Primary and secondary hemostatic disorders for clinical year medical students

1. HEMOSTASIS DISORDERS
Dr. Segenet Bizuneh
Assistant professor of Internal Medicine
University Gondar
1

2. Introduction
• The human hemostatic system provides a natural balance between
procoagulant and anticoagulant forces.
• The procoagulant forces include platelet adhesion and aggregation and fibrin
clot formation.
• Anticoagulant forces include the natural inhibitors of coagulation and
fibrinolysis.
• The major components of the hemostatic system
I. Patelets and other formed elements of blood, such as monocytes
and red cells
II. Plasma proteins (the coagulation and fibrinolytic factors and
inhibitors)
III. The vessel wall
2

3. Introduction: Steps in normal Hemostasis
• Platelet plug formation
• Fibrin clot formation
• Antithrombotic mechanisms
• Fibrinolytic system
3

4. Introduction: Platelet Plug formation
• Hemostasis is a dynamic process in which the platelet and the blood
vessel wall play key roles.
• Platelets become activated upon adhesion to von Willebrand factor
(VWF) and collagen in the exposed sub-endothelium after injury.
• The activated platelet surface provides the major physiologic site for
coagulation factor activation, which results in further platelet
activation and fibrin formation.
• Platelet adhesion results in the generation of intracellular signals that lead to
activation of the platelet glycoprotein (Gp) IIb/IIIa (αIIbβ3) receptor and resultant
platelet aggregation.
4

5. Introduction: Fibrin clot formation
• Plasma coagulation proteins (clotting factors) normally circulate in
plasma in their inactive forms.
• Two pathways of blood coagulation have been described in the past:
• Extrinsic, or tissue factor, pathway and
• Intrinsic, or contact activation, pathway
We now know that coagulation is normally initiated through tissue factor
(TF) exposure and activation through the classic extrinsic pathway but with
critically important amplification through elements of the classic intrinsic
pathway.
5

7. Thrombin
 Converts soluble plasma fibrinogen to an
insoluble fibrin matrix
 Activates factor XIII (fibrin-stabilizing
factor)

8. Coagulation Phases
Initiation Amplification Propagation Termination
Interaction of TF with
plasma derived activation
FVII
Thrombin activates
• Platelets
• FV and FVIII
• FIX
Production of large
amount of thrombin
Formation of stable buffer
at the site of injury and
interruption of blood loss
Process of coagulation is
restricted to prevent the
thrombotic occlusion of
the intact areas of the
vessels
Current hemostasis model

9. Introduction: Anti-thrombotic mechanisms
• To prevent clotting under normal circumstances.
• Endothelial cells have many antithrombotic effects.
• Endothelial cells produce
• Prostacyclin, nitric oxide, and ectoADPase/CD39
• These act to inhibit platelet binding, secretion, and aggregation.
• Anticoagulant factors
• Heparan proteoglycans, antithrombin, TF pathway inhibitor, and thrombomodulin.
• Activate fibrinolytic mechanisms
• Through the production of tissue plasminogen activator 1, urokinase, plasminogen
activator inhibitor, and annexin-2
9

10. Introduction: Anti-thrombotic mechanisms
• Antithrombin (or antithrombin III)
• The major plasma protease inhibitor of thrombin
• It neutralizes thrombin and other activated coagulation factors
• The rate of inactivating increases by a factor of several thousand in the presence
of heparin
• Inherited quantitative or qualitative deficiencies of antithrombin lead to a lifelong
predisposition to venous thromboembolism.
• Protein C
• A plasma glycoprotein that becomes an anticoagulant when it is activated by
thrombin
• Activated protein C acts as an anticoagulant by cleaving and inactivating
activated factors V and VIII.
• This reaction is accelerated by a cofactor, protein S, which, like protein C, is a
glycoprotein that undergoes vitamin K–dependent posttranslational modification
10

11. Introduction: The Fibrinolytic System
• Any thrombin that escapes the inhibitory effects of the physiologic
anticoagulant systems is available to convert fibrinogen to fibrin.
• In response, the endogenous fibrinolytic system is then activated to
dispose of intravascular fibrin and thereby maintain or reestablish the
patency of the circulation.
• Just as thrombin is the key protease enzyme of the coagulation
system, plasmin is the major protease enzyme of the fibrinolytic
system, acting to digest fibrin to fibrin degradation products.
• D-dimers can be measured in plasma as a relatively specific test of
fibrin (rather than fibrinogen) degradation.
• D-dimer assays can be used as sensitive markers of blood clot formation
11

13. Manifestations of Hemostasis Disorders
• They can be divided arbitrarily into two groups:
• Those seen more often in disorders of blood coagulation and
• Those most commonly noted in disorders of the vessels and platelets.
• The latter group is often called purpuric disorders because cutaneous
and mucosal bleeding usually are prominent.

14. Manifestations of Hemostasis Disorders

15. Manifestations of Hemostasis Disorders
• Patients with hematuria, hematemesis, and melena, bleeding from these
sites may also be associated with both purpuric and coagulation disorders.
• Severe menorrhagia may be the sole symptom of women with von
Willebrand disease (vWD), mild thrombocytopenia, or autosomally inherited
coagulation disorders.
• Recurrent gastrointestinal bleeding or epistaxis in the absence of other
bleeding manifestations is common in hereditary hemorrhagic telangiectasia.
• Bleeding into the central nervous system may complicate thrombocytopenia
and may occur after minor trauma in patients with coagulation disorders.
• The coexistence of bleeding and thromboembolic phenomena or bleeding
from previously intact venipuncture sites is suggestive of diffuse intravascular
coagulation (DIC).
15

16. Clinical Features of Inherited Vs Acquired
Bleeding Disorders
Inherited
• Onset of bleeding symptoms in
infancy
• A positive family history
• Commonly the deficiency of a single
coagulation factor
Acquired
• less severe than in the inherited
• Multiple hemostatic defects
commonly are present
• Drug History
16

17. .

18. Tests of Vascular and Platelet Phases
• Bleeding Time
 The rate at which a stable platelet plug is formed and, thus, provides a measure of
the efficiency of the vascular and platelet phases.
• BT is now obsolete b/c of the following drawbacks
i. It does not discriminate between vascular defects, thrombocytopenia, and platelet
dysfunction
ii. Normal bleeding time does not exclude a bleeding disorder
• Platelet count
• Two groups of techniques:
• Hemacytometer or
• Direct methods
• Microscopic estimation
• At 100× power, each platelet counted/field represents ~l0,000 platelets/µL.
• Consequently, a normal blood smear should demonstrate, on average, at least 14
platelets/high-power field
18

19. • Platelet Function Assays
• Platelet Aggregometry
• Light transmission aggregometry (LTA) is regarded as the gold standard of platelet
function testing and is still the most used test for the identification and diagnosis of
platelet function defects
• Platelet function analyzer- (PFA-) 100 and PFA-200 devices (Siemens,
Marburg, Germany)
• The most widely used test today
19

20. Tests of Coagulation Phase
• Activated Partial Thromboplastin Time
• The activated partial thromboplastin time (aPTT or PTT) is used to assess the
integrity of the intrinsic coagulation pathway (prekallikrein, high molecular
weight kininogen, factors XII, XI, IX, VIII) and final common pathway (factors
II, V, X, and fibrinogen), and to monitor heparin therapy.
• Prothrombin Time
• Used to assess the extrinsic pathway of clotting, which consists of tissue
factor and factor VII, and coagulation factors in the common pathway (factors
II [prothrombin], V, X, and fibrinogen)
• PT expressed as INR — In order to promote standardization
of the PT for monitoring oral anticoagulant therapy, the
WHO developed an international reference thromboplastin,
PT ratio be expressed as the International Normalized Ratio
or INR
20

21. • Thrombin Time and Related Techniques
• When thrombin is added to plasma, the time required for clot formation is a
measure of the rate at which fibrin forms.
• This test (thrombin time) yields abnormal results when the fibrinogen level is
<70 to 100 mg/dl, but it is unaffected by the levels of any of the other
coagulation factors
• It is greatly prolonged by heparin.
21

22. Prolonged PT normal PTT
Normal PT Prolonged PTT
Prolonged PT & PTT

23. PRIMARY HEMOSTASIS DISORDERS
The Platelet
• Platelets are released from the megakaryocyte, likely under the influence of
flow in the capillary sinuses.
• The normal blood platelet count is 150,000–450,000/μL with average life
span of 7 to 10 days.
• The major regulator of platelet production is the hormone thrombopoietin (TPO),
which is synthesized in the liver.
• Synthesis is increased with inflammation and specifically by interleukin 6.
• TPO binds to its receptor on platelets and megakaryocytes.
• Thus a reduction in platelet and megakaryocyte mass increases the level of
TPO, which then stimulates platelet production.
23

24. The Platelet
• Approximately one-third of the platelets reside in the spleen
• This number increases in proportion to splenic size, although the platelet
count rarely decreases to <40,000/μL as the spleen enlarges.
• Platelets are physiologically very active, but are anucleate, and thus have limited
capacity to synthesize new proteins.
• Activated platelets undergo release of their granule contents
• These include nucleotides, adhesive proteins, growth factors, and
procoagulants
• The platelet plug is stabilized by the fibrin mesh that develops simultaneously
as the product of the coagulation cascade.
24

25. The Vessel Wall
• Endothelial cells line the surface of the entire circulatory tree,
totaling 1–6 x 1013 cells, enough to cover a surface area equivalent to
about six tennis courts.
• The endothelium is physiologically active, controlling
• Vascular permeability,
• Flow of biologically active molecules and nutrients,
• Blood cell interactions with the vessel wall,
• The inflammatory response, and
• Angiogenesis.
25
The endothelium normally presents an antithrombotic surface
but rapidly becomes prothrombotic when stimulated, which
promotes coagulation, inhibits fibrinolysis, and activates
platelets.

26. Thrombocytopenia: <150,00/microl
• Thrombocytopenia results from one or more of three processes:
1. Decreased bone marrow production; be either inherited or acquired
2. Sequestration, usually in an enlarged spleen; and/or
3. Increased platelet destruction.
26
“Pseudothrombocytopenia" should be ruled out particularly in a patient
without an apparent cause for the thrombocytopenia
Pseudothrombocytopenia is an in vitro artifact resulting from
platelet agglutination via antibodies when the calcium content
is decreased by blood collection in EDTA.

27. Abnormal large platelet in autosomal dominant
macrothrombocytopenia
27

28. Schistocytes and decreased platelets in
microangiopathic hemolytic anemia.
28

29. Thrombocytopenia
• History, Physical Examination, CBC and peripheral morphology are all
critical
• Except in unusual inherited disorders, decreased platelet production
usually results from bone marrow disorders that also affect red blood
cell (RBC) and/or white blood cell (WBC) production.
• Because myelodysplasia can present with isolated thrombocytopenia,
the bone marrow should be examined in patients presenting with
isolated thrombocytopenia who are older than 60 years of age.
29

30. Thrombocytopenia
• P/E: Enlarged spleen, evidence of chronic liver disease, and other underlying
disorders.
• Mild to moderate splenomegaly may be difficult to appreciate
• A platelet count of approximately 5000–10,000 is required to maintain vascular
integrity in the microcirculation.
• When the count is markedly decreased, petechiae first appear in areas of
increased venous pressure, the ankles and feet in an ambulatory patient.
• Petechiae are pin-point, non-blanching hemorrhages and are usually a sign
of a decreased platelet number and not platelet dysfunction
• Wet purpura blood blisters that form on the oral mucosa, are thought to
denote an increased risk of life-threatening hemorrhage in the
thrombocytopenic patient.
• Excessive bruising is seen in disorders of both platelet number and function
30

31. 31

32. 32

33. Clinical case
• A 57-year-old woman, with considerable exposure to COVID-19 patients,
presented to a clinic with headache and malaise with the onset of 5 days
prior to admission. She did not report any respiratory symptoms, fever, chills
or gastrointestinal symptoms and was previously healthy, not taking any
medications. Laboratory results showed significant thrombocytopenia with
a platelet count of 48,000 (per/mm3) associated with a normal, neutrophil
dominant (75 %) white blood cell count of 7100 (per/mm3) and relatively
decreased lymphocytes (14 %).
• Upon admission she had a core body temperature of 36.9 ֯C.
• No abnormalities were detected during the physical examination.
• In the following laboratory studies, patient’s platelet count continued to
decline to 16,000 per/mm3
• COVID-19 test is postive
33

34. Infection-Induced Thrombocytopenia
• Many viral and bacterial infections result in thrombocytopenia and
are the most common non-iatrogenic cause of thrombocytopenia
• This may or may not be associated with laboratory evidence of
disseminated intravascular coagulation (DIC).
• Infections can affect both platelet production and platelet survival.
• In addition, immune mechanisms can be at work, as in infectious
mononucleosis,HCV and early HIV infection. AND COVID-19
• Late in HIV infection, pancytopenia and decreased and dysplastic
platelet production is more common
34

35. Drug-Induced Thrombocytopenia
• Many drugs have been associated with 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.
• Classic drug-dependent antibodies are antibodies that react with specific
platelet surface antigens, and result in thrombocytopenia only when the drug is
present (quinine and sulfonamides).
• Herbal and over-the-counter preparations may also result in thrombocytopenia.
35

36. Drug-Induced Thrombocytopenia
Abciximab Ibuprofen Diclofenac Quinine
Acetaminophen Iopanoic acid Digoxin Quinidine
Aminoglutethimide Levamisole Dipyridamole Rifampin
Aminosalicylic acid Linezolid Eptifibatide Simvastatin
Amiodarone Meclofenamate Ethambutol Sulfa-containing drugs
Amphotericin B Methicillin Famotidine Tamoxifen
Ampicillin Methyldopa Fluconazole Tirofiban
Carbamazepine Nalidixic acid Furosemide Trimethoprim/sulfameth
oxazole
Chlorpropamide Naproxen Glyburide Valproic acid
Danazol Oxyphenbutazone Gold Vancomycin
Captopril Phenytoin Hydrochlorothiazide
Cimetidine Piperacillin Imipenem/Cilastatin
Diatrizoate meglumine (Hypaque
Meglumine®)
Procainamide 36

37. Drug-Induced Thrombocytopenia
• The thrombocytopenia typically occurs after a period of initial
exposure (median length 21 days), or upon re-exposure, and usually
resolves in 7–10 days after drug withdrawal.
• The thrombocytopenia caused by the platelet GpIIb/IIIa 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.
37

38. Clinical Case
• A 73-year-old woman had a middle cerebral artery stroke and
developed recurrent seizures requiring medication. She then
developed pneumonia and respiratory failure and required an
intensive care unit (ICU) admission for mechanical ventilation. During
her ICU stay, the patient received her usual anticonvulsants and
aspirin. In addition, she required antibiotics, prophylactic
unfractionated heparin for thromboprophylaxis, sedation, and
diuretics.
• Because of worsening seizures, valproic acid was added on ICU day 4.
On day 12, the pneumonia was thought to be resolving, but an
extubation trial failed, and the platelet count was noted to have
gradually fallen to 36 × 109/L over the prior 6 days.
38

39. 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/μL.
2. Heparin-induced thrombocytopenia (HIT) is not associated with bleeding and,
in fact, markedly increases the risk of thrombosis.
 HIT results from antibody formation to a complex of the platelet-specific protein
platelet factor 4 (PF4) and heparin.
• A fraction of those who develop antibodies will develop HIT, and a portion of
those (up to 50%) will develop thrombosis (HITT).
• HIT can occur after exposure to low-molecular-weight heparin (LMWH) as
well as unfractionated heparin (UFH),
• It is about 10 times more common with UFH.
• Most patients develop HIT after exposure to heparin for 5–14 days
39

40. Heparin-Induced Thrombocytopenia
• The 4 T's have been recommended to be used in a diagnostic
algorithm for HIT:
• Thrombocytopenia,
• Timing of platelet count drop,
• Thrombosis and other sequelae such as localized skin reactions, and
• oTher causes of thrombocytopenia not evident.
40
HIT (anti-heparin/PF4) antibodies can be detected
However, HIT remains a clinical diagnosis.

41. Heparin-Induced Thrombocytopenia
• Treatment
• Early recognition is key in treatment of HIT
• Prompt discontinuation of heparin and use of alternative anticoagulants.
• Thrombosis is a common complication of HIT, even after heparin
discontinuation, and can occur in both the venous and arterial systems
• Patients with higher anti-heparin/PF4 antibody titers have a higher risk of thrombosis
• An alternative anticoagulant.
• The direct thrombin inhibitors (DTIs) argatroban and lepirudin are effective in HITT
• Because of the high rate of thrombosis in patients with HIT, anticoagulation
should be strongly considered, even in the absence of thrombosis
• In patients with thrombosis, patients can be transitioned to warfarin, with
treatment usually for 3–6 months.
41

42. Clincal case
• A previously well 28-year-old woman presents with a history of mild
nose bleeds and easy bruising for 8 days. She denied a history of
abnormal bleeding and had been perfectly healthy, participating in a
soccer league. There was no recent upper respiratory illnesses, no
recent travel, and no significant trauma other than on the soccer
field. Her only medication was a multivitamin pill with iron because
of menorrhagia. Physical examination revealed a thin, healthy
woman with normal vital signs. There were a few petechiae in her
conjunctivae and mouth, and a modest-sized, healing bruise on her
abdomen. There was no hepatosplenomegaly or palpable
lymphadenopathy.
• Her laboratory findings included a Hgb of 12.4 g/dL, WBC of 6.8 ×
109/L, and platelet count of 9 × 109/L, and her blood film was normal
except for markedly decreased but large platelets.
42

43. Immune thrombocytopenic purpura
• Also termed idiopathic thrombocytopenic purpura
• It is an acquired disorder in which there is immune-mediated
destruction of platelets and possibly inhibition of platelet release from
the megakaryocyte
• In children, it is usually an acute disease, most commonly following an infection,
and with a self-limited course.
• In adults, it usually runs a more chronic course
• ITP is termed secondary if it is associated with an underlying disorder
• Such as autoimmune disorders, particularly systemic lupus erythematosus (SLE),
and infections, such as HIV and hepatitis C, are common causes.
• The association of ITP with Helicobacter pylori infection is unclear.
43

44. Immune thrombocytopenic purpura
• 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.
• 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.
44

45. Immune thrombocytopenic purpura- Lab
Featues
• Bone marrow examination can be reserved for
• Older adults (usually >60 years) or
• Those who have other signs or laboratory abnormalities not explained by ITP,
or
• In patients who do not respond to initial therapy
• The peripheral blood smear may show large platelets, with otherwise
normal morphology.
• Depending on the bleeding history, iron deficiency anemia may be present.
45

46. Immune thrombocytopenic purpura- Lab
Featues
• Laboratory testing is performed to evaluate for secondary causes of
ITP and should include
• Testing for HIV infection and hepatitis C (and other infections if indicated);
• Serologic testing for SLE
• Serum protein electrophoresis, and immunoglobulin levels to potentially
detect hypogammaglobulinemia
• Selective testing for IgA deficiency or monoclonal gammopathies
• If anemia is present, direct antiglobulin testing (Coombs test) to rule out
combined autoimmune hemolytic anemia with ITP (Evans syndrome).
46

47. Natural History
• In children, 70 to 80 percent have a spontaneous complete remission
of the disease within six months.
• Spontaneous remissions are unusual in adults, occurring in 9 percent
in one series
• The frequency of spontaneous remissions in adults after a prolonged
duration of ITP is less clear
47

48. Immune thrombocytopenic purpura-
Treatment
• Since spontaneous remissions are unusual in adults with ITP,
treatment to increase the platelet count is always initiated in patients
with a platelet count below 30,000/microL.
• Patients with mild to moderate asymptomatic thrombocytopenia that
is discovered incidentally on a routine blood count should not be
treated.
48

49. 49

50. Immune thrombocytopenic purpura-
Treatment
• The treatment of ITP utilizes drugs that
• Decrease reticuloendothelial uptake of the antibody-bound platelet,
• Decrease antibody production, and/or
• Increase platelet production
50

51. 51

52. ITP: Treatment Of Life-threatening Bleeding
• Life-threatening bleeding may be seen at any age and at any time
during the course of this disease, but appears to be more common in
older patients
• Therapeutic options
• Platelet transfusions
• IVIG (1 g/kg, repeated the following day if the platelet count remains
<50,000/microL)
• Pulse methylprednisolone (1 g intravenously, repeated daily for three doses)
• Recombinant human factor VIIa
52

53. Immune thrombocytopenic purpura- Chronic
Refractory ITP
• Chronic Refractory ITP: is defined in the presence of ALL of the
following:-
• ITP persistent for >3 months
• Failure to respond to splenectomy and rituximab
• Platelet count <50,000/microL
53

54. 54

55. Inherited Thrombocytopenia
• Thrombocytopenia is rarely inherited, either as an isolated finding or as part
of a syndrome, and may be inherited in an autosomal dominant, autosomal
recessive, or X-linked pattern
• Many forms of autosomal dominant thrombocytopenia are now known to be
associated with mutations in the non-muscle myosin heavy chain
MYH9 gene.
• Interestingly, these include the May-Hegglin anomaly, and Sebastian,
Epstein's, and Fechtner syndromes, all of which have distinct distinguishing
features
• A common feature of these disorders is large platelets.
• Autosomal recessive disorders include congenital amegakaryocytic
thrombocytopenia, thrombocytopenia with absent radii, and Bernard Soulier
syndrome.
55

56. Thrombotic thrombocytopenic microangiopathies
• Thrombotic thrombocytopenic microangiopathies are a group of
disorders characterized by
• Thrombocytopenia
• Microangiopathic hemolytic anemia evident by fragmented RBCs and
laboratory evidence of hemolysis and
• Microvascular thrombosis.
• Includes:
• Thrombotic Thrombocytopenic purpura (TTP) and
• Hemolytic Uremic Syndrome (HUS)
• Syndromes complicating bone marrow transplantation, Certain medications,
Infections, Pregnancy and Vasculitis.
56

57. TTP & HUS Vs DIC
• In DIC, while thrombocytopenia and microangiopathy are seen, a
coagulopathy predominates, with consumption of clotting factors
and fibrinogen resulting in an elevated prothrombin time (PT), and
often activated partial thromboplastin time (aPTT).
• The PT and aPTT are characteristically normal in TTP or HUS
57

58. TTP
• TTP and HUS were previously considered overlap syndromes.
• However, in the past few years the pathophysiology of inherited and
idiopathic TTP has become better understood and clearly differs from HUS.
• TTP characterized by a pentad of findings that include
Microangiopathic hemolytic anemia
Thrombocytopenia
Renal failure
Neurologic findings
Fever
58
 The pathogenesis of idiopathic TTP is related to a
deficiency of, or antibodies to, the
metalloprotease ADAMTS13, that cleaves VWF.
 More common in: HIV, women and pregnant

59. 59

60. TTP
• Findings to support the TTP diagnosis include
• An increased LDH and indirect bilirubin
• Decreased haptoglobin, and
• Increased reticulocyte count, with a negative direct antiglobulin test
• The peripheral smear should be examined for evidence of
schistocytes
• Polychromasia: usually present due to the increased number of young RBCs,
and
• Nucleated RBCs: often present, which is thought to be due to infarction in
the microcirculatory system of the bone marrow.
60

61. TTP- Treatment
• Plasma exchange remains the mainstay of treatment of TTP.
• ADAMTS 13 antibody-mediated TTP (idiopathic TTP) appears to respond best
to plasma exchange.
• Plasma exchange is continued until the platelet count is normal and signs of
hemolysis are resolved for at least 2 days.
• Glucocorticoids should only be used as an adjunct to plasma
exchange.
• Refractory or relapsing TTP: Other immunomodulatory therapies
• Including rituximab, vincristine, cyclophosphamide, and splenectomy.
61

62. HUS
• HUS is a syndrome characterized by acute renal failure,
microangiopathic hemolytic anemia, and thrombocytopenia
• It is seen predominantly in children and in most cases is preceded by
an episode of diarrhea, often hemorrhagic in nature.
62

63. HUS
• Escherichia coli O157:H7 (EHEC ) is the most frequent, although not
only, etiologic serotype: diarrheal associated HUS.
• Mediated by Shiga toxin.
• HUS not associated with diarrhea (termed atypical HUS) is more
heterogeneous in presentation and course.
• Some children who develop DHUS have been found to have
mutations in genes encoding factor H
• This is a soluble complement regulator, and membrane cofactor protein that
is mainly expressed in the kidney.
63

64. HUS- Treatment
• Primarily supportive.
• In D+HUS, many (~40%) children require at least some period of
support with dialysis;
• The overall mortality is <5%.
• In D–HUS, the mortality is higher, approximately 26%.
• Plasma infusion or plasma exchange has not been shown to alter the
overall course.
• ADAMTS13 levels are generally normal in HUS.
64

65. Thrombocytosis
• Thrombocytosis is almost always due either to
• Iron deficiency
• Inflammation, cancer, or infection (reactive thrombocytosis); or
• An underlying myeloproliferative process [ET or PV] or, rarely, the 5q-
myelodysplastic process
• Patients presenting with an elevated platelet count should be
evaluated for underlying inflammation or malignancy, and iron
deficiency should be ruled out
65

66. Thrombocytosis
• Thrombocytosis in response to acute or chronic inflammation has not
been associated with an increased thrombotic risk.
• But, patients with markedly elevated platelet counts (>1 million),
usually seen in the setting of a myeloproliferative disorder, have an
increased risk of bleeding.
• This appears to be due, at least in part, to acquired von Willebrand
disease (VWD) due to platelet-VWF adhesion and removal.
66

67. Clinical case
• A 22-year old boy was brought to the emergency department by his
mother for oozing blood from his mouth following a fall nearly 6
hours ago. His mother related that he tended to bleed for prolonged
periods from his immunization sites, but there was no history of
bruising or hematomas. The patient was on antibiotics for a recent
ear infection. There was no known family history of a bleeding
disorder.
67
Hemoglobin 12.3 g/dl (10.5-13.5)
Hematocrit 35.4% (33.0-39.0)
WBC 7.9 x 10^9/L (6.0-17.5)
Platelets 368 x 10^9/L (156-369)
PT 11.3 s (10.0-12.8)
APTT 37.2 s (24.4-33.2
DIFFERENTIAL DIAGNOSIS:
•Von Willebrand disease
•Factor VIII and IX deficiency (Hemophilia A, B)
•Lupus anticoagulant (possible), factor VIII
inhibitor (rare at this age)
•Factors XI and XII deficiency (rare)

68. 68

69. von Willebrand Disease
• VWD is the most common inherited bleeding disorder.
• Estimates (lab data): a prevalence of approximately 1%.
• Estimates (Symptomatic individuals): suggest prevalence closer to
0.1% of the population.
69

70. von Willebrand Disease
• vWF serves two roles:
• As the major adhesion molecule that tethers the platelet to the exposed sub-
endothelium; and
• As the binding protein for FVIII, resulting in significant prolongation of the FVIII half-
life in circulation.
• The platelet-adhesive function of vWF is critically dependent on the presence of
large vWF multimers, while FVIII binding is not.
• Most of the symptoms of vWD are "platelet-like" except in more severe vWD
• In severe vWD, when the FVIII is low enough, it produces symptoms similar to
those found in Factor VIII deficiency (hemophilia A).
• vWD has been classified into three major types, with four subtypes of type 2
• Types 1, 2A, 2B, 2M, 2N & 3
• By far the most common type of VWD is type 1 disease
70

71. von Willebrand Disease: Classification
I) Type 1: a quantitative defect and the most common type (-75%).
2) Type 2: 4 subtypes (A, B, M, N}-all qualitative defects
• Type 2A: the 2"d most common type of vWD (10-15%) and the result of
too little of the large vWF multimer.
• Type 2B: Mutant vWF has increased affinity for platelets, causing
spontaneous binding of large vWF multimers to platelets and subsequent
clearing of the complex.
• Causes mild thrombocytopenia.
• Do not use desmopressin to treat because it causes increased release of
mutant vWF and increased clearance of platelet-vWF complex,
exacerbating thrombocytopenia.
71

72. von Willebrand Disease: Classification
• Type 2M: decreased affinity for platelets.
• Type 2N: an abnormal vWF protein with impaired ability to bind Factor VIII.
This leads to loss of protection for Factor VIII while in circulation and
therefore increased Factor VlII clearance and decreased Factor VIII levels.
Presentation is similar to classic hemophilia.
3) Type 3: rare and severe. Autosomal recessive.
Minimal-to-undetectable levels of vWF lead to spontaneous bleeding.
The presentation also resembles that of classic hemophilia.
72

73. von Willebrand Disease: Clinical manifestation
• Patients have predominantly mucosal bleeding symptoms, although
postoperative bleeding can also be seen.
• Bleeding symptoms are very uncommon in infancy and usually
manifest later in childhood with excessive bruising and epistaxis.
• Menorrhagia is a common manifestation of VWD.
• Menstrual bleeding resulting in anemia should warrant an evaluation for
VWD and, if negative, functional platelet disorders
73
 Individuals with type O blood have lower baseline levels of vWF.
 Levels of vWF increase during pregnancy and with estrogen use.
 The PTT is often increased because of decreased levels of Factor VIII.
 The bleeding time is prolonged.

74. von Willebrand Disease
74

75. von Willebrand Disease
• Acquired VWD is a rare disorder
• Most commonly seen in patients with underlying lymphoproliferative disorders,
• Including monoclonal gammopathies of underdetermined significance (MGUS), multiple
myeloma, and Waldenström's macroglobulinemia
• Laboratory evidence of acquired VWD is found in some patients with aortic
valvular disease.
• Heyde's syndrome (aortic stenosis with gastrointestinal bleeding) is attributed to
the presence of angiodysplasia of the gastrointestinal tract in patients with aortic
stenosis.
• However, the shear stress on blood passing through the stenotic aortic valve
appears to produce a change in VWF, making it susceptible to serum proteases.
• Consequently, large multimer forms are lost, leading to an acquired type 2 VWD,
but return when the stenotic valve is replaced
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76. von Willebrand Disease
Treatment
• Type 1: Mainstay of Rx is 1-deamino-8-d-arginine vasopressin (DDAVP, or
desmopressin),
• Results in release of VWF and FVIII from endothelial stores
• DDAVP can be given intravenously or by a high concentration intranasal spray (1.5
mg/mL).
• The peak activity when given intravenously is approximately 30 minutes, while it is 2
h when given intranasally.
• Major side effects: Hyponatremia
-Due to decreased free water clearance, restrict fluid for 24hrs after each dose
76

77. von Willebrand Disease
Treatment
• Other types
• Some patients with types 2A and 2M VWD respond to DDAVP such that it
can be used for minor procedures.
• For the other subtypes (B & N), for type 3 disease, and for major procedures
requiring longer periods of normal hemostasis, VWF replacement can be
given.
• Cryoprecipitate as the replacement product.
• Antifibrinolytic therapy using either ε-aminocaproic acid or tranexamic acid
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78. 78

79. Disorders of the Vessel Wall
• Metabolic and Inflammatory Disorders
• Acute febrile illnesses
• Monoclonnal or Polyclonnal gammopathies
• Mixed Cryoglobulinemia
• Scurvy (Vitamin C deficiency)
• Cushing Syndrome/ Prolonged steroid use
• Henoch-Schönlein Purpura ( IgA vasculitis)
79

80. CLINICAL CASE
• A 16-year-old male presented with fever and sore throat for 5 days.
He was given oral penicillin by his primary care doctor. After a day, he
developed an erythematous, non-pruritic rash which progressed
proximally from both feet to thighs and upper extremities including
palms and soles. Two days later, the patient developed abdominal
pain involving the right and left upper quadrant which was constant,
colicky in nature.
• Laboratory tests showed leukocytosis (WBC: 16,900/microL); Hb:
14 g/dL Serum Creatinine: 0.9 mg/dL; Urinalysis: no hematuria or
proteinuria; ESR: 58 mm/Hr; CRP: 5.6 mg/dL; Antistreptolysin O titer:
823 IU/L; ANA: Negative; HbsAg: Stool for occult blood: positive.
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81. Disorders of the Vessel Wall
• Metabolic and Inflammatory Disorders
• Henoch-Schönlein, or anaphylactoid, purpura is a distinct, self-limited type of
vasculitis that occurs in children and young adults.
• Patients have an acute inflammatory reaction with IgA and complement components in
capillaries, mesangial tissues, and small arterioles leading to increased vascular
permeability and localized hemorrhage.
• It is often preceded by an upper respiratory infection, commonly with streptococcal
pharyngitis, or is triggered by drug or food allergies.
• Patients develop a purpuric rash on the extensor surfaces of the arms and legs, usually
accompanied by polyarthralgias or arthritis, abdominal pain.
• All coagulation tests are normal but renal impairment may occur.
• Glucocorticoids can provide symptomatic relief but do not alter the course of the illness
81

82. Disorders of the Vessel Wall
• Inherited Disorders of the Vessel Wall
• Patients with inherited disorders of the connective tissue matrix, such as
Marfan's syndrome, Ehlers-Danlos syndrome, and pseudoxanthoma
elasticum, frequently report easy bruising
• Inherited vascular abnormalities can result in increased bleeding.
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83. CLINICAL CASE
• A 62 year old man was admitted following multiple episodes of
hematemesis that had resulted in anemia requiring transfusion.
Esophagogastroduodenoscopy revealed oropharyngeal, gastric and
duodenal angiodysplasias. The patient had a history of heavy
alcoholism, but reported no bleeding or transfusions. He had had no
previous surgical procedures and had no family history related to his
condition.
• LAB: Normal except moderate IDA.
83

84. Disorders of the Vessel Wall
• Inherited Disorders of the Vessel Wall ctd
• This is notably seen in hereditary hemorrhagic telangiectasia (HHT, or Osler-
Weber-Rendu disease)
• This is a disorder where abnormal telangiectatic capillaries result in frequent bleeding
episodes, primarily from the nose and gastrointestinal tract.
• Arteriovenous malformation (AVM) in the lung, brain, and liver may also occur in HHT.
• The telangiectasia can often be visualized on the oral and nasal mucosa.
• Expistaxis begins, on average, at the age of 12 and occurs in >95% of affected individuals
by middle age
84

85. SECONDARY HEMOSTASIS DISORDERS
Introduction
• The most common inherited factor deficiencies are the hemophilias.
• These are X-linked diseases caused by
• Deficiency of factor (F) VIII (hemophilia A) or
• Deficiency of factor IX (FIX, hemophilia B).
• Rare congenital clotting factory deficiencies: FII (prothrombin), FV, FVII, FX,
FXI, FXIII, and fibrinogen.
• These are commonly inherited in an autosomal recessive manner
• Commonly used tests of hemostasis provide the initial screening for clotting
factor activity, and disease phenotype often correlates with the level of
clotting activity.
• Isolated abnormal PT: FVII deficiency
• Isolated prolonged aPTT: Most commonly hemophilia or FXI deficiency.
• Prolongation of both PT and aPTT: Deficiency of FV, FX, FII, or fibrinogen
abnormalities
85

86. • The addition of the missing factor at a range of doses to the
subject's plasma will correct the abnormal clotting times.
• Acquired deficiencies of plasma coagulation factors are more
frequent than congenital disorders.
• The most common disorders include hemorrhagic diathesis of liver
disease, DIC, and vitamin K deficiency.
86

87. Hemophilias
• Hemophilia is an X-linked recessive hemorrhagic disease due to mutations in
the
• F8 gene (hemophilia A or classic hemophilia) or
• F9 gene (hemophilia B).
• The disease affects 1 in 10,000 males worldwide, in all ethnic groups
• hemophilia A represents 80% of all cases
• Male subjects are clinically affected; women, who carry a single mutated
gene, are generally asymptomatic.
• Family history of the disease is absent in ~30% of cases and in these cases,
80% of the mothers are carriers of the de novo mutated allele
87

88. Hemophilias
• Clinically, hemophilia A and hemophilia B are indistinguishable.
• The disease phenotype correlates with the residual activity of FVIII or
FIX and can be classified as
• Severe (<1%),
• Moderate (1–5%), or
• Mild (6–30%)
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89. Hemophilias
• Severe and moderate forms: characterized by bleeding into the joints
(hemarthrosis), soft tissues, and muscles after minor trauma or even
spontaneously.
• Mild form: Px experience infrequent bleeding that is usually secondary to
trauma.
• Among those with residual FVIII or FIX activity >25% of normal, the disease is
discovered only by bleeding after major trauma or during routine presurgery
laboratory test
• Early in life, bleeding may present after circumcision or rarely as intracranial
hemorrhages.
• The disease is more evident when children begin to walk or crawl.
• In the severe form, the most common bleeding manifestations are the
recurrent hemarthroses.
• Affect every joint but mainly affect knees, elbows, ankles, shoulders, and hips
89

90. • Coagulation profile: an isolated prolongation of the aPTT
• Patients have normal bleeding times and platelet counts
• The diagnosis is made after specific determination of FVIII or FIX
clotting activity.
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