disorders of platelets and vessel wall

1. BLEEDING DISORDERS
Dr RAJESH S
GUIDE Dr GURDEEP KAUR Madam

2. BLEEDING DISORDERS
 A bleeding tendency is a presentation with bleeding in a patient in
whom no anatomical cause for the bleeding (i.e., trauma to a
vessel for one of many possible reasons) can be discovered.
 It is then inferred that the bleeding is due to a functional impairment
of the normal hemostatic process.

3. What are bleeding disorders and
Coagulation disorders??

4. PETECHIAE
.
Characteristic of BLEEDING disorder

5. PURPURA
Also seen in BLEEDING disorder

6. Hemarthrosis
Characteristic of COAGULATION disorders

7. Ecchymoses
Typical of coagulation factor
disorders

8. HEMATOMA
Seen in COAGULATION disorders

10. HEMOSTASIS
VASCULAR
PHASE
PLATELET
PHASE
COAGULATION
PHASE

11. VASCULAR CAUSES OF BLEEDING
HERIDITARY
 Hereditary hemorrhagic telangiectasia
 Ehlers-Danlos syndrome
 Marfan’s syndrome
METABOLIC AND INFLAMMATORY
 Henoch-Schonlein syndrome
 Scurvy - Amyloid
 Steroid purpura
 senile purpura
 Rickettsial diseases
 Polyclonal gammopathies

12. Heriditary hemorrhagic telengiectesia(HHT)
 Heriditary hemorrhagic telengiectesia(Osler-Weber-Rendu disease) is a
disorder where abnormal telengiectatic capillaries result in frequent
bleeding episodes,primarily from the nose and gastrointestinal tract.
 AVM of lung,brain,and liver may be seen.
 pulmonary AVM in 40% of cases(in endoglin gene mutation type).
 Expistaxis begins, on average, at the age of 12 and occurs in >95% of
affected individuals by middle age.

13.  Rickettsiae causing Rocky Mountain spotted fever, replicate in
endothelial cells and damage them and hence causes petechiae and
purpura.
 Patients with scurvy (vitamin C deficiency) develop painful episodes of
perifollicular skin bleeding as well as more systemic bleeding symptoms.
Vitamin C is needed to synthesize hydroxyproline, an essential constituent
of collagen.
 Patients with Cushing's syndrome or on chronic glucocorticoid therapy
develop skin bleeding and easy bruising due to atrophy of supporting
connective tissue.
ROCKY MOUNTAIN SPOTTED FEVER

14. Henoch-Schönlein purpura:
 A distinct, self-limited type of vasculitis that occurs in children and young
adults.
 An acute inflammatory reaction with IgA and complement
components in capillaries, mesangial tissues, and small arterioles leading
to increased vascular permeability and localized hemorrhage.
 The syndrome is often preceded by an upper respiratory infection,
commonly with streptococcal pharyngitis.
 Patients develop a purpuric rash on the extensor surfaces of the arms
and legs, usually accompanied by polyarthralgias or arthritis, abdominal
pain, and hematuria from focal glomerulonephritis.
 Glucocorticoids can provide symptomatic relief but do not alter the
course of the illness.

15. PLATELET DISORDERS
QUANTITATIVE
DISORDERS
QUALITATIVE
DISORDERS
1.THROMBOCYTOPENIA
1.INHERITED DISORDERS
2.THROMBOCYTOSIS
2.ACQUIRED DISORDERS

16. THROMBOCYTOPENIA
 Thrombocytopenia is defined as a platelet count less than
150,000
 2.5 percent of the normal population will have a platelet
count lower than this.
Thrombocytopenia results from one or more of three
processes:
(1) decreased bone marrow production;
(2) sequestration, usually in an enlarged spleen; and/or
(3) increased platelet destruction.

17.  In evaluating a patient with
thrombocytopenia, a key step is
to review the peripheral blood
smear and to first rule out
"pseudothrombocytopenia"
 It is an in vitro artifact resulting
from platelet agglutination via
antibodies ,when the calcium
content is decreased by blood
collection in EDTA tube.
 If a low platelet count is obtained
in EDTA-anticoagulated
blood,Repeat platelet count
determined in blood collected
into sodium citrate (blue top
tube) or heparin (green top
tube).

18. INFECTION-INDUCED THROMBOCYTOPENIA
 Most common non-iatrogenic cause of thrombocytopenia.
 Can affect both platelet production and platelet survival.
 Immune mechanisms are proposed to be the cause, as in infectious
mononucleosis,Hiv and other viral Infections.
 “A study evaluating the role of bone marrow examination in fever of
unknown origin in HIV-infected patients found that for 86% of
patients, the same diagnosis was established by less-invasive
techniques, notably blood culture.”
 Thus, a bone marrow examination is not routinely recommended in
evaluation of thrombocytopenia in infections and it is recommended
when the diagnosis is needed urgently or when other, less invasive
methods have been unsuccessful.

19. Drug-Induced Thrombocytopenia
 A predictable decrease in platelet count occurs after treatment with
many chemotherapeutic drugs due to bone marrow suppression.
 All drugs should be suspect in a patient with thrombocytopenia without
an apparent cause and should be stopped, or substituted, if possible.
 Although not as well studied, herbal and over-the-counter preparations
may also result in thrombocytopenia.
 They are very commonly seen in Quinine and Sulfa drugs.
 Other examples include
Rifampin, Amiodarone, Ampicillin, Digoxin,Diclofenac,Ibuprofen,Linezolid,Furose
mide.

20. Drug-Induced Thrombocytopenia
 Classic drug-dependent antibodies are antibodies that react with specific
platelet surface antigens, and result in thrombocytopenia only when the drug is
present.
 The thrombocytopenia typically occurs after a period of initial exposure
(median length 21 days), or upon reexposure, and usually resolves in 7–10 days
after drug withdrawal.
 The thrombocytopenia caused by the platelet GpIIbIIIa inhibitory drugs, such as
abciximab, differs in that it may occur within 24 h of initial exposure. This appears
to be due to the presence of naturally occurring antibodies that cross-react
with the drug bound to the platelet.

21. HEPARIN INDUCED THROMBOCYOPENIA
 Heparin has been used as an anticoagulant medication since the late
1930s and is one of the most prescribed drugs.
 However, clinicians recognized that some patients developed a
syndrome of immune-mediated thrombocytopenia and thrombosis,
which came to be called heparin-induced thrombocytopenia (HIT).
Drug-induced thrombocytopenia due to heparin differs from that seen with
other drugs in two major ways.
 (1) The thrombocytopenia is not usually severe, with nadir counts rarely
<20,000/L.
 (2) Heparin-induced thrombocytopenia (HIT) is not associated with
bleeding and, in fact, markedly increases the risk of thrombosis.

22.  HIT occurs when IgG antibodies develop against neoantigens created
by multimolecular heparin/platelet factor 4 (PF4) complexes.
 The antiheparin/PF4 antibody can activate platelets through the FcRIIa
receptor and also activate monocytes and endothelial cells.
 Surgical patients develop the antibodies more often than medical or
obstetric patients because surgery results in platelet activation and PF4
release from platelet alpha granules.
 In general, antibodies can be identified in up to 15% of orthopedic
surgical patients and up to 50% of cardiopulmonary bypass patients.
 Therapeutic heparin doses are not required to stimulate antibody
production; even small amounts of heparin can result in antibody
formation and clinical HIT.

23.  Patients baseline platelet counts should be obtained before initiating heparin
therapy. A falling platelet count during therapy raises the suspicion of HIT, and in
the usual presentation
 The platelet count begins to drop after 5 to 10 days of heparin therapy. Patients
with recent heparin exposure (within 100 days) may have platelet counts that
fall before day 5, often within the first 24 hours. Delayed-onset cases also occur
but are uncommon.

25. WHEN TO GO FOR DIAGNOSTIC TESTING?
 The 4 T's have been recommended to be used in a diagnostic algorithm
for HIT: (Pre test Probability)
1.Thrombocytopenia
2.Timing of platelet count drop
3.Thrombosis and other sequelae such as localized skin reactions
4.oTher causes of thrombocytopenia not evident
Each feature is given a score and patients are classified as
high, intermediate, or low probability.
Such clinical scoring systems have good Negative predictive value for
patients with low scores;
patients with moderate or high clinical probability usually require lab testing

26. LABORATORY TESTING
1.ELISA
(with PF4/polyanion as the antigen)
• This tests for presence of
antibodies in serum against
heparin and PF4 complexes.
• Since many patients develop
antibodies but do not develop
clinical HIT, the test has a low
specificity for the diagnosis of
HIT.
2.Platelet activation assays
(Seratonin Release Assays)
• which measures the ability of the
patient's serum to activate
platelets in the presence of
heparin in a concentrationdependent manner.
• This test has lower sensitivity but
higher specificity than the ELISA.
• This remains to be GOLD
STANDARD test in HIT diagnosis.
Neverthless, HIT remains to be a CLINICAL DIAGNOSIS

27. Early Recognition, Stop Heparin(Don’t switch
to LMWH)
Go for Imaging Studies( Atleast lower
extremity duplex Dopplers)
The direct thrombin inhibitors (DTIs)
argatroban and lepirudin are to be started
If thrombosis present – treat for 3 to 6 months
If no evidence – treat for 1 month

28. TREATMENT OF HIT
 The direct thrombin inhibitors (DTIs) ARGATROBAN AND LEPIRUDIN are
effective in HITT.
 The DTI bivalirudin and the antithrombin-binding pentasaccharide
fondaparinux are also effective but not yet approved by the U.S. Food
and Drug Administration (FDA) for this indication.
 ARGATROBAN : The dose is 2 mcg/kg/min, adjusted by aPTT with a target
of 1.5-3 times the baseline. The initial dose should be reduced by 75% in
patients with liver dysfunction.
 LEPIRUDIN : The dose is 0.4 mg/kg via intravenous bolus, which should be
followed by an initial maintenance infusion of 0.15 mg/kg/h, adjusted for a
target activated partial thromboplastin time (aPTT) of 1.5-2.5 times the
baseline.
 It is important to remember that lepirudin is Metabolised by the kidneys
and argatroban by the liver.

29. Warfarin therapy in HIT
 Warfarin should be postponed until substantial platelet recovery. If
warfarin has already been started, vitamin K should be given.
 Introduction of warfarin alone in the setting of HIT or HITT may precipitate
thrombosis, particularly venous gangrene, presumably due to clotting
activation and severely reduced levels of proteins C and S.
 HIT patients typically present with an international normalized ratio (INR)
greater than 4, which corresponds to severe protein C depletion.
Preferably, warfarin should not started before the thrombocyte count is
greater than 150 x 109/L.
 Platelet transfusions should be avoided in heparin-induced
thrombocytopenia (HIT), as they may increase the thrombogenic effect.

30. Immune Thrombocytopenic Purpura (ITP)
 an acquired disorder in which there is immune-mediated destruction of
platelets and possibly inhibition of platelet release from the megakaryocyte.
Childhood form (most < 10 yrs old)
 May follow viral infection, vaccination
 Peak incidence in fall & winter
 ~50% receive some treatment
 ≥75% in remission within 6 mo
Adult form
 No prodrome
 Chronic, recurrences common
 Spontaneous remission rate about 5%

31. Childhood (acute) ITP
Adult (chronic) ITP

32. CLINICAL FEATURES
 ITP is characterized by mucocutaneous bleeding and a low, often very low,
platelet count, with an otherwise normal peripheral blood cells and smear.
 Patients usually present either with ecchymoses and petechiae, or with
thrombocytopenia incidentally found on a routine CBC.
 Mucocutaneous bleeding, such as oral mucosa, gastrointestinal, or heavy
menstrual bleeding, may be present. Rarely, life-threatening, including central
nervous system, bleeding can occur. Wet purpura (blood blisters in the mouth)
and retinal hemorrhages may herald life-threatening bleeding.

33. LABORATORY TESTING
Laboratory testing for antibodies (serologic testing) is usually not helpful due to the
low sensitivity and specificity of the current tests.
 Bone marrow examination :can be reserved for older adults (usually >60 years)
in patients who do not respond to initial therapy.
 Peripheral blood smear : May show large platelets
Iron deficiency anemia may be present.
 Testing for HIV infection and hepatitis C (to rule out secondary causes)
 Serologic testing for SLE, serum protein electrophoresis, and immunoglobulin levels
to potentially detect hypogammaglobulinemia .
 Direct antiglobulin testing (Coombs test) to rule out combined autoimmune
hemolytic anemia with ITP (Evans syndrome).

34. Rh0(D) immune globulin therapy:
 Only in Rh + Patients
 at 50–75 g/kg
 The mechanism of action of anti-D is not fully understood however, after
administration the anti-D coated red blood cell complexes
saturate Fcγ receptors sites on macrophages ,resulting in preferential
destruction of RBCs, therefore sparing antibody-coated platelets.

35. STEROIDS:
 Prednisone to be given at 1 mg/kg.
 Until platelet counts comes back to normal levels
 It takes around two to four weeks.
Intravenous Immunoglobulin(Ivig):
 Intravenous gamma globulin (IVIgG), which is pooled, primarily IgG
antibodies, also blocks the Fc receptor system, but appears to work
primarily through different mechanism(s).
 IVIgG is dosed at 2 g/kg total, given in divided doses over 2–5 days.

36. INITIAL THERAPY IN MILDER CASES
Rho(d) Immunoglobulin
Prednisone
IV Immunoglobulin IVig
Combination Therapy of above in severe cases
RITUXIMAB CD20 antibody
REFRACTORY ITP
SPLEENECTOMY
Thrombopoietin receptor agonists
Romiplostim(sc)
Eltrombopag(oral)

37. INHERITED THROMBOCYTOPENIA
AUTOSOMAL
DOMINANT
• May-Hegglin
anomaly
• Sebastian
• Epstein's
• Fechtner
syndromes,
AUTOSOMAL
RECESSIVE
• congenital
amegakaryocytic
thrombocytopenia
• A common feature
of these disorders is
• Bernard Soulier
syndrome
large platelets
• Thrombocytopenia
with absent radii
X-linked disorders
•
Wiskott-Aldrich
syndrome

38. Thrombotic Thrombocytopenic Purpura
 Classic pentad:
 Microangiopathic hemolytic anemia
 Thrombocytopenia
 Renal involvement
 Neurologic signs
 Fever
 Most cases in adults are caused by acquired autoantibodies that
inhibit ADAMTS13(a metalloprotease that cleaves vWF within plateletrich thrombi)
 Congenital form (Upshaw-Schulman syndrome) is the result of a
deficiency of ADAMTS13

40. DIAGNOSIS
TTP is a devastating disease if not diagnosed and treated promptly.
Findings to support the TTP diagnosis include an
 Increased lactate dehydrogenase
 Increased indirect bilirubin
 Decreased haptoglobin
 Increased reticulocyte count
 Negative direct antiglobulin test.
 The peripheral smear may show evidence of schistocytes .

41. TREATMENT
 Plasma exchange remains the mainstay of treatment of TTP.
 Plasma exchange is continued until the platelet count is normal and signs of
hemolysis are resolved for at least 2 days.
 The use of glucocorticoids seems a reasonable approach, but should only be used
as an adjunct to plasma exchange.
 Immunomodulatory therapies have been reported to be successful in refractory or
relapsing TTP, including rituximab, vincristine, cyclophosphamide, and
splenectomy.
 A significant relapse rate is noted, 25–45% within 30 days of initial "remission,"
and 12–40% with late relapses

42. THROMBOCYTOSIS
Thrombocytosis is almost always due either to
Iron deficiency
 Inflammation, cancer, or infection (reactive
thrombocytosis)
 An underlying myeloproliferative process [essential
thrombocythemia or polycythemia vera)

43. QUALITATIVE DISORDERS OF PLATELETS
INHERITED
 Glanzmann's thrombasthenia
(absence of the platelet GpIIbIIIa
receptor)
 Bernard Soulier syndrome
(absence of the platelet GpIb-IXV receptor).
ACQUIRED
 Antiplatelet therapy
 Uremia.
 Cardiopulmonary bypass
 Myeloproliferative and
myelodysplastic syndromes

45. GLANZMANN THROMBASTHENIA
 AR; Mutation in IIb-IIIa, the most abundant platelet surface
receptor
 Fundamental defect of thrombasthenic patients is the inability of the
platelets to aggregate.
 Clinical features include bleeding in skin, mucous membrane
(petichiae, echymoses), recurrent epistaxis, GI hemorrhage,
menorrhagia.
 Bleeding time prolonged.
 The hallmark of the disease is severely reduced or absent platelet
aggregation in response to multiple agonists ie ADP, thrombin, or
collagen (except Ristocetin)

46. BERNARD-SOULIER SYNDROME
 AR; characterized by moderate to severe thrombocytopenia, giant
platelets, and profuse/spontaneous bleeding.
 Basis for the disease is deficiency or dysfunction of the GP Ib-V-IX
complex.
 Prolonged bleeding time, thrombocytopenia (plt<20 K), peripheral
smear shows large platelets
 Aggregation studies show normal aggregation in response to all
agonists except Ristocetin (opposite pattern than thrombasthenia)

47. VON WILLEBRAND DISEASE
von Willebrand factor
 Synthesis in endothelium and megakaryocytes
 Forms large multimer
 Carrier of factor VIII
 Anchors platelets to subendothelium
 Bridge between platelets
 Inheritance - autosomal dominant
 Incidence - 1/5-10,000
 Clinical features - mucocutaneous bleeding

48. TYPES
1. Type I(70-80%) :a mild-to-moderate quantitative deficiency in vWF
2. Type II(10-15%) : is due to qualitative abnormalities of vWF and is
subdivided into type 2A VWD,2B,2M are due to various mutations causing
functional defects.
Type 2N - Mutations in VWF that preclude binding of FVIII. As FVIII is
stabilized by binding to VWF, the FVIII in patients with type 2N VWD
has a very short half-life, and the FVIII level is markedly decreased. This
is sometimes termed autosomal hemophilia.
3. Type III : a severe quantitative deficiency associated with very little or no
detectable plasma or platelet vWF, have a profound bleeding disorder.

49. Screening tests typically include
 Prothrombin time (PT)
 Activated partial thromboplastin time (aPTT),
 FVIII level
 Ristocetin cofactor (RCoF) activity
 vWF antigen (vWF:Ag).
Assay
vWF antigen
vWF activity
Multimer analysis
1
vonWillebrand type
2
3
Normal
Normal
Normal
Absent

50. DDAVP (deamino-8-arginine vasopressin)
 plasma VWF levels by stimulating secretion from endothelium
Duration of response is variable
Not generally used in type 2 disease
Dosage 0.3 µg/kg q 12 hr IV
Used in Type 1 Vwf disease
Cryoprecipitate
Source of fibrinogen, factor VIII and VWF
Only plasma fraction that consistently contains VWF multimers
Used in Type 2 and 3 Vwf disease.

51. Antifibrinolytic therapy using either E-aminocaproic acid or
tranexamic acid is an important therapy, either alone or in an adjunctive
capacity, particularly for the prevention or treatment of mucosal
bleeding.
 particularly useful in prophylaxis for dental procedures, with DDAVP for
dental extractions and tonsillectomy, menorrhagia, and prostate
procedures.
 It is contraindicated in the setting of upper urinary tract bleeding, due
to the risk of ureteral obstruction.

52. WHY IS THROMBOCYTOPENIA IN MALARIA?
 The Plasmodium species have no direct effect on platelets. Instead
Plasmodium attacks red blood cells (RBCs) and when the are damaged
they are trapped by the spleen which filters the blood.
 Because there are so many RBCs damaged the spleen takes up an
unusually high number of RBCs and becomes enlarged (splenomegaly).
 The platelets get trapped in the now clogged spleen and this causes the
thrombocytopenia.
Source:
Cohen & Powderly: Infectious Diseases, 2nd ed., Copyright © 2004 Mosby

53. IMMUNE-MEDIATED THROMBOCYTOPENIA OF MALARIA
(J G Kelton, J Keystone, J Moore, G Denomme, E Tozman, M Glynn, P B Neame, J Gauldie, and J Jensen)
 We studied 28 patients with malarial infections and noted that 16 of 17
thrombocytopenic patients had elevated levels of platelet-associated IgG
(PAIgG).
 In all thrombocytopenic patients studied, the level of PAIgG returned to
normal as the platelet count rose to normal levels.
 The thrombocytopenia that complicates at least some malarial infections is
caused by immune mechanisms; specific IgG binds to platelet-bound
malaria antigen through the Fab portion of the immunoglobulin molecule.

54. THROMBOCYTOPENIA IN DENGUE
Three possible triggers to induce thrombocytopenia in dengue virus
infection. (Funahara Y, Ogawa K, Fujita N, Okuno Y.)
1) DV antigen attached to human platelets without immune-mediated
reaction.(direct lysis)
2) A decrease in platelet count was more markedly demonstrated by
the binding of anti-DV antibody on the DV antigen associated with
platelets than by the binding of the antigen-antibody complex on
platelets.(immune mediated)
3) a modulation of endothelial cell by the infection of DV to the cell was
suggested as one of the causes of the thrombocytopenia.(endotheliumADAMTS13 related).

55. CAPILLARY LEAKAGE IN DENGUE
 Angiopoietin-1 (Ang-1) is stored in platelets and activates the
endothelial cell-specific tyrosine kinase receptor Tie-2, which in turn
leads to enhanced endothelial cell survival and stabilization and
maintains vascular integrity.
 On the other hand, the angiopoietin-2 (Ang-2), is derived from
endothelium and stored in Weibel-Palade bodies (WPBs).
 There was an inverse correlation between angiopoietin-1 and markers
of plasma leakage and a positive correlation between angiopoietin-2
and markers of plasma leakage
 The VWF activation factor was also higher in children with DHF/DSS: it
was highest in children who died.
 In all probability, high circulating levels of VWF in an active
conformation, together with low ADAMTS-13 levels, contribute to the
thrombocytopenia and complications of dengue

56. INHIBITION

57. THANK YOU