1. Bleeding and
Thrombotic Disorders

2. Bleeding and Thrombotic Disorders
Bleeding disorders
von Willebrand disease
Hemophilia A and B
DIC
TTP/HUS
ITP
Thrombotic disorders
Factor V Leiden

3. Platelet bleeding
Superficial (skin)
Petechiae
Spontaneous
Factor bleeding
Deep (joints)
Big bleeds
Trauma *
* Includes prolonged bleeding after dental work

4. Petechiae

5. Palatal petechiae

6. Palatal ecchymosis

7. Purpura

8. Bleeding after buttock injection in patient with hemophilia

9. Bleeding and Thrombotic Disorders
Bleeding disorders
von Willebrand disease

10. Von Willebrand Disease
Things you must know
Most common hereditary bleeding disorder
Autosomal dominant
vW factor decreased (or abnormal)
Variable severity

11. What’s von Willebrand Factor?
Huge multimeric protein
Made by megakaryocytes and endothelial cells
Glues platelets to endothelium
Carries factor VIII
Decreased or abnormal in vW disease
It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion.

13. clot Intrinsic Extrinsic X thrombin fibrinTF
VII IX
VIII X V
thrombin
Factor VIII levels are also performed because factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels, which explains the elevation in PTT time. Partial thromboplastin time (PTT) is a blood test that looks at how long it takes for blood to clot.
fibrin
clot

14. Symptoms of Von Willebrand Disease
Mucosal bleeding in most patients
Deep joint bleeding in severe cases

15. Lab Tests in Von Willebrand Disease
Bleeding time: prolonged

16. Bleeding and Thrombotic Disorders
Bleeding disorders
von Willebrand disease
Hemophilia A and B

17. Hemophilia A Things you must know Most common factor deficiency
X-linked recessive in most cases
(30% are spontaneous mutations)
Factor VIII level decreased
Variable amount of “factor” bleeding

22. Intrinsic
Extrinsic TF
VII IX
VIII X V
thrombin
fibrin
clot

23. Deep joint bleeding in patient with hemophilia

24. Knee of patient with hemophilia
Normal knee
Knee of patient with hemophilia
Hemophilic arthropathy of knee

25. Joint Deformity in Hemophilia

26. Hemophilia A Lab tests PTT prolonged Factor VIII level low
DNA studies abnormal
Treatment
DDAVP
Factor VIII

27. Hemophilia B Things you must know Factor IX level decreased
Much less common than hemophilia A
Same inheritance pattern
Same clinical and laboratory findings

28. Intrinsic
Extrinsic TF
VII IX
VIII X V
thrombin
fibrin
clot

29. Bleeding and Thrombotic Disorders
Bleeding disorders
von Willebrand disease
Hemophilia A and B
DIC
Disseminated intravascular coagulation (DIC) is a serious disorder in which the proteins that control blood clotting become over active.

30. Small blood clots form in the blood vessels
Small blood clots form in the blood vessels. Some of these clots can clog the vessels and cut off blood supply to organs such as the liver, brain, or kidneys. Lack of blood flow can damage the organ and it may stop working properly.
Over time, the clotting proteins in the blood are consumed or "used up.” When this happens, there is a high risk of serious bleeding, even from a minor injury or without injury.

31. Thrombosis
Hemorrhage

32. Bleeding and Thrombotic Disorders
Bleeding disorders
von Willebrand disease
Hemophilia A and B
DIC
TTP/HUS
Thrombotic Thrombocytopenic Purpura - Hemolytic Uremic Syndrome These cells that form the inside lining of the vessel wall are the “organ” that is abnormal in TTP-HUS. They can be injured by the different causes of TTP-HUS listed below. When these cells are injured, the smooth flow of blood cells is disrupted. Blood platelets are consumed at the many points of injury, because the function of blood platelets is to seal any leaks that occur in blood vessels and prevent bleeding. When these cells are damaged throughout the body, platelets stick to the damaged areas and the platelet count may decrease to very low levels. The platelets can also stick to each other and block blood flow. This is the critical problem that occurs in TTP-HUS; these platelet clumps are the blood clots or thrombi described by the first “T” in TTP.

33. Thrombotic Thrombocytopenic Purpura
Things you must know
Pentad: MAHA, thrombocytopenia, fever, neurologic defects, renal failure
Deficiency of ADAMTS13
Big vWF multimers trap platelets
Plasmapheresis or plasma infusions
microangiopathic hemolytic anemia (MAHA) is a microangiopathic subgroup of hemolytic anemia (loss of red blood cells through destruction) caused by factors in the small blood vessels. It is identified by the finding of anemia and schistocytes on microscopy of the blood film.

34. Some types of TTP-HUS have an autoimmune cause, in which the patient makes an antibody that blocks the function of one of their own enzymes, named ADAMTS13. ADAMTS13 is an enzyme in the blood that digests the protein that makes platelets stick together, called von Willebrand factor or VWF. When VWF is made in the cells that line the blood vessel, it is too big. ADAMTS13 is required to cut the VWF into smaller pieces, cutting it down to its normal size. When there is a deficiency of ADAMTS13 enzyme, the VWF is too large and too sticky for platelets. It can cause the platelet clumps that block blood vessels and cause TTP.

35. Rodent of unusual size (ROUS) -The Princess Bride, 1987
Nasty creatures
Rodent of unusual size (ROUS)
-The Princess Bride, 1987
Von Willebrand multimer of unusual size (MOUS)
- NEJM, 1982

36. Thrombotic Thrombocytopenic Purpura
Clinical pentad
Hematuria/jaundice (MAHA)
Bleeding/bruising (thrombocytopenia)
Fever
Bizarre behavior (thrombi in CNS)
Renal failure (thrombi in kidney)
Treatment
Plasmapheresis (in acquired TTP)
Plasma infusions (in hereditary TTP)

37. Hemolytic Uremic Syndrome
Things you must know
MAHA and thrombocytopenia
Most are related to E. coli infection
Toxin damages endothelium
Treat supportively
The central pathologic feature of both disorders is the formation of platelet thrombi in the microvasculature which may produce tissue ischemia and infarction. Immunohistochemically, the platelet thrombi contain large amounts of von Willebrand factor (VWF). These thrombi cause shearing stress on the red blood cells passing through the capillaries causing fragmentation ( thrombotic MAHA). The etiology of HUS is unknown. Recent studies have suggested that endothelial cells are damaged, thereby releasing large amounts of abnormal ultralarge VWF multimers into the circulation, which in turn, act as potent platelet aggregators.

38. Bleeding and Thrombotic Disorders
Bleeding disorders
von Willebrand disease
Hemophilia A and B
DIC
TTP/HUS
ITP

39. Idiopathic Thrombocytopenic Purpura
Things you must know
Antiplatelet antibodies coat platelets
Splenic macrophages eat platelets
Diagnosis of exclusion
Steroids or splenectomy
Autoimmune disease - Antiplatelet antibodies are produced by B cells and coat platelets so they can no longer work. The typical presentation is bruising in an otherwise healthy person.
In patients with ITP, the spleen is considered to be the primary site of platelet destruction and anti-platelet antibody production

40. Bruising after minor trauma in ITP

41. Bleeding and Thrombotic Disorders
Bleeding disorders
von Willebrand disease
Hemophilia A and B
DIC
TTP/HUS
ITP
Thrombotic disorders
Factor V Leiden
Factor V Leiden is the name of a specific gene mutation that results in thrombophilia, which is an increased tendency to form abnormal blood clots that can block blood vessels. Factor V Leiden thrombophilia is a genetically inherited disorder of blood clotting. Factor V Leiden is a variant (mutated form) of human factor V that causes an increase in blood clotting (hypercoagulability).

42. Factor V Leiden thrombophilia also increases the risk that clots will break away from their original site and travel through the bloodstream.
Blood clot sequelae

43. Deep venous thrombosis
People with factor V Leiden thrombophilia have a higher than average risk of developing a type of blood clot called a deep venous thrombosis (DVT). DVTs occur most often in the legs, although they can also occur in other parts of the body, including the brain, eyes, liver, and kidneys.
Deep venous thrombosis

44. Deep venous thrombosis

45. Pulmonary embolus

46. Thrombosis Risk Factors
Endothelial damage
Atherosclerosis
Stasis
Immobilization
Varicose veins
Cardiac dysfunction
Hypercoagulability
Surgery
Carcinoma
Estrogen/postpartum
Thrombotic disorders

47. When should you worry about a hereditary disorder?
no obvious cause
family history
weird location
recurrent
patient is young
miscarriages

48. Factor V Leiden Things you must know
Most common cause of unexplained thromboses
Inherited point mutation in factor V gene
Factor V can’t be turned off
High risk of thrombosis if homozygous

49. What is Factor V Leiden? A mutated factor V gene Single point mutation
Discovered in Leiden, Netherlands
Produces abnormal factor V
Participates in the cascade
Can’t be cleaved by protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogen, the activated form of which plays an important role in regulating anticoagulation, inflammation, cell death, and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa.

50. Yeah, so?
You can turn it on…
…but you can’t turn it off !

51. Intrinsic
Extrinsic TF
VII IX
VIII X V Va
thrombin
fibrin
clot

52. clot Intrinsic Extrinsic X thrombin fibrin TF VII IX VIII VIIIa V Va
protein C
fibrin
clot

53. What is the risk of getting a clot?
Heterozygotes: 7 times normal
Homozygotes: 80 times normal
Normal risk = 5 per 100,000 person-years!

54. Factor V Leiden Diagnosis PTT and INR not helpful Need genetic testing
Treatment
Don’t! Unless there is a thrombosis.
Then give oral anticoagulants
Prothrombin Time and International Normalized Ratio - Prothrombin time (PT) is a blood test that measures how long it takes blood to clot. A PT test may also be called an INR test. INR (international normalized ratio) stands for a way of standardizing the results of prothrombin time tests, no matter the testing method. So your doctor can understand results in the same way even when they come from different labs and different test methods.