Disorders of Primary Hemostasis and Thrombosis

• Disorders of primary hemostasis and thrombosis involve vasculature and platelets.

Vascular Abnormalities

• Disorders of the microcirculation, platelets, or plasma proteins may cause abnormal bleeding known as purpura.
• Petechiae appear as small, purplish hemorrhagic spots in the skin or mucous membranes.
• Ecchymosis presents as larger patches of bleeding into the tissues.

Types of Vascular Conditions

• Vascular conditions can arise due to mechanical force.
• Genetic structural malformation can result in vascular conditions.
• Vascular conditions may also be due to inflammation and obstruction of blood vessels or disorders of perivascular tissue.
• Miscellaneous causes of vascular conditions include infection, skin disease, and psychogenic reasons.

Blood Vessel Malformation

• Hereditary Hemorrhagic Telangiectasia (HHT), or Osler-Weber-Rendu disease, marks a type of blood vessel malformation.
• It involves genetic mutations and is an autosomal dominant trait.
• In HHT, there is a reduced amount of functional proteins available in the tissue lining the blood vessels.
• HHT results in skin and mucous membrane-associated epistaxis and other bleeding conditions.
• ENG, ACVRL1, and SMAD4 genes interact with growth factors that control blood vessel development.
• Type 1 HHT is associated with the ENG gene, while Type 2 is linked to the ACVRL1 gene.
• Type 3 HHT is currently unknown.
• Juvenile polyposis/HHT syndrome is caused by mutations in the gene SMAD4.

Other Vasculopathies

• These include conditions seen in patients with Multiple Myeloma or Systemic Amyloidosis.
• Moyamoya disease is also included in vasculopathies.
• Cerebral small vessel disease is another type.

Vasculitis

• Anti-neutrophil Cytoplasmic Antibody-Positive Vasculitis (ANCA) is a form of vasculitis.
• Other vasculitis forms include cryoglobulinemia.
• Hypergammaglobulinemic purpura is also a type of vasculitis.
• Henoch-Schönlein purpura (HSP) also falls under vasculitis.

Anti-neutrophil Cytoplasmic Antibody – Positive Vasculitis (ANCA)

• ANCA includes c-ANCA and p-ANCA types.
• ANCA is seen in SLE and Wegener's granulomatosis.
• It serves as serologic markers of primary necrotizing systemic vasculitis.

Cryoglobulinemia

• This condition involves cryoglobulin immune deposits that precipitate in dermal vessels.
• 90% of patients with Waldenström's primary macroglobulinemia (WM) have MYD88 L265P mutations.
• Symptoms involve cutaneous infarcts and petechiae.
• Platelet count remains normal, with chronic anemia and bleeding episodes.
• Bleeding is caused by abnormalities in platelet adhesiveness, while prothrombin time (PT) may be seen with low values of factor VIII.
• Intraluminal pressure is increased.

Hypergammaglobulinemic Purpura

• It is characterized by polyclonal hypergammaglobulinemia
• Secondary forms are associated with autoimmune disorders like Sjögren's syndrome and SLE, as well as chronic hepatitis C.

Henoch-Schönlein Purpura

• Henoch-Schönlein Purpura (HSP) occurs primarily in children aged 4 through 11 years old.
• Reddish-purple spots resembling bruises are a distinctive sign of HSP.
• HSP is an acute immunoglobulin A (IgA)-mediated disorder.
• Generalized small vessel vasculitis involves the skin, GI tract, kidneys, joints, and, rarely, the lungs and CNS.

Vascular Obstruction

• Thrombus, specifically blood clots, result in Disseminated Intravascular Coagulation.
• Emboli, by way of septic or thromboemboli, cause endocarditis or atrial fibrillation, respectively.
• Immunoglobulins, plasma proteins, fibrin, red blood cells, platelets, and fat cause multiple myeloma/Waldenström's primary macroglobulinemia, cryoglobulinemia, cryofibrinogenemia, polycythemia, thrombocytosis, and fat emboli syndrome, respectively.

DIC

• DIC is caused by a number of factors, including vascular damage leading to exposure of collagen, which activates XII.
• It is characterized by excess thrombin formation, conversion of fibrinogen to fibrin, and platelet deposition and consumption.
• Characterized by both thrombosis and hemolysis.

Cryofibrinogenemia

• It involves cryofibrinogen, which is a cold precipitable plasma protein.
• Lesions in associated cryofibrinogen disorders, such as Raynaud's phenomenon, result from fibrin thrombi obstructing small to medium-sized dermal blood vessels.

Septic Emboli

• Septic Emboli results from the development of tissue ischemia, necrosis of the skin and subcutaneous fate, and occasionally deeper tissues.
• They are associated with patients who have end-stage renal failure and undergoing hemodialysis.

Bleeding because of Perivascular Tissue

• Ehlers-Danlos syndrome (EDS) can cause bleeding from perivascular tissue.
• Marfan's syndrome is another syndrome that may lead to bleeding from perivascular tissue.
• Other syndromes that can cause bleeding from perivascular tissue include Loeys-Dietz syndrome
• Osteogenesis imperfecta
• Pseudoxanthoma elasticum
• Scurvy
• Steroid-induced purpura
• Solar purpura (senile purpura)

Ehlers-Danlos Syndrome (EDS)

• EDS involves abnormalities of collagen synthesis or processing.
• Defects in type 3 collagen, particularly abundant in the arterial wall and intestine.
• EDS results in excessive bleedings.
• Type IV EDS is prone to arterial aneurysms and dissections, and significant bleeding from spontaneous rupture of medium-sized abdominal arteries, and intestinal rupture.
• EDS IV involves structural defects in the proa1(III) chain of collagen type III encoded by COL3A1, inherited in an autosomal dominant pattern.

Pseudoxanthoma Elasticum (PXE)

• PXE is also known as Gröenblad - Strandberg syndrome, Grönblad-Strandberg syndrome.
• It involves an inherited connective tissue disorder resulting in calcification and mineralization of elastic fibers, especially in the internal elastic lamina of medium-sized arteries with subsequent rupture of the blood vessel.
• PXE is inherited as an autosomal recessive pattern – both copies of the genes in each cell have mutations.
• It is characterized by mutations in the ABC-C6 gene
• This gene results in nonfunctional MRP6 protein

Scurvy

• The absence of vitamin C in scurvy weakens collagen strands as a result of abnormal triple helical structures.
• This causes abnormal collagen due to defective perivascular supportive tissues.
• Patients are predisposed to capillary fragility, delayed wound healing, petechiae, and purpura.

Solar Purpura (Senile Purpura)

• In solar purpura, collagen and elastin are degraded.

Purpura Associated with Infections

• These infections include acute febrile illness with petechiae.
• Rickettsial diseases can cause purpura
• Brazilian purpura fever.
• Rat bite fever
• Hemorrhagic fever
• Vibrio vulnificus infection
• Strongyloides infection
• Bacterial toxin produce deendothelialization induced by an endotoxin

Purpura Related to Miscellaneous Causes

• Contact dermatitis can lead to purpura.
• Purpura can result from steroid use.
• Drug reactions can cause purpura.
• Vascular malignancy, specifically Kaposi sarcoma and vascular tumors.
• Purpura simplex
• Factitious or self-imposed purpura
• Religious stigmata.

Quantitative Platelet Disorders

• This category includes thrombocytopenia.
• Also, thrombocytosis is a quantitative platelet disorder.

Thrombocytopenia

• This may be due to artifactual causes like platelet clumping, giant platelets, and platelet satellitism.
• Decreased production of platelets, such as in hereditary thrombocytopenia, hypoplasia of megakaryocytes, or disorders of thrombopoiesis.
• Increased destruction of platelets (immunological or nonimmunological cause)
• Abnormal platelet distribution or pooling in splenic disorders, hypothermia, or dilution with massive transfusion.

Major Categories of Thrombocytopenic Conditions

• These conditions include disorders of production.
• Also, disorders of destruction or utilization.
• Disorders of platelet distribution and dilution.

Disorders of Production

• These are caused by hypoproliferation of the megakaryocytic cell line or ineffective thrombopoiesis.
• Acquired conditions or hereditary factors may cause hypoproliferation of the megakaryocytic cell line or ineffective thrombopoiesis.
• Acquired damage to hematopoietic cells of the bone arrow caused by factors such as irradiation, drugs (e.g., chloramphenicol and chemotherapeutic agents), chemicals (e.g., insecticides), and alcohol.

Disorders of Destruction or Utilization

• May be caused by immune mechanisms where there are antigens, antibodies, or complement.
• Posttransfusion purpura
• Can be drug induced.
• Bacterial sepsis.
• Immune thrombocytopenia
• Isoimmune Neonatal Thrombocytopenia
• Thrombocytopenia in pregnancy

Heparin-Induced Thrombocytopenia (HIT)

• There are two types - Nonimmune HIT (type I) and immune HIT (type II).

Nonimmune HIT

• It is a benign disorder affecting up to 10% of patients receiving heparin anticoagulant therapy.
• The mechanism of action is direct interaction between heparin and platelets.
• Platelet is >100,000/μL, with a rapid decline observed within the first 2 days of heparin administration.
• Platelet count returns to normal levels within 5 days despite continued heparin use or within 2 days if heparin therapy is discontinued.

Immune HIT

• The platelet count range falls between 20,000 to 150,000/μL.
• The lowest count is reached at about 5 days after the onset of the declining platelet count.
• The platelet count begins to rise approximately 2 days after heparin therapy is discontinued.
• Platelet count usually returns to normal within 4 to 10 days after discontinuing heparin.

Pathophysiology of HIT

• Immune HIT is caused by an antibody that recognizes heparin bound to PF4 on the platelet surface.
• The antibody binds to the heparin-PF4 complex, which then allows the antibody to bind the Fc receptor on the platelet.
• Interaction with the Fc receptor activates the platelet.
• Can results in loss of platelets, thrombocytopenia, and platelet aggregation (thrombosis).

Laboratory Data of HIT

• An enzyme-linked immunosorbent assay (ELISA) can provide labatory data.
• Other sources are platelet aggregation and serotonin release

Increased Utilization of Platelets

• Immune Thrombocytopenic Purpura (ITP) is a cause

• Can also arise due to Idiopathic Thrombocytopenic Purpura

• It is acquired immune-mediated disorder characterized by isolated thrombocytopenia along with a platelet count less than 100 × 10º /L and the absence of potential initiating and/or underlying causes of the thrombocytopenia.

• ITP is characterized by a low platelet count, normal bone marrow, and the absence of other causes of thrombocytopenia in both children and adults.

• ITP is classified by duration into newly diagnosed, persistent (3 to 12 months duration), and chronic (≥12 months).

• ITP is more common in females aged 10-40.

• Immune Thrombocytopenic Purpura occurs more often and is longer in adults than in children.

Clinical Signs and Symptoms of ITP

• Signs include purpura, Epistaxis, gingival bleeding, hematuria, GI bleeding, and intracerebral hemorrhage

Pathophysiology of ITP

• Platelet destruction occurs due to antibodies produced
• ITP occurs in children and adults. Adults have a chronic ITP that is a destructive thrombocytopenia cause by antibodies produced.

Types of ITP

• Acute ITP – 2 – 6 y/o, just recovered from a viral illness.
• Chronic ITP – 20 – 50 y/o; produce an IgG antibody that coats the platelets, causing them to be sequestered and subsequently destroyed in spleen.

Laboratory Data of ITP

1. Presence of thrombocytopenia, lack of anemia unless blood loss has occurred, and lack of white cell abnormalities
2. Absence of other causes of thrombocytopenias (e.g.) collagen vascular diseases or lymphoproliferative disorders)
3. Absence of infections, particularly human immunodefficiency virus (HIV)

Treatment for ITP

• May involve intravenous immunoglobulin (IVIg or WinRho, anti-D immune globulin)
• Splenectomy
• Platelet transfusion

Utilizations of Platelets

• Intravascular coagulation
• Vascular injury or occlusion
• Tissue injury
• Trauma
• Obstetrical complications
• Microbial sepsis

Thrombotic Thrombocytopenic Purpura

• It is characterized by formation of microthrombi in the microvasculature, and a high mortality rate
• Common signs are severe thrombocytopenia, microangiopathic hemolytic anemia, and fever.
• Neurologic symptoms, such as headache, stroke, and disease are common.

Types of TTP

• One type involves an Idiopathic cause where it is linked to enzyme ADAMTS13 known as a disintegrin-like and metalloprotease domain with thrombospondin-type motifs).
• It is responsible for the breakdown of large von Willebrand factor (vWF) multimers.
• A Secondary may be due to diagnosis in patients with a history of medications; such as with patients that have HIV, autoimmune disorders, allogeneic bone marrow transplant
• There is also a Hereditary cause in patients with (Upshaw-Schulman), and caused in result of inheritance of a deficiency of ADAMTS13.

Disorders of Platelet Distribution and Dilution

• Occur from the pooling of platelets in the spleen, which is frequent if splenomegaly is present.
• Develops when more than a double or triple increase in platelet production is required to maintain the normal quantity of circulating platelets.
• Disorders that produce splenomegaly with resultant splenic pooling or delayed intrasplenic transit include alcoholic or posthepatic cirrhosis with portal hypertension, lymphomas and leukemias, and lipid disorders such as Gaucher's disease.

Posttransfusion Thrombocytopenia

• Arises due to massive blood transfusion of units of packed RBC and plasma expanders.
• Results in reduced platelet count, or dilutional Thrombocytopenia.

Hereditary Defects of Platelet Function with Thrombocytopenia

• Include Fanconi's syndrome, constitutional aplastic anemia and its variants, ameiosis thrombocytopenia (TAR syndrome), X-linked amegakaryocytic thrombocytopenia, WAS, May-Hegglin anomaly, and Hereditary macrothrombocytopenia (e.g., Alport syndrome)
• Platelet morphology needs to be observed while examining a peripheral blood smear; abnormal variation in size should be noted.

Disorders of platelet size

• WAS - which demonstrate smallest platelets seen
• characterized large platelets and teh presence of Dohle-like bodies
• giant platelets and thrombocytopenia- Alport
• Bernard Soulier is largest. giant platelet.

Wiskott-Aldrich Syndrome (WAS)

• WAS involves susceptibility to infections and abnormal bleeding.

• There is a reduced ability to form blood clots as the result of unusually small, dysfunctional platelets.

• Defective gene is on short arm of chromosome where X-Linked recessive mutations occur

• WAS gene has protein call WASp, that relay signals from surface of the blood cells to the actin cytoskeleton

• A lack of the WASp causes impairment of platelet development.

• It can lead to a reduced size, microthrombocytonia, and dysfunctional platelets that have an intrinsic defect.

• Signs include purpura, increased infections-fungal, viral and bacterial, and atopic dermatitis.

• Hemolytic animea or idopathic thrombocytopenic.

• More risks for malignancy

Labratory data include sequencing

• Lab data determines presence of protein cells

MYH9-Related Thrombocytopenia Syndromes (May-Hegglin Anomaly)

• Autsomoal Dominant, SEbastion, or Fechctner systems.
• Platelet cytoskeletal protein can common mutations
• Some inheritance.
• Premature release of platelets Platelets small
• 22 chrom, - 40 econs.
• 31 mutations in 11 excons.

Clinical Signs and Symptoms of MYH9

• Mild symptoms. bleeding. Hemostatic deficit.

Lab Findings in MYH9

• Presence of Macrothrombocytopenia

• large and poorly granulated platelets coexist.

• Also presence of Dohle.

• ITP most important. platelet size.

• Immunostaininh good standards -platelets do not sowmajor deficits. .

• Change of platelets. curve is absent but can be found.

• A bone marrow may no be needeed

• Marrow NMM

• A work up for MYH9 should exclude anemia.

• Assess cataracts

• Test kidneys