Bleeding and Thrombotic Disorders

DR. RAKESH VERMA

 HEMOSTASIS
Primary vs. Secondary vs. Tertiary
Primary Hemostasis
Platelet Plug Formation
Dependent on normal platelet number & function
Secondary Hemostasis
Activation of Clotting Cascade Deposition & Stabilization of
Fibrin
Tertiary Hemostasis
Dissolution of Fibrin Clot
Dependent on Plasminogen Activation
Mechanisms of bleeding
Vascular Integrity
Platelets
Clotting factors
Fibrinolysis

Derangement of any of these factors can cause abnormal

bleeding
Key to diagnosis
History
History
History
Bleeding history
Epistaxis
Gingival hemorrhage
Mucosal Bleeding
Heavy Menses
Child birth
Easy bruisability
Bleeding following tooth extractions
Hematomas
Bleeding following surgery
Hemarthrosis
Medication History
Aspirin
Warfarin
NSAIDS
B- Lactam antibiotics
Clopidogrel and other antiplatelet agents
Herbal medications.
Nutritional history
Vit K deficiency
Vit C deficiency
Broad spectrum antibiotics
Clinical Clotting factor
Platelet disorder
Characteristics deficiency

Skin, mucous membranes

Deep in soft tissues (joints,
Site of bleeding (gingivae, nares, GI and
muscles)
genitourinary tracts)
Bleeding after
Yes Not usually
minor cuts
Petechiae Present Absent
Ecchymoses Small, superficial Large, palpable
Hemarthroses,
muscle Rare Common
hematomas
Bleeding after
Immediate, mild Delayed, severe
surgery
Petechiae 1-3mm
Purpura 3mm-10 mm
Ecchymosis >10mm
Hereditary
Deficiency of coagulation factors
Hemophilia
Fibrinogen deficiency
Von Willebrand disease
Platelet disorders
Glanzmann thrombasthenia
Bernard-Soulier syndrome
Platelet granule disorders
Fibrinolytic disorders
Alpha 2 antiplasmin deficiency
PAI 1 deficiency
Structural disorders
Hemorrhagic Telangiectasias
Ehler Danlos syndrome
Acquired
Thrombocytopenias
Liver disease
Vit K deficiency
Acquired antibodies to coagulation factors
DIC
Drugs
Vascular
 Lab testing
Platelet count
Bleeding time-Measure of the interaction of platelets with
the blood vessel wall.
BT raised in
Thrombocytopenia (platelet count usually below
50,000/microL),
Qualitative platelet abnormalities (eg, uremia),
von Willebrand disease (VWD),
Vascular purpura,
Severe fibrinogen deficiency
BLEEDING TIME vs. PLATELET COUNT
Activated platelets
 Platelet function assay
Expose platelets within citrated whole blood to high shear (5,000 to
6,000/sec) within a capillary tube and monitor the drop in flow rate
as the platelets form a hemostatic plug within the center of a
membrane coated with collagen and either ADP or epinephrine
Abnormal closure times are an indication of platelet dysfunction, they
are not specific for any disorder
The test is coagulation factor independent
PFA-100 is more sensitive (>70 percent) than the bleeding time (20
to 30 percent) in detecting all subtypes of von Willebrand's disease
(vWD)
Exception is type 2N vWD, in which the hemostatic defect resides in
the Factor VIII binding site on vWF
Platelet function assay
Collagen/epinephrine closure time (CEPI-CT)-
Abnormal in Aspirin intake

Collagen/adenosine diphosphate (CADT-CT)-

Normal in aspirin intake
 Prothrombin time (10-13sec)
Measure of the extrinsic pathway and common pathway
Bypasses the intrinsic pathway and uses tissue factor in
presence of calcium
Within the combined pathway, factors VII, X, and
prothrombin are vitamin-K dependent and are altered by
warfarin
Prolonged PT
Vitamin K deficiency
Liver disease, which decreases the synthesis of both
vitamin K-dependent and -independent clotting factors.
Deficiency or inhibition of factors VII, X, II
(prothrombin), V, or fibrinogen

Heparin does NOT prolong the PT

 aPTT
Measures the intrinsic and common pathways of coagulation
Uses partial thromboplastins
Prolonged in
deficiency of the clotting factors
inhibitor to any of the clotting factors except for factor VII
deficiency of prekallikrenin, high molecular weight kininogen
Lupus Anticoagulant.

Used to monitor heparin activity

 Thrombin time
Measure conversion of fibrinogen to fibrin monomers and the
formation of initial clot by thrombin
Prolonged in
Hypofibrinogenemia
Dysfibrinogenenimia
Increased fibrin split products (inhibit polymerisation of fibrin
monomers)
Heparin; increases TT but not Reptilase Time
Factor deficiencies/ inhibitors
A prolonged aPTT can be due to a deficiency (or
absence) of a coagulation factor or the presence of a
coagulation factor inhibitor
Mixing studies helps in differentiation. Patient sample is
mixed with normal plasma in 1:1, and if
PT or PTT get corrected shows deficiency of factors
PT or PTT get corrected partially or uncorrected shows
inhibitors
Lupus anticoagulants (antibody against phospholipids)
can result in a prolonged aPTT that is not correctable by
the addition of normal plasma
 Fibrinolysis
Fibrin and fibrinogen
degradation products
(FDP) are protein
fragments resulting
from the action of
plasmin on fibrin or
fibrinogen

Activator
Inhibitor
Pathway
 Fibrinolysis
FDP assays do not differentiate between fibrin degradation
products and fibrinogen degradation products
Fibrin D-dimers are degradation products of cross-linked
fibrin
D-dimers specifically reflect fibrinolysis of cross-linked fibrin
(ie, the fibrin clot) so are more reliable indicators of
thrombosis
 Normal PT and PTT

Thrombocytopenia
Factor 13 deficiency
Platelet dysfunction
Vascular purpuras
Psychogenic purpura
 Normal PT and Prolonged aPTT
Hemophilia A
Hemophilia B
Factor XI deficiency
Factor VIII inhibitor
Malignancy,
Clonal lymphoproliferative disorders,
Pregnancy,
Rheumatologic disorders
Lupus anticoagulant
Prolonged PT and normal aPTT

Factor VII deficiency

Warfarin therapy
Early liver disease
Early DIC
Prolonged PT and PTT

Vit K deficiency
Liver disease
Acquired inhibitor to factor V
Factor X deficiency
DIC
 Hemophilia
Hemophilia A (85%) and B(10-15%) are X-linked recessive
diseases
Severe disease -<1 % factor activity; bleeding is often
spontaneous
Moderate disease - 1 to 5 %; require mild trauma to induce
bleeding
Mild disease - >5 %; prolonged bleeding after dental work,
surgery, or injuries from moderate trauma.
The most common sites are into joints and muscles and from the
gastrointestinal tract
The hallmark of hemophilia is the hemarthrosis
Some female carriers of hemophilia A or hemophilia B will have
sufficient reduction of their factor VIII or factor IX through lionization
of the X chromosome to produce mild bleeding disorders in carriers

In severe hemophilia, APTT is usually two to three times the

upper limits. other screening tests platelet count, bleeding time,
prothrombin time, and thrombin time are normal. Specific assay
for factors will confirm the diagnosis.

Evaluation for inhibitors should also be performed. In such

patients the quantitative Bethesda assay for inhibitor should be
performed.
 Treatment
The two components to therapy are treatment of active bleeding and
inhibitor ablation via immune tolerance induction
Cryoprecipitate has high levels of factor VIII
Porcine Factor VIII
Recombinant human Factor VIII
A recombinant factor VIIa is for treating factor VIII or factor IX
inhibitor patients.
The choice of factor VIII product usually is based upon safety, purity,
and cost.
Prophylaxis is the Standard care of treatment for severe disease
Mild hemophilia A - Desmopressin acetate.
Desmopressin is ineffective in hemophilia B.
The prevention of trauma, avoidence of Aspirin and other nonsteroidal
anti-inflammatory drugs.
 Dosing
One international unit (IU) of clotting factor is that
amount present in 1 mL of pooled normal plasma

Dose of F VIII (IU) = Weight (kg) x (Desired % increase) x 0.5

Dose of F IX (IU) = Weight (kg) x (Desired % increase) x 1.4

Depends on the presence or absence of inhibitors.

 Other clotting factor deficiencies
Factor Feature Management
Factor XI deficiency autosomal, deficiency associated with FFP
Haemophilia C mild to moderate bleeding symptoms
Factor V mucocutaneous bleeding and hematomas are the FFP
Para-hemophilia most common symptoms, rarely hemarthroses;
severe menorrhagia is a frequent
symptom in women
Factor VII homozygous state, deficiency may have Recombinant factor VIIa
spontaneous intracranial hemorrhage and
frequent mucocutaneous bleeding
Factor X rare autosomal disorder that results in FFP
mucocutaneous and post-traumatic bleeding
Factor XIII symptoms of delayed hemorrhage, patients will FFP or cryoprecipitate
(Fibrin-Stabilizing have trauma one day and then develop a bruise or
Factor or
Transglutaminase
hematoma on the following day. Diagnosed by
Deficiency) clot solublility in the presence of 5 M urea
Contact factors Prolong PTT but no bleeding No treatment
XII,PK,HMWK
von Willebrands disease
Most common of the inherited bleeding disorders 1% -2% in
general population.
In 1926, Erik von Willebrand described the disease.
Multimeric molecules, synthesises in
Platelets alpha granules
Endothelial cells Weibel Palade bodies

Von Willebrand factor (VWF) binds to both platelets and

endothelial components, forming an adhesive bridge between
platelets and vascular subendothelial structures and between
adjacent platelets at sites of endothelial injury
 von Willebrand disease subtypes
Genetic Bleeding Response to
Type Defect
s symptoms DDAVP
Type 1 Quantitative: AD Mild Good
(common) Decreased vWF
Type 2 Qualitative:
(uncommon) Normal vWF levels
2A vWF not "sticky" enough AD/AR Variable Mild to mod.
Potentially
2B vWF too "sticky" AD Contraindicated
severe
Lacking receptor for platelet Mild to mod.
AD Fairly mild
2M binding
Similar to
Lacking receptor for factor VIII Mild
AR hemophilia
2N binding
A
Type 3 (rare) Absent vWF AR Severe No Response
 Laboratory findings in various platelet and coagulation disorders
Prothrombin Partial
Condition Bleeding time Platelet count
time thromboplastin time
Vitamin K Normal or mildly
Prolonged Unaffected Unaffected
deficiency or warfarin prolonged
Disseminated intravascular
Prolonged Prolonged Prolonged Decreased
coagulation
Prolonged or
Von Willebrand disease Unaffected Prolonged Unaffected
unaffected
Hemophilia Unaffected Prolonged Unaffected Unaffected
Aspirin Unaffected Unaffected Prolonged Unaffected
Thrombocytopenia Unaffected Unaffected Prolonged Decreased
Liver failure, early Prolonged Unaffected Unaffected Unaffected
Liver failure, end-stage Prolonged Prolonged Prolonged Decreased
Uremia Unaffected Unaffected Prolonged Unaffected
Congenital afibrinogenemia Prolonged Prolonged Prolonged Unaffected
Factor V deficiency Prolonged Prolonged Unaffected Unaffected
Factor X deficiency as seen
Prolonged Prolonged Unaffected Unaffected
in amyloid purpura
Factor XII deficiency Unaffected Prolonged Unaffected Unaffected
DIC Prolonged Prolonged Prolonged Decreased
 Blood component therapy
Component Constituent Indications Dose
FFP All clotting factors Many coagulation 15ml/kg (gives 20-
factor deficiency state 30%)

Cryoprecipitate I, VIII, XIII, vWF Corresponding 30ml/kg

deficiencies

Random donor Platelet atleast Thrombocytopenia 1unit/10kg

plateletI (RDP) 5.5x1010 Raise 30,000-
50,000/cumm

Single donor platelet Platelet atleast Thrombocytopenia 1 collection equals

(SDP) 3x1011 6RDP

Whole blood All Acute blood loss Severe trauma

 PLATELET

AND

BLOOD VESSEL DISORDERS

 Idiopathic (autoimmune)
Thrombocytopenic Purpura
The most common cause for acute onset of
thrombocytopenia in an otherwise well child

One to 4 wk after viral infection

autoantibody against the platelet surface

antibody-coated platelets are recognized by the Fc receptor on the splenic

macrophages

ingested, and destroyed

Presentation
1-4 yr child
Sudden onset of generalized petechiae and purpura.
leeding from the gums and mucous
Splenomegaly is rare
Chronic ITP or thrombocytopenia may be manifestation of a systemic illness such as
SLE.

Investigations
Severe thrombocytopenia
Platelet size is normal or increased
Prolong bleeding time
Hb, WBC, DLC can be normal
Normal or increased numbers of megakaryocytes

Management
70-80% with acute ITP, spontaneous resolution will occur within 6 mo
Platelet transfusion
Intravenous immunoglobulin - dose of 0.8-1 g/kg/day 1-2 days
Prednisone.
IV Anti- D Therapy
 Childhood Thrombocytopenia
Differential diagnosis
WELL
Large platelet Small platelet
Normal Hb & WBC Increase MCV
Congenital anomalies

Consumption Decrease
synthiesis

ITP TAR
Secondary to SLE Wiskott Aldrich
drug induced X- linked
Maternal ITP Amegakayocyte
NATP Toxins
2B vWD Radiations
Childhood Thrombocytopenia
Differential diagnosis
Ill
Decrease Fibrinogen
Small platelet
Increase FDPs
Hepato-spleenomegaly
Large platelet

Consumption Mass
Decrease
synthiesis
HUS Sequestration
TTP
Malignancy
Thombosis Haemangioma
Storage disorder
Sepsis Hyperspleenism
 Microangiopathic haemolytic anemia

Feature HUS TTP

Age usually <3 yr usually 3rd decade
Gender M=F F>M
Prodrome infection, diarrhea less common
Recurrence rare common
Triad: Pentad: CNS disturbance,
Acute renal failure, thrombocytopenia,
Diagnosis
thrombocytopenia, microangiopathic anemia,
microangiopathic anemia. renal dysfunction, fever.
Pregnancy, autoimmune
E. Coli (verotoxin), Shigella
Etiologic factors disease, malignancy, drugs.
gastroenteritis, pneumococcus
Decrease ADAM-TS
Renal dialysis, corticosteroids Plasma exchange,
Treatment do not help, transfuse only if corticosteroids, avoid
necessary. transfusions.
Prognosis Good Poor
 Congenital Abnormalities of Platelet Function
Platelet aggregation Platelet
Condition Other Managment
studies count
Glanzmann
Abnormal to all agonists Normal
thrombasthenia
Bernard-Soulier
Abnormal to ristocetin Decreased Giant platelets.
syndrome
Storage pool defect
1. Dense body
Abnormal platelet
deficiency Abnormal 2nd phase of
Normal granules on electron
aggregation Desmopressin
microscopy
2. Gray platelet
syndrome platelet transfusions

recombinant factor VIIa

Drug induced
enzyme effect stem cell transplants
Abnormal to arachidonic
ASA/NSAID inhibiting platelet
acid and abnormal
Abnormal COX or Normal granule release. This
secondary aggregation to
Tx synthase is the most common
ADP and epinephrine
cause of platelet
dysfunction.

Thrombotic disorders
A hereditary predisposition to thrombosis can be caused by deficiencies of the regulatory
proteins:
Protein C
Protein S
Antithrombin III
Plasminogen;
Factor V Leiden
Prothrombin mutation (G20210A)
Homocystinuria.
Lipoprotien (a)

Investigations
no screening tests
specific testing is required for each component
family history
Genetic DNA testing for factor V Leiden and the prothrombin mutation

Treatment
Fresh frozen plasma
Protein C concentrate,
Warfarin
DIC
A conditions resulting in consumption of clotting factors, platelets, and anticoagulant proteins.
Causing widespread intravascular deposition of fibrin leading to tissue ischemia and necrosis, a
generalized hemorrhagic state, and hemolytic anemia.

Clinical Manifestations.
Bleeding frequently occurs from venipuncture or surgical incision.
Petechiae and ecchymoses.
Infarction of skin, subcutaneous tissue, or kidneys.
Anemia caused by microangiopathic hemolytic anemia.

Lab
prolongation of the PT, PTT and TT.
Platelet counts may be profoundly depressed.
Smear shows fragmented, burr, and helmet-shaped, schistocytes.
FDPs, D-dimers elevated (The D-dimer is more specific for activation of coagulation and
fibrinolysis than the FDP )

Treatment two steps

(1) treat the trigger that caused the DIC
(2) restore normal homeostasis by correcting the shock, acidosis, and hypoxia that usually
complicate the DIC
Blood components
In DIC associated with sepsis, activated protein C (APC) drotrecogin alpha can be given
Heparin in patient who have vascular thrombosis