but the above numbers were made just for memory work only
Classic Four Reactions : Figure 53-7
REACTION 1 ( INTRINSIC OR CONTACT PHASE )
! 3 plasma CHONs forms a complex : Hageman factor (factor XII), high molecular
kininogen (HMWK) and prekalikrein (PK) " bind to subendothelial collagen " Factor
XII " XIIa" activates XIa
REACTION 2 ( EXTRINSIC )
! Complex : Factor VII + Ca + Tissue factor " major way to initiate coagulation
! Require calcium and Vitamin K : Factors II (prothrombin),IX, X (formed by the liver ) "
inhibited by Vitamin K antagonist ( warfarin )
REACTION 3 ( COMMON )
! Merging and interaction of the intrinsic and the extrinsic pathway
! Factor VIIa" X and IX
! Factor XIa" IX
! Factor X + VIIIa + IX
REACTON 4 ( FINAL STEP)
! Prothrombin (PT) ( with Factor Va + Ca )" thrombin
! Thrombin : fibrinogen " fibrin ( major role) , (+) platelet aggregation and secretion ,
factors V, VII and XIII
CLOT LYSIS / FIBRINOLYTIC PROCESS AND REPAIR
! Activators : Hageman factor fragments , urinary plasminogen activator
( uPA), or urokinase and tissue plasminogen activator ( tPA)

5. ! tPA and uPA ( endothelial cells) " binds with plasminogen " complex "
plasmin" lyses the clot/ fibrin polymer into small fragments and also
cause localized degradation of fibrin " cleared by the monocyte /
macrophage system
! Plasmin " binds to α2 plasmin inhibitor ( lack of this will cause excessive
bleeding due to unchecked fibrinolysis )
! (PAI) 1 – from the endothelium blocks the activation of tPA ;prothrombotic
HEMOSTATIC PLUG – does not propagate beyond the site of injury
REGULATORY FACTORS
! reduce the enzymes and cofactors and reduce reaction rates :
antithrombin , protein C and S , Tissue factor platelet inhibitor (TFPI )
! ANTITHROMBIN – forms complexes with coagulation factors Except
Factor VII ; Heparin accelerates heparin activity
! Protein C – converted to thrombomodulin ; inactivates factors V and VIII
and slows coagulation reactions; (+) release of tPA from endothelial cells
! Protein S – enhances protein C
! Reduced Protein C ,S and antithrombin" hypercoagulabe state
! Factor V (Leiden ) " resistant to protein C inhibition" 20-50% of
unexplained thromboembolism
! Red thrombi : veins ; slow blood flow, rich in fibrins and RBC; leg veins "
embolize to the pulmonary circulation
! White thrombi : arteries ; high blood flow ; rich in platelets ; little fibrin ;
emboli " occlusion of arteries like TIA and Stroke ( cerebral arteries ),

6. Amaurosis fugax ( retinal arteries ) , myocardial infarction ( coronary
arteries )
HISTORY :
! History of bleeding ( minor surgery, dental extraction , childbirth), family
history , multiple sites bleeding; warrants blood transfusion
PHYSICAL EXAMINATION
! Skin and mucous membranes ( most common )
! Purpura- collection of blood under the skin
! Petechiae – platelet disorder ( thrombocytopenia ) ; dermis, capillaries,
pinpoint lesions
! Echymoses – subcutaneous, small arterioles and venules; common
bruises
! Hematomas – deeper and palpable, platelet disorders and minor trauma
! Telangiectasia – dilated capillaries
! Senile purpura – loss of connective tissue support for the capillaries and
small veins; subcutaneous
! Menorrhagia – women; thrombocytopenia and thrombocytopathia
! Von Willebrand disease - GI Hge +/- angiodyplasia
! Bleeding into body cavities, retroperitoneum or joints : plasma coagulation
defects
! Joint deformities due to synovial thickening, erosions of the articular
cartilage, chronic inflammation and fluid collections : Deficiencies of
Factors VIII and IX (sex-linked , hemophilias)
! Femoral nerve compression – retroperitoneal hematomas causing
compression
! Pseudotumor syndrome – mimic malignant tumors ; soft tissue
accumulations
! Intracerebral Hge – most common cause of death of severe coagulation
disorders

7. ! HIV infection – due to infection form frequent blood transfusions and blood
products transfusions ; HIV also induces decreased platelet count and
bleeding
LAB TEST :
! Screening tests :
a. Bleeding time ( BT ) – measures platelet function
b. Platelet count- correlates with tendency to bleed ; normal = 150,000
to 450,000/ µl of blood
! 50,000 - 100,000 "mild prolonged BT ; < 50,000 " easy bruising,
purpura, mucosal bleeding, < 20,000 " spontaneous bleeding, internal or
intracranial bleed
! Partial thromboplastin time ( PTT ) – checks the plasma coagulation
function ;screens the intrinsic pathway; used in heparin infusion monitoring
! Prothrombin time – assess Factors II, IX, X ; screens the extrinsic or
tissue factor- dependent pathway ; used in warfarin monitoring
! Thrombin time (TT) or clotting fibrinogen level " if PT and PTT are
prolonged
! Specific coagulation factors assay

8. Table 53- 5 THROMBOTIC DISORDERS
INHERITED
Defective inhibition of coagulation factors
Factor V Leiden ( resistant to inhibition to protein C )
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Prothrombin gene mutation
Impaired clot lysis
Dysfibrinogenemia
Plasminogen deficiency
tPA deficiency
PAI-1 excess
Uncertain mechanism
Homocystinuria- ? endothelial damage
ACQUIRED
Diseases or syndromes
Lupus anticoagulant/ anticardiolipin antibody syndrome
Malignancy
Myeloproliferative disorders
Thrombotic thrombocytopenia
Estrogen treatment
Hyperlipidemia
DM
Hyperviscosity syndrome (e.g. polycythemia vera , Eisenmengerization in
congenital heart diseases )
Nephrotic syndrome
Congestive heart failure
Paroxysmal nocturnal hemoglobinuria
Physiologic states
Pregnancy ( especially postpartum )
Obesity
Postoperative state
Immobilization
Old age
DISORDERS OF PLATELET AND VESSEL WALL
• usually bleed into superficial sites such as the skin, mucous membranes, or
genitourinary or gastrointestinal tract
• responds to simple measures, such as pressure and packing, or requires
systemic therapy with glucocorticoids, desmopressin, plasma fractions, or
platelet concentrates.
• Most common vessel wall disorders :
(1) various forms of thrombocytopenia,
(2) von Willebrand’s disease (vWD), and

9. (3) drug-induced platelet dysfunction
PLATELET DISORDERS
• from the fragmentation of megakaryocytes, which are very large, polyploid
bone marrow cells produced by the process of endomitosis
• From marrow space, about one-third of the platelets are sequestered in
the spleen, while the other two-thirds circulate for 7 to 10 days
• Small fraction used in hemostasis" usually grow old in the circulation "
removed by the phagocytes
• normal blood platelet count : 150,000 to 450,000/_L.
• decrease in platelet count stimulates an increase in the number, size, and
ploidy of megakaryocytes, releasing additional platelets into the circulation
• reduction in platelet count increases the level of free TPO and thereby
stimulates megakaryocyte and platelet production.
• platelet count varies during the menstrual cycle, rising following ovulation
and falling at the onset of menses
• decreased in severe iron, folic acid, or vitamin B12 deficiency
• are acute phase reactants ;
• systemic inflammation, tumors, bleeding, and mild iron deficiency may
have an increased platelet count, a benign condition called secondary, or
reactive, thrombocytosis
• cytokines interleukin (IL) 3, IL-6, and IL-11 may stimulate platelet
production in acute inflammation
• myeloproliferative disorders such as polycythemia vera, chronic myeloid
leukemia, myeloid metaplasia, and essential thrombocytosis can be much
higher and cause either severe bleeding or thrombosis
Thrombocytopenia
• caused by one of three mechanisms—decreased bone marrow
production, increased splenic sequestration, or accelerated destruction of
platelets.
• examination of the peripheral blood film, an assessment of marrow
morphology by examination of an aspirate or biopsy, and an estimate of
splenic size by bedside palpation supplemented, if necessary,
by ultrasonography or computed tomography (CT)
• “Pseudothrombocytopenia,” a benign condition in which platelets
agglutinate or adhere to leukocytes when blood is collected with EDTA as
anticoagulant.

10. IMPAIRED PRODUCTION
• injure stem cells or prevent their proliferation
• varying degrees of anemia and leucopenia
• most common causes of decreased platelet production are marrow
aplasia, fibrosis, or infiltration with malignant cells, all of which produce
highly characteristic marrow abnormalities
• Cytotoxic drugs impair megakaryocyte proliferation
and maturation
• congenital amegakaryocytic hypoplasia and thrombocytopenia with absent
radii (TAR syndrome), produce a selective decrease in megakaryocyte
production
SPLENIC SEQUESTRATION
• one-third of the platelet mass is normally sequestered in the spleen,
splenectomy will increase the platelet count by 30%.
• Postsplenectomy thrombocytosis is a benign self-limited condition that
does not require specific therapy
• spleen enlarges, the fraction of sequestered platelets increases, lowering
the platelet count.
• most common causes of splenomegaly are portal hypertension secondary
to liver disease and splenic infiltration with tumor cells in
myeloproliferative or lymphoproliferative disorders

11. • leukemia, lymphoma, or a myeloproliferative syndrome have both marrow
infiltration and splenomegaly and develop thrombocytopenia from a
combination of impaired marrow production and splenic sequestration of
platelets
ACCELERATED DESTRUCTION
• Abnormal vessels, fibrin thrombi, and intravascular prostheses can all
shorten platelet survival and cause nonimmunologic thrombocytopenia.
• vasculitis, the hemolytic uremic syndrome (HUS), thrombotic
thrombocytopenic purpura (TTP), or as a manifestation of disseminated
intravascular coagulation (DIC).
• platelets coated with antibody, immune complexes, or complement are
rapidly cleared by mononuclear phagocytes in the spleen or other tissues,
inducing immunologic thrombocytopenia.
• viral or bacterial infections, drugs (often heparin), and a chronic
autoimmune disorder referred to as idiopathic thrombocytopenic purpura
(ITP)
• Immunologic thrombocytopenia : do not usually have splenomegaly and
have an increased number of bone marrow megakaryocytes.
DRUG INDUCED THROMBOCYTOPENIA
• Cancer chemotherapeutic agents may depress megakaryocyte production
• large quantities of alcohol has a marrow-depressing effect
• Thiazide diuretics impair megakaryocyte production and can produce mild
thrombocytopenia (50,000 to100,000/_L), which may persist for several
months after the drug is discontinued
• complement activation following the formation of drug antibody complexes
prompt rise in the platelet count when the suspected drug is discontinued
• most patients recover within 7 to 10 days and do not require therapy,
occasional patients with platelet counts _10,000 to 20,000/_L have severe
hemorrhage and may require temporary support
with glucocorticoids, plasmapheresis, or platelet transfusions
• avoid the offending drug in the future
• cleared from body storage depots quite slowly, such as phenytoin, may
induce prolonged thrombocytopenia

12. HEPARIN
• Between 10and 15% of patients receiving therapeutic doses " (heparin-
induced thrombocytopenia, HIT) "severe bleeding or intravascular
platelet aggregation and paradoxical thrombosis
• “white clot syndrome,” : can be fatal
• directly agglutinating platelets (type I HIT). The more serious form (type II
HIT) results from an immune reaction " complex formed between heparin
and the platelet-derived heparin-neutralizing protein, platelet factor 4.
• heparin–PF-4 antibody complexes " bind to platelet Fc receptor and
induce platelet activation and secretion.
• May use low molecular weight heparin LMWH " to avoid HIT however
80to 90% of the antibodies generated against conventional heparins
cross-react with low-molecular-weight heparins
• Argatroban is the current drug of choice
IDIOPATHIC THROMBOCYTOPENIC PURPURA
• following recovery from a viral exanthem or upper respiratory illness
(acute ITP) is common in children ( rare in adults ) and accounts for 90%
of the pediatric cases of immunologic thrombocytopenia
• 60% recover in 4 to 6 weeks and _90% recover within 3 to 6 months.
• infectious mononucleosis, acute toxoplasmosis, or cytomegalovirus
infection
• caused by immune complexes containing viral antigens that bind to
platelet Fc receptors or by antibodies produced against viral antigens that
cross-react with the platelet.

13. • differential diagnosis ( needs bone marrow exam ) includes atypical
presentations of aplastic anemia, acute leukemia or metastatic tumor.
• Chronic ITP. : indolent ; years : Women age 20 to 40 ; 3:1 M/F ratio
• abrupt fall in platelet count and bleeding ; history of easy bruising or
menometrorrhagia.
• autoimmune disorder with antibodies directed against target antigens on
the glycoprotein (Gp) IIb/IIIa or, less frequently, the Gp Ib/IX complex
• may be the initial manifestation of systemic lupus erythematosus (SLE) or
the first sign of a primary hematologic disorder
• should have a bone marrow examination and an antinuclear antibody
determination
• hepatic or splenic enlargement, lymphadenopathy, or atypical
lymphocytes should have serologic studies for hepatitis viruses,
cytomegalovirus, Epstein-Barr virus, Toxoplasma, and HIV.
TREATMENT :
• adults have a higher incidence of intracranial bleeding than children,
specific therapy may not be necessary unless the platelet count is
< 20,000/µL or there is extensive bleeding " intracranial bleeding
• glucocorticoids
• may require temporary phagocytic blockade with intravenous
immunoglobulin (IVIg) or anti-RhD
(WinRho)
• Emergency splenectomy : desperately ill and have not responded to any
medical measures
• IVIg and anti-RhD are only transiently effective and expensive. IVIg can
cause meningismus and headache, and some lots have carried
hepatitis C virus.
• Anti-RhD can cause hemolysis. These drugs should be used to raise the
platelet count temporarily and to support patients before surgery or
labor and delivery; they are not substitutes for splenectomy.
• Rituximab, an anti-CD20 monoclonal antibody used to treat lymphoma,
has also proven an effective approach to ITP and is probably
preferable to long-term glucocorticoid therapy. ; eliminates normal
B cells, including those producing the antiplatelet antibody. This B
cell depletion is transient (lasting 12 to 18 months, normally) and
has surprisingly few side effects or toxicities
FUNCTIONAL PLATELET DISORDERS
• three critical platelet reactions—adhesion, aggregation, and granule
release

14. von Willebrand’s Disease
• most common inherited bleeding disorder, occurring in 1 in 100 to 500
individuals
• heterogeneous multimeric plasma glycoprotein with two major functions: (1)
It facilitates platelet adhesion under conditions of high shear stress by
linking platelet membrane receptors to vascular subendothelium; and (2) it
serves as the plasma carrier for factor VIII, the antihemophilic factor, a
critical blood coagulation protein.
• normal plasma vWF level is 10 mg/L.
• single large vWF precursor subunit is synthesized in endothelial cells and
megakaryocytes, where it is cleaved and assembled into the disulfide-
linked multimers present in plasma, platelets, and vascular subendothelium
• autosomal dominant traits, and affected patients are heterozygous with one
normal and one abnormal vWF allele
Lab :
• prolonged bleeding time , a reduction in plasma vWF concentration,, a
parallel reduction in biologic activity as measured with the ristocetin,
cofactor assay, and reduced factor VIII activity
• mild defects may have laboratory values that fluctuate over time and may
occasionally be within the normal range
Three major types of vWD.
A. type I disease, the most common abnormality, have a mild to moderate
decrease in plasma vWF. In the milder cases, although hemostasis is
impaired, the vWF level is just below normal (50% activity, or 5 mg/L). In
type I disease, vWF antigen, factor VIII activity, and ristocetin cofactor
activity are decreased with a normal spectrum of multimers detected by
sodium dodecyl sulfate (SDS)–agarose gel electrophoresis.
B. Type II disease) : less common and characterized by normal or near-
normal levels of a dysfunctional protein
C. Type III disease). Type III very severe form of vWD phenotypically
recessive patients are usually the offspring of two parents (usually

15. asymptomatic) with mild type I disease.
Treatment
1. oral contraceptive agents that suppress menses.
2. Desmopressin- a vasopressin analogue that has minimal blood pressure–
elevating and fluid-retaining properties and raises the plasma vWF level in
both normal individuals and patients with mild vWD ; esp. Type 1 ; may
develop tachypylaxis; may worsen Type IIa ; ineffective on Type III
ACQUIRED vWF
• antibodies that inhibit vWF function or by lymphoid or other tumors that
selectively adsorb vWF multimers onto their surfaces.
• Anti-vWF antibodies following multiple transfusions, as well as in patients
with autoimmune and lymphoproliferative disorders
Platelet Membrane Defects
• two major platelet surface glycoproteins. vWF facilitates platelet adhesion
by binding to Gp Ib/IX,while fibrinogen links platelets into aggregates via
sites on the Gp IIb/ IIIa complex.
• Bernard-Soulier syndrome have markedly reduced platelet adhesion and
cannot bind vWF to their platelets due to deficiency or dysfunction of the
Gp Ib/ IX complex. reduced levels of another membrane protein (GpV that
associates with Gp Ib/II), mild thrombocytopenia, and extremely large,
lymphocytoid platelets; autosomal recessive traits ; platelets react
normally to all stimuli except ristocetin.
• Glanzmann’s disease, or thrombasthenia, are deficient or defective in the
Gp IIb/IIIa complex. Their platelets do not bind fibrinogen and cannot form
aggregates, although the platelets undergo shape change and secretion
and are of normal size; autosomal recessive traits
• markedly impair hemostasis, leading to recurrent episodes of severe
mucosal hemorrhage
• In contrast , thrombasthenic platelets adhere normally and will agglutinate
with ristocetin but will not aggregate with any of the agonists that require
fibrinogen binding, such as adenosine diphosphate (ADP), thrombin, or
epinephrine
• Treatment : transfusion with normal platelets" Alloimmunization
(developed inhibitor antibodies )
Platelet Release Defects
• most common mild bleeding disorders arise from the ingestion of aspirin
and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit
platelet production of thromboxane A2, (mediator of platelet secretion and
aggregation) " inhibit cyclooxygenase (COX) which converts arachidonic
acid to a labile endoperoxide intermediate that is critical for thromboxane
formation
• Aspirin - irreversibly acetylates the platelet enzyme so that a single dose

16. impairs hemostasis for 5 to 7 days. " partially inhibits platelet release and
aggregation with weak agonists, such as ADP and epinephrine, and
produces a mild hemostatic defect.
• COX-1, which is constitutively expressed and active in the normal platelet,
and COX-2, which is induced, especially in inflamed tissue.
• COX 2 – arthritis and pain ; long-acting reversible inhibitors that have no
adverse effects on platelet function ; chronic use may be associated with
high blood pressure and risk of thrombosis
• Penicillin ( high doses ), can coat the platelet surface, block platelet
release, and impair hemostasis.
• release defects generally have minimal symptoms such as easy bruising,
and bleeding is usually confined to the skin " prolonged oozing after
surgery ( especially mucosal )
• Platelet responses to collagen and thrombin are impaired at low doses but
normal at higher doses
• Uremic platelet dysfunction : clinically the most important. Mechanism :
not well understood; retention of phenolic and guanidinosuccinic acids,
excess prostacyclin production, or impaired vWF-platelet interactions ;
degree of uremia correlates with bleeding symptoms and anemia "
usually be reversed by dialysis and often improves after red cell
transfusion or treatment with erythropoietin ; factor VIII concentrate or
desmopressin, both of which raise plasma vWF levels, can also improve
hemostasis ; Conjugated estrogens improve hemostasis and can be used
as long-term therapy
Storage Pool Defects
• Platelet granules have considerable amounts of adenine nucleotides,
calcium, and adhesive glycoproteins such as thrombospondin, fibronectin,
and vWF, all of which promote platelet adhesion and aggregation.
• may be inherited as an isolated disorder or be part of systemic granule
packaging defects such as oculocutaneous albinism or the Hermansky-
Pudlak or Che´diak-Higashi syndromes
• cannot be distinguished from those with other functional platelet disorders,
since they all have easy bruising, mucosal bleeding, and a prolonged
bleeding time
• will usually aggregate in response to arachidonic acid in contrast to COX
defects
• decreased levels of specific granule constituents such as ADP and
serotonin and abnormalities in granule morphology that are best visualized
by electron microscopy
• acute or chronic leukemia or one of the myeloproliferative disorders
develop an acquired storage pool disorder due to dysplastic
megakaryocyte development
• liver disease and some patients with SLE or other immune complex–
mediated disorders may have circulating platelets that have degranulated

17. prematurely ; after prolonged cardiopulmonary bypass
• only mildly impaired hemostasis. " treated with platelet transfusion and
occasionally desmopressin
VESSEL WALL DISORDERS
• or nonthrombocytopenic purpura
• usually mild and confined to the skin and mucous membranes.
• bleeding time and tests of platelet function, are usually normal
• damage to capillary endothelium, abnormalities in the vascular
subendothelial matrix or extravascular connective tissues that support
blood vessels, or from the formation of abnormal blood vessels
THROMBOTIC THROMBOCYTOPENIC PURPURA
• fulminant, often lethal disorder that may be initiated by endothelial injury
and subsequent release of vWF and other procoagulant materials from the
endothelial cell.
• pregnancy, metastatic cancer, mitomycin C, high dose chemotherapy, HIV
infection, and certain drugs, such as the antiplatelet agent ticlopidine
• microvascular deposition of hyaline fibrin thrombi, thrombocytopenia,
microangiopathic hemolytic anemia, fever, renal failure, fluctuating levels
of consciousness, and evanescent focal neurologic deficits
• hyaline thrombi in arterioles, capillaries, and venules without any
inflammatory changes in the vessel wall is diagnostic
• severe Coombs-negative hemolytic anemia with schistocytes or
fragmented red blood cells in the peripheral blood smear, coupled with
thrombocytopenia, and minimal activation of the coagulation system
• Differential diagnosis : vasculitis and SLE " Platelet-associated IgG and
complement levels are usually normal in TTP

18. • Hemolytic anemia with fragmentation of erythrocytes and signs of
intravascular hemolysis, thrombocytopenia, diffuse and nonfocal
neurologic findings, decreased renal function, and fever
• neurologic and renal symptoms are usually seen only when the platelet
count is markedly diminished (< 20 to 30 X 103
/µL).
• Neurologic symptoms develop in > 90% of patients whose disease
terminates in death
• If the coagulation tests indicate major consumption of clotting factors, the
diagnosis of TTP is doubtful. A positive antinuclear antibody (ANA)
determination is obtained in < 20% of patients
• due to a deficiency in the activity of a specific metalloproteinase called
ADAMTS 13, a normal plasma constituent that cleaves the ultra-high-
molecular-weight (UHMW) forms of vWF secreted by endothelial cells to
yield the heterogeneous set of multimers normally present in plasma
• recurrent episodes of a TTP-like illness (Upshaw-Schulman syndrome)
and are deficient in ADAMTS 13; the syndrome is inherited as an
autosomal recessive trait ; asymptomatic carriers with 50% levels of
ADAMTS 13 are at increased risk of thromboembolism
• Treatment : exchange transfusion or intensive plasmapheresis coupled
with infusion of fresh-frozen plasma. " remove abnormal forms of vWF,
lower the concentration of ADAMTS 13 inhibitor, and replenish the
deficient enzyme.
• relapsing form of TTP require maintenance plasmapheresis and plasma
infusion, and a few patients are controlled only with glucocorticoids

19. • other tx : enzyme replacement and immunosuppression to block inhibitor
production.
HEMOLYTIC-UREMIC SYNDROME ( HUS )
• disease of infancy and early childhood that closely resembles TTP.
• fever, thrombocytopenia, microangiopathic hemolytic anemia,
hypertension, and varying degrees of acute renal failure.
• In many cases, onset is preceded by a minor febrile or viral illness, and an
infectious or immune complex–mediated cause has been proposed.
• Epidemics related to infection with a specific strain of Escherichia coli
(O157:H7) have been documented.
• The bacteria contain a Shigella-like toxin that damages endothelial cells.
• As in TTP, DIC is not found. In contrast to TTP, the disorder remains
localized to the kidney, where hyaline thrombi are seen in the afferent
arterioles and glomerular capillaries. Thrombi are not present in other
vessels, and neurologic symptoms, other than those associated with
uremia, are uncommon.
• No therapy is proven effective; however, with dialysis for acute renal
failure, the initial mortality is only 5% in children but may be higher in
adults.
• Between 10 and 50% of patients have some chronic renal impairment.
• ADAMTS 13 levels are normal, and no inhibitors of the enzyme are
present in this disorder
HENOCH-SCHONLEIN PURPURA
• or anaphylactoid, purpura is a distinct, self-limited type of vasculitis that
occurs in children and young adults.
• acute inflammatory reaction in capillaries, mesangial tissues, and small
arterioles that leads to increased vascular permeability, exudation, and
hemorrhage.
• Vessel lesions contain IgA and complement components.
• May be preceded by an upper respiratory infection or streptococcal
pharyngitis or be associated with food or drug allergies.
• a purpuric or urticarial rash on the extensor surfaces of the arms and legs
and on the buttocks as well as polyarthralgias or arthritis, colicky
abdominal pain, and hematuria from focal glomerulonephritis.
• Despite the hemorrhagic features, all coagulation tests are normal.
• may develop fatal acute renal failure, and 5 to 10% develop chronic
nephritis.
• Glucocorticoids provide symptomatic relief of the joint and abdominal
pains but do not alter the course of the illness.
METABOLIC AND INFLAMMATORY DISORDERS

20. • Acute febrile illnesses may cause capillary fragility and skin bleeding
• Immune complexes containing viral antigens or the viruses themselves
may damage endothelial cells
• rickettsiae that cause Rocky Mountain spotted fever or other infections
• Thrombocytopenia is also a frequent finding in acute infections
• whenever the platelet count is < 10,000/µL, gaps develop between
endothelial cells, which allow the diapedesis of red cells into the dermis,
forming petechiae.
• sulfonamides, penicillin, and allopurinol may cause vascular inflammation,
resulting in maculopapular or urticarial rashes " additive, and drug
reactions in thrombocytopenic individuals cause an intensely hemorrhagic
rash.
• Hyperglobulinemic purpura - Occasionally, patients with diffuse polyclonal
hyperglobulinemia will develop purpuric lesions on the lower limbs ; a
benign condition
• Vascular purpura may occur in patients with various monoclonal
gammopathies, including Waldenstrom’s macroglobulinemia, multiple
myeloma, and cryoglobulinemia " markedly increase serum viscosity and
may impair blood flow through capillaries and lead to retinal hemorrhage,
central nervous system dysfunction, and skin necrosis ; globulins may
impair platelet aggregation and adhesion and interfere with fibrin
polymerization
• mixed cryoglobulinemia develop a more extensive maculopapular lesion
due to immune complex- mediated damage to the vessel wall ; may be
associated with arthralgias, diffuse weakness, and unexplained nephritis.
• Plasmapheresis will temporarily lower the level of globulins, remove
immune complexes, and improve symptoms in these patients
• Scurvy (vitamin C deficiency) develop painful episodes of perifollicular skin
bleeding as well as bleeding into muscles and, occasionally, into the
gastrointestinal and genitourinary tracts. ; hyperkeratosis of skin, gum
swelling, and low levels of the vitamin in leukocytes ; Vitamin C is needed
to synthesize hydroxyproline, an essential constituent of collagen $
collagen synthesis is impaired
• Cushing’s syndrome : excess production of glucocorticoids, or patients on
large doses of glucocorticoids develop generalized protein wasting and
may show skin bleeding or easy bruising due to atrophy of the supporting
connective tissue around blood vessels.
• Senile purpura—dark purple, irregularly shaped hemorrhagic areas due to
abnormal skin mobility that tears small blood vessels. ; atrophy of
perivascular connective tissue on the extensor surfaces of the hands and
arms
• inherited disorders of the connective tissue matrix such as Marfan’s
syndrome, Ehlers-Danlos syndrome, and pseudoxanthoma elasticum also
have easy bruising.
• Ehlers-Danlos syndrome may develop aneurysms in intraabdominal
vessels and apoplectic rupture and hemorrhage due to defects in the

21. vascular collagen network.
• Osler-Rendu-Weber disease [hereditary hemorrhagic telangiectasia
(HHT)], an inherited autosomal dominant disorder, have frequent episodes
of nasal and gastrointestinal bleeding from abnormal telangiectatic
capillaries; may develop pulmonary arteriovenous fistulas
• 2 Genetic defects : involving proteins that bind to transforming growth
factor β (TGF- β); HHT-1 has mutations in endoglin, and HHT-2 has
mutations in ALK-1.
• Angiodysplasia of the colon have increased incidence of gastrointestinal
bleeding.
• Kasabach-Merritt syndrome, patients may have very extensive and
progressively enlarging vascular malformation that may involve large
portions of their extremities " Bleeding is secondary to DIC triggered by
stagnant blood flow through the tortuous vessels.

22. PART TWO :
DISORDERS OF COAGULATION AND THROMBOSIS
• Characteristically bleed into muscles, joints, and body cavities hours or
days after an injury
• Inherited plasma coagulation disorders are due to defects in single
coagulation proteins, with the two X-linked disorders, factors VIII and IX
deficiency, accounting for the majority.
• interval range for most coagulation factors is 50 to 150% of this average
value, and the minimal level of most individual factors needed for
adequate hemostasis is 25%
• Acquired coagulation disorders are both more frequent and more complex,
arising from deficiencies of multiple coagulation proteins and
simultaneously affecting both primary and secondary hemostasis.
• most common acquired hemorrhagic disorders are (1) disseminated
intravascular coagulation (DIC), (2) the hemorrhagic diathesis of liver
disease, and (3) vitamin K deficiency and complications of
anticoagulant therapy
• Risk factors such as atherosclerotic vascular disease, congestive heart
failure, malignancy, and immobility predispose patients to thrombosis
FACTOR VIII DEFICIENCY—HEMOPHILIA A
Pathogenesis and Clinical Manifestations
• Antihemophilic factor (AHF), or factor VIII coagulant protein - large (265-
kDa), single-chain protein that regulates the activation of factor X by
proteases generated in the intrinsic coagulation pathway ; synthesized in liver
and circulates complexed to the von Willebrand factor (vWF) protein. Factor
VIII molecule is present in low concentration (10 mg/L) and is susceptible to
proteolysis.
• One in 10,000 males is born with deficiency or dysfunction of the factor VIII
molecule" hemophilia A, is characterized by bleeding into soft tissues,
muscles, and weight-bearing joints
• Symptomatic patients usually have factor VIII levels < 5%,!
• !< 1% factor VIII activity have severe disease; they bleed frequently even
without discernible trauma
• < 5% have mild disease with infrequent bleeding that is usually secondary
to trauma.
• > 25% are discovered when they bleed after major trauma or surgery.
• bleeding occurs hours or days after injury, can involve any organ, and, if
untreated, may continue for days or weeks
• Symptoms often precede objective evidence of bleeding. (2) Signs of
bleeding may not appear until several days after well-documented trauma.
• large collections of partially clotted blood putting pressure on adjacent normal
tissues and can cause necrosis of muscle (compartment syndromes), venous
congestion (pseudophlebitis), or ischemic damage to nerves.

23. • often develop femoral neuropathy due to pressure from an unsuspected
retroperitoneal hematoma
• large calcified masses of blood and inflammatory tissue that are mistaken for
cancers (pseudotumor syndrome).
• usually diagnosed shortly after birth because of an extensive
cephalhematoma or profuse bleeding at circumcision.
• presents with pain followed by swelling in a weight-bearing joint, such as the
hip, knee, or ankle
• blood in the joint (hemarthrosis) causes synovial inflammation, and repetitive
bleeding erodes articular cartilage and causes osteoarthritis, articular fibrosis,
joint ankylosis, and eventually muscle atrophy
• Hematuria, without any genitourinary pathology, is also common " usually
self-limited and may not require specific therapy
• most feared complications of hemophilia are oropharyngeal and central
nervous system bleeding
• oropharyngeal bleeding may require emergency intubation to maintain an
adequate airway
• prolonged PTT with all other tests normal
• Differential Diagnosis : factor VIII deficiency and factor IX deficiency " must
determination of the assays
Treatment :
• For pain " Avoid the use of aspirin or aspirin-containing drugs, which impair
platelet function and may cause severe hemorrhage. Cyclooxygenase
inhibitors can be used, as they do not impair platelet function
• Plasma products enriched in factor VIII reduce the degree of orthopedic
deformity and permit virtually any form of elective and emergency surgery
• factor VIII concentrates has also produced serious complications, including
viral hepatitis, chronic liver disease, and AIDS
• Cryoprecipitate, which contains about half the factor VIII activity of fresh-
frozen plasma in one-tenth the original volume, is simple to prepare and is
produced in hospital
• Modification and Safety Measures adapted for Factor VIII : heating of
lyophilized factor VIII concentrates under carefully controlled conditions can
inactivate HIV without destroying factor VIII activity. Second, highly purified
factor VIII can be produced by adsorbing and eluting factor VIII from
monoclonal antibody columns. Third, recombinant factor VIII
• One unit of factor VIII infused, defined as the amount present in 1 mL normal
plasma, " raise the plasma level of the recipient by 2%/kg of body weight
• Factor VIII has a half-life of 8 to 12 h, making it necessary to infuse it
continuously or at least twice daily to sustain a chosen factor VIII level
• Desmopressin (DDAVP), alternative option , which transiently increases the
factor VIII level " increase the factor level two- to threefold but may cause
hyponatremia or may precipitate thrombosis in elderly
• Life-threatening bleeding into the central nervous system or major surgery

24. may require therapy for 2 weeks with levels kept at a minimum of 50%
normal.
• ε "!aminocaproic acid (EACA) four times daily for 3to 4 days after the dental
procedure. EACA is a potent antifibrinolytic agent that inhibits plasminogen
activators present in oral secretions and stabilizes
clot formation in oral tissue
• tranexamic acid, a longer-acting antifibrinolytic
• Blood products " AIDS transmission ? , multiple episodes of hepatitis, and
a majority have elevated hepatocellular enzyme levels and abnormalities on
liver biopsy ; Between 10 and 20% of patients also have
hepatosplenomegaly, and a small number develop chronic active or
persistent hepatitis or cirrhosis
• Other complications : Iron deficiency ( rare because it is recycled )
• Gene therapy : still investigational
GENETIC COUNSELLING :
• Precise diagnosis is possible early in pregnancy from either chorionic
villus biopsy or amniocentesis.
• Female carriers of hemophilia, who are heterozygotes, usually produce
sufficient factor VIII from the factor VIII allele on their normal X
chromosome for normal hemostasis
• true female hemophiliacs arise from consanguinity within families with
hemophilia or from concomitant Turner’s syndrome or XO mosaicism in a
carrier female.
FACTOR IX DEFICIENCY—HEMOPHILIA B
• Factor IX is a single-chain, 55- kDa proenzyme that is converted to an
active protease (IXa) by factor XIa or by the tissue factor–VIIa complex
• Factor IXa then activates factor X in conjunction with activated factor VIII
• Factor IX is one of six proteins synthesized in the liver that require vitamin
K for biologic activity. Vitamin K is a cofactor for a unique posttranslational
modification that inserts a second carboxyl group onto certain glutamic
acid residues on factor IX
• Vitamin K is a cofactor for a unique posttranslational modification that
inserts a second carboxyl group onto certain glutamic acid residues on
factor IX
• Factor IX gene is on the X chromosome
• Factor IX deficiency or dysfunction (hemophilia B, Christmas disease)
occurs in 1 in 100,000 male births
• indistinguishable clinically from factor VIII deficiency (hemophilia A) but
requires different treatment
• freshfrozen plasma or a plasma fraction enriched in the prothrombin
complex proteins
• Tx : Monoclonally purified or recombinant factor IX preparations

25. • Trace quantities of activated coagulation factors in prothrombin complex
concentrates may activate the coagulation system and cause thrombosis
and embolism " common in immobilized surgical patients and patients
with liver disease
• some centers have returned to fresh frozen plasma for factor IX–deficient
surgical patients, while others have recommended the addition of small
doses of heparin to the concentrate to activate antithrombin III during the
infusion and reduce hypercoagulability. The recombinant or monoclonally
purified products are less likely to be thrombogenic
FACTOR XI DEFECIENCY
• Factor XI is a 160-kDa dimeric protein activated to an active protease
(XIa) by factor XIIa, in conjunction with highmolecular- weight kininogen
and kallikrein
• inherited as an autosomal recessive trait and is especially common in
Ashkenazi Jews
• spontaneous bleeding is less, and hemarthroses are rare.
• posttraumatic bleeding or with bleeding in the perioperative period, and
occasional factor XI–deficient women have menorrhagia
• Daily infusions of fresh-frozen plasma are sufficient, since the half-life of
factor XI is approximately 24 h.
OTHER FACTOR DEFICIENCIES
• Deficiencies in factors V, VII, X, and prothrombin (factor II) are
exceedingly rare autosomal recessive disorders.
• Spontaneous or posttraumatic musculoskeletal bleeding or menorrhagia
can occur with these deficiencies, but hemarthroses are uncommon.
• TX : Fresh-frozen plasma or prothrombin concentrates
• Defects in the contact activation pathway involving Hageman factor (factor
XII), high-molecular-weight kininogen, and prekallikrein cause laboratory
abnormalities but no clinical bleeding because there is direct activation of
factor IX by the tissue factor–VIIa complex
AFIBRINOGENEMIA AND DYSFIBRINOGENEMIA
• Fibrinogen is an abundant plasma protein (2.5 g/L).
• Mutations have been identified that alter the release of fibrinopeptides
from the Aα and Bβ chains of fibrinogen, the rate of polymerization of
fibrin monomers, and the sites for fibrin cross-linking
• almost always inherited as autosomal dominant traits
• slightly prolonged PT and PTT, a prolonged thrombin time, and a disparity
in levels of fibrinogen measured with functional and immunologic assays.
• most patients have no symptoms or only moderate bleeding ; few have
hypercoagulable state and increase the risk of thrombosis, and others
have been associated with an increased incidence of abortion
• patients with liver disease, hepatomas, AIDS, and lymphoproliferative

26. disorders develop an acquired form of dysfibrinogenemia
!
FACTOR XIII DEFICIENCY AND DEFECTIVE FIBRIN CROSS-LINKING
• Factor XIII is a transglutaminase that stabilizes fibrin clots by forming ε-
amino– γ glutamyl cross-links between adjacent α and γ chains of fibrin
• extremely rare inherited syndrome ; usually bleed in the neonatal period
from their umbilical stump or circumcision
• may have poor wound healing, a high incidence of infertility among males
and abortion among affected females, and a high incidence of
intracerebral hemorrhage.
• isoniazid, may bind to cross-linking sites on fibrinogen and mimic factor
XIII deficiency by blocking enzyme activity
• Normal hemostasis requires only 1% of normal enzyme activity; a single
infusion of fresh-frozen plasma or a purified factor XIII–rich product
derived from human placenta called Fibrogammin
• Factor XIII has a 14-day half-life.
VITAMIN K DEFICIENCY
• Vitamin K is a fat-soluble vitamin that plays a critical role in hemostasis.
• mediates posttranslational modification of glutamate residues to -
carboxylglutamate, a critical step for the activity of vitamin K-dependent
proteins for calcium binding and proper assembly to phospholipid
membranes
• Dietary vitamin K is absorbed in the small intestine and stored in the liver.
; also synthesized by endogenous bacterial flora in the small intestine and
colon; however, the quantity of endogenous vitamin K absorbed from the
large intestine is debated.
• Vitamin K " converted to an active epoxide in liver microsomes and
serves as a cofactor in the enzymatic carboxylation of glutamic acid
residues on prothrombin complex proteins
• Three major causes of vitamin K deficiency are inadequate dietary intake,
intestinal malabsorption, and loss of storage sites due to hepatocellular
disease
• common in association with the use of broad-spectrum antibiotics
• Neonatal vitamin K deficiency, which causes hemorrhagic disease of the
newborn, has disappeared from western countries with the routine
administration of vitamin K to all newborn infants.
• Although a 30-day supply of vitamin K is stored in the normal liver, acutely
ill patients can become deficient within 7 to 10 day
• biliary tract surgery who have no dietary intake of vitamin K, have T-tube
drainage of bile, and are on broad-spectrum antibiotics
• chronic liver disease, particularly primary biliary cirrhosis, and in some
malabsorption states
• cephalosporins inhibit the reduction and recycling of vitamin K, much like
warfarin

27. • Deficiency of Vitamin K " prothrombin complex proteins (factors II, VII,
IX, X; proteins C and S) decrease
• shortest half-lives, factor VII and protein C, decrease first " may have a
prolonged PT and a normal PTT " Later, as the levels of the other
factors fall, the PTT will also become prolonged.
• Parenteral administration of 10 mg vitamin K rapidly restores vitamin K
levels in the liver and permits normal production of prothrombin complex
proteins within 8 to 10 h fresh-frozen plasma, which immediately corrects
the hemostatic defect
•
Coagulation Disorders Associated with Liver Failure
- liver is central to hemostasis because it is the site of synthesis and
clearance of most procoagulant and natural anticoagulant proteins and of
essential components of the fibrinolytic system
- - presence of prolonged TT, normal fibrinogen, and FDP levels suggests
dysfibrinogenemia ; Dysfibrinogenemia is a relatively common finding in
patients with liver disease due to impaired fibrin polymeratization
- Thrombocytopenia is common in patients with liver disease and may be
due to congestive splenomegaly (hypersplenism), or immune-mediated
shortened platelet life span (primary biliary cirrhosis). In addition, several
anatomic abnormalities secondary to underlying liver disease further
promote the occurrence of hemorrhage
- Normal levels of FV and low levels of FVII suggest vitamin K deficiency.
- Vitamin K levels may be reduced in patients with liver failure due to
compromised storage in hepatocellular disease, changes in bile acids, or
cholestasis that can diminish the absorption of vitamin K. Replacement of
vitamin K may be desirable (10 mg given by slow intravenous injection) to
improve hemostasis.

28. DISSEMINATED INTRAVASCULAR COAGULATION
• Explosive and life-threatening bleeding disorder or a relatively mild or
subclinical disorder.
• obstetric catastrophes, metastatic malignancy, massive trauma, and
bacterial sepsis
• Tumors and traumatized or necrotic tissue release tissue factor into the
circulation
• Endotoxin from gram-negative bacteria activates several steps in the
coagulation cascade
• direct effect on the activation of Hageman factor (factor XII), endotoxin
induces the expression of tissue factor on the surface of monocytes and
endothelial cells.
• stimuli cause the deposition of small thrombi and emboli throughout the
microvasculature
• early thrombotic phase of DIC is then followed by a phase of procoagulant
consumption and secondary fibrinolysis
• early thrombotic phase of DIC is then followed by a phase of procoagulant

29. consumption and secondary fibrinolysis. Continued fibrin formation and
fibrinolysis lead to hemorrhage from the coagulation factor and platelet
depletion and the antihemostatic effects of fibrin degradation products
• Most patients have extensive skin and mucous membrane bleeding and
hemorrhage from surgical incisions or venipuncture or catheter sites.
• peripheral acrocyanosis, thrombosis, and pregangrenous changes in
digits, genitalia, and nose—areas where blood flow is markedly reduced
by vasospasm or microthrombi
• laboratory manifestations include thrombocytopenia and the presence of
schistocytes or fragmented red blood cells that arise from cell trapping and
damage within fibrin thrombi; prolonged PT and PTT and thrombin time
and a reduced fibrinogen level from depletion of coagulation proteins; and
elevated fibrin degradation products (FDP) from intense secondary
fibrinolysis
• D dimer immunoassay, which measures cross-linked fibrin derivatives
(i.e., those that have been in blood clots), is a more specific FDP assay
• Low fibrinogen levels in DIC predict more bleeding

31. TREATMENT OF DIC
• an attempt to correct any reversible cause of DIC; (2) measures to control
the major symptom, either bleeding or thrombosis; and (3) a prophylactic
regimen to prevent recurrence in cases of chronic DIC.
• abruptio placentae or acute bacterial sepsis, prompt delivery of the fetus
and placenta or treatment with appropriate antibiotics will reverse the DIC
syndrome
• metastatic tumor causing DIC, control of the primary disease may not be
possible " long-term prophylaxis
• fresh frozen plasma to replace depleted clotting factors and platelet
concentrates
• acrocyanosis and incipient gangrene or other thrombotic problems "
anticoagulation with intravenous heparin
• use of heparin in the treatment of bleeding : still controversial ; reduce
thrombin generation and prevent further consumption of clotting proteins,
it should be reserved for patients with thrombosis or who continue to bleed
despite vigorous treatment with plasma and platelets

32. • Therapy will only stabilize the patient, prevent exsanguination or massive
thrombosis, and permit institution of definitive therapy
•